Faculty of Medicine • Masaryk University • Brno • Czech Republic
Department of Physiotherapy
Department of Functional Diagnostics and Rehabilitation
PROCEEDINGS
SYMPOSIUM
NONINVASIVE METHODS IN CARDIOLOGY 2009
DEDICATED TO THE 90TH
ANNIVERSARY
OF PROFESSOR FRANZ HALBERG
Edited by: Halberg F., Kenner T., Fišer B., Siegelová J.
2009
The Symposium takes place under the auspices of
Prof. PhDr. Petr Fiala, Ph.D., Rector of Masaryk University Brno
Prof. MUDr. Jan Žaloudík, CSc., Dean of Faculty of Medicine Masaryk
University Brno
Ing. Petr Koška, MBA, Director of The St. Anna Teaching Hospital in Brno
Mgr. Jana Mikulková, Director of National Centre of Nursing and Other
Health Professions
ISBN 978-80-7013-501-3
CONTENTS
A. FOLLOW-UP TO THE CORNELISSEN-SERIES
INHERITANCE OF FORM IN SPACE FROM PARENTS AND OF FORM
IN TIME FROM THE COSMOS: FROM BRNO‘S MENDEL
AND SIEGELOVA, RESPECTIVELY Cosmic inheritance rules: congruence
and selective assortment; implications for health care and science
Halberg F., Cornélissen G., Katinas G. S., Watanabe Y., Siegelova J. ...................................... 13
B. DEDICATIONS ACHIEVEMENTS NEAR 60 YEARS OF AGE
OF ACADEMICIANGERMAINE CORNÉLISSEN:
THE CORNÉLISSEN-SERIES REVISITED
1,2
Halberg F. ........................................................ 40
MUDr. Jiří DUŠEK, CSc: A FRUITFUL COOPERATION Halberg F.,
Cornélissen G., Schwartzkopff O., Watanabe Y., Siegelova J., Fiser B...................................... 49
STEPS TOWARD MIKULECKY‘S SEMIMILLENNIALS
IN THE EMERGENCE OF OUTSTANDING INDIVIDUALS
Halberg F., Cornélissen G., Hillman D., Siegelova J.,
Fiser B., Homolka P., Dusek J..................................................................................................... 64
C. MENDEL‘s LEGACY Omnis cyclus e cosmo:
MENDEL‘S CHRONOASTROBIOLOGICAL LEGACY FOR
TRANSDISCIPLINARY SCIENCE IN PERSONALIZED HEALTH CARE
Halberg F., Cornélissen G., Matalova A., Siegelova J.,
Sonkowsky R., Chibisov S. M , Ulmer W., Wilson D.,
Revilla M., Katinas G. S., Homolka P., Dusek J., Fiser B.,
Sanchez de la Pena S., Schwartzkopff O., Beaty L. A................................................................. 77
D. METHODS SELECTIVELY ENVIRONMENTALLY CONGRUENT
BIOTIC CIS-HALF-YEAR UNMASKED WITH NEIGHBORING
SPECTRAL COMPONENTS Cornélissen G., Halberg F.,
Sothern R. B. , Hillman D. C., Siegelova J. .............................................................................. 112
META-ANALYSIS OF HORREBOW‘S AND SCHWABE‘S
SCHOLARSHIP WITH A VIEW OF SAMPLING REQUIREMENTS
Cornélissen G., Halberg F., Sonkowsky R., Siegelova J.,
Homolka P., Dusek J., Fiser B................................................................................................... 141
TRANS-TRIDECADAL, DECADAL AND TIME-VARYING
CIS-HALF-YEARLY, CIS-YEARLY AND TRANS-YEARLY COMPONENTS
IN SOLAR FLARES WITH BIOSPHERIC SIGNATURES Cornélissen G.,
Halberg F., Hillman D., Siegelova J., Dusek J., Homolka P., Fiser B..................................... 159
CIRCADIAN AND CIRCASEPTAN STAGE DETERMINE
MISDIAGNOSES (PSEUDO-HYPERTENSION, PSEUDO-WHITE-COAT
HYPERTENSION AND PSEUDO-NORMOTENSION)
Cornélissen G., Halberg F., Otsuka K., Watanabe Y., Siegelova J., Dusek J.,
Homolka P., Prikryl P., Fiser B. ................................................................................................ 176
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E. CASE REPORTS AMPLITUDE RATIOS OF HALF-WEEKLY
VS. DAILY VARIABILITY IN DIASTOLIC BLOOD PRESSURE
IN PUTATIVE MAGNETOLABILITY Halberg F., Kino T.,
Siegelova J., Homolka P., Finley J., Cornélissen G., Dusek J., Fiser B................................... 192
CIS-HALF-YEAR IN THE SYSTOLIC BLOOD PRESSURE OF A YOUNG ADULT
Gorlov D., Halberg F., Cornélissen G., Gorgo Y........................................................................ 208
SOLAR SIGNATURES IN A BOY‘S BLOOD PRESSURE AND HEART RATE
Watanabe Y., Cornélissen G., Watanabe F., Tarquini R., Perfetto F.,
Siegelova J., Fiser B., Dusek J., Homolka P., Halberg F.......................................................... 211
WHITE-COAT HYPERTENSION IN A CARDIOLOGIST: DECADES
OF MONITORING LEAD TO TRANSIENT OCCUPATIONAL
MESOR-HYPERTENSION ABSENT DURING VACATION: STRAIN TEST
Watanabe Y., Cornélissen G., Beaty L. A., Siegelova J., Fiser B., Dusek J.,
Homolka P., Halberg F. ............................................................................................................. 226
ACCEPTABLE CONVENTIONAL STRESS TEST OUTCOME MAY
NOT DISPEL INDICATIONS OF A SPHYGMOCHRON
Halberg F., Rosch P., Cornélissen G.......................................................................................... 247
A TRANSTRIDECADAL BEL CYCLE IN HUMAN BLOOD
PRESSURE AND BODY WEIGHT Halberg F., Cornélissen G., Best W. R. ........................... 257
DIFFERENCES IN TIME STRUCTURAL ENVIRONMENTAL
CONGRUENCE OF VASCULAR VARIABLES IN AN ELDERLY MAN
Halberg F., Cornélissen G., Siegelova J., Homolka P., Dusek J., Fiser B................................ 271
DEATH FROM WOLFF-PARKINSON-WHITE SYNDROME DURING
MODERATE MAGNETIC STORM: CASE REPORT WITH
LITERATURE REVIEW Cornélissen G., Halberg F. ............................................................... 280
F. CHRONOBIOETHICS CHRONOMICS OF CHURCH MEMBERSHIPS
Halberg F., Cornélissen G.......................................................................................................... 299
G. ADDENDUM CIRCADIAN AMPLITUDE OF HUMAN HEART
RATE ALONG A GERIATRIC DEPRESSION SCALE
Cornélissen G., Otsuka K., Halberg F., Yamanaka G., Hotta N.,
Murakami S., Kubo Y., Matsuoka O., Takasugi E., Yamanaka T.,
Shinagawa M., Nunoda S., Nishimura Y., Shibata K., Saitoh H.,
Nishinaga M., Ishine M., Wada T., Okumiya K., Matsubayashi K.,
Yano S., Ishizuka S., Ichihara K., Siegelova J. ........................................................................ 314
AN ESSAY ON SOME ASPECTS OF CHRONOBIOLOGY
presentedby an every-day-physiologist in honour of Franz Halberg
Kenner T. .................................................................................................................................... 318
CHRONOBIOLOGY AND BAROREFLEX SENSITIVITY
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Fišer B., Siegelová J., Dobšák P., Dušek J................................................................................ 325
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RELATIONSHIP BETWEEN CIRCADIAN BLOOD PRESSURE
VARIATION AND AGE ANALYZED FROM 7-DAY MONITORING
IN HEALTHY SUBJECTS AND PATIENTS WITH ISCHEMIC
HEART DISEASE Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Siegelová J., Fišer B., Havelková A., Dušek J., Homolka P., Vank P.,
Pohanka M., Mašek M., Cornélissen G., Halberg F. ................................................................. 330
NON-INVASIVE EVALUATION OF ARTERIAL STIFFNESS
IN CZECH ADULT POPULATION USING THE DEVICE
VASERA® 1500 Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Dobšák P., Sosiková M., Dušek L., Souček M., Nováková M.,
Yambe T., Wolf J.-E., Vítovec J., Špinarová L., Soška V., Fišer B., Siegelová J. .................... 345
RESPIRATORY EXCHANGE RATIO AT MAXIMUM LOAD
BEFORE AND AFTER TERMINATION OF CONTROLLED
AMBULATORY REHABILITATION PROGRAM IN PATIENTS
AFTER ACUTE MYOCARDIAL INFARCTION
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Mífková L., Várnay F., Fišer B., Havelková A., Vank P.,
Pochmonová J., Svačinová H., Siegelová J............................................................................... 356
CARDIOVASCULAR EXERCISE TRAINING IN MEN AFTER
ACUTE MYOCARDIAL INFARCTION
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Havelková A., Mífková L., Pochmonová J., Anbais F. H.,
Erajhi A. A., Bártlová B., Fišer B., Várnay F., Dobšák P., Siegelová J. .................................. 365
THE EFFECT OF 8-WEEK REHABILITATION PROGRAM
IN MULTIPLE SCLEROSIS: COMBINATION OF AEROBIC
AND RESISTANT TRAINING
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Konečný L., Pospíšil P., Vank P., Mífková L., Pochmonová J.,
Havelková A., Siegelová J., Dobšák P. ...................................................................................... 374
BAROREFLEX SENSITIVITY IN PARKINSON‘S DISEASE
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Pospíšil, P., Konečný, L., Katzer, L., Tarasová, M., Fišer, B.,
Siegelová, J., Dobšák, P. ............................................................................................................ 388
5
6
Franz Halberg, M.D., Dr. h.c. (Montpellier), Dr. h.c. (Ferrara), Dr. h.c.
(Tyumen), Dr. h.c. (Brno), Dr. h.c. (L'Aquila), Dr. h.c. (People's Friendship
University of Russia, Moscow), Professor of Laboratory Medicine and
Pathology, Physiology, Biology, Bioengineering and Oral medicine, Director,
Halberg Chronobiology Center, University of Minnesota, Mayo Mail Code
8609, Dept of Laboratory Medicine, Minneapolis Campus
420 Delaware Street SE, Minneapolis, MN 55455, USA
7
Prof. Dr. Franz Halberg
90 years of age
Franz Halberg is a founder of modern chronobiology. Unlike other famous scientists devoting
there activities mostly to presentation of honorary lectures at international scientific
conferences Prof Halberg continues in scientific work. This fact demonstrates the list of his
scientific papers on WEB of Science which contains 1149scientific papers, Science Citation
Report of Franz Halberg contains 12670 citations, and his H-index is 51.Prof. Halberg has
dedicated almost 60 years of his life to chronobiological research.
Chronobiology, the study of mechanisms underlying diversity in time, and chronomics, the
mapping of chronomes - time structures, could complement genetics. It is the study of
mechanisms underlying diversity in space and also genomics, the mapping of the genomes.
Halberg made here focus on the chronobiologic-chronomic assessment of blood pressure and
heart rate variability as the alternative to the spotcheck of the blood pressure advocated by
official current guidelines. Chronobiology allows us to approach risks, diagnosis and
treatment dependent on appointment time, especially of the dynamics of time, gender, age,
ethnicity and geographical location.
His chronobiological studies represent a new original Minnesotan branch of science based
upon resolving the chronome and its mapping from womb to tomb. Womb -to- tomb
chronome initiative consists in extension of a unique existing data archive and reference
standard bank on variables of biomedical interests: heart rate, blood pressure, body
temperature, a host of chemical determinations on blood, saliva and urine.
Every biologic variable is characterized by chronomes, describing the structure of rhythms
and trends in its physiological and pathophysiological range of variations. The chronome
provides new endpoints for ruling in health or recognizing increased disease risk before the
occurrence of overt illness. Prof. Halberg ´s long lasting basic scientific work is directed, at
the beginning of the new century, to chronobiometry (physiological and statistical evaluation
of the genetically anchored and cosmically influenced time structures), chronobioengineering
(collecting physiological data by means of sophisticated equipment), chronobiological
diagnosis of disease risk syndromes, and the chronotherapy, improvement of prognosis and
8
treatment in different fields of medicine, and last but not least, chronoastrobiology focusing
on rhythms and broader chronomes to explore the origins of life.
Needless to say, not only those researchers who are deeply interested in this field, but also
others who are less interested, have all been strongly impressed by such incomparable records
of work achieved by Prof. Halberg. In recent years he has been strenuously promoting
chronobiological research further in the field of clinical medicine on the worldwide scale. We
feel honored to have had the possibility of cooperation with Prof. Halberg since 1980s. In the
year 2000, Prof. Franz Halberg from University of Minnnesota, USA, received the degree of
honorary doctor of Masaryk University and thus have the honor also to be members of
Masaryk University Brno. In the last 25 years, the cooperation between Masaryk University
and University of Minnesota was intensive and was enlaged also to the international project
BIOCOS.
The international project on The BIOsphere and the COSmos originated on June 30, 1997,
when the Russian Academy of Medical Sciences convened a special session at its
headquarters in Moscow to discuss and, at the end of this meeting, to unanimously endorse a
project on "The BIOsphere and the COSmos" (BIOCOS).
The role of chronomics within the context of Non-communicable Diseases and Mental Health
is mostly studied in cardiovascular variables but not limited only to the cardiovascular system.
The same methodology remains applicable to a wide range of problems. Cancer prevention
and optimization by the scheduling of treatment administration is another important problem.
But the main focus of BIOCOS in health promotion upon the circulation by “prehabilitation”,
to reduce the cost of rehabilitation by education of use of chronobiology.
Chronobilogy, studied by Franz Halberg, showed broad spectrum of rhythms in us and
around us; they are being marched up by the dozens but have not yet been recognized in terms
of their pertinence to everyday life. It should be taught that circadians, now a fashion in
molecular biology, tip the scale between life and death, as do extracircadians, the many
different more or less periodic changes evolved and built into human physiology under the
influence of the cosmos. Infradians are apparent in military-political affairs, including
aggression, notably crime, international battles and terrorism; in economics, in opinion polls,
in education and, most important, in health care. Chronobiologically interpreted blood
pressure and heart rate monitoring detects prehypertension, prediabetes and a premetabolic
9
syndrome in vascular variability disorders, that interact with a reliably diagnosed MESOR
hypertension that can carry a risk greater than a high blood pressure and that can coexist to
form vascular variability syndromes, unrecognized in a conventional health care but some of
them already treatable. It is not yet generally known that in the human newborn, variables
such as hear rate or blood pressure have an about-weekly component which is more
prominent than the 24-hour change and awaits testing as a gauge of risk, or that in the
incidence spectrum of sudden cardiac death (ICD10, code I46.1) an about 5-month and an
about 17-month (transyear) component, cyclic signatures of space weather, replace
Minnesota's midcontinental winters and summers. Dependent on geography, a host of
congruent spectral components is found in both spectra of the solar wind and other aspects of
space weather on the one hand and in the human circulation, in electrical accidents of the
heart and in the extreme depression of suicide on the other hand. When cardiovascular health
and its relation to the cosmos is viewed in 40 years of around-the-clock measurements, there
is selective congruence between about 5-month components in solar flares and in the heat rate
of a clinically healthy man. There are the latest discoveris from Prof. Franz Halberg.
Prof Halberg suffers by the fact, that his ideas overrun the development of science for tens of
years. He suggested the ambulatory 24 hours blood monitoring in 1948. The first scientific
study using this method in Czech Republic was published in 1994. Also the treatment of
oncology diseases on the chronobiological basis started many years after Halberg suggestion.
The last Halberg proposal for diagnosis of vascular variability disorders on the basis of
several day ambulatory blood pressure and heart rate monitoring or on the basis of several
days lasted self-monitoring is nowadays not broadly accepted; despite it enables the risk
stratification of hypertensive patients. The risk-stratification guided treatment is more
effective than the treatment based on diagnosis only.
I wish professor Halberg good health necessary to continue his scientific work for many
years. I also wish scientific community to accept all Franz Halberg ideas as quickly as
possible, because it is an interest of patients all over the world.
Ad multos annos!
Prof. MUDr. Jarmila Siegelová, DrSc.
Head, Dept. of Physiotherapy
Faculty of Medicine
Masaryk University
St. Anna´s Teaching Hospital
Pekařská 53
656 91 Brno
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Masaryk University
90th
ANNIVERSARY
The history of Masaryk University closely reflects the history of the Czech nation. The
independent Czechoslovak Republic was founded in October 1918. The second Czech
university in the country was established with the aim to promote the scientific and cultural
development and to create a centre of academic life in Moravia. The university was named
after T.G. Masaryk, the first Czechoslovak president, whose continuous and strong support
had played a decisive role in the establishment of the university.
In 1919, the Faculty of Law and the Faculty of Medicine started their teaching programmes,
in 1921 followed by the Faculty of Arts and Faculty of Science. In the first republic (1919-
1939), the university achieved high pedagogic and scientific recognition in many areas, in
medicine in the fields of physiology, anatomy, histology, surgery and internal medicine.
During the second world war, the Masaryk University was closed and many personalities of
the university staff and students were prisoned and lost their lives.
In 1945, teachers and students resumed work immediately. The political development in
Czechoslovakia after 1948 caused the change of the name of the University. The University
bore the name of J.E.Purkyně, a famous Czech physiologist, between the years 1960-1989.
The revolution in November 1989 marked a landmark in the life of the country. The
university in Brno resumed its original name Masaryk University in 1990.
At the end of the 20th
century the Masaryk University became a modern institution
promoting the advanced teaching in the fields of medicine, philosophy, law, natural science,
economics and administration, education and informatics, and providing research in all the
above mentioned fields. The Masaryk University contributed to the cultural and scientific
development of the Czech Republic.
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12
A. FOLLOW-UP TO THE CORNELISSEN-SERIES
INHERITANCE OF FORM IN SPACE FROM PARENTS AND OF FORM IN TIME FROM THE
COSMOS: FROM BRNO'S MENDEL AND SIEGELOVA, RESPECTIVELY
Cosmic inheritance rules: congruence and selective assortment; implications for health care
and science1
Franz Halberg1
, Germaine Cornélissen1
, George S. Katinas1
,
Yoshihiko Watanabe2
, Jarmila Siegelova3
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
Masaryk University, Brno, Czech Republic
Abstract. Countering the trend in specialization, we advocate the transdisciplinary
monitoring of blood pressure (BP) and heart rate (HR) for signatures of environmental cyclic and
other variabilities in space as well as terrestrial weather on the one hand, and for surveillance of
personal and societal health on the other hand. New rules (if confirmed novel laws) emerge as we
recognize our inheritance from the cosmos of cycles that constitute and characterize life and align
them with inheritance from parents. In so doing, we happen to follow the endeavors of Gregor
Mendel, who recognized the segregation and independent assortment of what became known as
genes. Circadians, rhythms with periods, τ, between 20 and 28 hours, and cycles with frequencies
that are higher (ultradian) or lower (infradian) than circadian, are genetically anchored. An
accumulating long list of very important but aeolian (nonstationary) infradian cycles,
characterizing the incidence patterns of sudden cardiac death, suicide and terrorism, with
drastically different τs, constitutes the non-photic Cornélissen-series (1).
Laws and rules. Between 1856 and 1863, Gregor Mendel cultivated and tested some 29,000
pea plants. Between 2000 and 2008, Jarmila Siegelova's team collected some 73,888 sets of
systolic (S) and diastolic (D) BP and HR measurements. With his 29,000 peas, Mendel collected
evidence for the laws of heredity: segregation and independent assortment. Siegelova's some
73,888 cardiovascular sets, and these and her earlier proceedings, led to the rules of cosmic
1 Dedicated to the senior author's daughter Francine Halberg on her 57th
birthday, June 28, 2009.
13
inheritance, which document the congruence and selective assortment of cycles around and in us.
In monitoring the solar wind's signatures, we follow the aging Mendel: about (~) 13.5 months
before his death Mendel considered an association of solar activity with worldwide auroras,
searching for what is now recognized as the solar wind, i.e., particle radiation from the sun.
Mendel did this 124 years before we learned on a 16-year series of SBP from an elderly man
(FH) that the same solar wind's far-transyear (1.2 years ≤ [τ - CI {95% confidence interval}] <
[τ + CI] < 1.9 years) and cis-half-year (of ~5 months length) are built into us as wobbly cycles
amplified in the presence of a counterpart in the solar wind, dampened in the absence of this
counterpart but not lost in us when the corresponding τ is no longer detected in the solar wind (2).
Thus, the Brnoese, Minnesotan and other BIOCOS monitoring is the aging meteorologist and
epidemiologist Mendel's legacy. It has led to a complement to the two laws of genetics. When we
align Mendel's inheritance from our immediate parents (i.e., the segregation and independent
assortment of genes) with the manifold cycles one inherits from the sun and the broader cosmos,
that is when we turn to cosmic inheritance, the two new rules are, first a wide transdisciplinary
spectrum of congruent τs around and in us, with their congruence defined and documented by
overlapping or overlying CIs of their τ, and second (if not quite independent assortment), then
selective congruence, among different environmental and biospheric variables at various
frequencies characterizing both.
Thus, we find that the HR of an adult (RBS) between 20 and 60 years of age is congruent
with the ~33-year BEL cycle in Wolf's relative sunspot numbers, while his BP is congruent with
an ~didecadal Hale cycle in the polarity change of the same Wolf numbers (3). Two variables of
the same circulation are locked into different environmental cycles. Selective congruence is again
documented by overlapping or overlying CIs of the τs of heliomagnetics gauged by solar wind
speed, geomagnetics gauged by the antipodal index aa and the estimation of 1 minute, a mental
function, among others, in the transyear region of the spectrum of RBS. It is selective in that at
some frequencies all three variables are congruent, or only two variables out of three at other
frequencies, or at still other frequencies there is a statistically significant spectral peak in a
14
biospheric or other variable with no congruent counterpart in other time series of the same
variable, of other related variables (no intradisciplinary congruence) or in variables of other
disciplines (no transdisciplinary congruence).
By the same token in the circaseptan spectral region, BP and HR are locked into different
helio- and geomagnetic variables of an elderly man (GSK) (2). An assortment of the congruence of
different physiological variables with the same environmental cycle is also encountered in another
elderly man (WRB) (4). In the parasemiannual spectral region of RBS, different variables of his
circulation can again show a different spectral behavior, as they do in a young man (DG) (5).
When congruence involves non-photic invisible cycles in the environment and conditions such as
human individuals' and populations' illnesses such as sudden cardiac death and terrorism,
respectively (1, 6, 7), it gains in interest and justifies in itself the monitoring of the congruences of
solar activity in the human circulation. But the justification also stems from what the given person
can learn immediately for his/her health care.
In these proceedings, a physician-scientist (YW) (8) and his son, starting as a child and
ending as an adolescent (FW) (9), set an example of family monitoring of BP and HR, the father
providing for more than two decades, mostly half-hourly around the clock measurements, the son
surveilled half-hourly for the first 40 days of his life (10) and self-measuring in childhood and
during adolescence once a day for 8 years (9). Thus YW gathered evidence for a
chronobiologically and longitudinally examined development (in well over two decades of his
half-hourly around-the-clock measurements) of his high BP, MESOR-hypertension, MH, which is
reversible, absent on Sundays and during a vacation spent at home (8). The MESOR, M, is a
Midline-Estimating Statistic Of Rhythm assessed parametrically by the fit of a 24-hour cosine
curve. YW's M detects abnormality, MH, when the complementary non-parametric approach by
stacking data does not (yet) find it in the prediction interval for single values, the "normal range"
of peers of the same gender and age.
YW documents that MH can persist in his systolic (S) BP when it is cleared from the
diastolic (D) BP. On the average, he shows no abnormality on Sundays and during a vacation. By
15
intervention, with timed dietary measures or exercise, and by continuing monitoring he may
provide more longitudinal data to reverse the workday elevation of the SBP MESOR as well,
rather than to find an eventual excessive elevation of the SBP and/or DBP also on Sundays and on
other days away from work. In the manipulation of sodium intake, it seems important to realize
great inter-individual differences, and further the importance of circadian stage, that can both lead
to decreases, rather than increases in BP in response to sodium. Alternatively, if progression
cannot be stopped and the BP-M is not normalized by the absence of work, it will be of interest to
see whether the parametric and the nonparametric approach reveal a concomitant DBP and SBP
failure to reverse to normality on weekends or do so in a sequence, and if the latter is the case,
which of the BP remains abnormal on Sundays first. Clearly, the over two decades of monitoring
by YW do not suffice to draw full inferences concerning the development of a human MH on
weekends as well as on workdays. In these proceedings, YW's contribution to the development of
workday MH is accompanied by the contribution of three elderly men (WPB, GSK and FH) who
are all treated for MH and whose data on the one hand indicate the need for continued surveillance
to avoid CHAT, Figures 1 and 2 (11), and two of them also allow the as-yet basic demonstration of
a transtridecadal spectral component in their circulation and in one case in body weight. FH's
follow-up record shows the need for continued surveillance to detect and, if so, to attempt to
eliminate CHAT and further to validate the extent of success -- e.g., by the use of coenzyme Q10
(Q-Gel) with the evening meal (12) in eliminating 7-day CHAT -- and to recognize any failure,
e.g., to eliminate 24-hour CHAT (data not shown).
The approach demonstrated in Figures 1 and 2 is practiced as yet by a minuscule minority in
noninvasive automatic cardiology in the spirit of Theodore C. Janeway (13) and Frederic C.
Bartter (14), who had to rely on self-measurement. Let us call this school chronomic, when it now
aligns make-ups in time -- chronomes -- of an organism with those of the sun's variability, the
original time structures or chronomes. Not only ~daily, ~half-weekly and ~weekly but many much
longer τs have been found to characterize human physiology and pathology at the levels of
individuals and societies, including ~5-month as well as ~6-month cycles, the former helio-, the
16
latter geomagnetic in origin, with signatures in BP, HR, cardiac arrhythmia and sudden cardiac
death, facts that must not allow their neglect. Yet practicable restrictions of focus at this time,
primarily on ~24-hour rhythmic behavior during a week and on the relation of these circadian
characteristics to half-weekly ones could provide novel information bringing millions of people
into the loop of self-help for preventive care. The chronomic approach can be implemented by
self-measurements and more readily and more densely, by self-help with automatic recording
thanks to modern technology. It has accumulated, with gaps, half-hourly data for up to well over
two decades yet as a minimum for seven days on sets of hundreds of individuals.
The data document day to day and other presumably normal variability in human BP and HR
around the clock and lead to the construction of reference ranges and, in their light, to the finding
of Vascular Variability Disorders (VVDs). These VVDs could be detected in current practice, as
could be the fact that a good drug combination for BP-lowering, such as 12.5 mg of
hydrochlorothiazide and 50 mg of losartan (Hyzaar), can exacerbate a SBP VVD (a circadian
overswing, CHAT) and induce this DBP abnormality with one timing of its administration and
eliminate CHAT with another timing, each particular timing tested for a month in the same patient
(15). The inferences drawn on the basis of long records comparing the same drug in the same dose,
taken by the same person with a different timing in relation to awakening, revealing drastically
different effects, constitute evidence that, sooner rather than later could be considered by those
who currently rely on their platinum standard of a single day's profile. A 24-hour record simply
does not suffice for a prognosis when in the same young neurosurgeon during office hours (09:00-
17:00), 77% acceptable measurements on one day alternate with 100% unacceptable (too high)
ones on another day (16; cf. 17-21).
If in turn current health care remains homeostatic, still assuming, rightly or (we believe
wrongly) that there is indeed a "true" BP and that this can be assessed, if not by single
measurements than by single 24-hour profiles, some recent suggestions sound reasonable. In 2009,
some advocate "... lowering BP in everyone over a certain age, rather than measuring it in
everyone and treating it in some" (22). A polypill containing three BP-lowering drugs, each at half
17
the standard dose -- a statin, folic acid and aspirin -- would serve the purpose of primary and
secondary prevention (23). Others (24) also "support the use of a 'polypill' to lower the risk of
cardiovascular disease in people likely to be at risk (such as all people over the age of 55) without
first checking their BP." This approach is logical and justified from the viewpoint of a health care
based on pseudo-evidence that is based upon a few spotchecks including at best a single
chronobiologically uninterpreted 24-hour profile, which checks a small fraction of a half-weekly
or weekly cycle, as if the pulse were taken for just a small fraction of one cycle, i.e, a fraction of a
second. When all VVDs requiring long-term surveillance are ignored, as is, for instance, the risk of
a stroke in 6 years which can be elevated by an undiagnosed VVD from ~5% to 100% in one study
(21), a polypill is an attractive and economical answer. But as we monitor with self-help, cost-free
to start with at half-hourly intervals for 7 days and continuously monitor when abnormality is
found, the merits of self-surveillance become obvious, also for checking on the demerits of the
polypill or any other treatment, such as the induction and exacerbation of CHAT, on a substantial
number of patients (15, 21).
The arguments that such monitoring is costly, complex and hence futuristic can be met with
modern computer-aided technology by the demonstration that self-surveillance is possible and is
now ongoing on a limited scale, and the complexity can be eliminated by the computer charged
with all complex calculations and providing free and clear interpretations.
Following Mendel's interest in the aurora. Human population and broader biospheric
monitoring has a long way to go in the biosphere to match the information gathered on the aurora,
where the record covers nearly a millennium, as analyzed in Figure 3 (25), which reveals a
transtridecadal cycle also found in environmental temperature (26) in the sediments of an African
lake (27) and in many other variables (3, 28-34).
According to Battersby (35), Galileo described the auroras as sunlight reflected in vapors rising from
the earth. Battersby also writes: "In the late 1600s, Edmond Halley [1656-1742] was the first to correctly
link the aurora to the Earth's magnetic field." According to Egeland (36), a close connection between the
aurora and the geomagnetic field was found around 1730 by Hierter and Celsius. It is the more interesting to
read in De Mairan's book (37) on that topic that he ruled out magnetism as underlying the aurora because
18
"magnetic matter is constant". Had he pursued his earlier botanical observation (38) that the sensitive plant
continued its sleep movements in continuous darkness, and had he measured geomagnetism concurrently,
he could have found an ~24-hour cycle in both and would perhaps not have ruled out constant magnetism in
the genesis of the aurora. It is the more interesting that in 1882 Mendel associated solar activity with the
aurora. A transtridecadal cycle in this phenomenon was first reported for the past 500 years without specific
comment by Sam Silverman (39).
In the case of yearly data on northern lights from a catalogue by Krivsky and Pejml (40), between the
years 1001 and 1500 our meta-analysis (illustrated in Figure 3) shows a BEL. The linear-nonlinear extended
cosinor (41-43) reveals a τ of 32.8 years, with the CI of this τ extending from 31.8 to 33.8 years and an
amplitude with a CI that does not overlap zero (Figure 3, row 3). Also by linear-nonlinear extended cosinor,
during the entire span from 1001 to 1900, a transtridecadal BEL τ is ~29.6 years long with a CI extending
from 29.0 to 30.3 years and an amplitude with a CI only slightly overlapping zero, Figure 3C (bottom row).
While the quality of the data analyzed (40) has been questioned, there is the fact that the greater the
noise in a time series, the more convincing is the validation of an anticipated result. This is indeed the case
in Figure 3, which also shows our analysis of data deemed more reliable by Schröder and Treder (44).
When the analysis of the data of Krivsky and Pejml is restricted to the span of the data published by
Schroeder and Treder, the results are in excellent agreement in Figure 3.
For the interval 1500 to 1948, as noted, a scholarly analysis and review by Silverman (39) supports
the hypothesis that a nonrandom albeit greatly variable transtridecadal pattern in solar activity includes a
spectral component of 33.3 years in the power spectrum of monthly auroral occurrence, in keeping with the
prior report of a climatic ~33-year cycle by Eduard Brückner (45), who fully realized the transdisciplinary
importance of his wet/cold-dry/hot cycle and offered public lectures on that topic.
"[In any event, the aurora can be] more than a pretty display. These storms are caused by violent
outbursts from the sun and can play havoc with satellites, scramble GPS signals, endanger astronauts and
even blow power lines on Earth" (35). This is as far as scientific journalism ventures, not yet to human
physiology. The effect of storms in the biosphere is rarely considered by the public, but is of particular
interest to neuroendocrinologists. It will be up to scholars of melatonin (46, 47), to further map the infradian
challenges found in the record-holding test pilot, Dr. Robert B. Sothern (RBS), author of a comprehensive
scholarly book in the field of rhythms (48). RBS yielded a model for motivation and consistency and
demonstrated in a record of ~5 HR measurements around the clock now covering over 40 years, a
transtridecadal cycle also found in Zürich (Wolf) sunspot numbers during the span covered by his data.
The BEL (3, 28-34) is one of the windows for non-photic mostly invisible effects of the cosmos upon
the biosphere. It also characterizes the aurora as the "greatest show on earth" for most of the past
millennium, with associations in the biosphere. NASA's flotilla of satellites, named THEMIS, sent into
space to analyze magnetic substorms as they happen and to understand the sequence of events that bring
about the northern lights, promises to tell us more about the physical mechanisms involved, but should be
19
checked for biospheric associations. Battersby writes: "During a geomagnetic storm there are typically
several substorms, but how the two are connected is unclear. So far during the mission, solar activity has
been low, but it should increase over the coming year or so, giving THEMIS a chance to watch a much
larger storm unfold" (35). We should concomitantly watch what happens in the biosphere as well. Longterm
monitoring, such as that ongoing for years or decades is needed to learn about infradians in a number
of frequency windows that also include a transyear (2, 49-52) and cis-half-years (2, 53), the latter involving
steroids and melatonin (54) in mediating effects of our cosmos, perhaps via the eyes (55).
Cycles with a τ of over 3 decades' length now documented in an individual's, RBS',
physiology and psychology are reminiscent of the documentation by W.J.S. Lockyer (33) that
these rather long cycles may stem from changes in the length of the sunspot cycle generated by the
cosmos and reflected in the interplanetary magnetic field. We can look with hindsight at what
could have been done in dealing, for instance, with sunspots by individuals who could not observe
too many ~35-year cycles. They, like ourselves, could probably measure not much more than part
of a single adult or part of an elderly 35-year cycle. If Carl Friedrich Gauss' least-squares had been
available in Horrebow's time, i.e., in the 18th
century, he did have enough data to objectively
document, with the cosinor method by least-squares, a cycle of ~9 years in his observation span
(54).
In either case, for the variable sunspot cycle at the times in history when it happened to be
studied in the 18th
and 19th
centuries, the necessary length of the time span needed for rejecting the
zero-mplitude assumption and to get reliable estimates of parameters was not longer than a single
cycle's length (54). Without extrapolating beyond the scope of the specific data analyzed, we find
the same success for the transtridecadal BEL (3, 28-34). These precedents should encourage
neuroendocrinologists, among many others, to sample systematically for very long spans, since
some if not many of the novel infradian rhythms, such as cis-half-years and transyears, may well
be modulated by transtridecadal cycles. The latter have implications as an aspect of the climate for
global temperature, that as Brückner lectured have contributed to population dynamics and many
other human affairs (30, 45).
20
Discussion. The challenge of circadians is complemented by the greater challenge of
infradians that require lifetime monitoring, preferably by unobtrusive and generally affordable
methods yet to be developed in nanotechnology. Before this goal is achieved, data collection by
available automatic instrumentation, as used by FH, YW, DG and FW, or manually by RBS, FW
and WRB, has to be relied upon so that infradian focus can be directed at major problems of
society such as those documented elsewhere (6). Data for this critical monitoring of solar activity
could be contributed by humans, rendering their health care cost-effective for stroke and other
severe vascular disease prevention by self-monitoring and obtaining data analyses automatically
and cost-free from a website, as BIOCOS did since 1991 (56; cf. 57), analyzing physiological data,
Figure 4, as well as those accumulating in archives, Figure 5. This website could thus serve for
service and research, both medical and transdisciplinary, and is being constructed by the Phoenix
Study Group, composed of volunteering members of the Twin Cities chapter of the Institute of
Electrical and Electronics Engineers (http://www.phoenix.tc-ieee.org). In the interim, analyses are
available from the international project on The BIOsphere and the COSmos, BIOCOS
(corne001@umn.edu).
Conclusion. All known τs in solar activity up to ~500 years length that may seem to be
negligible peaklets in the aurora, Figure 6, characterize human individuals' and populations'
variables including, as far as an individual's lifespan allows, HR, BP, body weight and mental
performance in health, and have signatures in societal variables including morbidity and mortality,
as had long been suggested, mostly without any inferential statistical documentation of the
uncertainties involved. These uncertainties (CIs) can now be mapped with their well-known τs,
such as the Horrebow-Schwabe decadal cycle, the Makarov and Sivaraman global solar cycle of
~17 years, Hale's ~didecadal bipolarity cycle, and for what we rediscovered as the BrücknerEgeson-Lockyer
(BEL) cycle which is reflected in the total solar flare index, in solar wind
parameters of the interplanetary magnetic field and in many human physiological and societal
variables including 2,556 years of international battles, thousands of years of tree rings, and cave
temperatures, and in the emergence on different continents of outstanding physicians, poets and
21
historians (the emergence of outstanding individuals a contribution by Prof. Miroslav Mikulecky)
(58; cf. 59). A major transdisciplinary point is that the presence of a biospheric counterpart may
support if not validate the corresponding environmental counterpart and vice versa. The eons of
evolution have likely contributed to the biospheric finding, whereas, e.g., any peaklets found in
Figure 6 by the cosinor analysis of a 900-year series of the aurora poses legitimate doubts about
possible artifacts. Such doubts are always part of science and the limitations of the kind of data
available are ever present; but when a peaklet found in the aurora at a trial τ of ~500 years has
biospheric counterparts, as indeed it does, it gains greatly in transdisciplinary interest.
The immediate now inferentially statistically documented health effect of new ~5- or ~16months
cycles relate to sudden cardiac death, suicide, crime and terrorism (6), in which non-photic
cycles characterizing the solar wind can altogether replace photic cycles such as the yearly
(circannual) change. While we develop unobtrusive, affordable monitoring tools for stroke and
other hard disease prevention, and these tools are already available as prototypes for general use,
let us also analyze the same data of our physiology and health departments' archives about our
pathology for monitoring space weather. While we contribute greenhouse gases, it is necessary to
know climatic changes as a result not only of human activity but of the external influences as well.
The most powerful such influence is solar variability, predictable only insofar as it is cyclic. What
is new is that we can gauge that variability by that of BP and HR. Let us not fly blind with respect
to both solar and human variability as these affect individual and societal health. A polypill will
neither explore the risk of societal disease nor will it lower this risk. If, perhaps, it has merit in
clinical trials, like any other antihypertensive treatment, it will represent increased risks that
require self-surveillance, which is the essential recommendation of the accompanying set of 19
presentations.
Acknowledgement
Prof. Jaroslav Strestik in Prague kindly provided the time series on the aurora borealis here
analyzed.
22
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
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2. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
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http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
4. Halberg F, Cornélissen G, Best WR. A trantridecadal BEL cycle in human blood pressure
and body weight. This issue.
5. Gorlov D, Halberg F, Cornélissen G, Gorgo Y. Cis-half-year in the systolic blood pressure of
a young adult. This issue.
6. Halberg F, Cornélissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles
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Suppl. 173: 153-181.
7. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutaske G, Wendt HW, Johnson P,
Gigolashvili M, Breus T, Sonkowsky R, Chibisov SM, Katinas G, Siegelova J, Dusek J,
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23
infarction and far- and near-transyears. Biomed & Pharmacother 2005; 59 (Suppl 1): S239-
S261.
8. Watanabe Y, Cornélissen G, Beaty LA, Siegelova J., Fiser B, Dusek J, Homolka P, Halberg
F. White-coat hypertension in a cardiologist: decades of monitoring lead to transient
occupational MESOR-hypertension absent during vacation: strain test. This issue.
9. Watanabe Y, Cornélissen G, Watanabe F, Tarquini R, Perfetto F, Siegelova J, Fiser B, Dusek
J, Homolka P, Halberg F. Solar signatures in a boy's blood pressure and heart rate. This
issue.
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extent, which, lacking this standard for comparison, would be considered within the limits of
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24
pressure determined each day at 6 in the afternoon provides especially convincing evidence
that this patient is a hypertensive. ... My plea today is that information contained in such
curves [cosinor fits] become a routine minimal amount of information accepted for the
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55. Halberg F, Cornélissen G, Schwartzkopff O, Katinas GS, Chibisov SM, Khalitskaya EV,
Mitsutake G, Otsuka K, Scheving LA, Bakken EE. Chronometaanalysis: magnetic storm
associated with a reduction in circadian amplitude of rhythm in corneal cell division.
Proceedings, International Conference on the Frontiers of Biomedical Science:
Chronobiology, Chengdu, China, September 24-26, 2006, p. 40-42.
56. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P,
Bakken E, International Womb-to-Tomb Chronome Initiative Group: Chronobiology in
space. Keynote, 37th Ann. Mtg. Japan Soc. for Aerospace and Environmental Medicine,
Nagoya, Japan, November 8-9, 1991. University of Minnesota/Medtronic Chronobiology
Seminar Series, #1, December 1991, 21 pp. of text, 70 figures.
57. Watanabe Y, Hillman DC, Otsuka K, Bingham C, Breus TK, Cornélissen G, Halberg F.
Cross-spectral coherence between geomagnetic disturbance and human cardiovascular
variables at non-societal frequencies. Chronobiologia 1994; 21: 265-272.
58. Mikulecky M. Solar activity, revolutions and cultural prime in the history of mankind.
Neuroendocrinol Lett 2007; 28: 749-756.
59. Halberg F, Cornélissen G, Regal P, Otsuka K, Wang ZR, Katinas GS, Siegelova J, Homolka
P, Prikryl P, Chibisov SM, Holley DC, Wendt RW, Bingham C, Palm SL, Sonkowsky RP,
Sothern RB, Pales E, Mikulecky M, Tarquini R, Perfetto F, Salti R, Maggioni C, Jozsa R,
Konradov AA, Kharlitskaya EV, Revilla M, Wan CM, Herold M, Syutkina EV, Masalov
AV, Faraone P, Singh RB, Singh RK, Kumar A, Singh R, Sundaram S, Sarabandi T,
Pantaleoni GC, Watanabe Y, Kumagai Y, Gubin D, Uezono K, Olah A, Borer K, Kanabrocki
EA, Bathina S, Haus E, Hillman D, Schwartzkopff O, Bakken EE, Zeman M.
Chronoastrobiology: proposal, nine conferences, heliogeomagnetics, transyears, near-weeks,
near-decades, phylogenetic and ontogenetic memories. Biomed & Pharmacother 2004; 58
(Suppl 1): S150-S187.
30
Legends
Figure 1. A difficult-to-eliminate circadian overswing (CHAT) (C) of a 24-hour
synchronized rhythm (A) of systolic (S) (I) and diastolic (D) (II) blood pressure (BP) (and heart
rate [III]) can be the unwelcome trade-off for a successful BP MESOR-lowering (B). Continuous
monitoring is required once a vascular variability disorder, such as a high blood pressure (BP),
and/or a circadian overswing, CHAT (short for Circadian Hyper-Amplitude-Tension), is
diagnosed. A circadian rhythm of systolic BP and heart rate of a physician-scientist, GSK, is
assessed by the fit of 24-hour cosine curves to data sections of 7 (left) and 28 (right) days, the
latter smoothing more than the former, in that transient episodes of abnormality such as an
overswing, shown in black, that last only for one or a few 24-hour spans, are likely eliminated. The
elimination of CHAT in GSK, based on surveillance by half-hourly measurements analyzed
weekly, was nonetheless a very long process, taking years, with only transient success and
frequent recurrences over many years. © Halberg.
Figure 2. Need for continued (systolic) blood pressure monitoring: CHAT recurs after
year(s) of absence, even in smoothed 28-day records analyzed. Continuous monitoring is required
once a vascular variability disorder, such as a high blood pressure (BP), and/or a circadian
overswing, CHAT (short for Circadian Hyper-Amplitude-Tension), is diagnosed. A circadian
rhythm of systolic (S) (I) and diastolic (D) (II) BP of an elderly man, FH, is assessed by the fit of
24-hour cosine curves to data sections of 7 and 28 days. Note the large black spot at the very end
of row C, showing the recurrence of a BP overswing, CHAT. Subsequently, for 3 consecutive
weeks, the 7-day (but not the occasional 1-day) CHAT was eliminated by 100 mg of coenzyme
Q10 (Q-Gel) taken with the evening meal. © Halberg.
Figure 3. In a series of northern lights covering 900 years, a transtridecadal cycle is seen
insofar as the CI, but not the point estimate of the period, τ, extends beyond 30 years. Data
analyzed were questioned with the implication that their analyses may be invalid, even though they
had yielded a result close to the anticipated finding. In view of that outcome and the observation
that a statistically significant result in noisy data in our opinion constitutes a stronger evidence
31
than the corresponding result in data with little or no noise, it seemed worthwhile to pursue the
problem further. For part of the span analyzed, another set of data, regarded as more reliable (44),
happened to be available. This afforded the opportunity for comparative analyses of that part of the
900-year span, 1545-1724, for which data deemed reliable were also available. It turned out that
the extended cosinor yielded for the span of Schröder and Treder (1545-1724), in the latter's data,
a component with a τ of 29.1 years and in the corresponding span from data of Krivsky and Pejml
a τ of 29.4 years, as seen from this figure, which also shows that the CI of Schröder and Treder
extending from 26.3 to 31.8 years overlies that of Krivsky and Pejml extending from 27.1 to 31.7
years. © Halberg.
Figure 4. Global cross-spectral association of a man's circulation with the planetary
geomagnetic disturbance index Kp. © Halberg.
Figure 5. Global cross-spectral association of the incidence of myocardial infarctions in
Moscow (1979-1981) and the Bz-GSK component of the interplanetary magnetic field. © Halberg.
Figure 6. Data from J. Strestik (1001-1900). Results to be interpreted with caution since the
average number of yearly observations increased as a function of time, likely in relation to
technological observational progress. Data inspection finds about 3 different spans: the earliest
with fewer observations, the middle one with more observations, and the more recent with
considerably more observations. Trial periods: 500, 300, 200, 120, 70. Nonlinear results (each
fitted separately): 477 [430, 524], 305 [282, 327], 227 [210, 245], 125.6 [118.4, 132.8], 67.2 [65.9,
68.6]. Composite model failed completely prompting removal of 300-year trial period. Results
from concomitant fit with conservative limits are in years:
503.5 [418.1, 588.9] A=8.21 [4.58, 11.83]
243.1 [216.2, 270.1] A=5.10 [1.19, 9.01]
117.4 [107.2, 127.6] A=3.06 [-.73, 6.86] [1.49, 4.64]1P
69.6 [ 67.4, 71.7] A=5.27 [1.55, 8.99].
32
Since the conservative 95% confidence limits of the 117.4-year period overlap zero, 1-parameter
limits (1P) are also given in this case. Periods of 243.1 and 117.4 are possibly 2nd and 4th
harmonics of 503.5, describing waveform. © Halberg.
33
Figure 1
34
Figure 2
35
Figure 3
36
Figure 4
37
Figure 5
38
Figure 6
39
B. DEDICATIONS
Achievements near 60 years of age of Academician Germaine Cornélissen:
the Cornélissen-series revisited1,2
Franz Halberg
University of Minnesota, Minneapolis, MN, USA
Abstract
Nearly 15 years ago, on November 22, 1994, in Ekaterinburg (formerly Sverdlovsk), Russia,
a conference of chronobiologists endorsed the name "Cornélissen-series" for broadening the
mapping of biological circadian systems, first by focus upon the half-week and week and
eventually by study of the broader and broader spectrum of biospheric multifrequency rhythms,
with as dense and long data series as possible. In the interim, in the context of her project on The
BIOsphere and the COSmos, BIOCOS, this task of building a novel transdisciplinary spectrum was
pursued, and further periods of decades, centuries, and thousands and millions of years were
documented. Much of the evidence was provided with unique success by Germaine Cornélissen,
PhD, Professor of Integrative Biology and Physiology at the University of Minnesota.
The Cornélissen-series extends the range of periods, τ, in and around us, to the spectral region of
millions of years in the diversity of genera on the ocean floor, to thousands of years in the
temperature record of caves, to about 500-year cycles in tree rings and cave temperatures and to
the 35-year BEL cycle in climate on earth, economics and political and military affairs as well as
in psychophysiology, to cite but a few examples.
Germaine's scientific ancestor in her discovery of (novel cyclic) signatures in the biosphere
of heliogeomagnetics was William Gilbert (1544-1603), the court physician to Queen Elizabeth I
and King James I of England, who crossed disciplinary barriers by writing a treatise on magnetism
(4), considered by Sydney Chapman and Julius Bartels (5), leaders in this field, as the first truly
scientific treatise, now updated transdisciplinarily (6). Germaine crossed from physics to
40
biomedicine and added transdisciplinary information, pertinent for everybody. While she excelled
in Gilbert's steps, she learned from the blunder of another distinguished scientist, the physicist
Jean-Jacques d'Ortous de Mairan (1678-1771), who in 1729 wrote a book on the aurora borealis
(7). He discussed in great detail whether magnetism underlies the aurora borealis, notably since
Edmond Halley (1656-1742) had speculated that magnetism was involved (8). De Mairan
ultimately explicitly ruled out magnetism as underlying the aurora because "magnetic matter is
constant". De Mairan, however, made a major contribution remembered primarily in biology (9):
he not only noted the sleep movements of a plant, a phenomenon known already to Androsthenes
in the fourth century BC; he also recorded the persistence of periodicity in the dark and suggested
in a broad extrapolation that these rhythms may be of interest in dealing with patients.
But de Mairan refrained from pursuing the problem further. As a physicist he felt that the
problem was beyond the scope of his discipline. He did not seize the opportunity to explore the
putative (exogenous and/or endogenous) features underlying the sensitive plant's sleep movements
that may only be the two sides of the same coin: one side may be light, the usually dominant
circadian and circannual synchronizer when present, the other may be the time structure of
terrestrial magnetism, either or both acting, if not continuously then intermittently, concomitantly
and/or in alternation. Geomagnetic disturbance may be an influencer and/or an interacting
circasemiannual synchronizer during the night at middle latitudes (10), becoming dominant with
its half-yearly signature at noon near the pole (11). Along the evolutionary scale, the actions of
both light and geomagnetism may well be coded in the genome, albeit the temporal location of the
(synchronizing) cycles is determined by the environment (12). Had De Mairan pursued the
problem of mechanism for the case of the sensitive plant's "sleep movements", irrespective of
whether he may have ruled magnetism out as a mechanism associated with sleep movements or
ruled it in, he would have found at least that magnetic disturbance, as he put it, is not constant, and
hence not incompatible with the aurora.
The erstwhile physicist Germaine Cornélissen, to whom this paper is dedicated near her 60th
birthday (November 22, 2009), did not adhere to any barriers after her training, which started with
41
masters in physics and education in 1971 and a PhD in physics in 1976. Her thesis (for which she
was supported by a fellowship) "Signal Analysis and its Application to the Problem of Frequency
Stability Definition", at the Laboratory of Frequency Standards, was directed by the late Prof. Jean
De Prins, University of Brussels (who could enjoy many of Germaine's presentations at
international meetings to which she invited him). A secondary project, "A proposal for a procedure
for the analysis of rapid eye movements", was carried out under the direction of Dr. Olga PetreQuadens,
Neurophysiology Laboratory, University of Antwerp, Belgium; again the advisor could
enjoy Germaine's invitations and presentations at international meetings. From 1976 on, Germaine
went through the ranks at the University of Minnesota as a Visiting Research Fellow, Research
Fellow, Assistant Professor, Senior Research Associate in the Departments of Laboratory
Medicine and Pathology and of Pediatrics (1994-2008) and Director of Biometry of the
Chronobiology Laboratories.
Germaine is currently the de facto director of the Halberg Chronobiology Center and is
Professor of Integrative Biology and Physiology at the University of Minnesota. She coordinates
the International Project on The Biosphere and the Cosmos (BIOCOS) (formerly the International
Womb-to-Tomb Chronome Initiative Group), and is a member of the Phoenix Group
(http://www.phoenix.tc-ieee.org/), comprised of members of the Twin Cities chapter of the
Institute of Electrical and Electronics Engineers (IEEE), the Société Francophone de
Chronobiologie, the International Society for Chronobiology, the American Association for the
Advancement of Science, the American Physical Society, the Biometric Society, the American
Statistical Association, the New York Academy of Science, the Academy of Integrative
Anthropology, the American Physiological Society, and the Book Committee of the National
Chapters of Phi Beta Kappa. She was secretary of the North American branch of the International
Society for Research on Civilization Diseases and the Environment (SIRMCE), and is a member
of the Scientific Council of SIRMCE.
Among her many honors, she is a recipient of the Hoechst Foundation Chronobiologia
Award, a member of the Sigma Xi Society, an honorary member of the Cardiff Scientific Society,
42
and was a foreign member of the Problem Commission on Chronobiology and Chronomedicine of
the Russian Academy of Medical Sciences. She has been profiled in "The Achievements of
Chronobiology and Chronomedicine" by the late N.I. Aslanyan and S.Kh. Madoyan, and was just
elected to membership in the Leibniz Society for the Sciences of Berlin, one of the oldest scientific
academies, functioning without interruption since its founding by Gottfried Wilhelm Leibniz in
1700.
Germaine has consistently followed the crossing of disciplinary barriers between physics and
health care, from which De Mairan had refrained. She had other predecessors: The give-and-take
between biology and physics continued when the erstwhile pharmacist and amateur astronomer
and botanist Samuel Heinrich Schwabe in 1844 (3) reported on the circadecadal sunspot cycle
explicitly as a periodicity. Schwabe's data by 1838 (2) sufficed to validate periodicity by cosinor
with the rejection of the zero-amplitude assumption as shown by Germaine. Furthermore, by 1776
Christian Horrebow (1718-1776) had accumulated a sufficient number of observations of sunspots
(1) for Germaine to further document a circadecadal cycle. The epochs of maximum and minimum
had been known since Galileo Galilei, Christopher Scheinert, Johannes Fabricius and Thomas
Harriot discovered the sunspots almost simultaneously (1610-1611).
The opinion leaders in astronomy of Schwabe's and earlier times (and perhaps in physics and
biology more generally today) had concluded that the study of cycles in sunspots was "not
profitable". Likewise, the opinion leaders of a contemporary homeostatic physiology share the
opinion of their predecessors in astronomy. The study of cycles in biology quite generally, as
compared to the reductionist fashions of the 1990s, continuing into the current millennium, does
not appear to be "profitable", potential monetary profit being the historically recurrent yardstick
misapplied to gauge the quality of research. In 1997, the physicists Douglas Hoyt and Kenneth
Schatten, in their book "The Role of the Sun in Climate Change" (13), while thoroughly discussing
A.V. Clough's research, felt that Clough overemphasized the search for cycles. Moreover, they
refer to "cyclomania" while using a citation from Sir Norman Lockyer: "Surely in Meteorology, as
in Astronomy, the thing to hunt down is a cycle [emphasis ours], and if that is not to be found in
43
the temperate zone, then go to the frigid zones or to the torrid zone to look for it, and if found, then
above all things, and in whatever manner, lay hold of, study it, record it and see what it means"
(14).
Germaine's scholarship in turn uses the foregoing Norman Lockyer citation without any
double entendre by proximity to cyclomania. She follows Sir Norman's admonition into the Arctic
with Kuniaki Otsuka's ECGs (15) and Andi Weydahl's salivary melatonin (16), and into the
Antarctic with data from Mark Engebretson's magnetometer (17) and with blood pressures from
Yoshihiko Watanabe (18). With Miroslav Mikulecky, she analyzed natality data in the tropical, if
not "torrid", Philippines (19). Germaine has thus explored Sir Norman's frigid and torrid zones,
and many other areas in between these sites. But one of her most important challenges remains, in
all zones on earth and beyond, the exploitation of vascular variability disorders for a universal
preventive health care delivery based on cyber-implemented self-help in collecting time series for
the multiple purposes the time series may serve -- stroke and other hard event prevention for
individuals first and foremost.
Dividends of her many analyses of data from all over the world relate both to medical and
transdisciplinary research. Medically, by her analyses of data, she compares the relative merits of
harbingers of risk elevation. In addition, she seeks an understanding of the effects of the sun in
dealing with aggression and other diseases of society. The effects of the sun, that could not be
gauged by Zürich sunspot numbers by Brückner, are now shown by Germaine to be expressed in a
transtridecadal cycle in the aurora (20), economics (21) and most importantly in the solar wind, in
plasma speed, proton temperature, sigma, Bz (22) and terrestrial weather, notably temperature, as
the newest member of the Cornélissen-series dubbed the BEL (22-26; cf. 27).
Just as Mendel was forgotten for a time as founder of genetics, Brückner, with a notable
exception, has been mostly forgotten, and when he is remembered his name may be written
incorrectly, i.e., "Bruckner" (without the umlaut) or "Brikner". When we find apparently new
cycles, we must take care not to overlook forgotten pioneers. Germaine's scholarship did not forget
Gilbert, Horrebow, Schwabe or Brückner. Most important, when we honor Germaine and Jiri
44
Dusek as we did Jarmila Siegelova and Bohumil Fiser, we must remember that Brno has produced
more than the father of genetics and a well-known meteorologist. In 1882, a year of high solar
activity, as documented by sunspots, the notes of Mendel (who in his last years also occupied
himself with observations of sunspots; 28, 29) associated difficulties in telephonic
communications and the aurora borealis in different geographic locations with solar activity, notes
that identify him as one of the earliest space scientists.
Footnotes
1. The joint published titles rest on analyses carried out or checked by Germaine and cover a
very wide range, whether we consider the length of cycles or the scope of the analyses and involve
a very long list of cooperating scientists from many disciplines and geographic locations. Thanks
are due to all of them, without whom the results could not have been obtained. Particular gratitude
is due to Prof. Jarmila Siegelova's team in Brno, Czech Republic, notably to Prof. Jiri Dusek,
whom we also honor today.
2. The authors are indebted to Ilya G. Usoskin (University of Oulu, Finland) for prompting
the analysis of Christian Horrebow's original observations (1). Germaine validated his data as
sufficient to establish the cyclicity of sunspots in inferential statistical terms by the 18th
century.
Germaine thereafter further detected in Samuel Heinrich Schwabe's records the minimal number of
cycles required to establish a sunspot periodicity, thereby indicating that by 1838 (2) there was
enough evidence to refer to a periodicity (2), which Schwabe did only in 1844 (3).
Supported by MSM0021622402
45
Thiele ThN. De Macularum Solis antiquioribus quibusdam observationibus Hafniae institutis.
Astronomische Nachrichten 1859; 50: 259-261.
1. Schwabe H. Über die Flecken der Sonne. Astronomische Nachrichten 1838; 15: 244-248 (no.
350).
2. Schwabe H. Sonnen-Beobachtungen im Jahre 1843. Astronomische Nachrichten 1844; 21:
254-256 (no. 495).
3. Gilbert W. De magnete, magneticisque corporibus, et de magno magnete tellure; physiologia
noua, plurimis et argumentis, et experimentis demonstrata [On magnetism, magnetic bodies,
and the great magnet Earth]. London: Short; 1600. 204 pp.
4. Chapman S, Bartels J. Geomagnetism. 3rd
Ed. Oxford: Clarendon Press; 1962. 1049 pp.
5. Rosch PJ, Markov MS (Eds.). Bioelectromagnetic Medicine. New York: Marcel Dekker;
2004. 850 pp.
6. de Mairan J. Traité physique et historique de l'Aurore Boréale. Par M. de Mairan. Suite des
Mémoires de l'Académie Royale des Sciences, Année M.DCCXXXI [Physical and historical
treatise of the Aurora Borealis. By M. De Mairan. Series of the Memoirs of the Royal
Academy of Sciences, for the year 1731]. Paris: Royal Printing Office; 1733. 570 pp. Second
Ed., 1754.
7. Battersby S. The greatest show on Earth. New Scientist (7 February) 2009; 201: 34-38.
8. de Mairan J. Observation botanique. Histoire de l’Académie Royale des Sciences; 1729. p.
35-36.
9. Tarquini B, Cornélissen G, Perfetto F, Tarquini R, Halberg F. Chronome assessment of
circulating melatonin in humans. In vivo 1997; 11: 473-484.
10. Martikainen H, Tapanainen J, Vakkuri O, Leppaluoto J, Huhtaniemi I. Circannual
concentrations of melatonin, gonadotrophins, prolactin and gonadal steroids in males in a
geographical area with a large annual variation in daylight. Acta endocrinol (Copenhagen)
1985; 109: 446-450.
46
11. Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. About 5-month
cycle in human circulating melatonin: signature of weather in extraterrestrial space? Poster
presentation, Fourth UN/ESA/NASA/JAXA Workshop on the International Heliophysical
Year 2007 and Basic Space Science: "First Results from the International Heliophysical Year
2007", Sozopol, Bulgaria, June 2-6, 2008.
12. Hoyt DV, Schatten KH. The Role of the Sun in Climate Change. New York/Oxford: Oxford
University Press; 1997. 279 pp.
13. Lockyer N. Contributions to Solar Physics. London: Macmillan; 1874, pp. 424-425.
14. Otsuka K, Oinuma S, Cornélissen G, Weydahl A, Ichimaru Y, Kobayashi M, Yano S,
Holmeslet B, Hansen TL, Mitsutake G, Engebretson MJ, Schwartzkopff O, Halberg F.
Alternating-light-darkness-influenced human electrocardiographic magnetoreception in
association with geomagnetic pulsations. Biomed & Pharmacother 2001; 55 (Suppl 1): 63s-
75s.
15. Weydahl A, Sothern RB, Cornélissen G, Wetterberg L. Geomagnetic activity influences the
melatonin secretion at latitude 70˚N. Biomed and Pharmacother 2001; 55: 57-62.
16. Cornélissen G, Engebretson M, Johnson D, Otsuka K, Burioka N, Posch J, Halberg F. The
week, inherited in neonatal human twins, found also in geomagnetic pulsations in isolated
Antarctica. Biomed & Pharmacother 2001; 55 (Suppl 1): 32s-50s.
17. Watanabe Y, Cornélissen G, Refinetti R, Czaplicki J, Kodera L, Shimizu J, Fujita T, Halberg
F. Cardiovascular monitoring at the South Pole reveals two simultaneous circadian
components in blood pressure. Proceedings, International Conference on the Frontiers of
Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 232-234.
18. Cornélissen G, Halberg F, Mikulecky M, Florida P, Faraone P, Yamanaka T, Murakami S,
Otsuka K, Bakken EE. Yearly and perhaps transyearly human natality patterns near the
equator and at higher latitudes. Biomed & Pharmacother 2005; 59 (Suppl 1): S117-S122.
19. Cornélissen G, Czaplicki J, Halberg F, Schröder W, Beaty LA, Strestik J, Mikulecky M,
Chibisov SM, Radysh IV, Blagonravov M, Schwartzkopff O. Partial validation of an about
47
29-year transtridecadal cycle in the aurora borealis. In: Proceedings, 14th
International
Symposium, Ecologo-Physiological Problems of Adaptation, 9-10 April 2009. Moscow:
People's Friendship University of Russia; 2009. p. 490-493.
20. Cornélissen G, Halberg F, Schwartzkopff O, Sanchez de la Peña S, Chibisov SM, Radysh IV,
Blagonravov M, Katinas GS. Economics and biology: the BEL. In: Proceedings, 14th
International Symposium, Ecologo-Physiological Problems of Adaptation, 9-10 April 2009.
Moscow: People's Friendship University of Russia; 2009. p. 486-489.
21. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F.
Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics. In: Halberg F, Kenner T, Fiser
B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology, Brno, Czech
Republic, Oct. 4-7, 2008. p. 106-115. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
22. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
23. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
24. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
25. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
26. Stehr N, von Storch H (Eds.) (Stehr B, Gamlin G, trans). Eduard Brückner: the sources and
consequences of climate change and climate variability in historical times.
Dordrecht/Boston: Kluwer Academic Publishers; 2000. 338 p.
27. Iltis H (Paul E, Paul C, trans). Life of Mendel. New York: Hafner Publishing; 1966. 336 p.
First published in English in 1932.
28. Dubec K, Orel V. Gregor Mendel's scientific activity in meteorology. Folia Mendeliana
1980; 65: 215-242.
48
MUDr. Jiří DUŠEK, CSc: A fruitful cooperation
Franz Halberg1
, Germaine Cornélissen1
, Othild Schwartzkopff1
, Yoshihiko Watanabe2
,
Jarmila Siegelova3
, Bohumil Fiser3
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA;
2
Tokyo Women’s Medical University, Medical Center East, Tokyo, Japan;
3
Masaryk University, Brno, Czech Republic
Earlier in these annual conference reports, we honored Profs. Jarmila Siegelova and Bohumil
Fiser, whose investigations on the chronomics of blood pressure have now placed Brno on the map
of international transdisciplinary science. The honor roll would not be complete without dedicating
an issue to MUDr. Jiří Dušek,CSc, the third member of Europe's leading chronomics team, born on
19 December 1946 in Vítkov, Czech Republic.
After finishing secondary school in 1963, Jiří attended the Faculty of Medicine at Hradec
Kralové and graduated in 1969 from Charles University Prague. In 1973 he took the postgraduate
examination in Internal Medicine (of a first degree); in 1978 he passed the postgraduate
examination for General Medicine (of a first degree); in 1980 he took the postgraduate
examination for Internal Medicine (of a second degree); and in 1990 he graduated and received his
Ph.D degree. After finishing his medical studies, he worked in the Department of Medicine at the
Military Hospital in Brno, Czech Republic. Later he became head of the outpatient medical
department in Brno. Since 2002 he has been a department head at the National Centre of Nursing
and Other Health Professions (part of the Ministry of Health) in Brno. His scientific interests are
occlusion plethysmography and essential hypertension.
Twenty years ago he started to cooperate with Prof. MUDr. Jarmila Siegelova, DrSc. and
Prof. MUDr. Bohumil Fišer, CSc, and, the first three authors are happy to add, with the University
of Minnesota in Minneapolis. Jiri has published many articles in Czech and foreign journals. His
publications include the appended record of cooperation with the University of Minnesota. The
49
broad range of topics apparent from the titles of his papers and their content attest better to his
accomplishments than this laudatio.
In summary, Jiří, with Profs. Siegelova and Fišer, has been a pillar of a cooperation that
began in 1990 between the Universities of Brno and of Minnesota, and thus between the
birthplaces of both genetics and chronobiology and chronomics. It was a problem to assess the
value of Gregor Johann Mendel's studies in his time; by the same token, it will be up to others to
weigh the importance of a chronobiologic interpretation of blood pressure monitoring as the start
of a universal educated self-help in health care. As a minimum, patients with a reliably diagnosed
high blood pressure can ascertain that they do not pay a high price for lowering their blood
pressure. As seen in Figure 1, discussed in last year's conference volume by Prof. Yoshihiko
Watanabe, the antihypertensive treatment at different circadian times can have opposite effects in
the same patient investigated (Su): desired ones in the afternoon and undesired ones in the
morning. It would be nice if Dušek, Fiser and Siegelova could get the credit for avoiding such a
circumstance in Brno. We are at the dawn of a health care switching to focus on variability as a
fact, replacing the fiction of time-unqualified normal ranges and equally imaginary baselines. If
this is accomplished, Jiří Dušek, as well as Bohumil and certainly the dynamo Jarmilka, following
in Pavel Prikryl's steps and with Pavel Homolka's contribution, will get the deserved credit.
50
51
Legend
Figure 1. Monitoring of blood pressure for treatment validation and optimization is not a
luxury when, as shown on top and in the middle of this figure, the same currently popular drug
Hyzaar (a combination of 12.5 mg of hydrochlorothiazide and 50 mg of Losartan) can do harm in a
patient (Su) in the morning, but is beneficial when taken in the same dose by the same person in
the evening some months later. Medication was changed systematically, on a usual routine of
living with diurnal activity and nocturnal rest. On each treatment timing in relation to awakening,
Su was studied for ~1 month with the blood pressure monitored for the last week, as described in
detail by one of us (YW). In the morning the medication raised the circadian amplitude of blood
pressure to an extent of exacerbating or inducing a circadian overswing (or CHAT), a risk greater
than a high blood pressure, whereas at another time the same dose lowered both the circadian
amplitude and MESOR, eliminating all abnormality, and thus offered benefit. The painting at the
bottom by Pieter Brueghel, "The Parable of the Blind Leading the Blind", is reproduced by kind
permission of the Fototeca della Soprintendenza of the BAS PSAE and of the Polo Museale of the
City of Naples, in order to emphasize that CHAT is silent to both the caregiver acting on the basis
of a conventionally interpreted (chronobiologically uninterpreted) 24-hour blood pressure profile
as well as to the majority of providers treating on the basis of single measurements in their office.
© Halberg.
52
1. Siegelova J., Prikryl P., Dusek J., Cornélissen G., Halberg F. Der Vergleich von circadianen rhythmischen Schwankungen
bei Hypertonikern und Normotonikern. Abstract, 14. Tagung der Wissenschaftlichen Sektion der Deutschen Liga zur
Bekämpfung des hohen Blutdruckes, Ulm, FRG, Nov. 29-Dec. 1, 1990.
2. Cornélissen G, Halberg F, Prikryl P, Dankova E, Siegelova J, Dusek J, International Womb-to-Tomb Chronome Study
Group: Prophylactic aspirin treatment: the merits of timing. JAMA 1991; 266: 3128-3129.
3. Prikryl P, Siegelova J, Cornélissen G, Dusek J, Dankova E, Fiser B, Vacha J, Ferrazzani S, Tocci A, Caruso A, Rao G, Fink
H, Halberg F, International Womb-to-Tomb Chronome Initiative Group: Chronotherapeutic pilot on 6 persons may guide
tests on thousands: Toward a circadian optimization of prophylactic treatment with daily low-dose aspirin. University of
Minnesota/Medtronic Chronobiology Seminar Series, #3, December 1991, 4 pp. text, 4 figures.
4. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. 24-Stunden-Baroreflex-Sensitivitätsmessung bei normotonen
Personen. Hochdruck 11: 101, 1991.
5. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Baroreflex sensitivity during 24 hours. Scripta medica (Brno) 64:
186, 1991.
6. Fiser B., Siegelova J., Dusek J., Cornélissen G., Halberg F. Baroreflex heart rate sensitivity during 24 hours period
evaluated by spectral analysis of blood pressure record. Scripta medica (Brno) 65: 315, 1992.
7. Fiser B., Siegelova J., Dusek J., Cornélissen G., Halberg F. Cosinor analysis of baroreceptor heart rate sensitivity during
24-hour period. Arch. int. Physiol. Biochim. Biophys. 100: A87, 1992.
8. Fiser B., Siegelova J., Dusek J., Halberg F., Cornélissen G. Circadian variation of baroreflex heart rate sensitivity in man.
Abstract, IV International Symposium on Control of Heart Rhythm, Slovak Academy of Sciences, Smolenice Castle, April 6-
9, 1992, #11.
9. Fiser B., Siegelova J., Dusek J., Halberg F., Cornélissen G. Is the circadian variability of baroreflex dependent upon sleep?
Abstract, 6th Int. Cong. Psychophysiology, Charité, Berlin, Germany, Sept. 2-6, 1992, p. 63.
10. Prikryl P., Prikrylova P., Halberg F., Siegelova J., Dusek J., Karpisek Z. Profylaxe kardiovaskulárnich chorob kyselinou
acetylosalicylovou: chronobiologická multicentrální studie. Abstract, XX Celostátní Internisticky Kongres s Mezinárodní
Ucasti Zlin, 1992, p. 60.
11. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Analysis of time parameters of respiratory cycle during 24
hours. Arch. int. Physiol. Biochim. Biophys. 100: A130, 1992.
12. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Conscious state and control of breathing: power spectral
density of respiratory and cardiovascular parameters. Abstract, 6th Int. Cong. Psychophysiology, Charité, Berlin, Germany,
Sept. 2-6, 1992, p. 219.
13. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Noninvasive determination of baroreflex heart rate sensitivity in
patients with mild hypertension during 24-hours. Abstracts, 14th Scientific Meeting, International Society for Hypertension,
Madrid, June 14-19, 1992, p. 326.
14. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Spectral analysis of the timing of respiratory cycle and
cardiovascular parameters during 24 hours period. Abstract, 2nd High Tatras International Health Symposium: Health
Management, Organization, and Planning in Changing Eastern Europe, Strbské Pleso, Czecho-Slovakia, October 16-18,
1992, p. 38.
15. Siegelova J., Fiser B., Dusek J., Halberg F., Cornélissen G. Circadian variations of baroreflex heart rate sensitivity in man.
Physiological Research 41: 15 pp., 1992.
16. Siegelova J., Fiser B., Dusek J., Halberg F., Cornélissen G. Control of respiratory cycle during 24-hours period. Abstract,
13th Martin's Days of Respiration, Martin, September 7-8, 1992, p. 16.
17. Siegelova J., Fiser B., Dusek J., Semrád B., Halberg F., Cornélissen G. 24-hodinové monitorování krevního tlaku u pacientu
s esenciálni hypertenzí. Abstract, XX Celostátní Internisticky Kongres s Mezinárodní Ucasti Zlin, 1992, p. 64.
18. Siegelova J., Fiser B., Dusek J., Semrád B., Mayer P., Sevela K., Halberg F., Cornélissen G. Circadian variations of blood
pressure in patients with essential and nephrogen hypertension. Scripta medica (Brno) 65: 316, 1992.
19. Siegelova J., Fiser B., Sevela K., Dusek J., Mayer P., Halberg F., Cornélissen G. 24-hodinové monitorování krevního tlaku u
pacientu s nefrogenné hypertenzí lecenych aceprilem. Abstract, XX Celostátní Internisticky Kongres s Mezinárodní Ucasti,
Zlin, 1992, p. 65.
20. Dusek J., Siegelova J., Fiser B., Al-Kubati M., Cornélissen G., Halberg F. Noninvasive determination of baroreflex heart rate
sensitivity in patients with essential hypertension during 24 hours. Abstract 173.38/P, IUPS Congress, Glasgow, 1993, p.
79.
21. Fiser B., Siegelova J., Dusek J., Cornélissen G., Halberg F. Is the circadian variability of baroreflex dependent upon sleep?
Int. J. Psychophysiol. 14: 122, 1993.
22. Fiser B., Siegelova J., Dusek J., Cornélissen G., Halberg F. Determination of heart rate-baroreflex sensitivity in man by
spectral analysis during 24-hour period. Scripta medica (Brno) 66: 11-14, 1993.
23. Fiser B., Siegelova J., Dusek J., Al-Kubati M., Cidl K., Semrád B., Cornélissen G., Halberg F. Determination of baroreflex
heart rate sensitivity in patients with essential hypertension during 24 hours using vasodilatation method. Proceedings, 1st
53
Int. Fair of Medical Technology and Pharmacy, Brno, Czech Rep., November 3-6, 1993, Kenner T., Marineaud J.P., Mayer
P., Semrád B., Siegelova J., Fiser B. eds., pp. 43-52.
24. Prikryl P, Siegelova J, Cornélissen G, Dusek J, Dankova E, Ferrazzani S, Tocci A, Caruso A, Rao G, Fink H, Halberg F.
Chronotherapeutic pilot on 6 persons may guide tests on thousands: toward a circadian optimization of prophylactic
treatment with daily low-dose aspirin. In: Otsuka K, Cornélissen G, Halberg F, editors. Chronocardiology and
Chronomedicine: Humans in Time and Cosmos. Tokyo: Life Science Publishing; 1993. p. 113-117.
25. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Conscious state and control of breathing power spectral density
of respiratory and cardiovascular parameters. Int. J. Psychophysiol. 14: 149-150, 1993.
26. Siegelova J., Fiser B., Dusek J., Mayer P., Semrad B., Halberg F., Cornélissen G. Cirkadianni variabilita krevniho tlaku u
pacientu v administrative. “Clovek a technika ocima ergonoma", Sbornik, Vysoka skola zemedelska, Brno, 1993, pp. 30-37.
27. Siegelova J, Fiser B, Dusek J, Semrád B, Cidl K, Sevela K, Halberg F, Cornélissen G. Blood pressure monitoring in patients
with essential hypertension during 24-hour. In: Kenner T, Marineaud JP, Mayer P, Semrád B, Siegelova J, Fiser B, editors.
Proceedings, 1st Int. Fair of Medical Technology and Pharmacy, Brno, Czech Rep.; November 3-6, 1993. p. 53-59.
28. Siegelova J., Fiser B., Dusek J., Semrád B., Cornélissen G., Halberg F. Baroreflex heart rate sensitivity measurement in
patients with essential hypertension (I WHO) during 24-hour period. Proceedings, 1st Int. Fair of Medical Technology and
Pharmacy, Brno, Czech Rep., November 3-6, 1993, Kenner T., Marineaud J.P., Mayer P., Semrád B., Siegelova J., Fiser B.
eds., pp. 36-39.
29. Siegelova J., Fiser B., Dusek J., Mayer P., Halberg F., Cornélissen G. Circadian variation of baroreflex heart rate sensitivity
using non-invasive determination in healthy subjects. Proceedings, 1st Int. Fair of Medical Technology and Pharmacy, Brno,
Czech Rep., November 3-6, 1993, Kenner T., Marineaud J.P., Mayer P., Semrád B., Siegelova J., Fiser B. eds., pp. 12-19.
30. Siegelova J., Fiser B., Dusek J., Semrad B., Halberg F., Cornélissen G. 24-hodinove monitorovani krevniho tlaku u pacientu
s esencialni hypertenzi. Vnitr. Lek. 39: 183-190, 1993.
31. Siegelova J, Fiser B, Dusek J, Sevela K, Halberg F, Cornélissen G. Circadian variability of blood pressure in patients with
essential hypertension and nephrogenous hypertension treated with enalapril. Scripta medica (Brno) 1993; 66: 99-104.
32. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Spectral analysis of the timing of respiratory cycle and
cardiovascular parameters during 24 hours period. 2nd High Tatras International Health Symposium: Health Management,
Organization, and Planning in Changing Eastern Europe, Strbske Pleso, Czecho-Slovakia, October 16-18, 1992, New York,
Bratislava, 1993, pp. 71-78.
33. Cornélissen G, Bingham C, Siegelova J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Halberg F. Cardiovascular disease risk
monitoring in the light of chronobioethics. Chronobiologia 1994; 21: 321-325.
34. Cornélissen G., Halberg F. Chronobiology of blood pressure: international cooperation with Dr. Jarmila Siegelova, Dr. Jiri
Dusek and Dr. Bohumil Fiser of Masaryk University. Scripta medica (Brno) 67 (Suppl. 1): 7-8, 1994.
35. Cornélissen G, Sothern RB, Wendt HW, Tarquini B, Antuñano M, Siegelova J, Fiser B, Dusek J, Prikryl P, Halberg F.
Statistical significance without biologic signification is not enough: illustrative example. Chronobiologia 1994; 21: 315-320.
36. Dusek J., Siegelova J., Fiser B., Cornélissen G., Halberg F. Chronobiology of blood pressure in waking man under light
mental load. Proc. Workshop, Chronobiology in Health and Disease—Control of Cardiovascular and Respiratory Functions,
Medical Faculty, Masaryk University, Brno, Czech Republic, July 2-4, 1994, pp. 33-37.
37. Halberg F, Bingham C, Siegelova J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Cornélissen G. "Cancer marker
chronomes" assessed in the light of chronobioethics. Chronobiologia 1994; 21: 327-330.
38. Siegelova J., Fiser B., Al-Kubati M., Dusek J., Cornélissen G., Halberg F. Airway resistance and cardiovascular parameters
during a 24-hour period. In: Proceedings, 3rd High Tatras International Health Symposium, Preventive and Clinical Medicine
in Changing Europe, Salat D., Badalik L., Krcmery V. (eds.), Sympos, Tatranska Polianka, Slovak Republic, 1994, pp. 386-
391.
39. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Chronobiology of blood pressure in essential hypertension.
Proc. Workshop, Chronobiology in Health and Disease—Control of Cardiovascular and Respiratory Functions, Medical
Faculty, Masaryk University, Brno, Czech Republic, July 2-4, 1994, pp. 13-25.
40. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Cosinor analysis of 24-hour variations of respiratory and
cardiovascular values in awake healthy man. Abstract, XIV Martin’s Days of Respiration, September 6-7, 1994, Martin,
Czech Rep. (?), p. 6.
41. Siegelova J., Fiser B., Dusek J., Halberg F., Cornélissen G. Cosinor analysis of blood pressure in patients with essential
and nephrogenous hypertension. Proc. International Workshop, Sun, Moon and Living Matter, Mikulecky M. (ed.),
Bratislava, Slovakia, June 29-July 1, 1994. Slovak Medical Society, Bratislava, 1994, pp. 116-121.
42. Siegelova J., Fiser B., Dusek J., Halberg F., Cornélissen G. Posobeni bdelehu stavu a lehke mentalni zateze na cirkadianni
variabilitu krevniho tlaku a zdravych osob. Ceska Ergonomicka Spolecnost uzemni organizace Brno a katedra automobilu
Vojenske akademie v Brne, Seminar: Cesty Rozvoje a Uplatnovani Ergonomie a Bezpecnosti Prace v Podminkach Denni
Praxe, 25 kvetna 1994, pp. 17-24. [In Czech.]
54
43. Dusek J., Siegelova J., Fiser B., Cornélissen G., Halberg F. Chronobiology of blood pressure in waking man under light
mental load. Scripta medica (Brno) 68: 62-63, 1995.
44. Dusek J., Siegelova J., Nekvasil R., Cornélissen G., Halberg F. Circaseptan rhythm in blood pessure and heart rate in
newborns. Abstract, MEFA ’95 Congress, Brno, Czech Republic, October 24-27, 1995, p. 10.
45. Dusek J., Siegelova J., Fiser B., Nekvasil R., Cornélissen G., Halberg F. Blood pressure variations in newborns. Abstract
#64, 1st Congress, Federation of European Physiological Societies, September 9-12, 1995, Maastricht, The Netherlands.
Pflügers Archiv / Eur. J. Physiol. 430 (Suppl.): R24, 1995.
46. Halberg F, Cornélissen G, Johnson D, Wrbsky P, Portela A, Beystrom B, Siegelova J, Fiser B, Dusek J, Nekvasil R,
Syutkina EV, Grigoriev AE, Abramian A, Mitish M, Yatsyk GV, Revilla M, Ardura J, Garcia Alonso L, Bakken E, Delmore P,
Maggioni C, Tarquini B, Mainardi G, Otsuka K, Watanabe Y, Kumagai Y, Wakasugi K, Saito Yuzo, Tamura K.
Chronobiologic environmental optimization starting with neonatal care: opportunities for health and device industries.
Handout, The Physical and Developmental Environment of the High-Risk Infant, Orlando, Florida, January 19-21, 1995, 70
pp.
47. Halberg F, Cornélissen G, Raab F, Schaffer E, Siegelova J, Fiser B, Dusek J, Prikryl P, Otsuka K. Automatic physiologic 7day
monitoring and chronobiology. Jpn J Electrocardiol 1995; 15 (Suppl. 1): S-1-5–S-1-11.
48. Halberg F, Cornélissen G, Siegelova J, Fiser B, Dusek J, Prikryl P, Otsuka K. Automatic physiology 7-day monitoring and
chronobiology. Policlinico (Chrono) 1995; 1 (2): 33-42.
49. Siegelova J, Cornélissen G, Dusek J, Prikryl P, Fiser B, Dankova E, Tocci A, Ferrazzani S, Hermida R, Bingham C,
Hawkins D, Halberg F. Aspirin and the blood pressure and heart rate of healthy women. Policlinico (Chrono) 1995; 1 (2): 43-
49.
50. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Cosinor analysis of 24-hour blood pressure profile in
hypertensives before and after treatment with ACE-inhibitor enalapril. EuroRehab 4: 203-206, 1995.
51. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Chronobiology of blood pressure in essential hypertension.
Scripta medica (Brno) 68: 60-61, 1995.
52. Cornélissen G, Halberg F, Johnson D, Gubin D, Gubin G, Otsuka K, Watanabe Y, Kumagai Y, Syutkin V, Syutkina E,
Grigoriev AE, Turti T, Mitish M, Siegelova J, Fiser B, Dusek J, Garcia Alonso L. Blood pressure and heart rate chronomes,
yardsticks of ontogeny and vascular disease risk. Keynote #114, 2nd World Congress of Cellular and Molecular Biology,
Ottawa, Canada, September 3-7, 1996. Cell Molec Biol 1996; 42 (Suppl.): S83-S84.
53. Cornélissen G., Siegelova J., Fiser B., Dusek J., Halberg F. Current limitations and promise of ambulatory blood pressure
monitoring. In: Proceedings, Cardiovascular Coordination in Health and Blood Pressure Disorders, Medical Faculty,
Masaryk University, Brno, Czech Republic, May 24, 1996, Halberg F., Kenner T., Fiser B., Siegelova J. eds., 1996, pp. 11-
13.
54. Dusek J., Siegelova J., Al-Kubati M., Fiser B., Cornélissen G., Halberg F. Blood pressure variability during 24 h in patients
with essential hypertension. Abstract, Aerosols in Diagnosis, Therapy, and Prophylaxis & Cardio-Respiratory Relations,
International Symposium, High Tatras, Sanatorium Helios, Slovakia, May 14-17, 1996, p. 19.
55. Fiser B., Siegelova J., Turti T., Syutkina E.V., Cornélissen G., Grigoriev A.E., Mitish M.D., Abramian A.S., Dusek J.,
Nekvasil R., Al-Kubati M., Muchova L., Halberg F. Neonatal blood pressure and heart rate rhythm: multiseptan over
circadian prominence. Abstract, International Workshop and Teaching Course: Spontaneous Motor Activity as a Diagnostic
Tool, Karl-Franzens-Univ., Graz, Austria, September 11-18, 1996, p. 64.
56. Fiser B, Siegelova J, Cornélissen G, Dusek J, Al-Kubati M, Watanabe Y, Halberg F. Chronometaanalysis of blood pressure
data from drug tests. Abstract, 2nd Int. Symp. of Chronobiology and Chronomedicine, Shenyang, China, Sept. 28-Oct. 2,
1996. p. 53-54.
57. Halberg F, Cornélissen G, Gubin D, Gubin G, Fiser B, Dusek J, Al-Kubati M, Siegelova J. Circadiani, circaseptani,
circasemiseptanique in chronomis seclusorum, præmaturorum, seniumque: in honorem Johannis Penazensis modo
Mendeliano, Goedeliano, Keplerianoque. In: Halberg F, Kenner T, Fiser B, Siegelova J, editors. Proceedings,
Cardiovascular Coordination in Health and Blood Pressure Disorders, Brno, Czech Republic: Medical Faculty, Masaryk
University; May 24, 1996. p. 8-10.
58. Siegelova J, Dusek J, Fiser B, Nekvasil R, Muchova M, Cornélissen G, Halberg F. Circaseptan rhythm in blood pressure
and heart rate in newborns. Scripta medica (Brno) 1996; 67 (Suppl. 2): 63-70.
59. Siegelova J., Fiser B., Dusek J., Al-Kubati M., Nekvasil R., Cornélissen G., Halberg F. Blood pressure and heart rate
coordination in newborn: circadian and circaseptan rhythms. Abstract, International Workshop and Teaching Course:
Spontaneous Motor Activity as a Diagnostic Tool, Karl-Franzens-Univ., Graz, Austria, September 11-18, 1996, p. 63.
60. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Limitace ambulantniho monitorovani krevniho tlaku. In: XII.
Pracovni Konference Arterialni Hypertenze a Prevence Kardiovaskularnich Chorob, Abstrakta, Dum techniky Brno, 1996, p.
10.
61. Siegelova J., Fiser B., Kadanka Z., Moran M., Dusek J., Al-Kubati M., Cornélissen G., Halberg F. Sleep apnea syndrome
and 24-h blood pressure. Electroenceph. Clin. Neurophysiol. 99: 393, 1996.
55
62. Siegelova J, Moran M, Fiser B, Kadanka Z, Dusek J, Al-Kubati M, Cornélissen G, Halberg F. Blood pressure monitoring in
healthy subjects, in patients with sleep apnea syndrom[e] and in patients with essential hypertension. Scripta medica (Brno)
1996; 67 (Suppl 2): 59-62. [In Czech.]
63. Siegelova J, Cornélissen G, Halberg F, Fiser B, Dusek J, Al-Kubati M, Machat R, Kumagai Y, Watanabe Y, Otsuka K. Selfstarting
cumulative sums for the individualized assessment of antihypertensive response and optimization by timing.
Keynote, 2nd Int. Symp. of Chronobiology and Chronomedicine, Shenyang, China, Sept. 28-Oct. 2, 1996. p. 48.
64. Siegelova J., Fiser B., Al-Kubati M., Dusek J., Cornélissen G., Halberg F. Baroreflex heart rate sensitivity in hypertensives:
the role of antihypertensive therapy. In: Proceedings, Cardiovascular Coordination in Health and Blood Pressure Disorders,
Medical Faculty, Masaryk University, Brno, Czech Republic, May 24, 1996, Halberg F., Kenner T., Fiser B., Siegelova J.
eds., 1996, pp. 18-34. [2221]
65. Siegelova J., Morán M., Fiser B., Kadanka Z., Dusek J., Al-Kubati M., Halberg F., Cornélissen G. Circadian variations in
blood pressure in patients with sleep apnea and essential hypertension. Abstract PS 103, 23rd Congress, International
Society of Internal Medicine, Manila, Philippines, February 1-6, 1996, p. 159. [2218]
66. Siegelova J., Morán M., Fiser B., Kadanka Z., Dusek J., Al-Kubati M., Halberg F., Cornélissen G. Circadian variations in
blood pressure in patients with sleep apnea and essential hypertension. Proceedings, 23rd Congress, International Society
of Internal Medicine, Manila, Philippines, February 1-6, 1996, Aquino A.V., Piedad F.F., Sulit Y.Q.M. (eds.), Monduzzi
Editore, Bologna, 1996, pp. 273-276.
67. Turti T, Syutkina EV, Cornélissen G, Grigoriev AE, Mitish MD, Abramian AS, Siegelova J, Fiser B, Dusek J, Al-Kubati M,
Muchova L, Uhlir M, Halberg F. Multiseptan-over-circadian prominence of neonatal blood pressure and heart rate in
Moscow, Russia. Scripta medica (Brno) 1996; 67 (Suppl. 2): 85-92.
68. Baevsky RM, Petrov VM, Cornélissen G, Halberg F, Orth-Gomér K, Åkerstedt T, Otsuka K, Breus T, Siegelova J, Dusek J,
Fiser B. Meta-analyzed heart rate variability, exposure to geomagnetic storms, and the risk of ischemic heart disease.
Scripta medica (Brno) 1997; 70: 199-204.
69. Gubin D., Cornélissen G., Halberg F., Fiser B., Dusek J., Al-Kubati M., Siegelova J., Gubin G. Aging is accompanied by
increased variability and acircadian dessimination of blood pressure (BP) biorhythms. Proc. XXXIII Int. Cong. International
Union of Physiological Sciences, St. Petersburg, Russia, June 30-July 5, 1997, abstract P041.42.
70. Gubin D, Cornélissen G, Halberg F, Gubin GD, Turti T, Syutkina EV, Grigoriev AE, Mitish MD, Yatsyk GV, Ikonomov O,
Stoynev A, Madjirova N, Siegelova J, Fiser B, Dusek J. Half-weekly and weekly blood pressure patterns in late human
ontogeny. Scripta medica (Brno) 1997; 70: 207-216.
71. Halberg F., Cornélissen G., Watanabe Y., Siegelova J., Fiser B., Dusek J., Al-Kubati M. Chronobiologic concepts: tempora
mutantur et nos mutamur in illis. Scripta medica (Brno) 70: 231-237, 1997.
72. Halberg F., Cornélissen G., Wendt H., Siegelova J., Dusek J., Fiser B. New trends in cosmobiophysics and the need for a
space weather report. Folia Mendeliana 31-32, Supplementum ad Acta Musei Moraviae, Scientiae naturales LXXXI-II: 13-
15,1996/1997 (© 1997).
73. Siegelova J., Cornélissen G., Dusek J., Fiser B., Watanabe Y., Otsuka K., Halberg F. Diagnosis and assessment of
treatment effects: a single 24-hour blood pressure (BP) monitoring (ABPM) profile. 5th International Fair of Medical
Technology and Pharmacy, MEFA Congress, Brno, Czech Republic, November 5-8, 1997, section 6 (Neinvazivni
vysetrovaci metody v kardiologii), abstract 8.
74. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Circaseptan variability in blood pressure in newborn. Abstract
#314, International Congress on Chronobiology. Chronobiology int. 14 (Suppl. 1): 158, 1997.
75. Siegelova J, Fiser B, Dusek J, Halberg F, Cornélissen G. 24-h blood pressure profile in essential hypertension after
verapamil, nitrendipine and enalapril treatment. Scripta medica (Brno) 1997; 70: 373-374.
76. Siegelova J., Fiser J., Kadanka Z., Moran M., Dusek J., Cornélissen G., Halberg F. Syndrom spankove apnoe a 24hodinove
monitorovani krevniho tlaku. Abstract, XIV konference o arterialni hypertenzi & VI konference preventivni
kardiologie, Plzen, 15.-17. rijna 1997, p. 43.
77. Siegelova J., Kadanka Z., Moran M., Fiser B., Homolka P., Dobsak P., Dusek J., Cornélissen G., Halberg F. 24-hour blood
pressure profile in patients with sleep apnea syndrome: the effect of therapy. 5th International Fair of Medical Technology
and Pharmacy, MEFA Congress, Brno, Czech Republic, November 5-8, 1997, section 6 (Neinvazivni vysetrovaci metody v
kardiologii), abstract 12.
78. Syutkina EV, Cornélissen G, Grigoriev AE, Mitish MD, Turti T, Yatsyk GV, Pimenov K, Breus TK, Studenikin MY, Siegelova
J, Fiser B, Dusek J, Johnson D, Halberg F. Neonatal intensive care may consider associations of cardiovascular rhythms
with local magnetic disturbance. Scripta medica (Brno) 1997; 70: 217-226.
79. Siegelova J, Cornélissen G, Dusek J, Fiser B, Watanabe Y, Otsuka K, Halberg F. Diagnosis and assessment of treatment
effects: a single 24-hour blood pressure monitoring profile. Scripta medica (Brno) 1998; 71: 209-214.
80. Siegelova J., Fiser B., Dusek J., Cornélissen G., Halberg F. Circadian variability of rate pressure product in hypertension
with enalapril therapy. Abstract, Investigator-Initiated Satellite Symposium to 17th Scientific Meeting, International Society of
Hypertension: Renin-angiotensin-aldosterone system: Where to block it ?, Prague, Czech Republic, June 4, 1998, p. 6.
56
81. Siegelova J., Fiser B., Dusek J., Dobsak P., Cornélissen G., Halberg F. Cirkadianni kolisani kardiovaskularnich velicin.
Abstract, Nove Trendy ve Funkcni Diagnostice a Rehabilitaci, Slavnosti Pracovni Schuze, 75 Let, Brno 27. unora 1998, p.
12.
82. Siegelova J., Fiser B., Dusek J., Placheta Z., Cornélissen G., Halberg F. Circadian variability of rate pressure product in
essential hypertension with enalapril therapy. Abstract 3, Neinvazivni metody v kardiovaskularnim vyzkumu, 6th
International Fair of Medical Technology and Pharmacy, MEFA Congress, Brno, Czech Republic, November 3-4, 1998.
83. Siegelova J., Kadanka Z., Moran M., Fiser B., Homolka P., Dobsak P., Dusek J., Cornélissen G., Halberg F. 24-h blood
pressure profile in patients with sleep apnea syndrom: the effect of therapy. Scripta medica (Brno) 71: 239-244, 1998.
84. Siegelova J., Fiser B., Dusek J., Kadanka Z., Moran M., Cornélissen G., Halberg F. Sleep apnea syndrom[e] and circadian
blood pressure variability: the effect of CPAP therapy. Abstract, XVI Martin Days of Respiration with international
participation, Martin, Czech Republic, September 16-17, 1998, p. 26.
85. Halberg F, Cornélissen G, Schwartzkopff O, Syutkina EV, Grigoriev AE, Mitish MD, Yatsyk GV, Studenikin MY, Gubin D,
Gubin G, Siegelova J, Fiser B, Dusek J, Homolka P, Watanabe Y, Otsuka K, Perfetto F, Tarquini R, Delmore P. Spin-offs
from blood pressure and heart rate studies for health care and space research (review). in vivo 1999; 13: 67-76.
86. Ulmer W., Cornélissen G., Revilla M., Siegelova J., Dusek J., Halberg F. Circadian and circaseptan dependence of the
beta-ATP peak of four different cancer cell cultures: implications for chronoradiotherapy. Abstract 13, MEFA, Brno, Czech
Rep., Nov. 3-6, 1999.
87. Amiranashvili AG, Cornélissen G, Amiranashvili V, Gheonjian L, Chikhladze VA, Gogua RA, Matiashvili TG, Paatashvili T,
Kopytenko YuA, Siegelova J, Dusek J, Halberg F. Circannual and circadecennian changes in mortality from cardiovascular
causes in Tbilisi, Republic of Georgia (1980-1992). MEFA 8th International Fair of Medical Technology and Pharmacy,
Brno, Czech Republic, 7-10 Nov 2000, abstract 16.
88. Cornélissen G, Otsuka K, Chen C-H, Kumagai Y, Watanabe Y, Halberg F, Siegelova J, Dusek J. Nonlinear relation of the
circadian blood pressure amplitude to cardiovascular disease risk. Scripta medica (Brno) 2000; 73: 85-94.
89. Fiser B, Cornélissen G, Siegelova J, Dusek J, Homolka P, Mazankova V, Halberg F. Increase in stroke deaths after 1997 in
the Czech Republic. MEFA 8th International Fair of Medical Technology and Pharmacy, Brno, Czech Republic, 7-10 Nov
2000, abstract 4.
90. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A, Gorgo Y, Zhao ZY, Weydahl A,
Sothern RB, Siegelova J, Fiser B, Dusek J, Syutkina EV, Perfetto F, Tarquini R, Singh RB, Rhees B, Lofstrom D, Lofstrom
P, Johnson PWC, Schwartzkopff O, International BIOCOS Study Group. Cross-spectrally coherent ~10.5- and 21-year
biological and physical cycles, magnetic storms and myocardial infarctions. Neuroendocrinol Lett 2000; 21: 233-258. [Invited
presentation, NATO Advanced Study Institute on Space Storms and Space Weather Hazards, Crete, Greece, June 19-29,
2000.]
91. Halberg F, Cornélissen G, Sanchez de la Peña S, Schwartzkopff O, Wall DG, Kysylyczyn J, Sarkozy S, Delmore P, Borer K,
Otsuka K, Siegelova J, Homolka P, Dusek J, Fiser B. [Why and how to implement 7-day/24-hour blood pressure
monitoring.] Addendum 1, Proceedings, 4th International Symposium of Chronobiology and Chronomedicine, Yantai, China,
Oct. 7-14, 2000, 37 pp. [Translated into Chinese.]
92. Halberg F, Cornélissen G, Siegelova J, Fiser B, Dusek J, Otsuka K, Delyukov AA, Gorgo Y, Gubin DG, Gubin GD,
Schwartzkopff O. The Cosmos and CHAT, prompting blood pressure and heart rate monitoring for Dérer's week.
Bratislavske lekarske listy 2000; 101: 260-271.
93. Halhuber MJ, Cornélissen G, Müller-Bohn T, Bartter FC, Delea CS, Siegelova J, Dusek J, Schwartzkopff O, Halberg F.
Circadian urinary glucocorticoid and other variation and rhythmic blood pressure coordination. MEFA 8th International Fair
of Medical Technology and Pharmacy, Brno, Czech Republic, 7-10 Nov 2000, abstract 27.
94. Hillman D, Katinas G, Cornélissen G, Siegelova J, Dusek J, Halberg F. About 10-yearly (circadecennnian) cosmo-heliogeomagnetic
signatures in Acetabularia. MEFA 8th International Fair of Medical Technology and Pharmacy, Brno, Czech
Republic, 7-10 Nov 2000, abstract 19.
95. Ikonomov OC, Stoynev AG, Penev PD, Peneva AV, Cornélissen G, Samayoa W, Siegelova J, Dusek J, Halberg F.
Circadian rhythm of blood pressure and heart rate in uncomplicated human pregnancy. Scripta medica (Brno) 2000; 73 (1):
44-55.
96. Katinas G, Hillman D, Siegelova J, Dusek J, Cornélissen G, Halberg F. About-weekly electrical potential, chloroplast
migration and oxygen production changes of Acetabularia in continuous light. MEFA 8th International Fair of Medical
Technology and Pharmacy, Brno, Czech Republic, 7-10 Nov 2000, abstract 20.
97. Siegelova J, Dusek J, Fiser B, Halberg F, Cornélissen G. Biological rhythms in medicine. J Oncol Pharm Practice 2000; 6:
15-16 (www.nature.com/jopp).
98. Siegelova J, Fiser B, Dusek J, Halberg F, Cornélissen G. Circadian variability of blood pressure. Abstract, Stabilität und
Oszillationen, 8. AKP-Tagung in Weiz bei Graz, 30.9.2000 - 3.10.2000, Tagung der Gruppe der Angewandten, Klinischen
und Pathologischen Physiologen der Deutschen Physiologischen Gesellschaft gemeinsam mit der Österreichischen
Physiologen Gesellschaft, 2000, p. 16.
57
99. Siegelova J, Fiser B, Dusek J, Placheta Z, Cornélissen G, Halberg F. Circadian variability of rate-pressure product in
essential hypertension with enalapril therapy. Scripta medica (Brno) 2000; 73: 69-75.
100. Siegelova J, Fiser B, Dusek J, Placheta J, Dobsak P, Svacinova H, Jancik J, Cornélissen G, Halberg F. Baroreflex
sensitivity in "essential hypertension" treated with trandolapril and diltiazem in combination. Abstract 22.11, APS
Conference, Baroreceptor and Cardiopulmonary Receptor Reflexes, Iowa City, IA, August 23-27, 2000. The Physiologist
2000; 43: 283.
101. Siegelova J, Homolka P, Dusek J, Fiser B, Cornélissen G, Halberg F. Extracircadian-to-circadian variance transpositions
early and vice versa late in life in the human circulation. Proceedings, 1st International Symposium, Workshop on
Chronoastrobiology & Chronotherapy (Satellite Symposium, 7th Annual Meeting, Japanese Society for Chronobiology),
Kudan, Chiyodaku, Tokyo, 11 Nov 2000, pp. 58-60.
102. Starbuck S, Cornélissen G, Siegelova J, Dusek J, Halberg F. Does religious motivation follow a circadecennian (about 10.5year)
cycle ? MEFA 8th International Fair of Medical Technology and Pharmacy, Brno, Czech Republic, 7-10 Nov 2000,
abstract 25.
103. Nintcheu-Fata S, Cornélissen G, Katinas G, Halberg F, Fiser B, Siegelova J, Masek M, Dusek J. Software for contour maps
of moving least squares spectra. Abstract 15, MEFA 9th International Fair of Medical Technology and Pharmacy, Brno,
November 6-11, 2001.
104. Ulmer W, Cornélissen G, Revilla M, Siegelova J, Dusek J, Halberg F. Circadian and circaseptan dependence of the betaATP
peak of four different cancer cell cultures: implications for chronoradiotherapy. Scripta medica (Brno) 2001; 74: 87-92.
105. Amiranashvili AG, Cornélissen G, Amiranashvili V, Gheonjian L, Chikhladze VA, Gogua RA, Matiashvili TG, Paatashvili T,
Kopytenko YuA, Siegelova J, Dusek J, Halberg F. Circannual and circadecennian stages in mortality from cardiovascular
causes in Tbilisi, Republic of Georgia (1980-1992). Scripta medica (Brno) 2002; 75: 255-260.
106. Dusek J, Fiser B, Siegelova J, Cornélissen G, Svoboda L, Homolka P, Jancik J, Svacinova H, Mazankova V, Schwartzkopff
O, Halberg F. Vzestup incidence cevni mozkove prihody po r. 1997 v Ceske Republice. Cor et Vasa 2002; 44: 18.
107. Fiser B, Cornélissen G, Siegelova J, Dusek J, Homolka P, Mazankova V, Halberg F. Increase in stroke deaths after 1997 in
the Czech Republic. Scripta medica (Brno) 2002; 75: 95-100.
108. Halberg F, Cornélissen G, Engebretson M, Fiser B, Siegelova J, Dusek J, Katinas G, Schwartzkopff O. Dedicne biosfericke
analogie nesvetelnych solarnich nebo galaktickych cyklu. Abstract, Clovek ve svem pozemskem a kosmickem prostredi,
Upice, 21-23 May 2002, pp. 30-31.
109. Halberg F, Cornélissen G, Otsuka K, Katinas GS, Schwartzkopff O, Halpin C, Mikulecky M, Revilla M, Siegelova J, Homolka
P, Dusek J, Fiser B, Singh RB. Chronomics* (*the study of time structures, chronomes) detects altered vascular variabilities
constituting risks greater than hypertension: with an illustrative case report. In: Mitro P, Pella D, Rybar R, Valocik G, editors.
Proceedings, 2nd Congress on Cardiovascular Diseases, Kosice, Slovakia, 25-27 April 2002. Bologna: Monduzzi Editore;
2002. p. 223-258.
110. Halberg F, Cornélissen G, Prikryl P, Katinas G, Dusek J, Homolka P, Karpisek Z, Sonkowsky RP, Schwartzkopff O, Fiser B,
Siegelova J, International BIOCOS Project Team. Chronomics complement genomics in Brno. What Johann Gregor Mendel
wished, Jarmilka Siegelova accomplished: Broadening system times and transdisciplinary time horizons. In: Halberg F,
Kenner T, Fiser B, editors. Proceedings, Symposium: The Importance of Chronobiology in Diagnosing and Therapy of
Internal Diseases. Faculty of Medicine, Masaryk University, Brno, Czech Republic, January 10-13, 2002. Brno: Masaryk
University; 2002. p. 7-56.
111. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber M, Müller-Bohn T, Delmore P,
Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente
F, Schaffer E, Rhodus N, Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7-day/24hour
chronobiologic blood pressure and heart rate screening: Part I. Biomedical Instrumentation & Technology 2002; 36: 89-
122.
112. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber M, Müller-Bohn T, Delmore P,
Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Peña S, Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente
F, Schaffer E, Rhodus N, Borer K, Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7-day/24hour
chronobiologic blood pressure and heart rate screening: Part II. Biomedical Instrumentation & Technology 2002; 36:
183-197.
113. Halhuber MJ, Cornélissen G, Bartter FC, Delea CS, Kreze A, Mikulecky M, Müller-Bohn T, Siegelova J, Dusek J,
Schwartzkopff O, Halberg F. Circadian urinary glucocorticoid and rhythmic blood pressure coordination. Scripta medica
(Brno) 2002; 75: 139-144.
114. Hillman D, Katinas G, Cornélissen G, Siegelova J, Dusek J, Jancik J, Masek M, Halberg F. About-10-yearly
(circadecennian) cosmo-helio-geomagnetic signatures in Acetabularia. Scripta medica (Brno) 2002; 75: 303-308.
115. Katinas G, Hillman D, Siegelova J, Dusek J, Svacinova H, Cornélissen G, Halberg F. About-weekly changes in electrical
potential, chloroplast migration and oxygen production in Acetabularia grown under continuous exposure to light. Scripta
medica (Brno) 2002; 75: 309-314.
58
116. Katinas G, Nintcheu-Fata S, Cornélissen G, Siegelova J, Masek M, Dusek J, Vlcek J, Halberg F. Moving least squares
spectra scrutinize chronomics in and around us. Abstract 14, Kongres MEFA, Brno, Czech Rep., 5-8 Nov. 2002.
117. Yamanaka T, Cornélissen G, Kazuma M, Kazuma N, Murakami S, Otsuka K, Siegelova J, Dusek J, Halberg F. Further
mapping of the natality chronome in Toda City (Japan) Maternity Hospital. Abstract 16, Kongres MEFA, Brno, Czech Rep.,
5-8 Nov. 2002.
118. Cornélissen G, Halberg F, Bakken EE, Wang ZR, Tarquini R, Perfetto F, Laffi G, Maggioni C, Kumagai Y, Prikryl P,
Homolka P, Dusek J, Siegelova J, Fiser B. Can society afford not to follow a chronobiological approach to blood pressure
screening, diagnosis and treatment? In: Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium,
Chronobiological Analysis in Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. p. 75-90.
[Dedicated to the 60th Anniversary of Prof. Bohumil Fiser.]
119. Cornélissen G, Halberg F, Otsuka K, Shinagawa M, Kubo Y, Ohkawa S, Fiser B, Siegelova J, Dusek J. Iatrogenic excessive
blood pressure variability (CHAT): implications for chronotherapy. Scripta medica (Brno) 2003; 76: 275-278.
120. Fiser B, Cornélissen G, Siegelova J, Dusek J, Mazankova V, Halberg F. Spektralni analyza padesatileteno zazmamu
mortality pro cevni Mozkovou prihodu v Ceske Republice. Abstract, XI. vyrocniho sjezdu Ceske kardiologicke spolecnosti,
11-14 kvetna 2003, Brno. Cor et Vasa 2003; 4 (Suppl): 21.
121. Halberg F, Cornélissen G, Otsuka K, Maggioni C, Schwartzkopff G, Fiser B, Dusek J, Siegelova J. Chronomics: the broad
scope of monitoring chronomes. A review. Scripta medica (Brno) 2003; 76: 269-273.
122. Halberg F, Cornélissen G, Stoynev A, Ikonomov O, Katinas G, Sampson M, Wang ZR, Wan CM, Singh RB, Otsuka K,
Sothern RB, Sothern SB, Sothern MI, Syutkina EV, Masalov A, Perfetto F, Tarquini R, Maggioni C, Kumagai Y, Siegelova J,
Fiser B, Homolka P, Dusek J, Uezono K, Watanabe Y, Wu JY, Sonkowsky R, Schwartzkopff O, Hellbrügge T, Spector NH,
Baciu I, Hriscu M, Bakken E. Season's Appreciations 2002 and 2003. Imaging in time: The transyear (longer-than-thecalendar
year) and the half-year. Neuroendocrinol Lett 2003; 24: 421-440.
123. Katinas GS, Dusek J, Siegelova J, Cornélissen G, Halberg F. Intra-individual variability of the circadian blood pressure
waveform in intermittent treated MESOR-hypertensive CHAT. Abstract #12, MEFA, Brno, Czech Republic, 04-07 Nov 2003.
p. 17.
124. Kelsey R, Cornélissen G, Kapfer D, Siegelova J, Masek M, Dusek J, Fiser B, Halberg F. Research in practice: inferential
statistical procedures applicable to the individual patient's response to benetensive treatment. Abstract #15, MEFA, Brno,
Czech Republic, 04-07 Nov 2003. p. 20.
125. Nintcheu-Fata S, Cornélissen G, Katinas G, Halberg F, Fiser B, Siegelova J, Masek M, Dusek J. Software for contour maps
of moving least-squares spectra. Scripta medica (Brno) 2003; 76: 279-283.
126. Otsuka K, Cornélissen G, Halberg F, Fiser B, Siegelova J, Sosikova M, Dusek J, Jancik J. Assessment of different
administration schedules of sotalol by electrocardiography. Scripta medica (Brno) 2003; 76: 297-300.
127. Schwartzkopff O, Halberg F, Cornélissen G, Katinas G, Wang ZR, Kröz M, Hecht K, Tarquini R, Perfetto F, Maggioni C,
Siegelova J, Dusek J, Fiser B, Singh RB, Bakken E. Self-experimentation: dangerous when first done by a few, now safe for
everybody's health? In: Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium, Chronobiological Analysis in
Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. p. 91-104. [Dedicated to the 60th Anniversary
of Prof. Bohumil Fiser.]
128. Schwartzkopff O, Katinas G, Singh RB, Sanchez de la Pena S, Zhao ZY, Uezono K, Prikryl P, Siegelova J, Fiser B, Dusek
J, Otsuka K, Cornélissen G, Halberg F. Self-surveillance and self-experimentation (SSSE) for preventing vascular diseases
needed to follow established successes of anesthesia and vaccine development. Abstract #13, MEFA, Brno, Czech
Republic, 04-07 Nov 2003. p. 18.
129. Siegelova J, Cornélissen G, Fiser B, Dusek J, Homolka P, Masek M, Jancik J, Svacinova H, Halberg F. Blood pressure and
heart rate monitoring in humans: the circaseptan and circadian rhythms. Abstract, 3rd International Workshop on The
Human Circulation: Noninvasive Haemodynamic, Autonomic and Vascular Monitoring, Graz, Austria, 9-11 May 2003.
Clinical Autonomic Research 2003; 13: 60-61.
130. Siegelova J, Fiser B, Dusek J, Placheta Z, Vlcek J, Svoboda L, Pazdirek J, Cornélissen G, Halberg F. Chronotherapy: ratepressure
produce in essential hypertension. In: Halberg F, Kenner T, Siegelova J, editors. Proceedings, Symposium,
Chronobiological Analysis in Pathophysiology of Cardiovascular System. Brno: Masaryk University; 2003. p. 118-121.
[Dedicated to the 60th Anniversary of Prof. Bohumil Fiser.]
131. Sothern RB, Cornélissen G, Engel P, Fiser B, Siegelova J, Vlcek J, Dusek J, Halberg F. Chronomics: instrumentation for
monitoring of peak expiratory flow. Scripta medica (Brno) 2003; 76: 313-315.
132. Watanabe Y, Cornélissen G, Watanabe F, Siegelova J, Dusek J, Halberg F. The trans- (~1.3) year in the blood pressure of
a 10-year-old boy. Abstract 17, MEFA, Brno, Czech Republic, 04-07 Nov 2003. p. 22.
133. Cornélissen G, Palermo J, Carandente F, Siegelova J, Fiser B, Dusek J, Halberg F. Chronomics: chronome of suicides in
Minnesota (1968-2002). Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech Republic,
2.-4.11.2004, p. 8.
59
134. Crawford VLS, Cornélissen G, Fiser B, Dusek J, Siegelova J, Halberg F. Infrannual changes in the incidence of myocardial
infarctions and strokes in Northern Ireland. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno,
Czech Republic, 2.-4.11.2004, p. 9.
135. Dusek J, Siegelova J, Fiser B, Brazdova Z, Homolka P, Vank P, Forejt M, Hollan J, Cornélissen G, Halberg F. Alterations of
circadian rhythm in blood pressure by lack of dark: 24-h ambulatory blood-pressure monitoring. Abstract, Noninvasive
methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech Republic, 2.-4.11.2004, p. 16.
136. Fiser B, Cornélissen G, Otsuka K, Chibisov S, Dusek J, Siegelova J, Halberg F. Blood pressure and heart rate readings for
solar science and health care. Abstract, 2nd International Conference, Pathophysiology and Contemporary Medicine,
Moscow, Russia, 22-24 April 2004. p. 472-473; and Science without Borders, Transactions of the International Academy of
Science H&E, 2003/2004; 1: 420-421.
137. Fiser B, Siegelova J, Dusek J, Moudr J, Cornélissen G, Halberg F. Assessment of high blood pressure risk for stroke --
chronobiological approach. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech
Republic, 2.-4.11.2004, p. 11.
138. Halberg F, Cornélissen G, Otsuka K, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Pena S, Schwartzkopff O,
Singh RB. Home ambulatory blood pressure and heart rate monitoring in practice and for science: transyears and
magnetoperiodism vs. photoperiodism. Abstract S8-02, 3rd Int Congress on Cardiovascular Disease, Taipei, Taiwan, 26-28
Nov 2004. Int J Cardiol 2004; 97 (Suppl 2): S12.
139. Halberg F, Cornélissen G, Panksepp J, Schwartzkopff O, Siegelova J, Fiser B, Dusek J. Near-transyears in geophysics and
autism. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech Republic, 2.-4.11.2004, p.
7.
140. Katinas GS, Chopra RK, Singh RB, Siegelova J, Fiser B, Dusek J, Cornélissen G, Halberg F. Design for timing
nutriceuticals. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech Republic, 2.-
4.11.2004, p. 19.
141. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornelissen G, Halberg F. Vztah mezi vekem a cirkadianni variabilitou
krevniho tlaku. Cor Vasa 2004; 46 (4) (Suppl): 81.
142. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornélissen G, Halberg F. Rozdily v krevnim tlaku mezi dnem a noci a
vik. Congress of Atherosclerosis, TIGIS, Prague 2004. Abstract, DMEV 2004, Suppl 3, p. 38.
143. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornélissen G, Halberg F. The relationship between age and circadian
blood pressure variation. J Hypertens 2004; 22 (Suppl 2): S210.
144. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornélissen G, Halberg F. Rozdily v krevnim tlaku mezi dnem a noci a
vek 26. Abstract, XXI. konference Ceske spolecnosti pro hypertenzi, XIII. konference pracovni skupiny Preventivni
kardiologie CKS, Konference pracovni skupiny Srdecni selhani CKS, Prague, 2004. p. 44.
145. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornélissen G, Halberg F. Circadian blood pressure variation analyzed
from 7-day monitoring. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress MEFA, Brno, Czech Republic, 2.-
4.11.2004, p. 12.
146. Siegelova J, Dusek J, Homolka P, Vank P, Vlcek J, Cornélissen G, Halberg F. The relationship between age and circadian
blood pressure variation. In: Cornélissen G, Kenner R, Fiser B, Siegelova J, eds. Proceedings, Symposium: Chronobiology
in Medicine. Dedicated to the 85th Anniversary of Professor Franz Halberg. Brno: Masaryk University; 2004. p. 110-116.
147. Siegelova J, Homolka P, Cornélissen G, Fiser B, Dusek J, Halberg F. Health watch in Brno, Czech Republic. Abstract S8-
13, 3rd Int Congress on Cardiovascular Disease, Taipei, Taiwan, 26-28 Nov 2004. Int J Cardiol 2004; 97 (Suppl 2): S15-
S16.
148. Siegelova J, Homolka P, Cornélissen G, Fiser B, Dusek J, Vank P, Masek M, Halberg F. Ambulatory blood pressure
monitoring: Health Watch in Brno, Czech Republic. Abstract, Noninvasive methods in cardiology, 2.11.2004, Congress
MEFA, Brno, Czech Republic, 2.-4.11.2004, p. 10.
149. Bhatt MLB, Singh RK, Cornélissen G, Srivastava M, Rai G, Singh R, Halberg Francine, Siegelova J, Fiser B, Dusek J,
Halberg F. Chronoradiotherapy guided by circadian rhythm in tumor temperature. Abstract, Noninvasive Methods in
Cardiology, Brno, Czech Republic, September 14, 2005, p. 19.
150. Cornélissen G, Delcourt A, Toussaint G, Otsuka K, Watanabe Y, Siegelova J, Fiser B, Dusek J, Homolka P, Singh RB,
Kumar A, Singh RK, Sanchez S, Gonzalez C, Holley D, Sundaram B, Zhao Z, Tomlinson B, Fok B, Zeman M, Dulkova K,
Halberg F. Opportunity of detecting pre-hypertension: worldwide data on blood pressure overswinging. Biomedicine &
Pharmacotherapy 2005; 59 (Suppl 1): S152-S157.
151. Cornélissen G, Halberg F, Schwartzkopff O, Gvozdjakova A, Siegelova J, Fiser B, Dusek J, Mifkova L, Chopra RK, Singh
RB. Coenzyme-Q10 effect on blood pressure variability assessed with a chronobiological study design. Abstract,
Noninvasive Methods in Cardiology, Brno, Czech Republic, September 14, 2005, p. 10.
152. Cornélissen G, Schwartzkopff O, Katinas G, Halberg F, Bakken EE, Holley D, Sundaram S, Sanchez S, Gonzalez C,
Delcourt A, Toussaint G, Siegelova J, Fiser B, Dusek J, Homolka P, Zeman M, Dulkova K, Otsuka K, Watanabe Y,
Tomlinson B, Fok B, Zhao ZY, Singh RB, Singh RK, Kumar A, Chibisov SM. Diagnosing blood pressure overswinging
60
chronomically worldwide. Abstract, III International Conference, Civilization diseases in the spirit of V.I. Vernadsky, People's
Friendship University of Russia, Moscow, Oct. 10-12, 2005, p. 34-35.
153. Cornélissen G, Watson D, Mitsutake G, Fiser B, Siegelova J, Dusek J, Vohlidalova L, Svacinova H, Halberg F. Mapping of
circaseptan and circadian changes in mood. Scripta medica 2005; 78: 89-98.
154. Dusek J, Siegelova J, Homolka P, Fiser B, Masek M, Cornélissen G, Halberg F. Ambulatory blood pressure monitoring
lasting seven days. J Hypertens 2005; 34 (Suppl 2): S154.
155. Fiser B, Siegelova J, Dusek J, Homolka P, Vank P, Cornélissen G, Halberg F. Seven-day blood pressure monitoring and
casual blood pressure measurement. Abstract, Noninvasive Methods in Cardiology, Brno, Czech Republic, September 14,
2005, p. 11.
156. Fiser B, Siegelova J, Dusek J, Moudr J, Cornélissen G, Halberg F. Assessment of high blood pressure risk for stroke. J
Hypertens 2005; 34 (Suppl 2): S151.
157. Gvozdjakova A, Kucharska J, Cornélissen G, Singh RB, Mikulecky M, Siegelova J, Fiser B, Dusek J, Halberg F. Coenzyme
Q10 and the circadian system of cardiac oxidative phosphorylation in rats. Abstract, Noninvasive Methods in Cardiology,
Brno, Czech Republic, September 14, 2005, p. 24.
158. Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, Johnson P, Gigolashvili M, Breus T, Sonkowsky R,
Chibisov SM, Katinas G, Siegelova J, Dusek J, Singh RB, Berri BL, Schwartzkopff O. Incidence of sudden cardiac death,
myocardial infarction and far- and near-transyears. Biomedicine & Pharmacotherapy 2005; 59 (Suppl 1): S239-S261.
159. Halberg F, Katinas G, Cornélissen G, Schwartzkopff O, Fiser B, Siegelova J, Dusek J, Jancik J. Ambulatory blood pressure
monitoring: the need of 7-day record. Scripta medica 2005; 78: 83-88.
160. Halberg F, Katinas G, Schwartzkopff O, Siegelova J. Fiser B, Dusek J, Cornélissen G. An about-2-year component in 15year,
largely half-hourly human blood pressure but not heart rate records. Abstract, Noninvasive Methods in Cardiology,
Brno, Czech Republic, September 14, 2005, p. 7.
161. Katinas G, Nintcheu-Fata S, Cornélissen G, Siegelova J, Dusek J, Vlcek J, Masek M, Halberg F. Moving least-squares
spectra scrutinize chronomics in and around us. Scripta medica 2005; 78: 115-120.
162. Regal P, Cornélissen G, Siegelova J, Fiser B, Dusek J, Halberg F. Chronomics, the site-specific magnetic environment and
an opportunity for the World Health Organization. Abstract, Noninvasive Methods in Cardiology, Brno, Czech Republic,
September 14, 2005, p. 9.
163. Schwartzkopff O, Cornélissen G, Halpin C, Katinas G, Siegelova J, Fiser B, Dusek J, Halberg F. Untreated transient longer
than 7-day CHAT, circadian hyper-amplitude-tension, in a 7-year perspective. Scripta medica 2005; 78: 75-82.
164. Schwartzkopff O, Schwartzkopff C, Katinas GS, Siegelova J, Fiser B, Dusek J, Cornélissen G, Halberg F. Chronomes, not
imaginary baselines, are needed as longitudinal reference values. Abstract, Noninvasive Methods in Cardiology, Brno,
Czech Republic, September 14, 2005, p. 8.
165. Singh RB, Cornélissen G, Kumar A, Bathina S, Siegelova J, Fiser B, Dusek J, Vohlidalova I, Halberg F. Effect of prayer on
heart rate variability in Asian Indians. Abstract, Noninvasive Methods in Cardiology, Brno, Czech Republic, September 14,
2005, p. 20.
166. Sonkowsky RP, Cornélissen G, Siegelova J, Fiser B, Dusek J, Masek M, Halberg F. Myriadennian cyclicities in the tradition
of Archimedes and the International System of Units (SI): invitation for comment. Abstract, Noninvasive Methods in
Cardiology, Brno, Czech Republic, September 14, 2005, p. 21.
167. Watanabe Y, Cornélissen G, Kodera I, Shimizu J, Ohmo G, Siegelova J, Fiser B, Dusek J, Vlcek J, Halberg F. Chronomics
of human blood pressure and heart rate in the Antarctic. Abstract, Noninvasive Methods in Cardiology, Brno, Czech
Republic, September 14, 2005, p. 22.
168. Yamanaka T, Cornélissen G, Kazuma M, Kazuma N, Murakami S, Otsuka K, Siegelova J, Dusek J, Sosikova M, Halberg F.
Further mapping of the natality chronome, in Toda City (Japan) Maternity Hospital. Scripta medica 2005; 78: 99-106.
169. Cornélissen G, Delcourt A, Toussaint G, Otsuka K, Watanabe Y, Siegelova J, Fiser B, Dusek J, Homolka P, Singh RB,
Kumar A, Singh RK, Sanchez S, Gonzalez C, Holley D, Sundaram B, Zhao Z, Tomlinson B, Fok B, Zeman M, Dulkova K,
Halberg F. Opportunity of detecting pre-hypertension: worldwide data on blood pressure overswinging. (Reprint of
Biomedicine & Pharmacotherapy 2005; 59 [Suppl 1]: S152-S157. Proceedings, International Conference on the Frontiers of
Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 123-129.
170. Cornélissen G, Halberg F, Katinas G, Schwartzkopff O, Holley D, Borer K, Homolka P, Siegelova J, Fiser B, Dusek J,
Otsuka K, Yano A, Delcourt A, Toussaint G, Sanchez de la Peña S, Gonzalez C, Zhao Z, Aslanian N, Singh RB, Kumar A,
Tarquini R, Perfetto F. Stroke and other vascular disease prevention by chronomics. Scripta medica (Brno) 2006; 79 (3):
141-146.
171. Cornélissen G, Halberg F, Katinas G, Watanabe Y, Sothern RB, Siegelova J, Fiser B, Dusek J, Homolka P, Prikryl P, Singh
RB, Otsuka K, Schwartzkopff O, Refinetti R. Chronotheranostics of MESOR-normotension vs. circadian overswing, i.e.,
CHAT. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology.
Brno, Czech Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University;
2006. p. 30-32.
61
172. Dusek J, Fiser B, Siegelova J, Holub J, Mazankova V, Cornélissen G, Halberg F. Decrease of myocardial infarction
mortality and seasonal mortality in the Czech Republic in the period from 1994 to 2003. J Hypertension 2006; 24 (Suppl 4):
245.
173. Dusek J, Siegelova J, Fiser B, Cornélissen G, Holub J, Mazankova V, Halberg F. Mortality data of stroke: 50-year record in
the Czech Republic. Abstract 367, 10th Annual Meeting, French Society of Pharmacology, 73rd Annual Meeting, Society of
Physiology, 27th pharmacovigilance meeting, 54th APNET Seminar and 4th CHU CIC meeting (Corum Montpellier 10-12
April 2006). Fundamental and Clinical Pharmacology 2006; 201: 206.
174. Dusek J, Siegelova J, Fiser B, Holub J, Mazankova V, Cornélissen G, Halberg F. Pokles celkove a sezonni umrtnosti pro
infarkt myokardu v Ceske Republice v letech 1994-2003. Supplementum Cor Vasa 2006; 48 (4): 21.
175. Fiser B, Cornélissen G, Siegelova J, Pohanka M, Tarasova M, Barlova B, Nosavcova E, Dusek J, Homolka P, Erajhi AA,
Abais FH, Holub J, Mazankova V, Halberg F. Stroke in the Czech Republic. In: Halberg F, Kenner T, Fiser B, Siegelova J,
eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic: Department of Functional
Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. p. 55-61.
176. Fiser B, Siegelova J, Dusek J, Holub J, Mazankova V, Cornélissen G, Halberg F. Spektralni analyza umrtnosti na infarkt
myokardu v Ceske Republice. Supplementum Cor Vasa 2006; 48 (4): 26.
177. Fiser B, Siegelova J, Dusek J, Holub J, Mazankova V, Cornélissen G, Halberg F. Spectral analysis of the myocardial
infarction mortality data in the Czech Republic. J Hypertension 2006; 24 (Suppl 4): 246.
178. Halberg F, Cornélissen G, Schwartzkopff O, Katinas G, Siegelova J, Fiser B, Dusek J, Homolka P, Vank P. Seven day
blood pressure measurement: contraversion in single 24-h profiles of blood pressure and heart rate. In: Halberg F, Kenner
T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic:
Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. p. 10-26.
179. Halberg F, Katinas G, Cornélissen G, Otsuka K, Sothern RB, Singh RB, Schwartzkopff O, Siegelova J, Fiser B, Dusek J,
Homolka P, Prikryl P, Refinetti R. Lessons about "loads" learned while detecting and greatly reducing residual MESORhypertension
and CHAT. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive
Methods in Cardiology. Brno, Czech Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of
Medicine, Masaryk University; 2006. p. 27-29.
180. Hillman D, Halberg F, Cornélissen G, Katinas G, Sothern RB, Otsuka K, Singh RB, Siegelova J, Fiser B, Dusek J, Homolka
P, Prikryl P, Schwatzkopff O. Need to standardize data collection and reference values. In: Halberg F, Kenner T, Fiser B,
Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic: Department of
Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. p. 36-38.
181. Katinas G, Halberg F, Cornélissen G, Otsuka K, Singh RB, Siegelova J, Fiser B, Dusek J, Homolka P, Prikryl P,
Schwatzkopff O. Chronobiologic serial sections complement spectra to seek social vs. physical signatures in human heart
rate circaseptans. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in
Cardiology. Brno, Czech Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk
University; 2006. p. 39-41.
182. Rostagno C, Cornélissen G, Halberg F, Tarquini R, Perfetto F, Jozsa R, Siegelova J, Fiser B, Dusek J, Homolka P, Prikryl
P, Bakken EE. Yet another cis-semiannual (cis-halfyear) spectral component in cardiac arrhythmia: in Italy. Proceedings,
International Conference on the Frontiers of Biomedical Science: Chronobiology, Chengdu, China, September 24-26, 2006,
p. 61-63.
183. Schwartzkopff O, Halberg F, Cornélissen G, Katinas G, Sothern RB, Siegelova J, Fiser B, Dusek J, Homolka P, Prikryl P,
Singh RB. Occasional transient CHAT occurs in the MESOR-normotensive individual. In: Halberg F, Kenner T, Fiser B,
Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech Republic: Department of
Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. p. 33-35.
184. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Cornélissen G, Halberg F. Blood pressure variation analyzed from
seven day monitoring. Abstract 366, 10th Annual Meeting, French Society of Pharmacology, 73rd Annual Meeting, Society
of Physiology, 27th pharmacovigilance meeting, 54th APNET Seminar and 4th CHU CIC meeting (Corum Montpellier 10-12
April 2006). Fundamental and Clinical Pharmacology 2006; 201: 205.
185. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Kohzuki M, Cornélissen G, Halberg F. Relationship between circadian
blood pressure variation and age analyzed from 7-day ambulatory monitoring. Abstract PM1-10-05, 21st Scientific Meeting,
International Society of Hypertension, Fukuoka, Japan, October 15-19, 2006. J Hypertension 2006; 24 (Suppl 6): 122.
186. Watanabe Y, Katinas G, Cornélissen G, Sothern RB, Siegelova J, Fiser B, Dusek J, Homolka P, Prikryl P, Singh RB,
Schwartzkopff O, Halberg F. Time course of blood pressures over 18 years analyzed separately by day and by week. In:
Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Symposium, Noninvasive Methods in Cardiology. Brno, Czech
Republic: Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University; 2006. p. 42-46.
187. Cornélissen G, Halberg F, Bakken EE, Wang Z, Tarquini R, Perfetto F, Laffi G, Maggioni C, Kumagai Y, Homolka P,
Havelkova A, Dusek J, Svacinova H, Siegelova J, Fiser B. Chronobiology of high blood pressure. Scripta medica (Brno)
2007; 80 (4): 157-166.
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188. Dusek J, Siegelova J, Fiser B, Forejt M, Homolka P, Vank P, Hollan J, Cornélissen G, Halberg F. Blood pressure and the
illumination of bedroom at night. P1.31, 17th European Meeting on Hypertension, Milan, June 15-19, 2007. J Hypertension
2007; 25 (Suppl 2): S33.
189. Fiser B, Siegelova J, Dusek J, Pohanka M, Masek M, Barak J, Moudr J, Cornélissen G, Halberg F. Analysis of baroreflex
function by means of mathematical model. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings, Noninvasive
Methods in Cardiology 2007, Brno, Czech Republic, November 11-14, 2007. Brno: Department of Functional Diagnostics
and Rehabilitation, Faculty of Medicine, Masaryk University (ISBN 978 80 7018 463 4); 2007. p. 90-93.
190. Halberg F, Cornélissen G, Katinas G, Dusek J, Homolka P, Karpisek Z, Sonkowsky RP, Schwartzkopff O, Fiser B,
Siegelova J. Chronomics and genetics. Scripta medica (Brno) 2007; 80 (4): 133-150.
191. Havelkova A, Siegelova J, Fiser B, Mifkova L, Chludilova V, Pochmonova J, Vank P, Pohanka M, Dusek J, Cornélissen G,
Halberg F. Physiotherapy and circadian blood pressure variability. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds.
Proceedings, Noninvasive Methods in Cardiology 2007, Brno, Czech Republic, November 11-14, 2007. Brno: Department of
Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University (ISBN 978 80 7018 463 4); 2007. p. 113-
120.
192. Havelkova A, Siegelova J, Fiser B, Mifkova L, Chludlikova V, Pochmonova J, Vank P, Pohanka M, Dusek J, Cornélissen G,
Halberg F. Circadian blood pressure variability and exercise therapy. Scripta medica (Brno) 2007; 80 (5): 191-196.
193. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Masek M, Havelkova A, Cornélissen G, Halberg F. Circadian blood
pressure variation analyzed from 7-day monitoring. In: Halberg F, Kenner T, Fiser B, Siegelova J, eds. Proceedings,
Noninvasive Methods in Cardiology 2007, Brno, Czech Republic, November 11-14, 2007. Brno: Department of Functional
Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University (ISBN 978 80 7018 463 4); 2007. p. 75-89.
194. Siegelova J, Dusek J, Fiser B, Homolka P, Vank P, Masek M, Havelkova A, Cornélissen G, Halberg F. The relationship
between circadian blood pressure variation and age analysed from 7-day monitoring. Scripta medica (Brno) 2007; 80 (4):
179-187.
195. Halberg F, Cornélissen G, Siegelova J, Fiser B, Dobsak P, Kenner T, Placheta Z, Dusek J, Homolka P, Al-Kubati M,
Schwartzkopff O, Blagonravov MB, Chibisov SM, Agarwal RK. Blood pressure or, rather, blood pressure variability
disorders, VVDs, discussed in Brno on October 6, 2008. Bulletin of People's Friendship University of Russia: Series
Medicine 2008; (7): 26-30.
196. Halberg F, Cornélissen G, Otsuka K, Sanchez de la Peña S, Schwartzkopff O, Watanabe Y, Pati AK, Wall DG, Delmore P,
Borer K, Beaty LA, Nolley ES, Adams C, Siegelova J, Homolka P, Dusek J, Fiser B, Prikryl P. Why and how to implement 7day/24-hour
blood pressure monitoring? Int J Geronto-Geriatrics 2005; 8 (1): 1-31. [Dated 2005 but published in June
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197. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Singh RB, Revilla M, Sanchez de la Pena S, Gonzalez C, Siegelova J,
Homolka P, Dusek J, Zeman M, Singh RK, Johnson D, Fiser B. Home C-ABPM for preventive and curative health care and
transdisciplinary science. World Heart J 2008; 1 (3): 233-261.
198. Halberg F, Cornélissen G, Siegelova J, Fiser B, Dobsak P, Kenner T, Placheta Z, Dusek J, Homolka P, Al-Kubati M,
Schwartzkopff O, Blagonravov MB, Chibisov SM, Agarwal RK. Blood pressure or, rather, blood pressure variability
disorders, VVDs, discussed in Brno on October 6, 2008. Bulletin of People's Friendship University of Russia: Series
Medicine 2008; (7): 26-30.
199. Halberg F, Schwartzkopff O, Cornélissen G, Hardeland R, Müller-Bohn T, Katinas G, Revilla MA, Beaty L, Otsuka K, Jozsa
R, Zeman M, Csernus V, Hoogerwerf WA, Nagy G, Stebelova K, Olah A, Singh RB, Singh RK, Siegelova J, Dusek J, Fiser
B, Czaplicki J, Kumagai Y, Chibisov SM, Frolov VA. Vaskuläres Variabilitäts-Syndrom (VVS) und andere Chronomik 2005-
2007. In: Hardeland R, ed. Sonderdruck aus Abhandlungen der Leibniz-Sozietät der Wissenschaften, Band 23: Facetten
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200. Siegelova J, Fiser B, Havelkova A, Dobsak P, Dusek J, Pohanka M, Cornélissen G, Halberg F. Ambulatory arterial stiffness
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Steps toward Mikulecky's semimillennials in the emergence of outstanding individuals
Franz Halberg*, Germaine Cornélissen*, Dewayne Hillman*, Jarmila Siegelova‡, Bohumil Fiser‡,
Pavel Homolka‡, Jiri Dusek‡
*Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
‡Masaryk University, Brno, Czech Republic
On his 82nd
birthday, June 22, 2009, this paper is dedicated to Prof. Miroslav MIKULECKY, the
first professor of medicine and department head to write a textbook on inferential statistical
methodology and to engage in a documentation of the role of the cosmos in clinical practice. About
500-year cycles in the emergence of outstanding physicians, historians and poets are to his credit,
and we dub these cycles Mikulecky's circasemimillennians.
Perspective. For as long as the human lifespan cannot be substantially prolonged, cycles of
about 500 years are a challenge for scholars of population dynamics; their underlying physiological
mechanisms must be studied with serial independence as to individuals over several generations.
This goal requires the monitoring of successive human generations from womb to tomb. This aim
may be reached more readily if human lifelong monitoring can be achieved by the development of
preferably affordable, unobtrusive automatic recorders of blood pressure and heart rate for use by
everybody interested. Good enough reasons must suffice for a prompt general implementation in
each generation in its own right. Such aims are to assess infradian rhythm abnormalities that may
complement the already-known circadian ones. Infradians include transtridecadals when each cycle
covers nearly half a lifetime. The discovery of circadian vascular variability disorders, VVDs, and
of their combination transforming them into vascular variability syndromes, VVSs, revealed that
VVSs constitute a high increase in risk of hard events (from 5% to 100% in one study). If
recognized, these risks, much greater than those of hypertension, can be reversed. This is one reason
for monitoring by the individual. The further finding of 35-year cycles in climate, economics and
international battles as well as in one's heart rate (HR) constitute reasons revolving around
clarifying the roots of societal (as well as the individual's) disease, such as crime and terrorism.
Background. Vindicating Brückner, Egeson and the Lockyers (BEL) (1-4), an about 35-year
periodicity was validated in inferential statistical terms (5-7). This cycle persists in climate to this
day in environmental temperature (8) as an intermittently statistically significant phenomenon in
64
some of Brückner's original data; we extend by far the scope of this spectral component in various
human affairs; and its submittal for publication by invitation (8) happened to coincide with other
reports on the same BEL cycle (9, 10) and its detection in the total solar flare index available from
1966 to 2007 (42 years) (this issue). With other papers in these proceedings (11, 12), we extend to
three persons the documentation of the physiological BEL as an approach to monitoring the sun by
human blood pressure and heart rate series, actually collected for a personalized health care. The
demonstration of the same transtridecadal cycle on two elderly men (11, 12) complements the
finding of the same BEL in a man aging from 20 to 60 years (7).
Papers on a 35-year climate cycle in heliogeophysics, psychophysiology, military politics, and
economics (8) and on global tropospheric temperature variations (9) both deal separately directly
with cycles in terrestrial climate and indirectly with the dynamics of the cosmos. A meta-analysis of
the latter paper (9; cf. 10) reveals a BEL, or Brückner-Egeson-Lockyer component (1-4; cf. 5-8),
further supporting the essence of the original papers on the 35-year climate cycle (1-4), showing
important influences of non-photics in various human affairs. Pertinent is that global tropospheric
temperature also reveals the BEL cycle. Still more convincing is a further recent paper, in the April
17, 2009 issue of Science: Shanahan et al. (10) show, without comment or citation, a 33-year BEL
peak. It stands out and is marked by the number 33 in Figure 4A of their paper on the history of
climate in Africa, computed with modern methods, reproduced with permission in Figure 1 (8).
The paper in Science on droughts in West Africa reflected in Lake Bosumtwi in Ghana
complements Eduard Brückner's studies (1) prompted by changing water levels of Russian lakes in
the 19th century. Shanahan et al. (10) confirm Brückner's alternating wet and dry periods (1) and
indirectly render timely the demonstration of an about 35-year period in the length of the
circadecadal Horrebow-Schwabe cycle in sunspot numbers reported by the son (3) of Sir Norman
Lockyer (4), the founder of the journal Nature and discoverer of helium. Brückner and the Lockyers
are not cited in pertinent contemporary papers (10, 13-15). Standards for citation are a matter of
discussion (16, 17). Two reasons for omission may be the lack of an inferential statistical validation
and lack of a putative underlying mechanism. Hence, two of us (GC and DH), with different
65
methods, happened to look at 42 years (1966-2007) of the solar flare index (the total from both solar
hemispheres), only to encounter again a prominent transtridecadal component, with nearly identical
point estimates but a relatively broad 95% confidence interval, shown elsewhere (18).
A transtridecadal periodicity is just one component among other cycles in climate that can also
be gauged by several biospheric variables, including an about 500-year periodicity (19). Section B
of Figure 2 in the recent paper in Science (10) also shows a Morlet wavelet with an about 500-year
periodicity that was reported earlier to characterize 3,200 years of stalagmite coloring, 2,790 years
of tree rings width and 2,556 years of international battles (19), Figure 2A (see bottom section
below dashed horizontal line). We do not have long enough series on solar flares to examine
whether the same periodicity prevails in them, as in Figures 2A-D, which also focus upon the
emergence of distinguished physicians, historians and poets on different continents, including times
prior to the Silk Road (19) when there was little intercontinental communication. The latter figures
confirm the scholarship of Prof. Miroslav Mikulecky and Dr. Emil Pales (20, 21), who originally
documented the circasemimillennial cycles in the appearance of outstanding individuals in
seemingly unrelated cultures on different continents. Circaseptennian cycles had been reported for
outstanding quantum physicists, among others (22-25; cf. 26, 27).
The varied interwoven facts, along windows of about 35 and about 500 years, among many
other resonant solar-terrestrial biospheric frequency bands, await scrutiny of the underlying nonphotic
as well as photic mechanisms, notwithstanding the claim "... that over the past 20 years all
the trends in the Sun that could have had an influence on the Earth's climate have been in the
opposite direction to that required to explain the observed rise in global mean temperatures" (28).
We better investigate the dynamics of climate with Gauss' least-squares, if not with the methods of
Joseph Fourier, the discoverer of the fact that gases in the atmosphere might increase the surface
temperature of the earth, what would later be called the greenhouse effect. Multifactorial situations
require multifactorial analyses. In this context, a prominent BEL cycle, which we find very
prominently in solar flares during the last 42 years, must not be ignored. These same solar flares
relate to human physiology (29-31) and pathology (32), including sudden human cardiac death
66
characterized by a cis-half-year of about 0.42 year and at a far-transyear of about 1.72 years,
deserving scrutiny for further biospheric counterparts, all features of the Cornélissen-series (33).
Acknowledgement. The authors are indebted to Dr. Taeil Bai, Senior Research Scientist,
Center for Space Science and Astrophysics, Wilcox Solar Observatory, Stanford University,
Stanford, California, USA, for a list of important flares since 1976, of interest in further analyses by
superposed epochs. Data analyzed herein (see Figure 2) are the total solar flare index available daily
over 42 years.
1. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
2. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
3. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
4. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
5. Halberg F, Cornélissen G, Czaplicki J, Prabhakaran Nayar SR, Siegelova J. Brückner-EgesonLockyer
(BEL) climate cycle in original Brückner's, Lockyer's and follow-up data. In: Halberg
F, Kenner T, Fiser B, Siegelova J (Eds.) Proc., Noninvasive Methods in Cardiology, Brno,
Czech Republic, Oct 4-7, 2008. p. 74-89. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
6. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F.
Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics. In: Halberg F, Kenner T, Fiser
B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology, Brno, Czech
Republic, October 4-7, 2008. p. 106-115. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
7. Sothern RB, Katinas GS, Fiser B, Siegelova J, Cornélissen G, Halberg F. A transtridecadal
cycle in human heart rate: Selective infradian, notably multidecadal solar-physiologic BEL
congruences. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive
Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 204-213.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
67
8. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle in
heliogeophysics, psychophysiology, military politics, and economics. Geophysical Processes
and Biosphere, in press.
9. Grafe A, Heider F. Geomagnetic activity and global trophospheric temperature variations.
Geophysical Processes and Biosphere, in press.
10. Shanahan TM, Overpeck JT, Anchukaitis KJ, Beck JW, Cole JE, Dettman DL, Peck JA,
Scholz CA, King JW. Atlantic forcing of persistent drought in East Africa. Science 2009; 324:
377-380.
11. Halberg F, Cornélissen G, Siegelova J, Homolka P, Dusek J, Fiser B. Differences in time
structural environmental congruence of vascular variables in an elderly man. This issue.
12. Halberg F, Cornélissen G, Best WR. A transtridecadal BEL cycle in human blood pressure and
body weight. This issue.
13. Friis-Christensen E, Lassen K. Length of the solar cycle: an indicator of solar activity closely
associated with climate. Science 1991; 254: 698-700.
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Prikryl P, Chibisov SM, Holley DC, Wendt RW, Bingham C, Palm SL, Sonkowsky RP,
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proposal, nine conferences, heliogeomagnetics, transyears, near-weeks, near-decades,
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Greece, India and China. Abstr., 23rd Semin., Man in his Terrestrial and Cosmic Environment,
Upice, Czech Republic, May 21–23, 2002.
21. Mikulecky M. Solar activity, revolutions and cultural prime in the history of mankind.
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26. Cornélissen G, Sothern RB, Halberg Francine, Halberg Franz. 7-year (circaseptennian)
patterns in psychology and biology? Comment on Verhulst and Onghena. Psychological
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29. Cornélissen G, Halberg F, Sothern RB, Siegelova J. Unmasking a cis-half-year with
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components. This issue.
30. Katinas GS, Halberg F, Cornélissen G, Sanchez de la Peña S, Czaplicki J, Siegelova J,
BIOCOS project. C-ABPM reveals solar cis-halfyear and transyear signatures in human
diastolic blood pressure. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 144-146.
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cycle in human circulating melatonin: signature of weather in extraterrestrial space? Poster
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Year 2007 and Basic Space Science: "First Results from the International Heliophysical Year
2007", Sozopol, Bulgaria, June 2-6, 2008.
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M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G,
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season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and
site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38.
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33. Halberg F. Historical encounters between geophysics and biomedicine leading to the
Cornélissen-series and chronoastrobiology. In: Schröder W (Ed.) Long- and Short-Term
Variability in Sun's History and Global Change. Bremen: Science Edition; 2000. p. 271-301.
Legends
Figure 1. (A) Multi-taper method (MTM) spectral analysis of the Bosumtwi X-ray
fluoroscopy data (10). Significant power is apparent on inter-annual (3.6- to 4.6-year), decadal (7.1-,
7.8-, 10.6-, and 13.8-year), multidecadal (33- to 42-year), and century (90-, 175-, 225-. and 302-
70
year) time scales. For clarity, only the portion of the power spectra >3.57 years (F = 0.28) is shown.
The oblique lines denote the 99 to 95% confidence interval. MTM analyses were performed with the
program k-spectra. Parameters p = 3, K = 5, and a null hypothesis of red noise were used in the
analysis. Labeled are periods (in years) for peaks that are significant at 95%. Note the prominent
spectral peak protruding above the 1% level of statistical significance with a period of 33 years
(arrow) corresponding to a BEL.
(B) Cross-spectral coherence computed for Lake Bosumtwi (600-year detrended first principal
component [PC1] of the full suite of elemental data [aluminum, Al; silicon, Si; potassium, K;
titanium, Ti; manganese, Mn; and iron, Fe]) and the Atlantic multidecadal oscillation
reconstruction. The horizontal line indicates the 90% confidence interval. The records are in phase
and highly coherent at a period of 30 to 50 years (indicated by gray shading). Reproduced from (10)
with kind permission.
Figure 2A. Mikulecky's circasemimillennial period in the emergence of outstanding
individuals (above dashed lines) and in international battles and in two series likely related to
climatic changes, namely tree ring widths and stalagmite coloring. © Halberg.
Figure 2B. Acrophase chart estimated at average period for Mikulecky's circasemimillennials.
© Halberg.
Figure 2C. Mikulecky's circasemimillennial synchronized cycles in the emergence in three
different geographical regions of famous physicians. © Halberg.
Figure 2D. Mikulecky's circasemimillennial synchronized cycles in the emergence in three
different geographical regions of famous historians and poets. © Halberg.
71
Figure 1
72
Figure 2A
73
Figure 2B
74
Figure 2C
75
Figure 2D
76
C. MENDEL's LEGACY
Omnis cyclus e cosmo:
Mendel's chronoastrobiological legacy for transdisciplinary science
in personalized health care
Franz Halberg1
, Germaine Cornélissen1
, Anna Matalova2
, Jarmila Siegelova3
, Robert Sonkowsky1
,
Sergei M. Chibisov4
, Waldemar Ulmer5
, Douglas Wilson6
, Miguel Revilla7
, George S. Katinas1
,
Pavel Homolka3
, Jiri Dusek3
, Bohumil Fiser3
, Salvador Sanchez de la Pena8
,
Othild Schwartzkopff1
, Larry A. Beaty1
1
University of Minnesota, Minneapolis, MN, USA
2
Mendelianum, Brno, Czech Republic
3
Masaryk University, Brno, Czech Republic
4
People's Friendship University of Russia, Moscow, Russia
5
Gelnhausen, Germany
6
Research Design Services, Durham and Newcastle Universities, Durham, UK
7
University of Valladolid, Spain
8
National Polytechnical Institute, ENMH-CIC, Mexico City, Mexico
Support: U.S. National Institutes of Health (GM-13981) (FH);
University of Minnesota Supercomputing Institute (GC, FH)
77
Dedication and Preamble
This presentation, a follow-up on an earlier paper by the senior author (1), is dedicated with
infinite gratitude to the memory of his father, Dr. Julius Halberg, who had guided his poetically
inclined son to science, medical school, and life in the USA. In the USA, his path led to research
into cyclicities in biological and other temporal variability. Chronomes -- time structures --
complement genetic and cosmo-spatial diversity near and far, a first major link to genomics and
then to Johann Gregor Mendel, recognized earlier as a geneticist, meteorologist and
epidemiologist, all in one person, who pursued these superficially diverse activities during a
productive if relatively short lifetime. From the relation of the fields of spatial and temporal
variability, the senior author's lifetime concerns, common reciprocal structures emerged in and
around us, in whatever was measured. A self-sustaining multifrequency rhythmic pattern of
variability was mapped. It organized chaos and underwent trends, while intermodulating, selfreproducing
and evolving. Rhythms turned out to be much more than the signature of the cycles in
our cosmos, which they are. They also constitute the mechanism of living matter and eventually
led to the spirituality of life. As we learn more and more about our chronomes, Figure 1, we
recognize them as a product of our cosmoi: chronomes are interwoven but resolvable as somewhat
wobbly recurrent patterns. Thus, we gained a perspective of an open system from the perspectives
of a chronomedicine, chronoecology and, eventually, a yet broader chronoastrobiology, all
transdisciplinarily dependent upon chronomics, the aligned study of biospheric and cosmic time
structures, that, while of interest in their own right, complement genomics.
Whatever one measures or renders measurable, repeatedly, densely and/or along longer and
longer time scales characterizing individuals, populations and eventually species, genera and their
habitats, gains from a resolution of cycles, defined as an inferentially statistically documented
recurrent phenomenon in a spectrum consisting of photic and other constituents. For each
component cycle, 1. the no-cycle (zero-amplitude) assumption is to be rejected and 2. point-andinterval
estimates of parameters are to be provided. Photic variations, notably about (~) 24-hour
cycles, are usually environmentally well synchronized, more than the non-stationary, aeolian non-
78
photics. Based on the foregoing criteria, non-photics and photics both qualify as cycles, until they
become rhythms, once they are replicated over many cycles and documented as to
intermodulations and their mechanisms. We are dealing with exophased endocycling: many builtin
periods in the biosphere can be exogenously synchronized and phase-shifted (whereby we
account for the "exophasing") while they persist in the absence of the external cycles, being partly
endogenous, the point we are trying to make by "endocycling".
Endeavors in science dealing more broadly with civilization and in particular with a hard-todefine
culture are best referred to their temporal as well as to spatial coordinates, and are thus
rendered more meaningful in the context of chronomes in us and around us, as Mendel put it, in
the context of "terrestrial and cosmic factors". The systematic mapping of the spatial environment
has been done by physicists for centuries on earth and for decades via satellites in space: it awaits
complementary systematic temporal mapping, in physics and in the biosphere. Mendel, the
meteorologist at heart, concomitantly mapped physical conditions and diseases, first with the head
of a hospital in Brno, and continued recording them after the latter's death, implementing
meteorology in relation to the epidemiology of disease. Mendel the meteorologist practicing
chronomics was the topic of a lecture delivered at a symposium held at the Mendelianum in Brno,
Czech Republic, here summarized with an update, and was also the topic of a keynote opening a
symposium given in Nagoya, Japan, published in 1991, with 70 figures (2). Many more figures
mapped in the interim are mostly available at least as bibliographic references, on our website
(http://www.msi.umn.edu/-halberg/). The present paper continues to summarize chronomics in the
framework of a long-standing cooperation between Brnoese and Minnesotan co-investigators.
Abstract
This paper reviews the development of chronobiology, the science (logos) of life (bios) in
time (chronos), and of chronomics, against the background of Mendel's contributions far beyond
genetics. In keeping with Mendel the meteorologist, we document for rhythms that light and food
are not the only external switches. The "master switch", light, can be overridden more often and
more critically than we visualize by feeding (3) or by a magnetic storm (4). Very important
79
hypothalamic "oscillators" (5) are not the only internal mechanism of rhythms. Time structures,
chronomes, reside in every biological unit, pro- or eukaryote, Figure 2 (6; cf. 5, 7). Chronomes in
us have a strong genetic component which, in turn, entered the genome in response to
environmental chronomes, explored meteorologically by Mendel. The more remote environmental
origin of rhythms and their less remote genetic aspect both qualify biological chronomes as the
legacy of Mendel the meteorologist as well as the geneticist.
Our continued resonance with the environment renders an exophased endocycling even more
interesting. The need for coordinated physical and biological monitoring, the topic of a project on
The BIOsphere and the COSmos, briefly BIOCOS, to complement genomics, can also be viewed as
the legacy of Mendel the meteorologist/cartographer. Some of Mendel's meteorological data were
meta-chrono-analyzed. Mendel himself published more often on meteorology than on what
became genetics. His legacies of paraphernalia are those of a meteorologist. Despite failing his
examination for certification as a regular teacher in 1850 -- his lowest marks were in biology and
geology (!) -- and although he reportedly never passed his teacher's license examination, Mendel
started the science that distinguished the rules of dominant vs. recessive behavior and eventually
led to the cloning of organisms and the debate about stem cells, again raising the question "What is
life?" (1, 8, 9). Mendel is the de facto teacher par excellence of this generation of genomics,
proteomics and nanochemistry by virtue of what became not only genetics but also chronomics in
Brno. Our advocacy of education in instrumented self-help for chronobiologic literacy includes
genetics and ecology, and qualifies as Mendelian. Chronobiologic literacy in everyday health care
serves for the quantification of normalcy. By resolving chronomes in the normal range, we act
positively rather than defining health negatively and only qualitatively (as the absence of disease,
i.e., of deviations outside that range) summarized as % morbidity and % mortality only for a
population, not for the individual.
From these several viewpoints that have as a common denominator focus upon the usual, we
view Johann Gregor Mendel as a chronobiologist. We view chronobiology in a broad perspective
of its now thoroughly documented roots in our genes and via our genome in the cosmoi, as they
80
were when and where life began and as they changed from then to now. Evolution, ecology,
genetics and chemistry, the legacies of Darwin, Haeckel, Mendel and Lavoisier respectively, and
their transdisciplinary fusion by Brückner, Egeson, Norman Lockyer, W.J.S. Lockyer, Chizhevsky
and Vernadsky in the spirit of Dokuchaev, like everything else, occur in time. They are part and
parcel of chronobiology and of a much broader temporal perspective from chronomics, an overdue
transdisciplinary cartography of the as-yet unknown.
Omnia metire quaecumque licet, et immensa ad mensuram tempestive et ergo significative
redige: Measure what is measurable and render measurable, meaningfully in time, what as
yet is not
A concern for measurement, revealing variability, led to basic and applied lessons in a broad
science, chronobiology, which explores our origins in the cosmoi and offers applications in
preventive as well as curative aspects of health and environmental care (10). Chronobiologic
concerns, basic or applied, require a dynamic perspective of life and the cosmoi. The need for such
a concern about the changes around us as well as in us was fully envisioned by Mendel's activities.
His signature impacts far beyond the pea patch of the monastery in Brno, where genetics was born.
There, Mendel read Darwin and made notes in the latter's book. He eventually added genetics to
natural selection and was concerned, in the struggle for survival, about the "dawn of empathy",
about going beyond life as a food chain to lay the basis for fields in which genetically coded life
could evolve toward spirituality, which as yet may have escaped classification by otherwise
meritorious approaches of physicists and biologists alike (11).
Mendel, the chronobiologist, recorded physical cycles in nature, some of them now shown to
be anchored in our genes. In his pre-satellite era, changes in solar wind speed escaped him, but he
collected original data on wind speed, meta-analyzed by us to emphasize Mendel's concern about
environmental effects, rather than merely to quantify another circannual pattern. Unfortunately,
this to-us available series of measurements is not long enough to examine the putative presence of
a transyear of ~1.3-years length, non-photic and unseen, and its possible beating with a calendaryearly
component. Transyears characterize our physiology from human babies and the elderly in
particular. The ~yearly and ~daily patterns in us and around us, and their importance have become
81
obvious (12, 13). Much less conspicuous are about half-weekly (circasemiseptan) and aboutweekly
(circaseptan) changes, unseen, non-photic, in our environment, well known in human
pathology since antiquity and now found to have counterparts in helio- and geomagnetic
phenomena, as well as in rainfall, where a physical near-match was reported (14).
Heliogeomagnetics also exhibit ~half-yearly (circasemiannual), ~10-yearly (circadecadal or
circadecennian), ~21-yearly (circadidecadal or circavigintunennian), and other natural, e.g.,
transtridecadal (15-17; cf. 18) physical cycles and even broader time structures, chronomes, Figure
1, that have biological counterparts and enlarge the scope of biological time measurement, leading
us to the essence and origins of life, the feedsidewards, at various levels of organization, Figure 3.
From dense and long time series and inferential statistical procedures applied thereto, we
learn that most if not all of the above mentioned and other bioperiodicities resonate with terrestrial
and more remote magnetic and/or other solar or galactic activity, a broad field in its own right
explored largely without concern for time structures (19). Solar and, perhaps, more remote astral
dynamics (recorded by space-borne vehicles, traceably gauged by velocity, proton density and
temperature changes in the solar wind) and some of their consequences, include associations with
biota. Modern technology complements the tools available in Mendel's time, to build on his legacy
and to examine the relative importance of factors in us vs. those around us in determining our
"behavior" in the broadest possible sense, including the spheres of the mind (= noos) -- the
noosphere -- and of spirituality, the soul, that some researches based on spirituality, located in the
pineal, and others in the gut, insofar as melatonin's circadian rise in the intestine, can precede those
in plasma, the hypothalamus and the pineal (20).
It took the last quarter-century to explore molecularly the genetics of the ~daily rhythms.
Their built-in nature was one reason for coining the various circa-rhythms, "about" (= circa)
referring to a frequency characteristic of the biological system approximating an environmental
periodicity, yet deviating from precisely that length. Other important considerations for "circa" are
being accepted more slowly. One of them is the fact that we are dealing with uncertainties, i.e.,
with statistical rather than purely deterministic entities. To determine their variability and, once
82
this is done, to quantify their characteristics, we need inferential statistical procedures for both the
testing of a cycle's occurrence and for determining the interval as well as point estimates of its
parameters, e.g., as 95% confidence intervals.
Some of the uncertainties encountered reflect the operation of unknown distant as well as of
proximal measurable drummers. Cases in point are subtle geophysical associations with
myocardial infarctions (21) relating, in their turn, to events from interplanetary space and to
Horrebow-Schwabe's ~0.5-year, Hale's ~21-year and Brückner, Egeson and Lockyer's ~35-year
cycles (15-18) in solar activity that in turn may be subject to galactic influences. There may also
be effects on biota from outside our galaxy, within our cosmos and/or other cosmoi (19). These as
yet must be documented.
A hint of possible extra-solar system effects could be provided by any finding in physiology
consistently preceding events in solar or interplanetary physics, such as a southward turn of the
north-south component, Bz, of the interplanetary magnetic field (IMF). Thereby, the question is
raised whether an extra-solar-system factor influences both the IMF and human physiology.
Furthermore, an explanation for ~10-year cycles in microbial sectoring, i.e., as probable genetic
changes of air bacteria, that are in near-antiphase with the solar activity cycle of similar length, is
the possibility that the effect upon the human heart, whether it occurs during a magnetic storm in
the laboratory (4) or on the neonatal intensive care unit along the scale of a day or with an ~10year
solar cycle (22) may be an effect of the displacement by geomagnetic storms of the flux of
galactic cosmic rays and thus the mutagenic effect of a driver from our own galaxy or from
another.
Chronomes and Mendel
By objectively and consistently measuring meteorological as well as biological variation
patterns with time and by seeking reproducible patterns in what others may have regarded as
random variation, and in particular by interpreting them contrary to the dogma of his era, Gregor
Mendel was a scholar not only in chronobiology but also in chronomics: he recorded samples as
well as publishing terrestrial weather reports. Meteorological observations from 1856 on were
83
incorporated by 1862 into publications of the observations of all meteorological stations in
Moravia. From 1878 to 1883, Mendel ran a weather station in Brno. In the spirit of Mendel, we are
led beyond the molecular genetics of a time-invariant genome to its expression in chronomes. We
here draw and test generalizing inferences concerning structures in time. In the chronomes of
organisms, the major element, the circa-rhythms, are integrated from within on the one hand, while
they are also adapted to external chronomes, including cyclic among other (environmental)
patterns, with the perspective broadening from an impenetrable normal range, over clocks and
calendars to chronomes, Figure 4.
In its turn, the spectrum of rhythms renders chaotic-appearing changes predictable and
diagnostically useful (23, 24) while on the basic side it may point to sites of life's origins by the
behavior of rhythms in our ontogeny and phylogeny (25). An example is the prominent biological
week found early in human life (26, 27) and again in the human elderly (28). These patterns during
aging may "recapitulate" phylogeny and perhaps also those temporal features of cosmogeny,
including some prevailing in times long past, when life started on earth and/or beyond in our
cosmos and/or in other cosmoi. Data on hundreds of human babies from different geographical
areas are pertinent as to ontogeny, as is evidence on dozens of unicells and more limited data
obtained early in the ontogeny of the crayfish (29), rats (30) and piglet (31).
The value of chronomes of blood pressure and heart rate variability, apart from their basic
interest, relates to self-help for health care, based on a chronobiologic literacy. Too much blood
pressure and too little heart rate variability serve in diagnosing an elevation of disease risk, prior to
overt illness. The task of detecting Vascular Variability Disorders (VVDs) and their combinations
in disease risk syndromes prompts the need for every-man, -woman and -child to benefit from
general education in chronobiology. This bioscience complements, by rendering more interesting
and more useful, the learning of other sciences such as mathematics, physics and chemistry.
Topics in hard science can all be taught by chronomedical examples for self-help in health care, in
the spirit of Mendel the teacher who was recognized as such only after his death; Mendel the
researcher, who was recognized as the father of genetics only decades after his death; and Mendel
84
the chronobiologist, whom we recognize as such well over a century after his death. Unlike single
sample-based time-unqualified homeostatic biology, which can be misleading, chronobiology
renders the teaching of the hard sciences interesting and useful in health and environmental care
(32). To be specific, the teaching of the blood pressure measurement certainly is of homeostatic
interest, but as such misleading if decisions are based on single measurements or single 24-hour
profiles. It is critical to learn in middle or preferably in elementary school that taking a single timeunqualified
measurement, from a biomedical viewpoint, can be equivalent in some patients to
flipping a coin (33).
Since his focus includes the chronomes of the environment, with which those of life are
intricately interwoven, Mendel, the chronobiologist, set yet another example by providing
systematic data that allow the resolution of 1-year synchronized circannual and of other
meteorological rhythms, once his data in meticulous handwriting are transformed into an
electronic format. His legacy prompts findings discussed herein in their historical context. The
multifrequency components of the chronomes in us are interwoven among themselves, with other
chronome elements, and with chronomes around us, as feedsidewards par excellence, for the
resolution of what can be regarded as a transdisciplinary "biggest problem".
Sequence within a circadian cycle: RNA before DNA
There is the chronobiologic question of what comes first in a single circadian (or other)
cycle. Toward this goal, it seemed reasonable by the fifties to fill in the Gs (that stand for Gaps in
knowledge) in the cell cycle of that time. These gaps remain exactly what the word means: it had
to be realized that the cell cycle is a sequence of more than two events, such as DNA labelling and
mitosis, and that referring to the rest as one of the Gs can be equivalent to building on quicksand
(as if the gaps were more than lack of specific knowledge of what happens during a gap). For
instance, the effects of agents such as pituitary growth hormone, GH (34), an ACTH analogue
(35), or an immunomodulator (36), as already demonstrated, depend critically on a circadian,
circaseptan or circannual cell cycle time and probably on many other as-yet not tested, e.g.,
circatrigintan, transannual rhythm stages, some of which are already mapped.
85
For replacing the Gs, in the 1950s we used a battery of techniques. For locating intracellular
sites, we combined differential centrifugation and histology with wet chemistry and radioactive
tracers. Physiological markers were the circulating blood eosinophils (gauging the adrenal cortex
and medulla) and core temperature (as a marker of hypothalamic mechanisms underlying a
mammalian circadian system). We determined the relative specific activities, i.e., the specific
activity of chemically isolated phospholipid-, RNA- or DNA-phosphorus in relation to the specific
activity of pool (acid soluble or inorganic) phosphorus. This approach yielded a biochemical
sequence of events, starting with phospholipid labeling at the membrane, which preceded RNA
formation in the cytoplasm. There was no need to obscure these features by reference to a gap, as
G1. We dissected events in time further to find that RNA formation preceded the formation of
DNA, rather than the reverse, with RNA preparing perhaps the cell for DNA synthesis and for the
subsequent (again clearly following rather than coincident) division of the cell with an
intermediate peak in glycogen content.
Thus, by the 1950s, what was to become chronobiology revealed that a circadian cell cycle in
immature growing mouse liver starts at the membrane with phospholipid labeling. RNA-, not
DNA-synthesis follows. With cosinor methodology for time series analysis, we could demonstrate
a statistically significant lead in phase of phospholipid labelling over RNA formation. In
mammalian liver, there is a lag of ~9 hours between RNA formation and DNA synthesis, with
non-overlapping 95% confidence intervals, when the results are analyzed by cosinor. The results
of the 1950s found extension by the 1960s. We learned from Leland Edmunds that the sequence of
a peak in murine RNA formation (a result of synthesis) has a counterpart in RNA content, which
leads that in DNA, in the unicell Euglena, within a single cell, not complicated by the presence of
metabolizing cells that are not yet dividing (37). From there, it is just one further step to analyzing
the sequence of gene expression in the mammalian heart (38).
The spectrum of ultradian rhythms broadens
The ultradian courtship song of the fruit fly is associated with circadian genetics (39), as may
be developmental changes in the roundworm Caenorhabditis elegans (40). Ultradians and
86
infradians can replace circadians in the case of circulating endothelin (41-44) and in the numbers
of endotheliocytes (45). Ultradians can also characterize gut hormones (46) and have been
detected in molecular biology (47). Among non-photic infradian cycles in the environment, some
long known counterparts of the ~10.5-year Schwabe and the ~21-year Hale cycles are now marked
by signatures of the solar wind in the form of near-transyears (1.00 year < [τ {period} - CI {95%
confidence interval}] < [τ + CI] < 1.20 years), far-transyears (1.2 years ≤ [τ - CI] < [τ + CI] < 1.9
years) and a cis-half-year found by Rieger (48), or an ~0.42-year cycle. Counterparts in physiology
(49) must be aligned with those in pathology (50).
Circaseptans
An ~weekly or circaseptan pattern critically interacts with the outcome of an attempt to
optimize, by timing, the effect of an immunomodulator in a mammal (36). In manipulating a
unicell, the increasing interval in numbers of days between consecutive changes of an LD12:12
lighting regimen reveals an ~7-day pattern in the intact organism that changes to a half-weekly or
circasemiseptan pattern after enucleation of the unicell (51). For the electrical potential of
Acetabularia standardized in LD12:12 and released into continuous light, the circaseptan
component is more prominent than the circadian. Both a circaseptan and a semicircaseptan pattern
fit the declining vitality (gauged by the glutathione content) of the anucleate human platelet (52).
Both these patterns fit data on growth or colony advance of E. coli (53).
A circaseptan pattern is apparent for cell settling in another unicell, Euglena gracilis Klebs;
in the same unicell, Euglena, cell division also shows a circaseptan pattern (54). A mutation is
associated with a change of this circaseptan pattern into a circasemiseptan one, in keeping with
extremely limited yet further pertinent data (55). The multiseptans are just one set of harmonics of
the sun's (solar latitude-dependent) rotation periods (56; cf. 57) and must be separated from
periodicities associated with the moon. Among others, ~10- and ~5-day periods, described by G.
Hildebrandt may also have been favored by an internal integrative evolution, complementing
Darwinian adaptations.
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The multiseptans may be linked to the circadian component, if, as seems to be the case in a
hamster, a mutation involving a shortening of the circadian is associated with a circaseptan-tocircasemiseptan
change of retinal melatonin production (insofar as curve-fitting to extremely short
time series can allow speculation) (58).
The original documentation of the endogenicity of circaseptans was based originally on the
monographic description of a case of human desynchronization from the societal week for ~3
years (59). It was strengthened by the observation that it related to only one variable -- 17ketosteroid
excretion, the breakdown product of some hormones -- and not to another variable, the
urine volume, 7-day synchronized by a bottle of beer and an extra cup of tea each Sunday (59).
The 17-ketosteroid also free-ran from the planetary geomagnetic index Kp and in records from
hundreds of human newborns, showing a prominence of circaseptans, with amplitudes larger than
those of the circadians in Brno, Moscow and Minneapolis.
There is a need for broader-than-circadian focus and the technology is available to
implement it. Until this is done, however, short time series are valuable, as long as it has been
made clear that inferences from data covering only one or a few putative cycles serve for
hypothesis formulation and need added longitudinal or transverse validation in the same individual
or across similar individuals, respectively. In the case of unicells, further experimental validation
is required, with data inspection by the naked eye complemented with inferential curve-fitting.
With these caveats, the chronobiology of unicells, just like that of arabidopsis, if not peas, and of
mammals all add new dimensions to Mendel's legacy. One of these is the possible linkage of a
built-in week and half-week in our chronomes to circadian and faster rhythms. The other related
chronobiologic dimension is our resonance with events in the cosmos, which almost certainly has
molded our genetic time structure. New components are being uncovered with periods of ~half a
year, as in epileptic attacks (60) or in circulating melatonin of people living at high latitudes (61);
of ~7 years, e.g., in marine invertebrates or in atmospheric pollution, or of ~10.5 and ~21 years, in
neonatal morphology and adult physiology (62-64). These rhythms, found in biology, all have
prominent counterparts in geomagnetic disturbance, responding to magnetic storms and other
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events within and beyond the solar system, that need to be made amenable to concerted
contemporaneous biomedical and purely physical measurement. Cis-half-years, transyears,
decadals and multidecadals continue to be documented in this year's proceedings. Segregation and
independent assortment are now known as laws of inheritance originating in Mendel's pea patch.
In Siegelova's non-invasive cardiology "patch", the congruence of novel solar-terrestrialbiospheric
periods and their independent assortment (selective congruence) await further study by
chronomics.
Mendeliana
Against the foregoing chronobiologic background, we look back to the time some decades
ago in Brno, when the centenary of the publication of Gregor Mendel's research with Pisum was
marked by an international memorial symposium, and again to the time when under the ambitious
title "The past, present and future of genetics" in Kuparovice, then Czechoslovakia, Mendel's role
in the foundation and early development of genetics was reconsidered (65). To the wealth of
memorabilia in these volumes and others, we add chrono-meta-analyses of some of Mendel's data
in meteorology, Table 1.
Mendel measured wind speed in 16 directions in 1862 and summarized his data on a monthly
basis. In 50% of the cases, a circannual component was the most prominent in the least squares
spectrum spanning frequencies of 1 to 5 cycles per year. The circannual component is statistically
significant in four cases (P<0.05) and is of borderline statistical significance in another two cases.
As seen in Table 1, there seems to be a gradual change in the circannual acrophase of maximal
wind speed as a function of the direction from which the wind blew: three clusters can be
recognized, one from south to west-northwest with circannual acrophases occurring around
September; one from northwest to east-northeast with acrophases occurring around May; and one
from east to south-southeast, with acrophases occurring around December-January.
Hardly surprisingly, a circannual rhythm also characterizes environmental temperature
(P<0.001). Mendel's data further allow the demonstration of an ~yearly rhythm in cloudiness
(P<0.001) and rainfall (P=0.004), but not in atmospheric pressure (P=0.411). The largest positive
89
deviation in temperature is found in mid-July (acrophase = -205° from December 22, 1861, the
latter date chosen as zero phase) in keeping with some rather high temperatures experienced
whenever the senior author had the privilege of visiting Brno in mid-summer. The temperature
acrophase corresponds to that of maximal rainfall (acrophase = -203°), whereas maximal
cloudiness occurs in early January (acrophase = -15°). The predictable yearly changes in these
variables can be quite large, those in temperature averaging 17.7° Reaumur.
Whether applied to data from physics or biology, computer methodology isolates and
quantifies predictable features in serial data, that need not be regarded as "too complex". For
chronobiologists, Mendel's finest legacy is his function as a role model for perseverance against
the greatest of odds. In this context, Mendel provides solid advice, found in his handwriting, in a
verse he took from Johann Wolfgang von Goethe, constituting Insert I (66; cf. 67).
One of us (AM) emphasizes Goethe's and Mendel's verse as her motto when describing
Mendel's personality. We also owe her the reference to the painting that symbolizes Mendel's
interests: a setting of a telescope, globe, compass needle, scrolls of maps, thermometer and pocket
sundials. Some of the objects (telescope, thermometer, pocket sundials) were found among
Mendel's relics. These artifacts symbolize Mendel's interest in meteorology. Perhaps, in view of
his telescope, we may read into this legacy an interest by Mendel in a budding chrono-astrobiology
far beyond earthly meteorology.
We owe Ivo Cetl the chronology of Mendel's scientific activities (65). Mendel published his
studies on plant hybridization later than his findings in meteorology. His interest in the weather
continued for much longer than any other of his concerns. Historians may indicate rightly that to
establish a new science one needs no more than a good publication or two. The chronobiologic
perspective we convey here is that Mendel's concerns in plant hybridization are interrelated with
those in meteorology and apiculture. They should lead to more than local or terrestrial weather
forecasting. We have an opportunity to benefit from space weather forecasting (68), perhaps to
reduce traffic accidents, myocardial infarctions or strokes and epilepsy. On the basic side, we may
also find in the cosmoi the origin for some of the now-genetically-anchored, heretofore neglected
90
components in the spectrum of biological rhythms, such as the ~5 and ~16-month and ~7-, ~10-,
~21-, ~35- and ~500-year cycles in nature, inanimate and animate (69-73), including those in
ourselves (10, 49).
If the genetics of structure in time as well as in space have their origin in the resonance of
organisms with the dynamics of the cosmoi, the "theological" week, regarded by too many as all
culture and not nature (74), may have a physico-chemical basis (75). A computation of the
oscillating frequency during the diffusion of ions in a magnetic field such as that of an organism
shows values for a period of ~1 week (75). Accordingly, this presentation takes us from Mendel's
interest in the weather over space weather forecasting to the origin of Mendel's "hard" genetics in
the light of Darwin's "soft" genetics. At its start, life may have been a mere resonance with the
chronomes in cosmoi near and far. Eventually, the environmental frequencies became anchored as
chronomes in RNA and then in DNA-based systems, with some features of integration with our
environs, "recapitulated" perhaps whenever a cell is born, in a cyclic fashion with choices among
several time scales. The biological week and the ~5-month cycles as well as those of ~6 months,
now built into us, still resonate with distant drummers, whether they originated as a response to the
solar wind, to the moon and/or to even more remote stimuli. As we undertake the journey from
rhythms to a budding chrono-astrobiology, we learn about new health effects that are both
mirrored by our genetically anchored chronomes and still influenced by the environment.
Solar monitoring: where Gregor Mendel and Jarmila Siegelova meet
In his letter III to Carl Naegeli (76), dated November 6, 1867, Mendel wrote: "... I am no
longer fit for botanical excursions, since the heavens have blessed me with an overweight which,
in further parties on foot, notably in climbing hills, becomes too readily sensed as a consequence
of general gravity" ("... auch tauge ich nicht mehr recht für botanische Excursionen, da mich der
Himmel mit einem Uebergewichte gesegnet hat, welches sich bei weiteren Fusspartien, namentlich
aber beim Bergsteigen, in Folge der allgemeinen Gravitation, sehr fühlbar macht.") Refraining
from hiking, Mendel late in life made observations on sunspots. Iltis (77) reports the following
notes that are the more noteworthy since the time of the observations, albeit a solar maximum was
91
not remarkable, Figures 5 and 6: "17 [November 17, 1882] vesp. aurora in Geneva and Pola; 18th
,
a.m., disturbance in telephone communications; 17th
, 18th
, aurora in San Francisco extending to
Boston (very imposing!)." Iltis comments: "In [Mendel's] drawings of sunspots we find for the 18th
and 19th
of the same month a large group of spots near the central meridian of the sun's disk" (77).
Thus, about 8 decades before Mariner 2 documented the solar wind, the scholar of heredity and of
earthly weather looked for the link between solar activity and terrestrial affairs, Figures 5 and 6.
Herein lies the challenge of noninvasive cardiology, notably in Brno: to monitor both
personal and societal health, the latter by solar surveillance via BP and HR across generations, to
map the spectral region between BEL cycles of ~35 years and Mikulecky's circasemimillennials.
We may become able to do so with modern instrumentation developed by the Phoenix Study
Group, composed of volunteering members of the Twin Cities chapter of the Institute of Electrical
and Electronics Engineers (http://www.phoenix.tc-ieee.org). An unobtrusive and affordable
software and hardware combination with modern computer technology is an important step toward
universal preventive cardiac health care, so that as long as health prevails, all is being done by
cost-free self-help, as practiced now in BIOCOS, and we contribute concomitantly to what is today
basic science, but tomorrow may lead to countermeasures against ills of society, influenced
unfavorably by solar activity.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
92
1. Halberg F, Cornélissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles
tipping the scale between death and survival (= "life"). Progress of Theoretical Physics 2008;
Suppl. 173: 153-181.
2. Halberg F, Breus TK, Cornélissen G, Bingham C, Hillman DC, Rigatuso J, Delmore P,
Bakken E, International Womb-to-Tomb Chronome Initiative Group: Chronobiology in
space. Keynote, 37th Ann. Mtg. Japan Soc. for Aerospace and Environmental Medicine,
Nagoya, Japan, November 8-9, 1991. University of Minnesota/Medtronic Chronobiology
Seminar Series, #1, December 1991, 21 pp. of text, 70 figures.
3. Halberg F, Visscher MB, Bittner JJ. Eosinophil rhythm in mice: Range of occurrence; effects
of illumination, feeding and adrenalectomy. Amer J Physiol 1953; 174: 109-122.
4. Chibisov SM, Cornélissen G, Halberg F. Magnetic storm effect on the circulation of rabbits.
Biomedicine & Pharmacotherapy 2004; 58 (Suppl 1): S15-S19.
5. Halberg F, Halberg E, Barnum CP, Bittner JJ. Physiologic 24-hour periodicity in human
beings and mice, the lighting regimen and daily routine. In: Withrow RB (Ed.)
Photoperiodism and Related Phenomena in Plants and Animals. Ed. Publ. No. 55.
Washington DC: AAAS; 1959. p. 803-878.
6. Halberg F. The 24-hour scale: A time dimension of adaptive function organization. Perspect
Biol Med 1960; 3, 491-527.
7. Halberg F, Barnum CP, Silber RH, Bittner JJ. 24-hour rhythms at several levels of
integration in mice on different lighting regimens. Proc Soc exp Biol (NY) 1958; 97, 897-
900.
8. Schrödinger E. What is Life? Cambridge: Cambridge University Press; 1945. 91 pp.
9. Halberg F. Chapter on "Medizin" in: Jahrbuch der Internationalen Hochschulwochen des
Österreichen College. Salzburg: Igonta Verlag; 1946. p. 336-351.
10. Halberg F, Cornélissen G, Otsuka K, Siegelova J, Fiser B, Dusek J, Homolka P, Sanchez de
la Pena S, Singh RB, BIOCOS project. Extended consensus on means and need to detect
93
vascular variability disorders (VVDs) and vascular variability syndromes (VVSs). LeibnizOnline
Nr. 5, 2009 (http://www.leibniz-sozietaet.de/journal). 35 pp.
11. Halberg F, Cornélissen G, Conti A, Maestroni G, Maggioni C, Perfetto F, Salti R, Tarquini
R, Katinas GS, Schwartzkopff O. The pineal gland and chronobiologic history: mind and
spirit as feedsidewards in time structures for prehabilitation. In: Bartsch C, Bartsch H, Blask
DE, Cardinali DP, Hrushesky WJM, Mecke W (Eds.) The Pineal Gland and Cancer:
Neuroimmunoendocrine Mechanisms in Malignancy. Heidelberg: Springer; 2001. p. 66-116.
12. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
13. Halberg Franz, Cornélissen G, Katinas G, Syutkina EV, Sothern RB, Zaslavskaya R, Halberg
Francine, Watanabe Y, Schwartzkopff O, Otsuka K, Tarquini R, Perfetto P, Siegelova J.
Transdisciplinary unifying implications of circadian findings in the 1950s. J Circadian
Rhythms 2003; 1: 2. 61 pp. www.JCircadianRhythms.com/content/pdf/1740-3391-2-3.pdf
14. Abbot CG. Solar variation and weather, a summary of the evidence, completely illustrated
and documented. Washington DC: Smithsonian Miscellaneous Collections 146, No. 3 (Publ.
4545); 1963. 67 pp. + 4 plates.
15. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
16. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
17. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
18. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle
in heliogeophysics, psychophysiology, military politics, and economics. Geophysical
Processes and the Biosphere, in press.
19. Gregori GP. Galaxy – Sun – Earth relations: The origin of the magnetic field and of the
endogenous energy of the Earth, with implications for volcanism, geodynamics and climate
control, and related items of concern for stars, planets, satellites, and other planetary objects.
94
A discussion in a prologue and two parts. Beiträge zur Geschichte der Geophysik und
Kosmischen Physik, Band 3, Heft 3, 2002, 471 pp. ISNN: 1615 - 2824 – NE: Gregori,
Giovanni P. © Science Edition, Arbeitskreis Geschichte Geophysik / W. Schröder, Germany
2002.
20. Zeman M, Jozsa R, Cornélissen G, Stebelova K, Bubenik G, Olah A, Poeggeler B, Huether
G, Hardeland R, Nagy G, Csernus V, Pan W, Otsuka K, Halberg F. Chronomics: circadian
lead of extrapineal vs. pineal melatonin rhythms with an infradian hypothalamic exploration.
Biomed & Pharmacother 2005; 59 (Suppl 1): S213-S219.
21. Cornélissen G, Halberg F, Breus T, Syutkina EV, Baevsky R, Weydahl A, Watanabe Y,
Otsuka K, Siegelova J, Fiser B, Bakken EE. Non-photic solar associations of heart rate
variability and myocardial infarction. J Atmos Solar-Terr Phys 2002; 64: 707-720.
22. Syutkina EV, Cornélissen G, Halberg F, Johnson D, Grigoriev AE, Mitish MD, Turti T,
Abramian AS, Yatsyk GV, Syutkin V, Tarquini B, Mainardi G, Breus T, Pimenov K, Wendt
HW. Could the blood pressure of newborns track the solar cycle? Abstract, 4° Convegno
Nazionale, Società Italiana di Cronobiologia, Gubbio (Perugia), Italy, June 1-2, 1996. p. 62-
63.
23. Otsuka K, Cornélissen G, Halberg F. Circadian rhythmic fractal scaling of heart rate
variability in health and coronary artery disease. Clinical Cardiology 1997; 20: 631-638.
24. Burioka N, Cornélissen G, Maegaki Y, Halberg F, Kaplan DT, Miyata M, Fukuoka Y, Endo
M, Suyama H, Tomita Y, Shimizu E. Approximate entropy of the electroencephalogram in
healthy awake subjects and absence epilepsy patients. Clinical EEG and Neuroscience 2005;
36: 188-193.
25. Halberg F, Otsuka K, Katinas G, Sonkowsky R, Regal P, Schwartzkopff O, Jozsa R, Olah A,
Zeman M, Bakken EE, Cornélissen G. A chronomic tree of life: ontogenetic and
phylogenetic 'memories' of primordial cycles - keys to ethics. Biomed & Pharmacother
2004; 58 (Suppl 1): S1-S11.
95
26. Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T,
Schwartzkopff O, Bakken E, Halberg F. Methodology: partial moving spectra of postnatal
heart rate chronome. Neuroendocrinol Lett 2003; 24 (Suppl 1): 139-144.
27. Siegelova J, Cornélissen G, Schwartzkopff O, Halberg F. Time structures in the development
of children. Neuroendocrinol Lett 2003; 24 (Suppl 1): 126-131.
28. Gubin D, Cornélissen G, Halberg F, Gubin G, Uezono K, Kawasaki T. The human blood
pressure chronome: a biological gauge of aging. In vivo 1997; 11: 485-494.
29. Fanjul Moles ML, Cornélissen G, Miranda Anaya M, Prieto Sagredo J, Halberg F. Larger
infradian vs. circadian prominence of locomotor activity in young vs. older crayfish.
Abstract, 6° Convegno Nazionale de Cronobiologia, Chianciano, Italy, November 27-28,
1998. p. 65.
30. Díez-Noguera A, Cambras T, Cornélissen G, Halberg F. A biological week in the activity
chronome of the weanling rat: a chrono-meta-analysis. Abstract, 4° Convegno Nazionale,
Società Italiana di Cronobiologia, Gubbio (Perugia), Italy, June 1-2, 1996. p. 81-82.
31. Thaela M-J, Cornélissen G, Halberg F, Rantzer D, Svendsen J, Pierzynowski SG. Extracircadian
(about-weekly, half-weekly and 8-hourly) variation in pancreatic secretion of
piglets. Proc. XXXIII Int. Cong. International Union of Physiological Sciences, St.
Petersburg, Russia, June 30-July 5, 1997, abstract P041.36.
32. Ahlgren A, Halberg F. Cycles of Nature: An Introduction to Biological Rhythms.
Washington, DC: National Science Teachers Association; 1990. 87 pp. (Library of Congress
Catalog Card #89-063723; ISBN #0-87355-089-7. National Science Teachers Association,
1742 Connecticut Ave. N.W., Washington, DC 20009, www.nsta.org.)
33. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group:
Resolution from a meeting of the International Society for Research on Civilization Diseases
and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995:
Fairy tale or reality? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18
figures. http://www.msi.umn.edu/~halberg/
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34. Halberg F, Haus E, Cardoso SS, Scheving LE, Kühl JFW, Shiotsuka R, Rosene G, Pauly JE,
Runge W, Spalding JF, Lee JK, Good RA. Toward a chronotherapy of neoplasia: Tolerance
of treatment depends upon host rhythms. Experientia (Basel) 1973; 29: 909-934.
35. Günther R, Herold M, Halberg E, Halberg F. Circadian placebo and ACTH effects on urinary
cortisol in arthritics. Peptides 1980; 1: 387-390.
36. Halberg E, Halberg F. Chronobiologic study design in everyday life, clinic and laboratory.
Chronobiologia 1980; 7: 95-120.
37. Edmunds LN, Halberg F. Circadian time structure of Euglena: a model system amenable to
quantification. In: Kaiser H (Ed.) Neoplasms—Comparative Pathology of Growth in
Animals, Plants and Man. Baltimore: Williams and Wilkins; 1981. p. 105-134.
38. Sothern RB, Cornélissen G, Yamamoto T, Takumi T, Halberg F. Time microscopy of
circadian expression of cardiac clock gene mRNA transcription: chronodiagnostic and
chrono-therapeutic implications. La Clinica Terapeutica 2009; 160 (2): e25-e34.
39. Kyriacou CP, Hall JC. Circadian rhythm mutations in Drosophila melanogaster affect a
short-term fluctuation in the male's courtship song. Proc Nat Acad Sci USA 1980; 77: 6929-
6933.
40. Jeon M, Gardner HF, Miller EA, Deshler J, Rougvie AE. Similarity of the C. elegans
developmental timing protein LIN-42 to circadian rhythm proteins. Science 1999; 286: 1141-
1146.
41. Tarquini B, Perfetto F, Tarquini R, Cornélissen G, Halberg F. Endothelin-1's chronome
indicates diabetic and vascular disease chronorisk. Peptides 1997; 18: 119-132.
42. Tarquini B, Cornélissen G, Perfetto F, Tarquini R, Halberg F. About-half-weekly
(circasemiseptan) component of the endothelin-1 (ET-1) chronome and vascular disease risk.
Peptides 1997; 18: 1237-1241.
43. Herold M, Cornélissen G, Loeckinger A, Koeberle D, Koenig P, Halberg F. About 8-hourly
variation of circulating human endothelin-1 (ET-1) in clinical health. Peptides 1998; 19: 821-
825.
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44. Loeckinger A, Herold M, Cornélissen G, Halberg F, Fiser B. Circaoctohoran (about 8hourly)
chronome component of circulating human endothelin-1 in health. Scripta medica
(Brno) 1998; 71: 199-208.
45. Katinas GS, Halberg F, Cornélissen G, Hawkins D, Bueva MV, Korzhevsky DE,
Sapozhnikova LR, Rhodus N, Schaffer E. About 8- and ~84-hour rhythms in endotheliocytes
as in endothelin-1 and effect of trauma. Peptides 2001; 22: 647-659.
46. Löckinger A, Köberle D, St. König P, Saria A, Herold M, Cornélissen G, Halberg F.
Neuropeptide chronomics in clinically healthy young adults: circaoctohoran and circadian
patterns. Peptides 2004; 25: 533-542.
47. Hughes ME, DiTacchio L, Hayes KR, Vollmers C, Pulivarthy S, Baggs JE, Panda S,
Hogenesch JB. Harmonics of circadian gene transcription in mammals. PLoS Genet 2009;
5(4): e1000442. doi:10.1371/journal.pgen.1000442
48. Rieger E, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day periodicity in
the occurrence of hard solar flares? Nature 1984; 312: 623-625.
49. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-
38. http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
50. Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. About 5-month
cycle in human circulating melatonin: signature of weather in extraterrestrial space? Poster
presentation, Fourth UN/ESA/NASA/JAXA Workshop on the International Heliophysical
Year 2007 and Basic Space Science: "First Results from the International Heliophysical Year
2007", Sozopol, Bulgaria, June 2-6, 2008.
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51. Schweiger H-G, Berger S, Kretschmer H, Mörler H, Halberg E, Sothern RB, Halberg F.
Evidence for a circaseptan and a circasemiseptan growth response to light/dark cycle shifts in
nucleated and enucleated Acetabularia cells, respectively. Proc Natl Acad Sci USA 1986;
83: 8619-8623.
52. Radha E, Halberg F. Rhythms of isolated platelet glutathione, aging and the internal
evolution of species. Progress in Clinical and Biological Research 1987; 227A: 173-180.
53. Halberg F, Conner RL. Circadian organization and microbiology: Variance spectra and a
periodogram on behavior of Escherichia coli growing in fluid culture. Proc minn Acad Sci
1961; 29, 227-239.
54. Edmunds L, Balzer I, Cornélissen G, Halberg F. Toward a chronome of Euglena gracilis
(Klebs). Neuroendocrinol Lett 2003; 24 (Suppl 1): 192-199.
55. Woolum JC, Cornélissen G, Hayes DK, Halberg F. Spectral aspects of Acetabularia's light
transmission chronome: effects of enucleation. Neuroendocrinol Lett 2003; 24 (Suppl 1):
212-215.
56. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
57. Halberg F, Cornélissen G, Berk M, Dodd S, Henry M, Wetterberg L, Nolley E, Beaty L,
Siegelova J, Fiser B, Wolff C, BIOCOS project. Solar signatures in Australian suicide
incidence: gender differences in prominence of photic vs. nonphotic spectral components. In:
Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in
Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 44-62.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
58. Halberg F, Cornélissen G, Otsuka K, Gubin D, Zaslavskaya R, Johnson D. Basic and applied
chronobiologic frontiers in 1996. Lettura magistrale, 4° Convegno Nazionale, Società
Italiana di Cronobiologia, Gubbio (Perugia), Italy, June 1-2, 1996, p. 12-18.
59. Halberg F, Engeli M, Hamburger C, Hillman D. Spectral resolution of low-frequency, smallamplitude
rhythms in excreted 17-ketosteroid; probable androgen induced circaseptan
desychronization. Acta endocrinol (Kbh) 1965; 50 (Suppl 103): 5-54.
99
60. Halberg F, Cornélissen G, Sonkowsky RP, Lanzoni C, Galvagno A, Montalbini M,
Schwartzkopff O. Chrononursing (chronutrics), psychiatry and language. New Trends in
Experimental and Clinical Psychiatry 1998; 14: 15-26.
61. Tarquini B, Cornélissen G, Perfetto F, Tarquini R, Halberg F. Chronome assessment of
circulating melatonin in humans. In vivo 1997; 11: 473-484.
62. Halberg F, Cornélissen G, Otsuka K, Watanabe Y, Katinas GS, Burioka N, Delyukov A,
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3. Leipzig: B.G. Teubner Publ.; 1905. p. 189-265. "... auch tauge", III, 6 Nov. 1867, p. 211.
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Legends
Figure 1. Measurable time structure (chronome) of a variable. More and more components in
the spectrum of physiological variation are found to have numerical physical environmental
counterparts and, vice versa, environmental counterparts have been found for some unusual
physiological cycles, believed to be purely societal, such as the week, and for new cycles shorter
than 6 months and longer than 12 months, signatures of the solar wind. Physical or biological
spectra, organizing irregular chaotic and complex variations and trends in endpoints of rhythms,
chaos, and complexity constitute time structures, or chronomes. The mapping of physical and
biological chronomes proceeds as yet opportunistically in a project on The BIOsphere and the
COSmos (BIOCOS). A data base of reference values thus accumulates with a target length of at
least 7 days beat-to-beat for the electrocardiogram and again for at least 7 days at intervals from
15-60 minutes, in the case of human blood pressure. Such mapping is critical for a quantification
of health in the range of otherwise neglected physiological variation. Chronome maps are the
invaluable and indispensable reference values for the detection of disease risk syndromes.
"Measure what is measurable and render meaningfully measurable in time what as yet is not" is
what chronomes are all about. © Halberg.
Figure 2. Sketch of factors and pathways known to participate in frequency synchronization
among circadian rhythms themselves, as well as in synchronization between rhythm(s) and
environmental synchronizer(s). Note intracellular mechanisms documented by 1960 (5-7). ©
Halberg.
Figure 3. Left: Chronomodulation at different levels: in the left half, interplanetary solar and
galactic factors (top right) are conceived as modulating socioecological conditions in the habitat
(top left), acting upon the healthy or sick organism as a whole. Right: Results on lack of effect,
attenuation, or amplification by aqueous pineal homogenate of corticosterone production by
bisected adrenals are summarized on top. Those in the second diagram from the top refer to the
effect of the bilateral ablation of the suprachiasmatic nuclei (SCN) on circadian amplitude and
acrophase. Loss of circadian rhythm (documented by a zero amplitude) is the result of SCN
102
removal in the case of locomotor activity and water drinking but not in a vast majority of other
rhythms sampled at 4-hour or shorter intervals for 24 hours or longer spans and analyzed by
inferential statistical means. The third diagram from the top refers to chronomodulation by
feedsidewards observed for the effect of ACTH 1-17 upon metaphysical DNA labeling in the rat.
Intermodulations in the case of an invading microorganism of sufficient virulence to elicit a host
response are sketched at the bottom. Feedsideward: Multiple interactions among several rhythmic
entities resulting in a predictable rhythmic sequence of attenuation, no effect, and amplification,
implemented by a modulator acting on the interaction between the actor and reactor. As shown in
the diagrams, the role played by the modulator, the actor, and the reactor can vary among the
interacting entities, and these systems can be exposed to different influences and an integrator.
actor ↔ reactor;
modulator ↔ actor;
modulator ↔ reactor;
feedsideward;
integrator;
influencers.
© Halberg.
Figure 4. The chronomes in us, that came about as a function of chronomes around us, to be
eventually coded genetically, await further exploration in health care, notably for stroke
prevention. © Halberg.
Figure 5. On November 17, 1882, Mendel made the connection between sunspots and the
aurora during a solar maximum that was not unusual whether it is viewed in the context of
centuries (top), that of years (second row), of months (third row) or of days (bottom row). ©
Halberg.
Figure 6. Mendel's drawings of sunspots show almost-daily changes in their appearance;
sometimes the sun's disk is free of spots. These observations led him to postulate a connection
between sunspots and the aurora. From (60).
103
Insert I: Mendel's citation (from Goethe's "Lila" [66]) is pertinent to the switch (from the
fictions of homeostasis, secularity, baselines and other current dogmas) to chronobiology
Feiger Gedanken,
Bängliches Schwanken,
Weibisches Zagen,
Ängstliches Klagen,
Wendet kein Elend,
Mach dich nicht frei.
Allen Gewalten
Zum Trutz sich erhalten,
Nimmer sich beugen,
Kräftig sich zeigen ...
(Cowardly thoughts,
anxious vacillation,
spineless* hesitation,
anguished complaint,
does not alleviate misery,
does not set you free.
Opposing all force
while maintaining one's course,
never to bend,
to show oneself strong ...)
*Goethe's "weibisches" literally translates as "woman-like", connoting "effeminate". We here
change this reference into a gender-neutral one on the assumption that hesitation is not specific to
a supposedly "weaker sex", as documented by women warriors (67).
104
Figure 1
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Figure 3
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Figure 4
108
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Figure 5
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Figure 6
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Wednesday, July 1, 2009 8:00:22
Table 1: BOLD WHEN STATISTICALLY SIGNIFICANT CIRCANNUAL VARIATION OF
WIND SPEED IN GREGOR MENDEL's HANDWRITTEN RECORDS (1862)*
Results from single cosinor
Direction PR P MESOR±SE Double Amplitude Acrophase±SE
Cluster 1
s 2 0.899 8.5±0.7 0.90±1.92 -292±124
ssw 46 0.063 1.7±0.2 1.62±0.58 -299±21
sw 12 0.550 1.5±0.2 0.64±0.58 -248±51
wsw 25 0.270 1.3±0.2 0.88±0.50 -252±33
w 10 0.004 6.9±0.3 3.28±0.70 -295±12
wnw 52 0.038 5.2±0.2 2.16±0.70 -257±18
Cluster 2
nw 36 0.137 15.4±0.9 5.42±2.42 -174±26
nnw 45 0.067 8.0±0.5 4.18±1.54 -142±21
n 30 0.206 12.5±0.7 3.80±1.96 -167±29
nne 34 0.156 2.3±0.2 1.36±0.64 -148±27
ne 7 0.735 2.5±0.4 0.82±1.02 -170±72
ene 18 0.408 2.1±0.1 0.34±0.24 -113±41
Cluster 3
e 10 0.627 6.3±0.4 1.22±1.24 -36±58
ese 20 0.367 2.4±0.2 0.96±0.64 -28±38
se 65 0.009 8.3±0.5 5.62±1.38 -17±14
sse 71 0.004 6.3±0.4 4.80±1.02 -348±12
Results from population-mean cosinor
Cluster PR P MESOR±SE Amplitude (% MESOR)
(95% CI)
Acrophase
(95% CI)
1 34.5 0.030 4.2±1.5 23.55 (9.72, 37.39) -275˚ (-232, -302)
2 28.3 0.023 7.1±3.0 18.12 (9.12, 27.12) -154˚ (-137, -175)
3 41.5 0.116 5.8±1.9 24.04 ( ) -10˚ ( )
*s: south; w: west; n:north; e: east. PR=percent rhythm; P=P-value from test of zero-amplitude
(no-rhythm) hypothesis; SE=standard error; 95% CI=95% confidence interval. Units in original
handwritten record not readily legible. When all amplitudes are set equal to 1 to summarize
acrophases only, a circannual component is statistically significant in all 3 clusters (P≤0.001).
Biological significance of record is historical, showing the environmental concern of the founder
of genetics.
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D. METHODS
SELECTIVELY ENVIRONMENTALLY CONGRUENT BIOTIC CIS-HALF-YEAR
UNMASKED WITH NEIGHBORING SPECTRAL COMPONENTS
Germaine Cornélissen1
, Franz Halberg1
, Robert B. Sothern1
,
Dewayne C Hillman1
, Jarmila Siegelova2
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Masaryk University, Brno, Czech Republic
This paper is dedicated to the memory of Jean De Prins,
a great teacher, an inspiring mentor, and above all, a dear friend
Support: U.S. National Institutes of Health (GM-13981) (FH),
University of Minnesota Supercomputing Institute (GC, FH)
112
Abstract
Three spectral components with periods of about (~) 0.41, ~0.5 and ~1.0 year had been found
with serially independent sampling in human circulating melatonin. The time series consisted of
around-the-clock samples collected for 24 hours at 4-hour intervals from different patients over
several years. Some of these components had been found to be circadian stage-dependent, the
daytime measurements following mostly a circannual variation, whereas a half-year characterized
the nighttime samples. The latter were incorporated into a circasemiannual map. The relative brevity
of the series prevented a check for the coexistence of all three spectral components, even if each
component seemed to have a raison d'être. In time series of transdisciplinary data, a 1.00-year
synchronized component is interpreted as representing the seasons. The half-year may qualify the
circannual waveform, but it is also a signature of geomagnetics. An ~0.41-year (~5-month)
component is the signature of solar flares. It has been called a cis-half-year (cis = on this side of a
half-year) and may be detected only intermittently. Charles L. Wolff predicted the existence, among
others, of ~0.42- and ~0.56-year components as beat periods of rotations at different solar latitudes.
The multiple components characterizing circulating melatonin could also be found in a (to our
knowledge unique) data set of a clinically healthy scientist (RBS). Herein, we focus on vascular
data self-measured by RBS as he aged from ~20 to ~60 years. A multi-component model consisting
of cosine curves with periods of 0.41, 0.50 and 1.00 year was fitted to weekly means of systolic (S)
and diastolic (D) blood pressure (BP) and heart rate (HR) collected ~5 times a day over 39 years by
RBS. All three components can coexist for a while, although all of them are Aeolian, in the sense
that they are nonstationary in their characteristics and come and go by the criterion of statistical
significance. Intermittently, BP and HR are synchronized selectively with one or the other aspect of
RBS’ physical environment, namely the seasons (at ~1.0 year), earth magnetism (at ~0.5 year)
and/or solar flares (at ~0.42 year). Cosmic-biotic transfer of information, albeit hardly of energy
(the biospheric amplitudes are very small) may be mediated in this set of frequency windows. As
found earlier, RBS’ circulation is also frequency-trapped environmentally in multidecadal windows,
HR being locked into the transtridecadal Brückner, or rather Brückner-Egeson-Lockyer, BEL cycle,
while his BP follows Hale's didecadal cycle in the changing polarity of sunspots.
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The ~0.41-year HR cycle may be associated with changes in solar flares, the cis-half-year
amplitude of HR showing a cross-correlation coefficient of 0.79 with the total solar flare index
(from both solar hemispheres) at a lag of ~3.2 years. The superposed time courses of these two
variables indicate the presence of a shared Horrebow-Arago-Schwabe sunspot cycle of ~11 years,
the cis-half-year in HR being more prominent after the total solar flare index reaches its ~11-year
peak. Differences in the time-varying behavior of BP vs. HR are also described.
An analogy between external scrubbing and self-surveillance of internal rhythms
Paul J. Rosch reminds us that:
Alexander Gordon, a [Scottish] physician, suggested in 1795, that [puerperal] fevers were
contagious processes, that physicians were the carrier, and that "I myself was the means of carrying
the infection to a great number of women." Thomas Watson, Professor of Medicine at King's
College Hospital, London, wrote in 1842 [one year before Oliver Wendell Holmes published 'The
Contagiousness of Puerperal Fever']: "Wherever puerperal fever is rife, or when a practitioner has
attended any one instance of it, he should use most diligent ablution." (1)
Nonetheless, with all the evidence backing such claims, Ignaz Semmelweis ended up in a mental
institution, where he died in 1865 probably from septicemia. Sutcliffe and Duin (2) cite Oliver Wendell
Holmes as indicating that (Pasteur's) "little army of microbes [had not yet been] moved up" to support
Semmelweis' and eventually Lister's position for indispensable antisepsis.
With respect to preventive measures for maintaining cardiac and mental health and preventing morbid
events such as strokes and criminality in individuals and terrorism in society, we are in the same situation
today as Semmelweis was with respect to antisepsis. In our case, a broad spectrum of rhythms in us and
around us, albeit already mapped, has not yet been recognized in terms of pertinence to everyday life. Like
circadians (3-5), now a fashion in molecular biology, the many different more or less periodic extracircadians
(6) evolved and were adaptively built into human physiology under the influence of the non-photic
cycles of our cosmos. Infradians are apparent in military-political affairs, including aggression, notably
crime, international battles and terrorism, in economics, in opinion polls, in education and, most important, in
health and disease, including infection (7-10). Like circadians, infradians also tip the scale between life and
death.
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Double purpose of physiological surveillance: self-help in healthcare and photic-nonphotic
environmental monitoring
Chronobiologically-interpreted BP and HR monitoring detects pre-hypertension, pre-diabetes
and a pre-metabolic syndrome in Vascular Variability Disorders (VVDs), as conditions of increased
vascular disease risk (11-14) and as complications of a (reliably-diagnosed) MESOR-hypertension,
a VVD in its own right. Another VVD is an excessive circadian amplitude of BP (CHAT, short for
Circadian Hyper-Amplitude-Tension). This condition carries a risk of cerebral ischemic event
greater than a high BP. It can coexist with other VVDs to form Vascular Variability Syndromes
(VVSs). VVDs are not being screened for in our current conventional health care system. Once
diagnosed, some VVDs can be treated.
It is not yet generally known that in the human newborn, variables such as BP and HR have
infradians such as an about-weekly component, which is usually more prominent than the 24-hour
variation, awaiting testing as a gauge of risk. It is also not generally known that the incidence
patterns of sudden cardiac death (ICD10, code I46.1) is characterized by ~5-month (cis-half-year)
and ~17-month (far-trans-year) components, cyclic signatures of space weather, in the absence of
yearly changes, notwithstanding the large difference between Minnesota's mid-continental winters
and summers. A host of spectral components is shared between natural physical environmental
variables, such as the solar wind and other aspects of space weather, and biological variables, such
as those of the human circulation, electrical accidents of the heart (15) and suicides (16). They are
said to be congruent when the 95% confidence intervals (CIs) of their (shared) periods are overlying
or overlapping.
When cardiovascular and mental health and their relation to the cosmos are viewed in 40 years
of self-measurements by RBS, there is selective congruence of the ~5-month component between
RBS’ HR and the total solar flare index (SFI). An ~0.41-year cis-half-year component in HR is
modulated by solar flares, and both solar flares and the cis-half-year amplitudes of RBS’ HR show
the Horrebow-Arago-Schwabe pattern of sunspot numbers (Figure 1, left). Their cross-correlation
function (Figure 1, section D) reaches a maximum of r=0.79 at a 3.16-year lag, raising the question
whether the effect of solar flares is direct or indirect, perhaps mediated by terrestrial magnetism.
115
Congruence of an ~33-year cycle between RBS’ HR and Wolf's sunspot numbers (Figure 2) was
reported earlier (17), as were other congruences of RBS’ HR and BP with space weather (Figure 3).
Horrebow-Arago-Schwabe modulation of cis-half-year in and around us
Both solar flares (Figure 1, left, top and bottom) and Wolf sunspot numbers (Figure 1, left,
middle) are characterized by a prominent ~11-year cycle. The prominence of the cis-half-year in
RBS’ HR, gauged by the 0.41-year amplitude estimated over a 4-year interval displaced in 2.5month
increments, also follows a similar ~11-year cycle (Figure 1, left, bottom). It is detected with
statistical significance (filled rectangles) only part of the time, usually following a peak in solar
flares and sunspot numbers. The cross-correlation function between the cis-half-year amplitude of
HR versus the total solar flare index reaches a maximum of 0.79 at a 3.16-year lag (Figure 1, right,
top). Whether the effect is direct or indirect should be examined further, beyond the congruence of
periods and phases, as they change with time, against the background of already demonstrated prior
global congruences at a trial period of ~33 years, Figures 2 and 3. Congruences can be selective, as
noted in Figure 3: RBS’ HR displays a transtridecadal congruence with Wolf numbers, while RBS’
BP responds to Hale's sunspot bipolarity cycle.
Can biospheric behavior teach physical lessons?
The original task was to examine the degree of ubiquity and, in this sense, the consistency in
different variables, if any, of an ~0.42-year cis-half-year component. It had been found to
characterize sudden cardiac death (ICD10, code I46.1) in Minnesota and in a number of other
geographic locations (15; cf. 18-20), Figure 4. It was also detected in the SBP of an elderly subject
(FH) during nearly 16 years of monitoring, at 70-86 years of age (15), Figure 5, and in a 10-year
DBP record (analyzed by gliding spectrum) of another elderly man (GSK) (21). The 39-year BP and
HR record of RBS, at 20-59 years of age, lent itself well to the examination of the cis-half-year as it
may change as a function of time.
Looking for intermittently coexisting cycles
Linear least-squares spectra of weekly means of SBP, DBP and HR of RBS showed only a
small peak at a period of ~0.42 year that was not statistically significant, contrasting with its
detection in the BP of two elderly men (FH and GSK). The task was to determine whether the cis-
116
half-year was definitively absent in RBS during his 39 years of self-measurements or whether its
detection was obscured by the presence of other larger neighboring spectral peaks and/or by its nonstationary
Aeolian nature. Prominent yearly and half-yearly variations indeed characterized the BP
and HR of RBS. The half-year may be an expression of the non-sinusoidality of the circannual
component, but it may also represent the expression of a geomagnetic signature of its own right. The
~0.42-year cis-half-year was anticipated from its detection in two other long-term series, being
congruent with solar flares, where this component was documented by Rieger et al. (22) and others,
Table 1. An ~0.56-year component in solar activity, also of interest as another beat period of the
solar rotation according to Charles L. Wolff (23, cf. 16), remains beyond the scope of this analysis.
In order to answer the above question, multiple-component serial sections were carried out,
including with the 0.42-year cis-half-year the other two major neighboring components with periods
of 0.5 and 1.0 year. Specifically, a 3-component model was fitted by cosinor, consisting of cosine
curves with periods of 1.0, 0.5, and 0.41 year (or 8766, 4383, and 3615 hours), to data in a 209week
(~4-year) interval displaced throughout the time series by increments of 11 weeks (~0.21 year
or a half cis-half-year cycle).
Like many other non-photic components, the cis-half-year in the BP and HR of RBS was
found to be present only intermittently and with characteristics that varied as a function of time.
Specifically, based on this moving 3-component model, the following results were obtained. For
SBP, the 1.0-year component reached statistical significance (P<0.05) in 157 of 167 (partly
overlapping) intervals (94.0%). The 0.5-year and 0.41-year components were statistically significant
in 110 (65.9%) and 39 (23.4%) intervals, respectively. In the case of DBP, the 1.0-year, 0.5-year,
and 0.41-year components reached statistical significance in 152 (91.0%), 61 (36.5%), and 38
(22.8%) intervals, respectively, and in the case of HR, statistical significance was reached in 112
(67.1%), 61 (36.5%), and 37 (22.2%) intervals, respectively. Whereas in RBS (but not in FH and
GSK), the yearly component and its second harmonic are undoubtedly the most consistent and the
most prominent, the cis-halfyear is also detected with statistical significance at a rate higher than
would be expected by chance alone and according to a non-random pattern in time that prompts the
search for a similar clustering in environmental variables (Figure 1, left, bottom). All three
components could be detected concomitantly in 33 (19.8%), 18 (10.8%), and 10 (6.0%) intervals for
SBP, DBP, and HR, respectively.
117
Results are illustrated in Figures 6-8, where statistical significance (P<0.05) is represented as
dark-filled symbols, borderline statistical significance (0.05<P<0.10) as lightly-filled symbols, and
non-significance (P>0.10) as open symbols. It can readily be seen that instances when the cis-halfyear
reaches statistical significance do not occur at random but mostly as clusters in time. Large
changes in the amplitude of all three components are also observed for all three variables.
The occasional (intermittent) presence of all three components coexisting concomitantly in the BP and
HR data of RBS was of interest in relation to another study in Florence, Italy, on circulating melatonin,
offering a fresh interpretation to results obtained earlier. In the course of ~4 years, blood samples had been
obtained at 4-hour intervals for 24 hours from each of 172 subjects for the determination of melatonin (24).
Original analyses of the serially-independent data pooled from all subjects stacked over an idealized year had
reported the presence of a circannual variation characterizing daytime samples, contrasting with the detection
of a half-yearly component in nighttime samples (24). A recent reanalysis of these data without stacking
revealed the presence of a cis-half-year instead of the originally reported half-year, Figure 9 (25).
Phase behavior of the year, half-year, and cis-half-year components in BP and HR
Figures 10-12 illustrate the time course of the acrophases of the three components with periods
of 1.0, 0.5, and 0.41 year, fitted concomitantly in ~4-year intervals displaced in ~0.21-year
increments. The acrophases are shown only when the zero-amplitude test could be rejected at
P<0.10. The yearly component is detected most of the time for SBP and DBP, but less often for HR.
There are large changes in the circannual acrophases as a function of time, with a range larger than
4 and 5.5 months for SBP and DBP, respectively, and exceeding 7.5 months for HR, indicating that
this component is much less stable than could be anticipated from the strong seasonal changes in the
environmental temperature of Minnesota. The 1.0-year component may be modulated by lowerfrequency
components. The 0.5-year and 0.41-year components are only sporadically detected and
their time course shows an intermittency contrasting with the relative consistency of the yearly
component.
Global analyses assess additional components characterizing BP and HR
Apart from the cis-half-year, other non-photic components characterize RBS's data. One of
these components has an anticipated period of ~0.55 year, too close to 0.5 and 0.41 year to be
118
reliably resolved in ~4-year intervals. Additional global analyses were hence performed on the
entire 39-year series (1968-2006). Because some low-frequency components account for a much
larger portion of the overall variance, analyses were processed in two steps. In the first step,
components with periods longer than ~4 years were assessed nonlinearly together with a fixed
yearly component and its second harmonic of 6 months. The model was then subtracted from the
weekly means. In the second step, residuals were nonlinearly analyzed (allowing the period to vary
as a parameter to be estimated) to try to resolve the remaining components of interest and to
determine their (period) length. A composite model using the nonlinearly estimated periods was
then fitted linearly to determine the extent of their statistical significance.
Low-frequency components considered had trial periods of 25, 11.1, 6.5, and 4 years. They
were fitted concomitantly with fixed 1.0- and 0.5-year harmonically-related components. Nonlinear
results indicated that all components could be resolved for SBP, the periods and their CIs being
estimated as 22.56 [21.20, 23.92], 11.44 [10.92, 11.96], 6.66 [6.44, 6.88], and 4.03 [3.91, 4.15]
years. In the case of DBP, all infra-annual components were also validated nonlinearly
conservatively, whereas the half-year could only be assessed on the basis of a (more "liberal") 1parameter
CI of the amplitude that did not overlap zero. The period estimates for DBP were 20.55
[19.00, 22.10], 10.75 [10.14, 11.37], 6.70 [6.38, 7.03], and 3.96 [3.82, 4.10] years. In the case of HR
as well, only the half-year had only a 1-parameter CI of the amplitude that did not overlap zero. The
period estimates for HR were 32.68, 13.59 [13.03, 14.15], 5.82 [5.71, 5.93], and 3.99 [3.91, 4.08]
years. The selective multidecadal congruence is visualized in Figure 3.
Residuals from the above models indicated the presence of components with trial periods of
1.65, 1.38, 1.25, 0.55, and 0.41 year(s), corresponding to spectral peaklets in the global spectra of
the weekly means. Nonlinearly, the three trans-yearly components were validated for SBP. Albeit
the conservative approach yielded CIs of the amplitude that overlapped zero, the 1-parameter CI of
the ~0.55-year and 0.41-year amplitudes did not overlap zero. With this qualification, period
estimates and their CIs were 1.682 [1.646, 1.718], 1.400 [1.371, 1.428], 1.245 [1.226, 1.263], 0.548
[0.542, 0.555], and 0.413 [0.408, 0.417] year(s). In the case of DBP, the ~1.25-year component
could not be validated and the other four components all had (if not conservative) 1-parameter CIs
119
of the amplitude that did not overlap zero. With this qualification, the period estimates and their CIs
were 1.695 [1.653, 1.738], 1.393 [1.339, 1.448], 1.235 [1.159, 1.310], 0.548 [0.537, 0.559], and
0.412 [0.407, 0.418] year(s). In the case of HR, a slightly different trial period had to be used for the
first transyear: instead of a trial period of 1.65 years, one of 1.86 years was used. This component
and the ~1.38-year component were both validated conservatively. The other three all had a 1parameter
(but not a conservative) CI of the amplitude that did not overlap zero. With this
qualification, period estimates and their CIs were 1.806 [1.760, 1.851], 1.394 [1.371, 1.417], 1.247
[1.223, 1.271], 0.550 [0.541, 0.559], and 0.411 [0.408, 0.415] year(s).
A 5-component model using the periods estimated nonlinearly was then fitted, the periods
differing slightly for each variable. This model and each of its constituent components was
statistically significant for SBP and for HR, but in the case of DBP, only the ~1.69-year and ~1.39year
components reached statistical significance, whereas the 0.41-year component only reached
borderline statistical significance (P=0.054). The other two components with periods of ~1.24 and
~0.55 year(s) were not statistically significant and had to be removed from the model.
Infra-annual modulations of the 1.0-year, 0.5-year, and 0.41-year amplitudes of BP and HR
In order to explore possible environmental influences underlying the changes in amplitude of
the 1.0-year, 0.5-year, and 0.41-year components of SBP, DBP, and HR, the amplitude estimates
from the 3-component serial sections were further analyzed by least squares spectra, with the
understanding that P-values obtained in the following analyses cannot be taken at their face value
since the serial sections were pergressive with an increment 1/19 the length of the interval. With this
qualification, Figure 13 summarizes the results, rough estimates of the periods corresponding to
spectral peaks marked in each case. Apart from some low-frequency components that may
contribute sidelobes in global spectra of the weekly means, the following two observations may
deserve further investigation. First, perhaps because of the relatively large changes in amplitude and
acrophase of the yearly component as a function of time, the 1.0-year amplitudes are characterized
by an ~1.1-year component for SBP and DBP and by an ~1.2-year component for HR. Second, the
cis-half-year amplitudes of HR are characterized by a prominent ~11-year component.
120
Figure 14 (see also Figure 1) illustrates the ~11-year modulation of the cis-half-year amplitude
of HR. Figure 15 shows that the cis-half-year amplitudes of DBP similarly lag after solar flares.
RBS’ HR and DBP as well as the total solar flare index are in synchrony with a decadal HorrebowSchwabe
cycle. As shown in Figure 2 (and discussed elsewhere), HR and Wolf numbers are also
modulated by the transtridecadal Brückner-Egeson-Lockyer (BEL) cycle (17, 26, 27).
Methodologically and basically revealing is that the search for another biotic cis-half-year has
not only validated the latter in the longest available series of BP and HR, but has found neartransyears
in SBP and DBP, whose presence had also been documented in physics (prompted by
their presence in the elderly's BP). Whether the near-transyear is a nonlinear modulation by a lower
frequency in physics, e.g., in solar magnetism or a component in its own right, it has a biological
counterpart. Further, as to reciprocal periods of the beats of the rotations at different solar latitudes,
Charles Wolff's predicted periods have been found not only as a cis-half-year but also as a transhalf-year
of 0.55 year. At one end of the CI, its period is within one decimal of Wolff's 0.56-year
prediction (23). Moreover, both these periods have been validated along with a very likely
geomagnetic component of 0.50 year.
Conclusion
Multiple spectral component signatures of time-varying solar activity are likely to characterize
any time series covering years. When an anticipated component is not detected by the fit of a single
component, a concomitant fit of several components is indicated. Apart from this methodologic
truism that bears emphasis as the control information for any and all studies, we here demonstrate
the intermittency of cis-half-years in the adult human circulation and their temporal association with
an about 11-year cycle in solar flares, with a lag somewhat longer than 3 years.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
121
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125
Figure 1. Horrebow-Arago-Schwabe pattern of solar flares (top and bottom, left) and of Wolf
numbers (middle, left) is shared with changes in cis-half-year amplitude of RBS’ HR (bottom, left).
The cross-correlation function of the latter with the total solar flare index reaches a maximum of
0.79 at a 3.16-year lag (top, right). © Halberg.
126
Figure 2. Congruences were reported earlier (17) at a period of ~33 years between RBS’ HR and
Wolf's sunspot numbers. Whereas this component is rather weak in the physical variable, it is much
more prominent in HR, as apparent from the least squares spectra. © Halberg.
127
Figure 3. Summary of relative congruences between RBS’ HR and BP and non-photic
environmental variables, including the one shown in Figure 2 (top left). Note a didecadal
congruence between RBS’ BP and Hale’s bipolarity cycle of sunspots. © Halberg.
128
Figure 4. A cis-half-year (cY/2) had been found in the incidence patterns of sudden cardiac death in
Minnesota (15) and in some other geographic locations, as summarized in this map. © Halberg.
129
Figure 5. A cis-half-year had been found in the SBP of an elderly subject (FH) during nearly 16
years of around-the-clock monitoring (with interruptions), at 70-86 years of age (15). © Halberg.
130
Figure 6. Statistical significance (P<0.05) of 1.0-year (top), 0.5-year (middle), and 0.41-year (cishalf-year,
bottom) components fitted concomitantly to the SBP data of RBS is represented as darkfilled
symbols, borderline statistical significance (0.05<P<0.10) as lightly-filled symbols, and nonsignificance
(P>0.10) as open symbols. It can readily be seen that instances when the cis-half-year
reaches statistical significance do not occur at random but mostly as clusters in time. Large changes
in the amplitude of all three components are also observed for all three variables. © Halberg.
131
Figure 7. Statistical significance (P<0.05) of 1.0-year (top), 0.5-year (middle), and 0.41-year (cishalf-year,
bottom) components fitted concomitantly to the DBP data of RBS is represented as darkfilled
symbols, borderline statistical significance (0.05<P<0.10) as lightly-filled symbols, and nonsignificance
(P>0.10) as open symbols. It can readily be seen that instances when the cis-half-year
reaches statistical significance do not occur at random but mostly as clusters in time. Large changes
in the amplitude of all three components are also observed for all three variables. © Halberg.
132
Figure 8. Statistical significance (P<0.05) of 1.0-year (top), 0.5-year (middle), and 0.41-year (cishalf-year,
bottom) components fitted concomitantly to the HR data of RBS is represented as darkfilled
symbols, borderline statistical significance (0.05<P<0.10) as lightly-filled symbols, and nonsignificance
(P>0.10) as open symbols. It can readily be seen that instances when the cis-half-year
reaches statistical significance do not occur at random but mostly as clusters in time. Large changes
in the amplitude of all three components are also observed for all three variables. © Halberg.
133
Figure 9. In melatonin data that were serially-dependent along the 24-hour scale, each person
providing blood at 4-hour intervals for 24 hours, but serially-independent after pooling across 172
subjects examined in the course of ~4 years, a cis-half-year rather than half-year is invariably
detected observed, characterizing the individual MESORs and circadian amplitudes as well as both
daytime and nighttime samples considered separately. A map of the nonlinear estimates of cis-halfyear
periods and their CIs (bottom) is provided with an abstract definition of congruence (top). ©
Halberg.
134
RBS: Systolic Blood Pressure
3-component model fitted to data in 4-year interval moved by 0.2 year
-480
-420
-360
-300
-240
-180
-120
-60
0
12/31/1969 12/31/1977 12/31/1985 12/31/1993 12/31/2001
Time (calendar date)
SBP-φ(degrees)
1.0 year
0.5 year
0.41 year
Acrophases shown only when P(A=0)<0.10
Figure 10. Time course of the acrophases of the three components (with periods of 1.0, 0.5, and 0.41
year) fitted concomitantly to the SBP data of RBS. Acrophases are shown only when the zeroamplitude
test could be rejected at P<0.10. The 1.0-year component is detected most of the time,
and all three components are occasionally detected concomitantly, albeit only intermittently. ©
Halberg.
135
RBS: Diastolic Blood Pressure
3-component model fitted to data in 4-year interval moved by 0.2 year
-480
-420
-360
-300
-240
-180
-120
-60
0
12/31/1969 12/31/1977 12/31/1985 12/31/1993 12/31/2001
Time (calendar date)
DBP-φ(degrees)
1.0 year
0.5 year
0.41 year
Acrophases shown only when P(A=0)<0.10
Figure 11. Time course of the acrophases of the three components (with periods of 1.0, 0.5, and 0.41
year) fitted concomitantly to the DBP data of RBS. Acrophases are shown only when the zeroamplitude
test could be rejected at P<0.10. The 1.0-year component is detected most of the time,
and all three components are occasionally detected concomitantly, albeit only intermittently. ©
Halberg.
136
RBS: Heart Rate
3-component model fitted to data in 4-year interval moved by 0.2 year
-480
-420
-360
-300
-240
-180
-120
-60
0
12/31/1969 12/31/1977 12/31/1985 12/31/1993 12/31/2001
Time (calendar date)
HR-φ(degrees)
1.0 year 0.5 year
0.41 year
Acrophases shown only when P(A=0)<0.10
Figure 12. Time course of the acrophases of the three components (with periods of 1.0, 0.5, and 0.41
year) fitted concomitantly to the HR data of RBS. Acrophases are shown only when the zeroamplitude
test could be rejected at P<0.10. The 1.0-year component detected most of the time in the
case of SBP and DBP is less consistent for HR. All three components are occasionally detected
concomitantly, albeit only intermittently. © Halberg.
137
Figure 13. Least squares spectra of the amplitude estimates from the 3-component serial sections,
with periods of 1.0-year (top), 0.5-year (middle), and 0.41-year (bottom) of SBP (left), DBP
(middle), and HR (right) of RBS. P-values obtained in these analyses cannot be taken at their face
value since the serial sections were pergressive with an increment 1/19 the length of the interval.
Perhaps because of the relatively large changes in amplitude and acrophase of the yearly component
as a function of time, the 1.0-year amplitudes have an ~1.1-year spectral peak for SBP and DBP and
by an ~1.2-year spectral peak for HR. The cis-half-year amplitudes of HR are characterized by a
prominent ~11-year component. © Halberg.
138
Figure 14. As also summarized in Figure 1, the cis-half-year amplitude of HR (bottom) shares an
~11-year cycle with Wolf numbers (top). © Halberg.
139
Figure 15. Similarly to HR, the cis-half-year amplitudes of DBP are cross-correlated with solar
flares, reaching a peak association of 0.564 at 3.37-year lag after the total solar flare index. ©
Halberg.
140
META-ANALYSIS OF HORREBOW'S AND SCHWABE'S SCHOLARSHIP
WITH A VIEW OF SAMPLING REQUIREMENTS
Germaine Cornélissen1
, Franz Halberg1
, Robert Sonkowsky1
,
Jarmila Siegelova2
, Pavel Homolka2
, Jiri Dusek2
, Bohumil Fiser2
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, Minnesota, USA
2
Masaryk University, Brno, Czech Republic
Abstract
Christian Pedersen Horrebow (1718-1776), a Danish astronomer, son of Peder (Nielsen)
Horrebow (1679-1764), whom he succeeded as head of the astronomical observatory associated
with the University of Copenhagen, deserves credit for a thorough sunspot data collection between
1761 and the time of his death (16 years), continued by his successor only until 1777 (1). The
rejection of the "no-cycle", i.e., "zero-amplitude" assumption, in sunspots with data covering, with
gaps, not more than a single cycle is here documented by a chrono-meta-analysis as a statistically
and, in retrospect, transdisciplinarily significant phenomenon. Samuel Heinrich Schwabe (1789-
1876) started another series of sunspot numbers in 1826 and continued it for 17 years. He published
data in 1838 without referring to a cycle (2). Meta-analyses demonstrate that his data over a single
cycle suffice for establishing statistical significance. Schwabe would not have had to wait for 6
more years (3) before explicitly reporting a solar periodicity as he did in 1844. Both Horrebow's and
Schwabe's meta-analyzed data are here discussed in the context of minimal sampling requirements
on relatively long cycles that must be assessed in limited data covering but a single cycle or less, in
the case of even shorter accumulating time series, if not in sunspots then in human heart rate (4).
Problem
In the early 1950s, it was relatively easy to gain the cooperation of members of a medical
fraternity at the University of Minnesota to give blood at 90-minute intervals around the clock for
one or two 24-hour spans and longer, in order to map their circadian rhythmic change in the count
of certain blood cells. Even venipunctures every 90 minutes around the clock were tolerated without
any blinking of eyes (5). We dealt with a large amplitude rhythm, not only in eosinophil cells but
also in the cortical adrenal hormones that depressed them. Clinical laboratory practice ended up
141
with a morning and/or evening cortisol, justified superficially by the 24-hour synchronization
prevailing for the adrenal cortical cycle under ordinary conditions of life, albeit by reliance upon
two spotchecks, one will lose invaluable diagnostic information not only in the case of cortisol but
also in that of blood pressure.
The task of sampling about 10-year and about 35-year cycles (6, 7) is much harder when these
are to be mapped on a given person. It then becomes necessary to consider what may be minimal
sampling requirements to obtain a rough estimate of a given component’s characteristics on the
basis of limited data that may cover less than a full cycle. In particular, given components covering
three decades or more, we aim at assessing them as soon as possible.
Background
Carl Friedrich Gauss (1777-1855), whose least-squares procedures we use herein for curvefitting,
was born the year after Christian Pedersen Horrebow died (in 1776). Joseph Fourier at that
time was 8 years of age. Horrebow provided a first series of sunspot numbers, with gaps, at the time
probably examined only by eyeballing, without Fourier's approach or Gauss' curve-fitting.
Horrebow's counting of sunspots was continued for only a little while after his death, perhaps a
year, since Clar. Baggio, Horrebow's immediate successor, had other interests, according to
Thorwald Nicolai Thiele (1838-1910), then a student of astronomy (later an actuarial mathematician
and statistician in addition to being an astronomer, and eventually Horrebow's successor as director
of the astronomical observatory of the University of Copenhagen, from 1875 to 1907) (8). As Thiele
wrote (1859): "Anno 1770 Horrebovius obiit Clar. Baggio, qui ei successit, aliis rebus intento,
nullae vel paucae sequentibus annis macularum observations factae sunt."
Horrebow, cited by Thiele, had written that "... astronomers to date have taken too little care to
make frequent observations of sunspots, undoubtedly because they think nothing can be
accomplished thereby which would be of great importance to astronomy or physics. ... It is,
however, to be hoped, by making diligent observations in this matter, that a definite cycle of
heavenly bodies will be discovered; then at last it will be time to investigate as to how [heavenly]
bodies, which are governed and illuminated by the sun, are brought into existence by the sun spots."
(... astronomis adhuc parum curae fuit crebras macularum observationes facere, sine dubio quod
142
nihil inde effici posse iis videbatur, quod astronomiae aut physicae magno opere interesset.
Sperandum tamen est, diligenter observando etiam hac in re, ut in motibus ceterorum corporum
coelestium periodum certam inventum iri; tum demum tempus erit inquirere, quonam modo corpora,
quae a sole reguntur et illustrantur, maculis solis efficiantur." The follow-up visualized by
Horrebow was realized by Samuel Heinrich Schwabe, who provided additional data that can be
examined to focus on the length of sunspot series available in the 18th
and 19th
centuries that are
required with modern computational tools to document a sunspot cycle in the circadecadal range of
periodicities.
As a minimum, to detect a cyclic component of anticipated period (or a period near it), the
zero-amplitude (no-rhythm) assumption needs to be rejected, usually at a probability level of 5% or
less. Unknown components can be detected by spectral analysis or other similar procedure (9-11), in
which case they need further validation, on the basis of complementary data, or if the time series is
long enough, by the separate analysis of different sections. Several methods are available for rhythm
detection and parameter estimation, as well as for model building when multi-frequency
components characterize a given data series. The extended cosinor is used herein to examine several
sets of related sunspot data published by Thiele (1), Schwabe (2, 3), and Hoyt and Schatten (12, 13),
respectively. It seems interesting, in connection with Thiele's article first, that there is no
bibliography and a reference to Schwabe is found only in the text, without a citation of prior
publications.
Analysis of Horrebow's data
A time plot (chronogram) of the data tabulated by Thiele (Figure 1, top) shows about 1.5
sunspot (solar activity) cycles (with gaps), guesstimated from Horrebow's 204 monthly values
between 1761 and 1776 and the addition of Baggio's data from 1777 (1). A least squares (14, cf. 9-
11) spectrum (Figure 1, middle) reveals peaks corresponding to periods of about 9.5, 4.2 and 2.0
years.
Nonlinear analyses resolve the 9.4-year and the 2.1-year components but not the 4.2-year
component. Periods and their 95% confidence intervals (CIs) are 9.554 [8.75, 10.36] and 1.971
143
[1.85, 2.09] years, with corresponding amplitudes of 4.47 [3.44, 5.50] and 1.26 [0.27, 2.25]
(sunspots). The resulting two-component model is fitted to the data in Figure 1 (bottom).
All three components can be resolved nonlinearly after log-transformation (y = log10(x+1)),
with periods and 95% CIs of 8.863 [7.80, 9.93], 5.037 [4.21, 5.87] and 2.153 [1.99, 2.31] years and
corresponding amplitudes of 0.42 [0.32, 0.51], 0.17 [0.07, 0.27], and 0.09 [0.01, 0.17] (sunspots),
when fitted concomitantly. Figure 2 illustrates the 3-component model fitted to the log-transformed
data. Figure 3 shows the same model after back-transformation together with the original data.
Analyses of data from Hoyt and Schatten
Hoyt and Schatter (12, 13) provide three monthly data sets, the standard Wolf numbers (WN),
the Group numbers (GN), and the Group Wolf numbers (GWN) from 1761 to 1777. The Group
numbers coincide with the data published by Thiele (except for one small discrepancy of 0.2 for one
of the monthly values). Because GN and GWN were both available on the same months but had
missing values, one additional series was considered, consisting of the usual Wolf numbers
(available for all months) omitting the monthly values when those were not available for the GN and
GWB. A plot of the data as a function of time reveals a much sharper and higher maximum for the
GWN than for the WN, Figure 4.
Least squares spectra (Figure 5) show peaks corresponding to an about 9.4-year component for
WN and GWN, shifted to a slightly shorter period of about 8.9 years in decimated WN (to match the
GWN data). About 4.1-year and about 2.1-year components characterize all three data sets, and an
about 1.15-year or 1.16-year smaller peak is also detected for WN (not accounting for multiple
testing), whether all data or the decimated data are analyzed, respectively, but not for GWN. An
about 2.7-year peaklet is also found for WN. Nonlinear analyses validate the about 9.4- and 4.1-year
components but not those with periods of about 2.7 and 1.15 years. The about 2.1-year component is
resolved for GWN but not for WN, Table 1. The fact that this component is detected with borderline
statistical significance for the decimated WN but not for the original WN suggests that it may be
artifactual, related to the missing data.
Nonlinear analyses of the log-transformed data yield a 3-component model that differs
between the WN (original or decimated) and the group WN. In the former case, the three
144
components have periods of about 9.2, 4.5 and 3.1 years (the 3.1-year component being statistically
significant when fitted singly, but reaching only borderline statistical significance when fitted
concomitantly with the other two components), whereas in the latter case, the periods are about 9.2,
4.5 and 2.1 years. The same difference in model is found whether the components are fitted
separately or concomitantly. Results from the concomitant fit of the three major components
characterizing the log-transformed WN, decimated WN, and GWN are listed in Table 2. Figure 6
shows the 3-component models fitted to the original (top) and log-transformed (middle) data. Figure
6 (bottom) shows the original data and the model obtained for the log-transformed data after backtransformation.
As can be seen from Figure 6, the model seems to provide a better fit for the original
or decimated WN than for the GWN. It is possible that the three components selected for WN
represent harmonics of the solar activity cycle and describe a non-sinusoidal waveform, even though
they were fitted as independent components. This was not the case for GWN, and there appears to
be an overfit during 1762-1764, when data were missing. This overfit is also observed for the
Horrebow data in Thiele (1) (Figure 3), but to a much smaller extent.
Analyses of Schwabe's data
Two series (1826-1837 and 1838-1843) of yearly sunspot numbers were combined into one
and analyzed by linear-nonlinear least squares rhythmometry (9-11). We wished to find the minimal
number of yearly data on whose basis the solar activity cycle could have been documented by
rejecting the no-cycle (zero-amplitude) assumption, had Schwabe used the method of least-squares
that had been available since 1801 when Gauss had developed it to locate Ceres, the asteroid that
was lost after Giuseppe Piazzi (1746-1826) initially observed it (14). A trial period of 11 years was
used. The results in Figure 7 need to be qualified by the fact that using a trial period of 11 years
assumes the existence of prior information, which was not the case at the time of the original
documentation of a cycle in solar activity, unless Schwabe knew about Horrebow's data. Moreover,
if he knew about Horrebow's observations, he could have used the equivalent of a cosinor spectrum
and located a peak around 9.4 years. Against this background, several time series were prepared
using all 18 data and progressively removing one value starting from the latest available (the early
data were always kept). The shortest series contains the first 5 values. An 11-year cosine curve was
145
fitted nonlineary to each time series, covering the entire 18-year span or only the first 17, 16, 15, …
or 5 years, to obtain estimates of the period as well as of the MESOR, amplitude and acrophase.
Results are shown in Figure 7 as a function of the decreasing observation span, for the MESOR
(top), the estimated period length (middle), and the corresponding amplitude, each with a measure
of its CI. An about 9-year cycle can be documented with as few as 9 values (9 years), Figure 7.
Thorvald Nicolai Thiele (1838-1910) -- of Thiele differential equation fame ("the fundament
of modern life insurance mathematics"; 8) -- concluded: "Sed antequam postera aetas huic rei plus
lucis attulerit, in periodo regulari decem fere annorum acquiescendum esse videtur" (But until a
subsequent age adds more light to this matter, it seems necessary to be satisfied with a regular
period of about ten years) (1). It seems pertinent to note that both Horrebow's and Schwabe's data
allowed by 1838 the demonstration of a circadecadal cycle with a measure of its uncertainty on the
basis of data covering only 9 years.
In Thiele's and Schwabe's time, the circadecadal cycle in sunspot numbers was shorter than its
average length in all available data. The higher resolution of Figure 8 versus Figure 9 using a 12year
versus a 35-year interval suggests that in 1826, the solar activity cycle was actually the shortest
between 1799 and 1947 (15).
In any event, we must not resign ourselves that data covering a full cycle is invariably required
for the demonstration of cycles that characterize major features of solar variability. We certainly
must not generalize to the detection of their reflection in the biosphere. With the linear-nonlinear
extended cosinor, the zero-amplitude assumption could be rejected for a circatridecadal BEL cycle
in the heart rate of an elderly man based on only 22 years of measurements (4), i.e., with only 73.3%
of the cycle's total length covered by the data.
Support: GM-13981 (FH) and University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402.
1. Thiele ThN. De Macularum Solis antiquioribus quibusdam observationibus Hafniae institutis.
Astronomische Nachrichten 1859; 50: 259-261.
146
2. Schwabe H. Über die Flecken der Sonne. Astronomische Nachrichten 1838; 15: 244-248 (no.
350).
3. Schwabe H. Sonnen-Beobachtungen im Jahre 1843. Astronomische Nachrichten 1844; 21:
254-256 (no. 495).
4. Halberg F, Cornélissen G, Siegelova J, Homolka P, Dusek J, Fiser B. Differences in time
structural environmental congruence of vascular variables in an elderly man. This issue.
5. Halberg F, Visscher MB, Flink EB, Berge K, Bock F. Diurnal rhythmic changes in blood
eosinophil levels in health and in certain diseases. Journal-Lancet (Minneapolis) 1951; 71:
312-319.
6. Halberg F, Cornélissen G, Czaplicki J, Prabhakaran Nayar SR, Siegelova J. Brückner-EgesonLockyer
(BEL) climate cycle in original Brückner's, Lockyer's and follow-up data. In: Halberg
F, Kenner T, Fiser B, Siegelova J (Eds.) Proc., Noninvasive Methods in Cardiology, Brno,
Czech Republic, Oct 4-7, 2008. p. 74-89. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
7. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle in
heliogeophysics, psychophysiology, military politics, and economics. Geophysical Processes
and the Biosphere, in press.
8. Berger A. Mathematik der Lebensversicherung. Vienna: Springer; 1939. Cited in Norberg R.
Thiele differential equation. In: Hazewinkel M (Ed.) Encyclopaedia of Mathematics. Berlin:
Springer-Verlag; 2002. ISBN 1402006098. http://eom.springer.de/T/t130080.htm
9. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
10. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
11. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Res. 2007; 38: 275-325. http://dx.doi.org/10.1080/09291010600903692
12. Hoyt DV, Schatten KH. A new interpretation of Christian Horrebow's sunspot observations
from 1761 to 1777. Solar Physics 1995; 160: 387-392.
13. Hoyt DV, Schatten KH. The Role of the Sun in Climate Change. New York/Oxford: Oxford
University Press; 1997. 279 pp.
147
14. Gauss CF. Theoria motus corporum cœlestium in sectionibus conicis solem ambientium.
Hamburg: Perthes & Besser; 1809.
15. Schwartzkopff O, Cornélissen G, Bingham C, Homolka P, Katinas G, Sonkowsky RP, Halberg
F, International BIOCOS Project Team. Long-term, when-needed lifelong monitoring
concerns governments, ethics committees and everybody. In: Halberg F, Kenner T, Fiser B
(Eds.) Proceedings, Symposium: The Importance of Chronobiology in Diagnosing and
Therapy of Internal Diseases. Faculty of Medicine, Masaryk University, Brno, Czech
Republic, January 10-13, 2002. Brno: Masaryk University; 2002. p. 97-121.
148
Table 1:
Periods characterizing sunspots counted by Hoyt and Schatten
(components fitted separately)
Series Period [95%CI] (years) Amplitude [95%CI] (sunspots)
Trial Period: 9.4 years
Wolf numbers (WN) 9.374 [8.90, 9.84] 42.65 [35.46, 49.84]
Decimated WN (matching GWN) 8.914 [8.40, 9.42] 46.63 [38.78, 54.48]
Group WN (GWN) 9.492 [8.71,10.28] 52.99 [41.18, 64.80]
Trial Period: 4.1 years
WN 4.129 [3.64, 4.62] 13.30 [ 2.33, 24.27]
Decimated WN 4.201 [3.73, 4.68] 18.29 [ 5.11, 31.47]
GWN 4.152 [3.54, 4.77] 18.45 [ 1.39, 35.50]
Trial Period: 2.1 years
WN 2.023 [1.87, 2.17] 9.88 [-1.40, 21.16] NS
Decimated WN 2.050 [1.88, 2.22] 13.07 [-0.04, 26.19] BS
GWN 2.068 [1.92, 2.22] 18.00 [ 1.10, 34.91]
149
Table 2:
Composite model characterizing sunspot numbers in the 18th
century (Hoyt and Schatten)
Analysis of log10-transformed data
Series Period [95%CI] (years) Amplitude [95%CI] (sunspots)
Wolf numbers (WN) 9.356 [8.72, 9.99] 0.44 [0.35, 0.53]
4.540 [4.21, 4.87] 0.20 [0.11, 0.29]
3.122 [2.79, 3.46] 0.09 [-0.00, 0.18]
Decimated WN (matching GWN) 9.122 [7.79,10.45] 0.46 [0.33, 0.60]
4.762 [3.77, 5.75] 0.19 [0.08, 0.30]
3.105 [2.56, 3.65] 0.08 [-0.04, 0.20]
Group WN (GWN) 8.566 [7.45, 9.68] 0.63 [0.46, 0.80]
5.155 [4.34, 5.97] 0.30 [0.12, 0.48]
2.189 [2.04, 2.34] 0.15 [0.03, 0.27]
150
Figure 1. Yearly sunspot data (with interruptions) from Horrebow (published by Thiele) (top) are
characterized by three spectral peaks corresponding to periods of about 9.55, 4.17, and 1.97 years
validated nonlinearly when considered separately (middle). The composite 2-component model is
fitted to the data (bottom). © Halberg.
151
Three-Component Model Fitted to Horrebow’s Data on Sunspots (Published by Thiele) *
0.0
0.3
0.6
0.9
1.2
1.5
1760 1762 1764 1766 1768 1770 1772 1774 1776 1778 1780
Time (calendar year)
Sunspots(LogN)
Astronomische Nachrichten No 1193. De Macularum Solis antiquioribus quibusdam observationibus
Hafniae institutis, scripsit Th. N. Thiele, astr. Stud. John G. Wolbach Library, Harvard-Smithsonian
Center for Astrophysics - Provided by the NASA Astrophysics Data System
0.64 + 0.42cos(2π(t-t0)/8.86-0.4)
+ 0.17cos(2π(t-t0)/5.04-3.1)
+ 0.09cos(2π(t-t0)/2.15-0.5)
t0: 1761
Period
(years)
Amplitude (N
spots)
8.86 7.80 9.93 0.42 0.32 0.51
5.04 4.21 5.87 0.17 0.07 0.27
2.15 1.99 2.31 0.09 0.01 0.17
[95% CI] [95% CI]
* Data log10-transformed prior to analysis
Figure 2. After log-transformation, a 3-component model validated nonlinearly is fitted to the
sunspot data from Horrebow. © Halberg.
Three-Component Model Fitted to Log-transformed Data Shown after Back-transformation with
Original Horrebow’s Data (Published by Thiele)
0
4
8
12
16
20
1760 1762 1764 1766 1768 1770 1772 1774 1776 1778 1780
Time (calendar year)
Sunspots(N)
Astronomische Nachrichten No 1193. De Macularum Solis antiquioribus quibusdam observationibus
Hafniae institutis, scripsit Th. N. Thiele, astr. Stud. John G. Wolbach Library, Harvard-Smithsonian
Center for Astrophysics - Provided by the NASA Astrophysics Data System
Period
(years)
Amplitude (N
spots)
8.86 7.80 9.93 0.42 0.32 0.51
5.04 4.21 5.87 0.17 0.07 0.27
2.15 1.99 2.31 0.09 0.01 0.17
[95% CI] [95% CI]
Back-transformed from log10-model
Figure 3. The 3-component model fitted to the log-transformed sunspot data from Horrebow is
back-transformed to be displayed with the original data. Note slight overfit at the beginning of the
record when data are missing. © Halberg.
152
Figure 4. Yearly sunspot numbers (WN) and group sunspot numbers (GWN) reported by Hoyt and
Schatten. As some yearly values are missing for GWN, the WN data have been decimated to match
the GWN data in order to assess any influence of gaps on the assessment of the solar activity cycle.
© Halberg
153
Figure 5. Least squares spectra of sunspot numbers (WN) and group sunspot numbers (GWN)
reported by Hoyt and Schatten reveal the presence of similar cyclical components, as well as some
differences. Small differences are also observed in relation to the missing values, suggested by a
comparison of spectra of the original and decimated WN (to match GWN). © Halberg.
154
Figure 6. Three-component model fitted to the original (top) and log-transformed (middle) sunspot
(WN) and group sunspot (GWN) data reported by Hoyt and Schatten. Model obtained on logtransformed
data is back-transformed for display with original data (bottom). As for the data from
Horrebow (Figure 3), there is even a more pronounced overfit at the beginning of the record, in
association with the gap in the data series. © Halberg.
155
Figure 7. Results from nonlinear analyses of Schwabe’s data, analyzed over the entire 18-year span
and on progressively shorter series obtained by removing each time the last yearly value, in an
attempt to determine what is the shortest series suitable for an assessment of the solar activity cycle
at the time. Even with only the first 9 yearly data, it is possible to derive point and 95% confidence
intervals for all parameters. Results shown for the MESOR (top), period length (middle), and
amplitude (bottom). © Halberg.
156
Figure 8. Chronomic serial section estimating by nonlinear least squares the cycle length of Wolf
numbers based on 12-year intervals. For measurements starting in 1826 when Schwabe made his
observations, the solar activity cycle happened to be the shortest, in keeping with results in Figure 7.
Had Schwabe examined 12 years of sunspots at other times, he may have had to wait longer to
observe a full solar activity cycle or he may have been unlucky if the span coincided with one of the
few instances when convergence could not be reached. © Halberg.
157
7
9
11
13
15
17
19
1700 1750 1800 1850 1900 1950 2000
Time (calendar year)
Period(years)
PERIOD LENGTH OF SOLAR CYCLE SINCE 1700
estimate
95% confidence interval
Figure 9. Nonlinear estimate of the solar activity cycle length, gauged by Wolf numbers analyzed in
intervals of 35 years progressively displaced by 5 years throughout the time series. Results plotted
at the midpoint of each interval. At the time of Schwabe’s data, a shorter solar activity cycle is again
found, but its length is somewhat longer as data over a longer interval of 35 years (rather than 12
years in Figure 8) was considered for analysis. With such a longer interval, convergence is
invariably achieved. © Halberg.
158
TRANS-TRIDECADAL, DECADAL AND TIME-VARYING CIS-HALF-YEARLY, CISYEARLY
AND TRANS-YEARLY COMPONENTS IN SOLAR FLARES WITH
BIOSPHERIC SIGNATURES
Germaine Cornélissen1
, Franz Halberg1
, Dewayne Hillman1
,
Jarmila Siegelova2
, Jiri Dusek2
, Pavel Homolka2
, Bohumil Fiser2
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Masaryk University, Brno, Czech Republic
Aim. As a step toward aligning and examining mechanisms of possibly interacting
environmental and biospheric periods, the latter involving sudden cardiac death (SCD) and cardiac
arrhythmia, we analyze the longest series of the total solar flare index (SFI) available to us.
Background. Aeolian behavior has been described as time-varying in amplitude (A) by waxing
and waning, in acrophase (φ) by jumping, if not drifting, and in period (τ) by drifting, bifurcation,
rejoining, disappearance and reappearance. As noted in moving spectra by Mursula and Zieger (1), a
given periodicity can change its period from 1.7 to 1.5 years, and in our analyses (2) even further to
1.3 years. To account for such drifts over a wide range of periods, far-transyears have been defined
as components with periods such that 1.2 years ≤ [τ - CI {95% confidence interval}] < [τ + CI] <
1.9 years, whereas near-transyears are defined as 1.00 year < [τ - CI] < [τ + CI] < 1.20 years (2). By
"τ - CI" or "τ + CI", we mean the lower or upper limit of the 95% confidence interval of the period,
in keeping with the notation of a mean given ± 1SE or ± 1SD. The actual width of the error
(uncertainty) is then 2SE or 2SD. As for large-sample normally-distributed data sets, 95%
confidence limits can be approximated as the mean ± 2SE, the entire width of a 95% confidence
interval is then 2CI. By analogy, the nonlinear period estimate is given as τ ± CI, and the entire
width of the 95% confidence interval of τ is 2CI.
About 154-day periodicities also have biospheric counterparts (Table 1). These cis-half-years
(from cis = on this side of the half-year) are found in some cases of cardiac arrhythmia (2-4) and
SCD (ICD10, code I46.1) (2, 4-6). A range for the cis-half-year period has not been given yet
because of the great variability of this component, which also prompted an attempt of studying its
time-varying behavior in the solar flare index by a chronomic serial section. Such an examination is
159
important since signatures of both far-trans-years and cis-half-years in cardiac arrhythmia recorded
as such (Table 2) (2) or by implanted devices in which they trigger therapy (3; cf. 7) are found
intermittently. It remains to be seen whether and, if so, how environmental change may be
associated with biospheric consequences. Cis-half-years in the incidence pattern of arrhythmia
triggering therapy from implanted devices are geographic site-dependent (3). In Minnesota, a site
where the incidence patterns of both arrhythmia and SCD have been examined, a cis-half-year is
found in both. Cis-half-year and trans-year components also characterize SCD in Tokyo (5),
Hungary (2), Austria (6), and, transiently, in the Czech Republic (2). Furthermore, a cis-half-year
was found in human heart rate studied around the clock for over 40 years and was modulated by a
circadecadal Horrebow-Schwabe sunspot cycle, being statistically significant mostly with a lag of
slightly over 3 years after the times of maximal solar activity (8).
Methods. Daily data on the total solar flare index, available from 1966 to 2007 were averaged
over consecutive weekly intervals. The latter were analyzed by the extended cosinor (9-11). A least
squares spectrum was obtained, using a fundamental period of 42 years. Periods of spectral peaks
corresponding to anticipated components were used as initial values in the nonlinear program to
obtain point and 95% confidence intervals for the periods. In order to examine how the
characteristics of some of these components changed as a function of time, single- and multiplecomponent
(chronomic) serial sections were carried out.
Results. The least squares spectrum of SFI is shown in Figure 1, suggesting the presence of a
BEL cycle (12-16) with a period of about 35 years, only slightly shorter than the total length of the
time series. A prominent spectral peak at a period of about 10.5 years corresponds to the HorrebowSchwabe
cycle. Other spectral peaks of less prominence include a trans-year of about 1.7 years, a
cis-year of about 0.7 year, and multiple components in the cis-half-year spectral region, shown in
greater detail in Figure 2. Each component considered separately was further assessed nonlinearly.
Point and 95% confidence intervals of the periods are listed next to the spectral peaks in Figures 1
and 2. Chronomic serial sections served to study how the characteristics of the trans-year, cis-year,
and the sole cis-half-year validated nonlinearly varied as a function of time. For this purpose, a
relatively long interval of 7.2 years had to be chosen, which was displaced in 0.72-year increments,
160
Figure 3. The MESOR, displayed on top (left), is readily seen to vary according to the about 10.5year
solar activity cycle. The amplitudes (left) and acrophases (right) of each component of the cishalf-year
(second row), cis-year (third row), and trans-year (bottom row) are shown with different
symbols depending on whether the zero-amplitude test was rejected at the 0.05 probability level or
not (Figure 3).
As seen in Figure 3 (row 2, left), the 0.42-year component has the largest amplitude for a
while, around 1980, the time of Rieger et al.'s finding (17), predicted by Charles L. Wolff (18),
Table 1. All three components can intermittently be detected with statistical significance (filled
symbols), notably around 1982 when the cis-half-year is most prominent. The alternation between
statistical significance and lack of statistical significance (empty symbols) does not seem to occur at
random. The 0.42-year component tends to be detected with statistical significance at times of
overall peak incidence in solar flares. Albeit not globally, the 0.42-year component assumes
amplitudes (of up to 2.5 arbitrary units) larger than those of the cis-year and trans-year (reaching a
maximum of only about 1.5 arbitrary units). At the beginning of the record, however, statistical
significance is reached in only 5 intervals for the 0.42-year component, and in only 2 intervals for
the 0.71-year cis-year, whereas it is more consistent, lasting until the mid-1980s for the 1.74-year
trans-year. The Aeolian nature of all three components is best seen from the time course of the
acrophases (Figure 3, right), showing mostly abrupt phase jumps for the cis-half-year, phase jumps
and drifts for the trans-year, whereas the acrophase of the cis-year is more consistent, at least when
this component is detected with statistical significance.
Discussion. BEL cycles in human health and other affairs, some congruent with those in solar
flares, lend further weight to original data by Brückner (12). His original data are shown
macroscopically in Figure 4 (top), as part of a set of transdisciplinary transtridecadal cycles assessed
time-microscopically, with results from our spectral analyses also shown in Figure 4 (bottom).
These include analyses of four decades of heliogeomagnetics (13), 2,556 years of international
battles published by Wheeler (19), a 2,189-year record of tree rings (20), a 173-year record of
military-political affairs compiled by Chizhevsky (21), a 460-year record of the South English Price
Index gauging an aspect of economics (22, 23), as well as biospheric data, namely four decades of
161
around-the-clock self-measurements of heart rate (14-16) and of a mental function (1-minute time
estimation) (16, 24) by a clinically healthy man, and three decades of blood pressure and body
weight of a clinically healthy man (25).
Space weather, mirrored in the circulation of human blood, can be tracked biologically as a
dividend from self-assessed preventive health care, involving the manually (16) (or preferably
automatically and ambulatorily) recorded heart rate and blood pressure for detecting and treating
heretofore ignored vascular variability disorders (VVDs). In exchange for the data, the BIOCOS
project (corne001@umn.edu) currently provides cost-free analyses for those motivated to survey
themselves and can also serve any community with a computer-savvy member so as to start focus
for the population on problems of societies' as well as individuals' health. Biospheric variability
includes spectral components with a length of about three decades mapped in Figure 4 (16).
Whereas they are signatures of our environment, these may also be partly built-in, as are circadian
rhythms. In Brückner's data, the frequency of cold winters has a point estimate of its period outside
the 30- to 40-year range, but its CI covers part of that range. By the same token, the point estimate
of the aurora over nearly a millennium is slightly shorter than 30 years (not shown), but its CI
extends beyond the length of 30 years (26) and in the analysis of a 500-year span, the point estimate
of the period is transtridecadal (27).
Similar periods do not necessarily mean causal relations, and any parallelisms of their
behavior are best studied over long time spans. The circumstance that the environmental spectral
components are non-stationary to the point of intermittency allows the study of the biospheric
consequences of their presence and absence. Environmental cycles also vary in terms of geography.
The latter aspect is apparent for far-transyears that, in some locations, may coexist with a calendaryearly
component and in other sites may replace the calendar year, whereas in yet other geographic
locations, or in other variables, the calendar year stands out most prominently or alone (16).
Table 1 lists only part of the very large literature revolving around the cis-half-year in physics,
most of it without measures of the uncertainty of the periods on hand and without consideration of
spectral components other than a cis-halfyear. Figure 5 compares acrophases of the cis-half-year,
cis-year, and trans-year, each component fitted separately. The relatively narrow CIs in most cases
162
are qualified by the fact that a single-component model is fitted, using different intervals for each
component. Notably for the cis-half-year and the cis-year, the interval used for analysis in Figure 5
is shorter than the 7.2-year span considered in Figure 3, where all three components were fitted
concomitantly. In view of the prominent about 10.5-year cycle characterizing solar flares reflecting
changes in solar activity, it was of interest to compare the least squares spectra of solar flares
(Figure 1) and of Wolf numbers recorded during the same 42-year span (Figure 6) to see whether
both variables also shared similar BEL cycles. Whereas a BEL cycle is apparent in both variables,
its amplitude is much larger in solar flares (more than 50% of the about 10.5-year amplitude) than in
Wolf numbers (less than 20% of the about 10.5-year amplitude). Other differences between Figures
1 and 6 require further study for their biospheric associations, to be mapped further.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
163
Mursula K, Zieger B. The 1.3-year variation in solar wind speed and geomagnetic activity. Adv
Space Res 2000; 25: 1939-1942.
1. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla
M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G,
Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P,
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season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and
site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38.
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2. Cornélissen G, Benser M, Halberg F. Patterns of incidence of tachyarrhythmias recorded in
implantable cardioverter-defibrillators during 2001-2005. PS-004, Proceedings, 2nd World
Congress of Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 63.
3. Cornélissen G, Halberg F, Rostagno C, Otsuka K. A chronomic approach to cardiac
arrhythmia and sudden cardiac death. S4-2, Proceedings, 2nd World Congress of
Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 56-59.
4. Hamamatsu A, Cornélissen G, Otsuka Ku, Halberg F, Chibisov S (presenter). Linear-nonlinear
rhythmometry documents a transyear and a cishalfyear in sudden cardiac death (ICD 10, code
I46.1) in Tokyo. In: Proceedings, International Symposium, Problems of ecological and
physiological adaptation, People's Friendship University of Russia, Moscow, 30-31 Jan 2007.
Moscow: People's Friendship University of Russia; 2007. p. 542-545.
5. Cornélissen G, Schnaiter D, Halberg F, Mitsutake G, Otsuka K, Fiser B, Siegelova J, Jozsa R,
Olah A, Bakken EE, Chibisov S (presenter). A cis-half-year characterizes the incidence of
sudden cardiac death also in and near Austria. In: Proc., International Symposium, Problems
of ecological and physiological adaptation, People's Friendship University of Russia, Moscow,
30-31 Jan 2007. Moscow: People's Friendship University of Russia; 2007. p. 545-551.
6. Stoupel E, Kusniec J, Mazur A, Abramson E, Israelevich P, Strasberg B. Timing of lifethreatening
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164
7. Cornélissen G, Halberg F, Sothern RB, Hillman DC, Siegelova J. Selectively environmentall
congruent biotic cis-half-year unmasked with neighboring spectral components. This issue.
8. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
9. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
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ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
10. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692.
11. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
12. Halberg F, Cornélissen G, Czaplicki J, Prabhakaran Nayar SR, Siegelova J. Brückner-EgesonLockyer
(BEL) climate cycle in original Brückner's, Lockyer's and follow-up data. In: Halberg
F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology,
Brno, Czech Republic, October 4-7, 2008. p. 74-89.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
13. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F.
Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics. In: Halberg F, Kenner T, Fiser
B, Siegelova J (Eds.) Proc., Noninvasive Methods in Cardiology, Brno, Czech Republic,
October 4-7, 2008. p. 106-115. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
14. Sothern RB, Katinas GS, Fiser B, Siegelova J, Cornélissen G, Halberg F. A transtridecadal
cycle in human heart rate: Selective infradian, notably multidecadal solar-physiologic BEL
congruences. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proc., Noninvasive Methods
in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 204-213.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
15. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle in
heliogeophysics, psychophysiology, military politics, and economics. Geophysical Processes
and the Biosphere, in press.
16. Rieger E, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day periodicity in
the occurrence of hard solar flares? Nature 1984; 312: 623-625.
165
17. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
18. Wheeler RH. War 599 B.C.-1950 A.D. Indexes of International and Civil War Battles of the
World. New York: Foundation for the Study of Cycles; 1951. 15 pp.
19. Nintcheu-Fata S, Katinas G, Halberg F, Cornélissen G, Tolstykh V, Michael HN, Otsuka K,
Schwartzkopff O, Bakken E. Chronomics of tree rings for chronoastrobiology and beyond.
Biomed & Pharmacother 2003; 57 (Suppl 1): 24s-30s.
20. Chizhevsky AL (de Smitt VP, trans and condensed). Physical factors of the historical process.
Cycles 1971; 22: 11-27. http://www.cyclesresearchinstitute.org/Chizhevsky /chizhevsky1.pdf
21. Goldstein JS. Long Cycles: Prosperity and War in the Modern Age. New Haven: Yale
University Press, 1988, 433 pp. "Crackpot" cyclic weather theories, pp. 59-60.
22. Goldstein JS. The predictive power of long wave theory, 1989-2004. In: Devezas TC (Ed.)
Kondratieff Waves, Warfare and World Security. Amsterdam: IOS Press; 2006. p. 137-144.
23. Halberg F, Cornélissen G, Sothern RB, Otsuka K, Revilla M, Siegelova J, Fiser B. Circadian
stage-dependent infradian-modulated changes in a mental function during aging. In: Halberg
F, Kenner T, Fiser B, Siegelova J (Eds.) Proc., Noninvasive Methods in Cardiology, Brno,
Czech Republic, October 4-7, 2008. p. 26-31.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
24. Halberg F, Cornélissen G, Best WR. A transtridecadal BEL cycle in human blood pressure and
body weight. This issue.
25. Cornélissen G, Czaplicki J, Halberg F, Schröder W, Beaty LA, Strestik J, Mikulecky M,
Chibisov SM, Radysh IV, Blagonravov M, Schwartzkopff O. Partial validation of an about 29year
transtridecadal cycle in the aurora borealis. In: Proceedings, 14th
International
Symposium, Ecologo-Physiological Problems of Adaptation, 9-10 April 2009. Moscow:
People's Friendship University of Russia; 2009. p. 490-493.
26. Silverman SM. Secular variation of the aurora for the past 500 years. Rev Geophys 1992; 30
(4): 333-351.
Support: GM-13981 (FH) and University of Minnesota Supercomputing Institute (GC, FH).
166
Figure 1. Least squares spectrum from extended linear-nonlinear cosinor of the total solar flare
index. © Halberg
167
Figure 2. Focus upon the spectral region around 0.4 year reveals multiple peaklets, prompting the
chronomic serial section in Figure 3. © Halberg
168
Figure 3. Intermittency of statistical significance of three spectral components fitted concomitantly.
© Halberg
169
Figure 4. Degree of generality of the BEL transtridecadal cycle in Brückner's original data and
beyond. © Halberg
170
Figure 5. Time course of acrophases of three spectral components, each fitted separately.
Acrophases are bracketed by their 95% confidence intervals. © Halberg
171
Wolf Numbers 1966-2007 [42 years]
0
10
20
30
40
50
60
70
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
Frequency (cycles/year)
Amplitude
32.3y [, ]
10.5y
[, ]
* Transtridecadal Brückner-Egeson-Lockyer (BEL) cycle validated by its many biospheric counterparts, as are some
of the other spectral components.
16.8
6.9
5.1
3.3
1.085
Figure 6. Least squares spectrum of Wolf's relative sunspot numbers over 42-year span matching
record of solar flare index (spectrum shown in Figure 1). © Halberg
172
Table 1: Point estimates of a cis-half-year (about 154-day) periodicity, sometimes given with
estimates of uncertainty and hypothesis testing
Period
(in days, except
where noted)
Reference
154.3
Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983;
264: 667-676.
154
Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. A 154-day
periodicity in the occurrence of hard solar flares? Nature 1984; 312: 623-625.
158
Kiplinger AL, Dennis BR, Orwig LE. Detection of a 158-day periodicity in the
solar hard X-ray flare rate. Bull Am Astronom Soc 1984; 16: 891.
152
Bogart RS, Bai T. Confirmation of a 152-day periodicity in the occurrence of
solar flares inferred from microwave data. Astrophys J 1985; 299: L51-L55.
152-158 Dennis BR. Solar hard X-ray bursts. Solar Physics 1985; 100: 465-490.
152
Bai T, Sturrock PA. The 152-day periodicity of the solar flare occurrence rate.
Nature 1987; 327: 601-604.
near 155
Lean JL, Brueckner GE. Intermediate-term solar periodicities -- 100-500 days.
Astrophys J 1989; 337: 568-578.
152
Özgüç A, Ataç T. Periodic behavior of solar flare index in solar cycles 20 and
21. Solar Physics 1989; 123: 357-365.
154 (± 0.6)
Bai T, Cliver EW. A 154 day periodicity in the occurrence rate of proton
flares. Astrophys J 1990; 363: 299-309.
near 155
Carbonell M, Ballester JL. A short-term periodicity near 155 day in sunspot
areas. Astron Astrophys 1990; 238: 377-381.
153
Dröge W, Gibbs K, Grunsfeld JM, Meyer P, Newport BJ, Evenson P, Moses
D. A 153 day periodicity in the occurrence of solar flares producing energetic
interplanetary electrons. Astrophys J Suppl Ser 1990; 73: 279-283. Applying
Rayleigh test for periodicity.
155
Silverman SM. The 155-day solar period in the sixteenth century and later.
Nature 1990; 347: 365-367. "[A]lthough values between 150 and 160 days have
been reported, I refer to it here as the 155-day period, for convenience"
154
Bai T, Sturrock PA. The 154-day and related periodicities of solar activity as
subharmonics of a fundamental period. Nature 1991; 350: 141-143.
173
Period
(in days, except
where noted)
Reference
154
Kile JN, Cliver EW. A search for the 154 day periodicity in the occurrence rate
of solar flares using Ottawa 2.8 GHz burst data, 1955-1990. Astrophys J 1991;
370: 442-448.
152-158
Verma VK, Joshi JC, Uddin W, Paliwal DC. Search for a 152-158 days
periodicity in the occurrence rate of solar flares inferred from spectral data of
radio bursts. Astron Astrophys Suppl Ser 1991; 90: 83-87.
near 155
Carbonell M, Ballester JL. The periodic behaviour of solar activity: the near
155-day periodicity in sunspot areas. Astron Astrophys 1992; 255: 350-362.
152
Verma VK, Joshi JC, Paliwal DC. Study of periodicities of solar nuclear
gamma ray flares and sunspots. Solar Physics 1992; 138: 205-208.
154
Bai T, Sturrock PA. Evidence for a fundamental period of the sun and its
relation to the 154 day complex of periodicities. Astrophys J 1993; 409: 476-
486.
151-155
Lou YQ. Rossby-type wave-induced periodicities in flare activities and
sunspot areas or groups during solar maxima. Astrophys J 2000; 540: 1102-
1108.
153.9
Hady AA. Analytical studies of solar cycle 23 and its periodicities. Planetary
and Space Science 2002; 50: 89-92.
near 160
Ballester JL, Oliver R, Carbonell M. The near 160 day periodicity in the
photospheric magnetic flux. Astrophys J 2002; 566: 505-511.
near 5-month
Han Yanben, Han Yonggang. Time variation of the near 5-month period of
sunspot numbers. Chinese Sci Bull 2002; 47 (23): 1967-1973. "Many scholars ...
found similar periods of solar activity from other observations of the Sun. However,
these periods are different, such as about 152-, 154-, 156-day, etc. Here we name it a
near 5-month period (N5MP) since it is not definite."
153
Bai T. Periodicities in solar flare occurrence analysis of cycles 19-23.
Astrophys J 2003; 591: 406-415.
near 160
Ballester JL, Oliver R, Carbonell M. Return of the near 160 day periodicity in
the photospheric magnetic flux during solar cycle 23. Astrophys J 2004; 615:
L173-L176.
This incomplete list (added contributions are cited in the references provided) suffices to indicate
the variable nature of the period being discussed. Specifications of the solar (Schwabe) cycle in
which they are found point indirectly to the intermittency of the components being discussed.
174
17
T:\SKRIPTA\SIEGELOVÁ 2009\PODKLADY\08-Aeolian.doc
Wednesday, July 1, 2009 8:07:28
Table 4. Do we need more than heating and air conditioning? Do we have to compensate for magnetics?
Periodicities in human electrocardiograms show a circa-cis-semiannual (cis-halfyear) cycle matching the rhythm of hard solar flares,
but no transyear, in one about10-year Schwabe cycle stage and vice versa in another stage: in most of various cardiac arrhythmias, a
transyear (TY) is prominent during a span of maximal solar activity (1989–1990) and a cis-halfyear during the descending phase of
solar cycle #22 (1983–1984)*
Arrhythmia Period = 1 y TY (trial period = 1.3 y) Cis-halfyear (trial period = 0.42 y)
P A φ Period (95% CI) A (95% CI) Period (95% CI) A (95% CI)
1983-1984
S 0.034 0.058 -234 0.932 0.647 1.216 0.06 0.00 0.13 0.431 0.400 0.462 0.11 0.04 0.18
Ps 0.079 0.042 -228 0.974 0.605 1.343 0.04 -0.02 0.10 0.439 0.413 0.464 0.12 0.06 0.17
V1 0.002 0.087 -207 1.024 0.760 1.288 0.09 0.01 0.16 0.432 0.401 0.463 0.12 0.05 0.20
Vm 0.034 0.056 -214 1.000 0.647 1.353 0.06 -0.01 0.12 0.438 0.408 0.467 0.11 0.05 0.18
Pv 0.255 0.008 -70 1.000 0.484 1.516 0.00 0.00 0.02 – – – – – –
Pp 0.151 0.009 -230 1.000 0.546 1.454 0.00 0.00 0.02 – – – – – –
1989-1990
S 0.386 0.024 -11 – – – – – – 0.528 0.456 0.599 0.06 0.00 0.11
Ps <0.001 0.069 -64 1.347 1.042 1.652 0.09 0.03 0.14 – – – – – –
V1 0.001 0.103 -66 1.439 1.044 1.834 0.13 0.04 0.22 – – – – – –
Vm 0.162 0.036 -67 1.690 0.979 2.400 0.10 0.04 0.15 – – --- – – –
Pv 0..826 0.003 -5 – – – – – – 0.361 0.331 0.390 0.02 0.00 0.04
Pp 0.095 0.016 -4 1.289 0.879 1.700 0.02 0.00 0.05 – – – – – –
*Data from Tbilisi (Georgia) from Dr Levan Tvildiani. P: P-value from zero-amplitude (no-rhythm) test; A: Amplitude (in number of
cases per day); φ: Acrophase, in (negative) degrees, with 360° period length; 0°= 1 Jan 1983. S: supraventricular extrasystoles; Ps:
supraventricular paroxysmal tachycardia; V1: ventricular single extrasystoles; Vm: ventricular multiple extrasystoles; Pv: paroxysmal
ventricular tachycardia; Pp: paroxysm of atrial fibrillation. A cycle with a period shorter than a half-year, also found in Wolf's relative
sunspot numbers (see Cornélissen et al. 2005I) spectra on page S7 and described for hard solar flares by Rieger A. et al. 1984. If we
find out how precisely these cosmic, perhaps solar, signatures act, we may shield from, or rather compensate for their unseen and not
obviously identified effects as need be.
175
CIRCADIAN AND CIRCASEPTAN STAGE DETERMINE MISDIAGNOSES
(PSEUDO-HYPERTENSION, PSEUDO-WHITE-COAT HYPERTENSION
AND PSEUDO-NORMOTENSION)
Germaine Cornélissen1
, Franz Halberg1
, Kuniaki Otsuka2
, Yoshihiko Watanabe2
,
Jarmila Siegelova3
, Jiri Dusek3
, Pavel Homolka3
, Pavel Prikryl3
, Bohumil Fiser3
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
Masaryk University, Brno, Czech Republic
A cardiologist (YW) was found to have MESOR-hypertension (MH) in the last 5 months of
around-the-clock blood pressure (BP) and heart rate (HR) monitoring at half-hourly intervals with
interruptions, continuing for 22 years (1). MH was present on workdays, absent on Sundays and
during a vacation (i.e., it was a workday-MH) (1). This finding on a physician constitutes a true
“white-coat” hypertension. It constitutes a hint that with continuous BP and HR monitoring,
chronobiology may perhaps develop criteria to determine whether the response to a "stimulus"
(such as the everyday tasks of a cardiologist) is desirable (benetensive) or undesirable (maletensive)
(2). In any event, this observation by Professor Watanabe documents that the diagnosis of MH can
depend on the day of the week. Continuous chronobiologically-interpreted BP and HR monitoring
may reflect Sir William Osler's "wear and tear" (3) and may serve to measure Hans Selye's (4)
brilliant, genial, but as yet anecdotal separation of stress (wear; by stressors, in Selye's terminology)
and strain, which may be welcome, as eustress, or undesirable if not harmful, as distress (tear), and
to which Paul Rosch has added his scholarship in bioelectromagnetism (5).
Disciplined systematic self-measurements of BP and HR were and are feasible with
conventional manually handled sphygmomanometers and were highly recommended in the absence
of automatic monitors (6, 7). Automatic self-surveillance is easier and cost-effectively affordable
when monitors are acquired by a circle of family and friends with cost-free analyses. With this
opportunity currently offered by a project on The BIOsphere and the COSmos, there is no
justification for a spotcheck diagnosis, even when the spotcheck includes a 24-hour profile (8).
From the viewpoint of circadian rhythms, a 24-hour BP profile covers only a single cycle and from
176
the viewpoint of the many infradian cycles, it covers only a very small fraction of a cycle, as if one
took the pulse for only one second or for a small fraction of a second, respectively! A tabula rasa
eliminating single BP measurements and even a single 24-hour profile is essential to reduce the
large number of misdiagnoses. Reliance on a minimum of 7-day/24-hour records must be insisted
on to validate health, whereas added weeks of monitoring are essential to confirm a diagnosis in the
presence of abnormalities, such as vascular variability disorders (VVDs), and certainly to monitor
the response to treatment. VVDs include MH. The reliable estimation of a BP-MESOR (short for
Midline-Estimating Statistic Of Rhythm) is desirable to eliminate the blunders resulting from
differences found as a function of the time of day of BP measurement in current conventional care
delivery. Failure to consider the usually prominent circadian rhythm in BP leads to the
misdiagnoses of hypertension, white-coat hypertension, and masked hypertension, pseudodiagnoses
resting on the quagmire of a single 24-hour profile that disregards the often present large
day-to-day variability in BP, and hence eliminates neither false-positive nor false-negative
diagnoses.
Figure 1 (9) shows theoretically that given systolic/diastolic (S/D) BP MESORs of 130/80
mmHg, the circadian rhythm results in contradictory diagnoses in the morning's vs. the afternoon's
office hours, as documented also by a clinical example, Figure 2 (10). When the “white-coat”
happens to be dental surgery performed on diurnally-active, nocturnally-resting patients, systolic or
mean arterial white-coat hypertension in the morning can be white-coat hypotension in the
afternoon, Figure 3, the difference in BP response being statistically significant. Somewhat similar
results are observed for DBP and HR, Figure 3. In each case, the response to periodontal surgery
was assessed for the given patient, taking into consideration both that patient’s usual circadian
variation in BP and HR on days and at times other than surgery, and the effect of posture, patients
being mostly in a reclined position during periodontal surgery (11, 12).
The data underlying Figure 3 stem from a study completed for an advanced degree by Frank Raab,
DDS (11, 12, cf. 13), which included 24 presumably normotensive patients. Each patient had 3 dental
appointments, the last one consisting of periodontal surgery. Consecutive appointments were kept at the
same clock hour for each patient but differed among patients, with 6 groups of originally 4 patients each seen
at one of 6 different clock hours. (Only one did not complete the first stage of the study.) Clinic hours were
slightly extended to accommodate the study. Each appointment was bracketed with ambulatory BP and HR
monitoring at 15-minute intervals, first for 4 days, then for 2 days, and finally for 3 days. During each
appointment, measurements were taken more often, and at the end of the last appointment, additional dense
177
measurements were taken in the supine and sitting position in order to make adjustments for the effect of
posture when analyzing the data.
The response in BP and HR was determined as follows: Data during appointments were removed
from each record to assess the circadian variation and to estimate values the BP and HR would have assumed
at appointment times, were they taken under similar ordinary conditions. Data during appointments,
corrected for posture, were averaged for each patient at each appointment. The response in BP and HR was
determined as the difference between the actual (corrected) values during the last appointment (periodontal
surgery) and the estimated value these variables would have been under usual conditions, Figure 3.
Because patients were randomly assigned to 6 different appointment times and because a circadian
stage-dependent response rhythm was anticipated, the change in BP and HR seen in each patient could be
assigned to the treatment time. The time effect is statistically significant, whether responses from all 23
patients were analyzed by one-way analysis of variance (a procedure checking only for a time effect without
assuming a model, i.e., a necessarily circadian variation) or by the cosinor fit of a 24-hour cosine curve (14-
16, a method assuming that the response follows a circadian variation), Figure 3. Patients having surgery in
the morning have an increase in their BP and HR during surgery (“White-Coat HYPERtension”), whereas
patients having surgery in the afternoon have a decrease in their BP and HR during surgery (“White-Coat
HYPOtension”). Whether the response of a variable is an increase or decrease depends on both the subject's
genetics (17) and social schedule. When specifying a time of day, one must specify the routine of living with
respect to the circadian system, such as diurnal activity and nocturnal rest, as was the case in this study. From
the viewpoint of infradian rhythms, it is also important to note the calendar date, with particular reference to
any magnetic storm or excessive magnetic quiet (18).
With respect to the circadian stage-dependent response of BP and HR to a “white coat” in
preparation for periodontal surgery, there was an intervention of greater severity than the exposure
to a care provider, and hence the response may be more than a mere "white-coat effect". The results,
however, are similar to those seen for a white-coat effect uncomplicated by an anticipated
intervention. This is demonstrated in Figure 4, based on single casual measurements taken in the
care office in the physician's presence that are compared with measurements taken 30 minutes later
in the physician's absence. In the morning, the white-coat effect was an average rise in BP of a
magnitude of about 20 mmHg. By comparison, comparable patients seen in the afternoon around
16:00 had an average white-coat effect of only 6 mmHg magnitude. The difference in response is
statistically significant (P=0.005). These results are averages, and some patients seen in the
afternoon actually responded by a decrease in SBP in the physician's presence, just like the dental
patients undergoing periodontal surgery. This is actually what happened for HR that increased by 3
178
beats/min for patients seeing the physician in the morning but decreased by 4 beats/min for patients
seeing the same physician in the afternoon.
Great inter-individual differences (19, 20) also need to be considered. As an illustrative
example, Figures 5 and 6 show that not all subjects respond to sodium loading with an increase in
BP. Not only are there some subjects who have no statistically significant change in BP, but some
subjects also respond with a decrease in BP. Moreover, the response to sodium intake is also
circadian stage-dependent. In a study by Kawasaki et al. (21), the usual daily salt intake was
redistributed to have either higher intake at lunch and lower intake at dinner or vice versa. BP was
measured by ambulatory monitoring. As compared to the span when subjects had their usual salt
intake, there was only a small numerical (not statistically significant) increase in both SBP and DBP
when these subjects had the same total daily salt intake but with a higher amount at lunch and a
smaller amount at dinner. By contrast, when sodium intake was reduced at lunch and increased at
dinner, both the SBP and DBP of these subjects were statistically significantly decreased, Figure 7.
This finding must eventually further consider the also statistically significant inter-individual
differences which we found with Frederic C. Bartter on his metabolic ward at the NIH, Figures 5
and 6 (10).
Concern about variability has merit far beyond its role in clarifying reasons for opposite or
differing diagnoses or differences in dietary responses. Assessing variability in BP and HR
uncovers risks of vascular morbid events assessed from actual outcomes within 6 years of the
monitoring session. In addition to MH, other VVDs that are not currently screened for can increase
vascular disease risk from about 5% to about 100%. This fact in itself warrants the determination of
minimal sampling requirements, starting with a 7-day record in health and deserving continuous
monitoring when abnormality is detected, as apparent from a follow-up study of the dental patients,
Figure 8 (13).
The need for the minimal sampling requirement of one week becomes further apparent from
a 7-day BP record of measurements every half-hour by day and every hour by night. The data stem
from a 70-year old Japanese woman obtained within the scope of the BIOCOS project. By
comparison to reference standards from peers matched by gender and age, her circadian SBP
characteristics were acceptable overall as well as during the first 3 days of monitoring, but were
abnormal during the last 4 days when systolic CHAT (Circadian Hyper-Amplitude-Tension) was
diagnosed each day, Figure 9. Whether the goal is to improve the reliability of a diagnosis of a
179
VVD, to guide treatment, or equally importantly to practice "stress relief", novel endpoints of
response are needed, such as the parameters of the many rhythms characterizing physiologic
variables. Their alterations can serve to indicate earliest harbingers of risk elevation. A conventional
stress test cannot invariably be a valid substitute (22). By detecting VVDs, the foe in terms of
misdiagnosis becomes the friend by warning of increased risks, which await further testing on an
appropriate scale. But the evidence already available (23) suffices to suggest that we must not fly
blind (24, 25). A true white-coat hypertension is now documented in a cardiologist on himself (1).
As to pseudo-hypertension and pseudo-white-coat hypertension, they are interim misdiagnoses
prompting us to note that the first motto of health care is "Do no harm". Harm can be done when
patients who are mistreated (in that the treatment induces a VVD) are placed at a higher risk and
when patients in need of treatment do not get it, even if, on the average, there is some benefit to be
anticipated from a polypill given to everyone above a certain age without measuring BP (26-28).
“Flying blind” is bound to hurt some patients!
Acknowledgement: The authors are indebted to Professor Paul Rosch for an essay that prompted the
consideration of pseudo-white-coat hypertension and of the different, sometimes opposite effects of
sodium intake.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
180
1. Watanabe Y, Cornélissen G, Beaty LA,Siegelova J, Fiser B, Dusek J, Homolka P, Halberg F.
White-coat hypertension in a cardiologist: Decades of monitoring lead to transient
occupational MESOR-hypertension absent during vacation: strain test. This issue.
2. Halberg F, Cornélissen G, Spector NH, Sonkowsky RP, Otsuka K, Baciu I, Hriscu M,
Schwartzkopff O, Bakken EE. Stress/strain/life revisited. Quantification by blood pressure
chronomics: benetensive, transtensive or maletensive chrono-vasculo-neuro-immunomodulation.
Biomed & Pharmacother 2003; 57 (Suppl 1): 136s-163s.
3. Osler W (Ed.) Modern medicine: its theory and practice. Vol 4: Diseases of the circulatory
system diseases of the blood diseases of the spleen, thymus and lymph-glands.
Philadelphia: Lea and Febiger; 1908. p. 430-443.
4. Selye H. Stress without Distress. Philadelphia/New York: J.P. Lippincott; 1974. 171 pp.
5. Rosch PJ, Markov MS (Eds.) Bioelectromagnetic Medicine. New York: Marcel Dekker; 2004.
850 pp.
6. Halberg F, Johnson EA, Nelson W, Runge W, Sothern R. Autorhythmometry procedures for
physiologic self-measurements and their analysis. Physiol Tchr 1972; 1: 1-11.
7. Levine H, Halberg F. Circadian rhythms of the circulatory system. Literature review.
Computerized case study of transmeridian flight and medication effects on a mildly
hypertensive subject. U.S. Air Force Report SAM-TR-72-3. Brooks AFB, Texas: USAF
School of Aerospace Medicine, Aerospace Medical Division (AFSC); April 1972. 64 pp.
8. Halberg F, Cornélissen G, Wall D, Otsuka K, Halberg J, Katinas G, Watanabe Y, Halhuber M,
Mueller-Bohn T, Delmore P, Siegelova J, Homolka P, Fiser B, Dusek J, Sanchez de la Pena S,
Maggioni C, Delyukov A, Gorgo Y, Gubin D, Carandente F, Schaffer E, Rhodus N, Borer K,
Sonkowsky RP, Schwartzkopff O. Engineering and governmental challenge: 7-day/24-hour
chronobiologic blood pressure and heart rate screening. Biomedical Instrumentation &
Technology 2002: Part I, 36: 89-122; Part II, 36: 183-197.
9. Cornélissen G, Halberg F. Impeachment of casual blood pressure measurements and the fixed
limits for their interpretation and chronobiologic recommendations. Ann NY Acad Sci 1996;
783: 24-46.
10. Bartter FC. Periodicity and medicine. In: Scheving LE, Halberg F, Pauly JE (Eds.)
Chronobiology. Tokyo: Igaku Shoin Ltd.; 1974. p. 6-13.
11. Raab FJ II. Automatic ambulatory monitoring of circadian blood pressure and heart rate
variations associated with periodontal therapy. M.S. Thesis, University of Minnesota, March
1992, 88 pp. + tables and figures.
12. Raab FJ, Schaffer EM, Guillaume-Cornélissen G, Halberg F. Interpreting vital sign profiles
for maximizing patient safety during dental visits. JADA 1998; 129: 461-469.
13. Schaffer E, Cornélissen G, Rhodus N, Halhuber M, Watanabe Y, Halberg F. Blood pressure
outcomes of dental patients screened chronobiologically: a seven-year follow-up. JADA 2001;
132: 891-899.
14. Halberg F, Tong YL, Johnson EA. Circadian system phase – an aspect of temporal
morphology; procedures and illustrative examples. Proc. International Congress of Anatomists.
In: Mayersbach H v (Ed.) The Cellular Aspects of Biorhythms, Symposium on Biorhythms.
New York: Springer-Verlag; 1967. p. 20-48.
15. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
181
16. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692.
17. Sothern RB, Cornélissen G, Yamamoto T, Takumi T, Halberg F. Time microscopy of
circadian expression of cardiac clock gene mRNA transcription: chronodiagnostic and chronotherapeutic
implications. La Clinica Terapeutica 2009; 160 (2): e25-e34.
18. Halberg F, Cornélissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles
tipping the scale between death and survival (= "life"). Progress of Theoretical Physics 2008;
Suppl. 173: 153-181.
19. Bittle CC, Molina DJ, Bartter FC. Salt sensitivity in essential hypertension as determined by
the cosinor method. Hypertension 1985; 7: 989-994.
20. Cornélissen G, Kawasaki T, Uezono K, Delea C, Halberg F. II: Blood pressure rhythms and
salt. Ann Ist Super Sanita 1993; 29: 667-677.
21. Kawasaki T, Itoh K, Cugini P. Influence of reapportionment of daily salt intake on circadian
blood pressure rhythms in normotensive subjects. J Nutr Sci Vitaminol 1994; 40; 459-466.
22. Halberg F, Rosch P, Cornélissen G. Acceptable conventional stress test outcome may not
dispel indications of a sphygmochron. This issue.
23. Halberg F, Cornélissen G, Otsuka K, Siegelova J, Fiser B, Dusek J, Homolka P, Sanchez de la
Pena S, Singh RB, BIOCOS project. Extended consensus on means and need to detect
vascular variability disorders (VVDs) and vascular variability syndromes (VVSs). LeibnizOnline
Nr. 5, 2009 (http://www.leibniz-sozietaet.de/journal). 35 pp.
24. Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka K, Watanabe Y, Kumagai Y,
Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff O. Circadian HyperAmplitude-Tension,
CHAT: a disease risk syndrome of anti-aging medicine. J Anti-Aging
Med 1998; 1: 239-259.
25. Fossel M. Editor's Note (to Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka K,
Watanabe Y, Kumagai Y, Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff O.
Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging medicine.
J Anti-Aging Med 1998; 1: 239-259). J Anti-Aging Med 1998; 1: 239.
26. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of
cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations
from prospective epidemiological studies. BMJ 2009; 338:b1665. doi:10.1136/bmj.b1665.
27. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ
2003; 326: 1419. doi:10.1136/bmj.326.7404.1419.
28. McManus RJ, Mant J. Management of blood pressure in primary care. BMJ 2009; 228:b940.
doi:10.1136/bmj.b940.
182
Figure 1. Abstract demonstration that for variables such as blood pressure that are usually
characterized by a prominent circadian rhythm, the time of day can determine the diagnosis:
normotension in the morning vs. hypertension in the afternoon when fixed limits are used to
interpret single time-unspecified measurements. © Halberg.
183
Figure 2. Clinical documentation that the diagnosis of normotension vs. hypertension can depend on
the time of day of the blood pressure measurement(s), as illustrated in the abstract in Figure 1. ©
Halberg.
184
Figure 3. “White-coat hypertension” in the morning can be “White-coat hypotension” in the
afternoon. In this study of dental patients, the “white-coat” effect is more than a response to the
physician’s presence, consisting of periodontal surgery. © Halberg.
185
Figure 4. Regular uncomplicated “white-coat” effect. © Halberg.
186
Figure 5. Inter-individual differences in response to sodium intake. © Halberg.
187
Figure 6. Inter-individual differences in response to sodium intake. © Halberg.
188
Figure 7. Circadian stage-dependent effect of sodium intake. © Halberg.
189
Figure 8. Follow-up study on dental patients, with focus on outcomes 7 years after monitoring
assessed in two recalls (I and II, left and middle). No untoward event occurred among patients with
blood pressure abnormality in two, one or none of the sessions, whereas both patients who
experienced a vascular problem had been diagnosed with CHAT and/or other abnormalities in all
three sessions (13). The prognostic value of a consistently (in three of three sessions) deviant
chronobiological assessment is illustrated by the relative risk obtained as the ratio of incidences
between the two groups being compared (right). P-values were derived using Fisher exact test. N:
Number. CI: Confidence interval. © Halberg.
190
40
80
120
160
200
4/7/09
00:00
4/8/09
00:00
4/9/09
00:00
4/10/09
00:00
4/11/09
00:00
4/12/09
00:00
4/13/09
00:00
4/14/09
00:00
4/15/09
00:00
Time (calendar date)
SystolicBloodPressure(mmHg)
24-hour double amplitudes (mmHg):
18.1 19.2 20.6 40.8* 43.7* 36.9* 51.6*
* CHAT
Ura0244 (F, 70y)
Figure 9. The need to determine minimal sampling requirements is illustrated by this case of a 70year
old Japanese woman who was monitored around-the-clock for 7 days. Overall, all parameters
are within acceptable limits of clinically healthy peers matched by gender and age. Day-to-day
analyses, however, indicate the presence of CHAT during each of the last 4 days but not during the
first 3 days of monitoring. © Halberg.
191
E. CASE REPORTS
AMPLITUDE RATIOS OF HALF-WEEKLY VS. DAILY VARIABILITY
IN DIASTOLIC BLOOD PRESSURE IN PUTATIVE MAGNETOLABILITY
Franz Halberg1
, Tomoshige Kino2
, Jarmila Siegelova3
, Pavel Homolka3
, Judy Finley1
,
Germaine Cornélissen1
, Jiri Dusek3
, Bohumil Fiser3
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Program in Reproductive and Adult Endocrinology, National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda, MD, USA
3
Masaryk University, Brno, Czech Republic
Aim. To find whether a set of self-measurements at about half-hourly intervals covering a
week from a presumably magnetolabile 61-year-old woman (JF) has any spectral alteration of
systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) variabilities, reference ranges
were computed, among others, for the ratios of the half-weekly vs. daily extent of change (double
amplitude, 2A) approximated by the separate fits of 84-hour and 24-hour cosine curves. JF's DBP
ratio was found to be outside the 95% prediction interval (PI) for 84-hour/24-hour A ratios of 178
week-long records from Brno, Czech Republic. It was also outside the PI computed on the basis of
the 49 records from women in Brno. Results were replicated in a second weeklong record of
measurements at 3-hour intervals. A histogram computed for the foregoing purpose may be of more
general use as a reference standard and will have to be refined by age, ethnicity and geography.
Case Report. Figures 1A-1C are chronobiologic serial sections for SBP, DBP and HR. The
original self-measurements are in the top row. Statistical significance from the zero-24-hour
amplitude (no circadian rhythm) test is given in the penultimate row of P-values, with a dashed line
indicating P=0.05. An interval of 24 hours was used for analyses, displaced by 3-hour increments,
for the least-squares fit of a 24-hour cosine curve. A circadian rhythm is demonstrated most of the
time (P<0.05) for HR (Figure 1C), also seen from the dots bracketing most of the 24-hour HR
acrophases (third row of Figure 1C). As acrophases are circular variables, they are double plotted,
their uncertainties overlapping 360˚. In Figures 1A-C, the MESOR (M; midline-estimating statistic
of rhythm) is displayed as the lower curve in the second row. The distance between the two curves
192
represents the circadian amplitude. Dots below the lower curve and above the upper curve are the
standard errors for M and A, respectively. In the case of SBP, statistical significance is reached only
part of the time during the first few days (Figure 1A). A circadian rhythm in DBP is only detected
with statistical significance in very few intervals (Figure 1B). The relatively dense selfmeasurements
notwithstanding, there is a failure to demonstrate a circadian rhythm in BP most of
the time. The acrophases drift but little, and only for BP when the circadian rhythm is statistically
significant. Overall, a circadian rhythm is demonstrable nonlinearly by the extended cosinor for all
three variables, Table 1.
When data are stacked over an idealized 24-hour span, they are within the limits of Caucasian
peers matched by gender and age for SBP and DBP (Figures 2A and 2B), and are partly below the
lower 5% prediction limit for HR (Figure 2C). Figure 3 allows a comparison of the three variables
on consecutive days, while Figure 4 shows a spectral alteration found in JF, also found in a
subsequent weeklong record of measurements at 3-hour intervals.
BIOCOS. In the course of a project on The BIOsphere and the COSmos (BIOCOS), automatic
series of BP and HR were obtained at half-hourly intervals for 7 days, among others, on 178
patients in Brno. Whereas some were treated, most of them were clinically healthy and followed
their usual routine of daily activity and nocturnal rest. A cosinor spectrum (1-4) was computed for
each series linearly in frequency in the frequency range of 1 cycle in 7 days to 1 cycle in 4.8 hours.
For the construction of a reference database, 178 weeklong records from Brno were used. The
circadian (CD) and circasemiseptan (CSS) As of SBP and DBP were estimated and their ratios were
computed as CSS-A/CD-A and log10-transformed to preserve symmetry. Histograms validate the
approximate normality of the distribution of the log-transformed A ratios.
The CSS-A/CD-A of SBP, DBP and HR values from JF (9-15 June 2009) were similarly
computed. For BP but not for HR, the CSS-A/CD-A is larger than unity, estimated as 1.065 (0.027)
and 1.576 (0.198) for SBP and DBP, respectively (log10-transformed ratios given in parentheses).
In order to determine whether these ratios are larger than usually seen, PIs were determined
from the Brno database. Using data from all 178 profiles, the average log10(CSS-A/CD-A) and PI
are estimated as -0.552 [-1.220, 0.117] for SBP and -0.547 [-1.188, 0.093] for DBP. In view of
193
known gender differences in average BP, PIs were also computed on the basis of data from women
only, yielding estimates of log10(CSS-A/CD-A) and PI of -0.418 [-0.982, 0.146] and -0.551 [-1.110,
0.008] for SBP and DBP, respectively. Since some of the women in the database were on antihypertensive
medication, limits were computed for untreated and treated women separately,
yielding means and PIs of -0.486 [-1.043, 0.070] and -0.352 [-0.935, 0.230] for the SBP of
untreated and treated women, respectively. For DBP, results were -0.569 [-1.072, -0.067] and
-0.533 [-0.-1.171, 0.105], respectively, Figure 4. Whereas the log10(CSS-A/CD-A) of SBP of JF
invariably resides within the PI of the reference database, that of DBP is always larger than the
upper 95% prediction limit. The untreated women contributing data in the reference database were
on the average 45.6 ± 12.1 (SD) years of age (range: 20-70 years). The treated women were on the
average 54.2 ± 12.8 years of age (range: 20-77 years). JF is 61 years of age and takes 50 mg
spironolactone, an antihypertensive medication, between 5am and 6am and again upon awakening,
which recurred on a presumably free-running sleep-wake schedule progressively from 5pm to 9pm
during the span of measurements. These results were replicated in a second weeklong record of
measurements every 3 hours, with CSS-A/CD-A ratios of 1.383 (0.141) and 1.785 (0.252) for SBP
and DBP, respectively.
Several factors may have contributed to the unusually larger circasemiseptan-than-circadian
prominence in JF’s BP, notably for DBP that exceeds the upper 95% prediction limit of peers. First,
data were collected with a manual monitor that required waking up to take measurements during the
rest span. Such a procedure is usually associated with higher BP readings, a fact contributing to a
smaller circadian amplitude, since BP is usually lower during sleep. Moreover, in a comparison of
self-measurements with automatic monitoring, there can be differences (5). Second, the rest-activity
schedule of JF may also have been unusual, the rest span occurring at times differing from those of
the reference population. It also may have differed from one day to another (although no deviation
from 24 hours was found by nonlinear analyses of the data), another fact that can be expected to be
accompanied by a smaller circadian amplitude. It is not likely that the actual number of
measurements may have played a role: with 233 data collected during a week, this represents almost
70% of a full 7-day/24-hour record obtained automatically by ambulatory BP monitoring.
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Circaseptan-to-circadian and circasemiseptan-to-circadian amplitude ratios are known to vary
as a function of age, being larger early and late in life (6). At 61 years of age, JF is not expected to
have a reversal of the circadian-to-infradian prominence yet. They are also known to differ between
clinically healthy subjects and individuals with a depressed mood, the latter having a larger
infradian prominence than the former (7). Whether the infradian prominence relates to
magnetolability and/or to a state of not feeling well which has a tendency to recur in JF without any
known underlying medical reason will require further monitoring, if not continued surveillance.
Affordable automatic monitoring devices are urgently needed for this purpose so that the circadian
variation can be assessed without the need to disturb the rest/activity cycle known to influence BP.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
1. Halberg F. Chronobiology. Annu Rev Physiol 1969; 31: 675-725.
2. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
3. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.). Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
4. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692.
5. Stinson SM, Cornélissen G, Scarpelli PT, Halberg F. Self-measurement and ambulatory
monitoring of blood pressure: a subject's chronobiological perspective. Biomed &
Pharmacother 2002; 56 (Suppl 2): 333s-338s.
6. Gubin D, Cornélissen G, Halberg F, Gubin G, Uezono K, Kawasaki T. The human blood
pressure chronome: a biological gauge of aging. In vivo 1997; 11: 485-494.
7. Yamanaka G, Otsuka K, Hotta N, Murakami S, Kubo Y, Matsuoka O, Takasugi E, Yamanaka
T, Shinagawa M, Nunoda S, Nishimura Y, Shibata K, Saitoh H, Nishinaga M, Ishine M, Wada
T, Okumiya K, Matsubayashi K, Yano S, Ishizuka S, Ichihara K, Cornélissen G, Halberg F.
195
Depressive mood is independently related to stroke and cardiovascular events in a community.
Biomed & Pharmacother 2005; 59 (Suppl 1): S31-S39.
196
Appendix: Self-description by JF, a putative magnetolabile woman
JF is a 61 year old Caucasian female who had a seemingly healthy childhood. She was reared in a
stable home with two younger siblings, a stay-at-home mother, and a supporting blue-collar father. Social
life was built around the church. Some maternal conflict based on personality differences occurred, but home
life was mostly problem-free. School was a joy; grades were high.
JF married immediately following high school and continued her education by studying with her
husband in his work on two graduate degrees. Early marriage was spent mothering two daughters and
working in the churches where her husband served as pastor. Her healthiest time was during both
pregnancies.
In the early 1980s JF and her husband founded an itinerant speaking and writing ministry that involved
extensive national and international travel. JF found the ministry fulfilling and enjoyed the intensity of the
travel. It was a mystery, however, why she could hike through busy airports one week without any problems,
and in other weeks was hampered by leg and foot pain so intense that she could barely make it past two gates
without stopping for a break. Observing the tides during an extended stay on the beach helped: she was able
to hike miles along the sandy beach during the weeks midway between the new moon and the full moon, and
between the full moon and the new moon; but near both the times of the full and new moon she was barely
able to make it to the shore. Subsequently, this knowledge helped predict JF's ability to hike in airports.
Sometime in the late 1980s JF began to be unable to meet some of the travel demands. By 1990 her
husband detected two specific time spans of her inabilities: Jan/Feb and Jun/Jul/Aug. Since the apparent
semimonthly change seemed to have a geomagnetic connection, they first connected these spans with the
solstices, but the timings seemed more consistent with the perigee and apogee of the earth's revolution
around the sun. This knowledge was employed in scheduling engagements and also proved thoroughly
faithful to predict JF's inability to participate if engagements were scheduled during the two seasonal spans.
By 2000 JF's very predictable semiannual physical symptoms that rendered her unable to function were
dominating her life and the new inclusion of seizure-like events prompted serious evaluation. To provide
better health insurance, JF's husband decided to take a hiatus from the traveling part of their ministry and
secure part-time employment with a local firm that provides excellent medical coverage to part-time
employees. While the medical help received during the following years provided relief from many
symptoms, nobody was able to address the semiannual spans of abnormal sleep. JF decided to turn to science
and to research as much as possible to find solutions.
On May 15, 2005, JF experienced many of the semiannual symptoms including muscle twitches,
diagnosed as a myoclonus seizure. This was the first time JF experienced these symptoms outside of the
Jan/Feb and Jun/Jul/Aug time periods. Later she observed a news article about an extreme solar storm that
had occurred on that day. Once again a geomagnetic event appeared to trigger JF's symptoms and the
planetary k-index became a dependable indicator for minor symptoms throughout the year and for intensified
symptoms during the two semiannual time spans of illness.
197
By February 2009 JF and her family were beginning to sense that her older daughter (age 41) was
experiencing some of the same semiannual changes that JF experienced at her age. These symptoms on a
lesser level of intensity were also occurring in conjunction with an increase in the planetary k-index.
Suspicion had also arisen that increases in the Kp were the cause of JF's granddaughter (age 2) awakening
from her normal full night of sleep for no apparent reason desiring nothing more than to play.
Circasemiannual Cycle in JF's Health?
As JF has sought medical help for the myriad symptoms manifested during the semiannual time
periods of Jan/Feb and Jun/Jul/Aug, it has become very clear that what ever is occurring during those time
periods creates a break down in her immune system. Several documented events of poor health in JF's earlier
years consistently fall into one of the two time periods:
Jun 1953 Mumps
Jan/Feb 1954 Hospitalization for kidney infection after 2 weeks of strep throat and sulfa drug
treatment
Jun 1967 Kidney infection following birth of first child
Jun or Jul 1977-81 Repeated vaginal yeast infections
Jun 1985 Sought help from gynecologist for exhaustion and headaches
Jun 1986 Sought help from care giver for exhaustion and headaches
The multiple symptoms that occur and reoccur only during the semiannual cycles make it difficult to
isolate the exact root cause of the problems. JF has been diagnosed and treated for carpal-tunnel syndrome,
chronic fatigue syndrome, rheumatoid arthritis, kidney stones, myoclonus seizures, and meningitis induced
by cytomegalovirus. She has been repeatedly placed on and taken off thyroid medication and has exhibited
insulin resistance. Just recently she was tested for Vitamin D deficiency and found to be deficient. When
each of these diagnoses was treated, there was improvement in the severity of her semiannual time spans of
illness.
With these multiple symptoms treated, the following remains steadfast and untreated:
The onset of a semiannual "cycle" usually begins at a full moon or new moon with the following two weeks
of complete exhaustion and sleeping day and night. Then a 7-9 hour sleep cycle is established and moves
later each day, the later awakening with daily delay varying between 15 minutes and 1 hour. These sleeping
hours are dictated by an excessive burst, presumably of stress hormones, that are described by JF as
unbearable. In her own words: "When the time for sleep arrives I have a surge of what I assume is cortisol.
[Her laboratory determinations of circulating cortisol for blood drawn during the then-usual sleep span are at
the top, but within the normal range.] My body quivers both inside and out and it is as though I am driven to
sleep in order to escape. (It is at these times that I have had myoclonus seizures in the past.) Sometimes the
quivering is accompanied by heart palpitations. I have heart palpitations other times as well, but the
198
quivering only occurs during the sleep time. I awaken several times throughout the sleeping hours with the
same quivering and quickly go back to sleep to escape. Being awake when this is going on is unbearable.
The myalgia is overwhelming and I often hyperventilate and cry. I do not have the capacity to communicate
with my husband during this time. It reminds me of the physical stress that I saw in both of my daughters
right after child delivery. It usually ends before my final awakening after 7-9 hrs of sleep." Eventually the
time of these events leads to a 24 hour awake time. All of this cycle takes place in about a month. The
monthly cycle is repeated twice in the winter and three times in the summer. There is not a gradual entrance
nor exit with the semiannual spans of illness. They occur as though someone turned a switch off and then
finally back on.
JF reports that during the awake hours of these time spans she experiences heart palpitations, myalgia,
arthritis, brain fog, lethargy, nerve tingling, and neuropathy in varying degrees. Usually greater activity
produces more intense symptoms. A rise in the planetary k-index will also increase the symptoms. There are
usually 1-3 days of improved function in between the new moon and the full moon and the full moon and the
new moon.
The semimonthly cycles experienced by JF seem to be dictated by the full moon and the new moon.
These spans of 1-4 days involve much fluid retention accompanied by much pain throughout the body. They
come to an abrupt end by excessive urination. Sometimes outside of the semiannual spans these semimonthly
cycles are barely noticeable. Within the semiannual cycle periods they are quite intense.
JF is eager to find solutions to these problems and is committed to accomplish the task for herself and
for science, and especially for her daughter and her granddaughter.
199
Figure 1A. Chronobiologic serial sections of JF's systolic blood pressure. © Halberg.
200
Figure 1B. Chronobiologic serial sections of JF's diastolic blood pressure. © Halberg.
201
Figure 1C. Chronobiologic serial sections of JF's heart rate. © Halberg.
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90
100
110
120
130
140
150
160
170
00:00 04:00 08:00 12:00 16:00 20:00 00:00
Time (Clock Hours)
SBP(mmHg)
Time-varying
90% Prediction
Limits
Figure 2A. Plexograms comparing JF's systolic blood pressure data (red) stacked over an idealized
24-hour day with reference values computed as time-specified 90% prediction limits derived on the
basis of around-the-clock profiles from clinically healthy women of the same age group. ©
Halberg.
203
50
60
70
80
90
100
110
00:00 04:00 08:00 12:00 16:00 20:00 00:00
Time (Clock Hours)
DBP(mmHg)
Time-varying
90% Prediction
Limits
Figure 2B. Plexograms comparing JF's diastolic blood pressure data (blue) stacked over an
idealized 24-hour day with reference values computed as time-specified 90% prediction limits
derived on the basis of around-the-clock profiles from clinically healthy women of the same age
group. © Halberg.
204
40
50
60
70
80
90
100
110
00:00 04:00 08:00 12:00 16:00 20:00 00:00
Time (Clock Hours)
HR(beats/min)
Time-varying
90% Prediction
Limits
Figure 2C. Plexograms comparing JF's heart rate data (green) stacked over an idealized 24-hour day
with reference values computed as time-specified 90% prediction limits derived on the basis of
around-the-clock profiles from clinically healthy women of the same age group. © Halberg.
205
50
70
90
110
130
150
170
06/09
00:00
06/10
00:00
06/11
00:00
06/12
00:00
06/13
00:00
06/14
00:00
06/15
00:00
06/16
00:00
Time (calendar date in 2009)
BloodPressure(mmHg)
30
40
50
60
70
80
90
HeartRate(beats/min)
SBP DBP HR
Figure 3. Time course of JF's systolic and diastolic blood pressure and heart rate. © Halberg.
Figure 4. Histogram of circasemiseptan (84-hour) to circadian (24-hour) amplitude (A) ratios of
diastolic blood pressure in a patient population reveals infradian prominence in a putatively
magnetolabile patient (JF). © Halberg.
206
Table 1: Circadian characteristics with a measure of their 95% confidence intervals (CIs) of
blood pressure (BP) and heart rate (HR) of a magnetolabile patient (JF, F, 61y)
Variable (units) MESOR* Period (hours) [CI] Double Amplitude* [CI]
Systolic BP (mmHg) 128.5 [125.6, 131.3] 24.49 [23.22, 25.75] 10.6 [1.8, 19.3]
Diastolic BP (mmHg) 84.5 [82.3, 86.7] 23.38 [21.43, 25.32] 6.0 [0.1, 11.9]
HR (beats/min) 60.4 [59.2, 61.5] 24.40 [22.99, 25.81] 4.5 [1.8, 7.2]
*Decimals can be ignored.
Support: GM-13981 (FH) and University of Minnesota Supercomputing Institute (GC, FH).
207
CIS-HALF-YEAR IN THE SYSTOLIC BLOOD PRESSURE OF A YOUNG ADULT
Dmitry Gorlov1
, Franz Halberg2
, Germaine Cornélissen2
, Yuri Gorgo1
1
Human and Animal Physiology Dept, Taras Shevchenko Natl Univ of Kiev, Kiev, Ukraine
2
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
Around the clock monitoring of systolic (S) and diastolic (D) blood pressure (BP) and heart rate
(HR) with the TM-2421 ambulatory monitor from A&D (Tokyo, Japan) served for mapping the
circadian system of a few variables of the circulation of a young adult (DG). Data were collected
around-the-clock, mostly at 30-minute intervals, with interruptions and averaged over consecutive
2-hour intervals for almost one year. The data were analyzed by the extended cosinor (1-3), with
particular focus on the cis-half-year component with an anticipated period of about 0.42 year,
previously reported for circulating melatonin (4) and the incidence of sudden cardiac death (5).
As a large-amplitude circadian component characterizes all three variables (Figure 1), initial values
used in the nonlinear analysis included a fixed 24-hour component and a 0.42-year cis-half-year.
Parameter estimates with their 95% confidence intervals (CIs) are summarized in Table 1.
Table 1
Nonlinear estimates of the cis-half-year assessed concomitantly with a fixed 24-hour component
Variable (units) 24h double amplitude
[CI]
“Cis-half-year” period
[CI] (years)
Cis-half-year double
amplitude [CI]
SBP (mmHg) 21.60 [18.58, 24.62] 0.428 [0.376, 0.480] 6.68 [3.72, 9.64]
DBP (mmHg) 14.76 [12.78, 16.72] 0.619 [0.456, 0.782] 2.86 [0.84, 4.86]
HR (beats/min) 10.42 [8.44, 12.40] 0.490 [0.367, 0.613] 2.52 [0.66, 4.38]
A cis-half-year was detected in these data covering slightly less than one year only for SBP and not
for DBP or HR. DBP had a trans-half-year, whereas HR had a half-year component. There appears
to be a putative selective congruence in the para-semiannual range of the spectrum of a clinically
healthy adult, as reported earlier for the circadecadal range for another clinically healthy adult
(RBS) (6) and in the circaseptan range of an elderly man (GSK) (7). Different variables of the
circulation of a given person can lock into synchrony with different environmental periodicities. In
this case of DG, his HR locked into the geomagnetic half year, while his SBP showed a solar cishalf-year.
The CI of the trans-half-year is also compatible with the presence of a signature of the
solar 0.56-year predicted by Charles Wolff as a beat of solar rotation periods (8).
208
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
1. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
2. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812
3. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian rhythms.
Biological Rhythm Res. 2007; 38: 275-325. http://dx.doi.org/10.1080/09291010600903692
4. Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. About 5-month
cycle in human circulating melatonin: signature of weather in extraterrestrial space? Poster
presentation, Fourth UN/ESA/NASA/JAXA Workshop on the International Heliophysical
Year 2007 and Basic Space Science: "First Results from the International Heliophysical Year
2007", Sozopol, Bulgaria, June 2-6, 2008.
5. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T,
Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB,
Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O,
Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group.
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38.
http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
6. Sothern RB, Katinas GS, Fiser B, Siegelova J, Cornélissen G, Halberg F. A transtridecadal
cycle in human heart rate: Selective infradian, notably multidecadal solar-physiologic BEL
congruences. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive
Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 204-213.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
7. Halberg F, Cornelissen G, Sothern RB, Katinas GS, Schwartzkopff O, Otsuka K. Cycles
tipping the scale between death and survival (= "life"). Progress of Theoretical Physics 2008;
Suppl. 173: 153-181.
8. Wolff CL. The rotational spectrum of g-modes in the sun. Astrophys J 1983; 264: 667-676.
209
Figure 1. A prominent circadian rhythm is readily apparent (at a frequency of 365.25 cycles/year)
(right) for all three variables. The second harmonics with a period of about 12 hours can also be
seen. A cis-half-year is detected for systolic blood pressure (top left), corresponding to a peak at a
frequency between 2 and 3 cycles/year. © Halberg.
210
SOLAR SIGNATURES IN A BOY'S BLOOD PRESSURE AND HEART RATE
Yoshihiko Watanabe1
, Germaine Cornélissen2
, Fumihiko Watanabe1¶
,
Roberto Tarquini3
, Federico Perfetto3
, Jarmila Siegelova4
, Bohumil Fiser4
,
Jiri Dusek4
, Pavel Homolka4
, Franz Halberg2
1
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
2
Halberg Chronobiology Center, Univ. of Minnesota, Minneapolis, MN, USA
3
University of Florence, Florence, Italy
4
Masaryk University, Brno, Czech Republic
¶
Secondary school pupil.
Corresponding author:
Franz Halberg, M.D.
Professor of Laboratory Medicine and Pathology,
Physiology, Biology, Bioengineering and Oral Medicine
Co-director, Halberg Chronobiology Center
University of Minnesota - Campus Mail Code 8609
420 Delaware St. S.E.
Minneapolis, MN 55455, USA
PHONE +1 (612) 624.6976
FAX +1 (612) 624.9989
E-MAIL halbe001@umn.edu
URL http://www.msi.umn.edu/~halberg/
Running title: Solar signatures in circulation
Support: U.S. National Institutes of Health (GM-13981) (FH);
University of Minnesota Supercomputing Institute (GC, FH).
211
Abstract
Objective. To track, in a boy's circulation, components with a period, τ, of ~1.3 years, fartransyears,
and ~5 months, cis-half-years, found in adults' sudden cardiac deaths and circulating
melatonin as a putative signature of the solar wind's speed.
Design. The time course during childhood and adolescence of signatures of a 1-year cycle
and of periodicities of about ~16 and ~5 months, the latter also reported for the incidence of solar
flares, is here explored longitudinally in daily measurements during 8 years of the systolic (S) and
diastolic (D) blood pressure (BP) and heart rate (HR) of a boy, FW.
Setting. On awakening at home.
Results. Original data show an increase in BP removed by the fit of a linear trend and a
decrease in HR detrended by a second-order polynomial and further the anticipated components in
the detrended data.
Main findings. When original or detrended data are analyzed by linear-nonlinear spectral
cosinor analysis, a far-transyear, an about (~) 16-month cycle is most prominent in SBP and DBP
and a calendar year is more prominent in HR, and a cis-half-year, i.e., an ~5-month cycle is third
in prominence. When the cis-half-year is investigated by a chronobiologic serial section,
consisting of the least-squares fit of a cosine function with a period determined nonlinearly, it is
consistently statistically significant (P<0.010) mostly for SBP, less so, only intermittently for
DBP, and is restricted to only a few of the intervals analyzed for HR.
Conclusion. Statistically significant transyears and cis-half-years coexist with a 1-year
synchronized spectral component and in the case of BP, but not of HR, the transyear is most
prominent.
How interpreted. Selective congruence with different environmental cycles characterizes the
human circulation and differs among variables; non-photic transyear components can exceed in
childhood and adolescence the prominence of the calendar year in a boy living in Tokyo. 304
words.
Key words: solar activity, childhood, adolescence, blood pressure, heart rate, periodicity,
chronomics
Background
In several geographic locations like Minnesota but not in others (Halberg et al. 2006), among
others, components with a τ of ~1.3 and of ~0.42 year(s) characterize the incidence of human
sudden cardiac death (SCD) after revision 10 of the International Classification of Diseases
212
(ICD10), code I46.1. The broadly defined far-transyear range (1.2 years ≤ [τ - CI {95% confidence
interval}] < [τ + CI] < 1.9 years) has a component in Minnesota and Tokyo in the absence of a
calendar-yearly component while in Arkansas and in the Czech Republic, the far-transyear
coexists with a 1-year component, and in North Carolina, USA, only an ~1-year component is
found during the spans examined, Figure 1 (Halberg et al. 2006). The cis (= on this side of)-halfyear
is found in Austria, Hungary, Minnesota (USA) and Tokyo (Japan) (Halberg et al. 2005,
2006; Cornélissen et al. 2007b; Hamamatsu et al. 2007) and during part of the span examined in
the Czech Republic. Both nonphotic components are also found in cardiac arrhythmia again
intermittently in the Republic of Georgia (Halberg et al. 2006). In Minnesota but not overall,
arrhythmias triggering a therapeutic response from implanted pacemaker-cardioverterdefibrillators
show a cis-half-year (Cornélissen et al. 2007a), as do arrhythmias in the Republic of
Georgia (Halberg et al. 2006).
A cis-half-year is also found in the BP of two elderly men, FH (Halberg et al. 2006) and GK
(Katinas et al. 2008), in the 17-ketosteroid excretion of an adult man over 15 years (Halberg et al.
2008; cf. Halberg et al. 1965), in the melatonin circulating in the blood of 172 patients, each
studied for only a day at 4-hour intervals (Cornélissen et al. 2008) and in the HR of a man studied
over 40 years (Sothern et al. 2008), in the latter only when the fit of the cis-half-year is carried out
concomitantly with the fit of coexisting 1.0 and 0.5-year periods, with the latter converging to an
0.4 year (unpublished). We here explore the cis-half-year and the far-transyear (cf. Watanabe F. et
al. 2008) during childhood and adolescence in a boy (FW) and demonstrate, during ages 8-15
years, a particularly prominent far-transyear in BP, Table 1, an anticipated signature of changing
patterns in the solar wind's speed (Halberg et al. 2006) and a cis-half-year, notably in SBP, also a
signature of solar flares (Rieger et al. 1984), as extensively confirmed (Kiplinger et al. 1984;
Bogart and Bai 1985; Dennis 1985; Bai and Sturrock 1987) with slightly varying results due to
nonstationarities and a modulation by the ~11-year Horrebow-Schwabe cycle in sunspot numbers
(unpublished).
Case report
FW's paternal grandfather died at 47 years of age of renal failure with malignant
hypertension associated with a pheochromocytoma. His maternal grandfather took medication for
high BP; his maternal grandmother had breast, gastric and uterine cancer by the time of her death.
His paternal grandmother underwent six surgeries for uterine cancer, colonic cancer and
degeneration of the spine and of each knee joint. His mother had surgery for breast cancer in the
213
summer of 2006. The boy's BP and HR were monitored around the clock, mostly at 30-minute
intervals for 40 days (October 20-November 28, 1992) during the first 40 days of his life
(Watanabe et al. 2003).
Method
Linear imputation spectra revealed an anticipated far-transyear of 1.35-year length in SBP
and DBP in both original and detrended data and an ~0.39-year cis-halfyear that led to serial
sections of each time series, with a 4-year interval displaced by 1-week increments throughout the
time series. Below the original data shown in the top row, serial sections are shown in the second
rows of Figures 1-3, prepared with the fit of a τ of 0.4 year found to be near the peak in a first
imputational cosinor spectrum (Halberg et al. 1965).
Results
Table 1 presents a summary of analyses of all data showing the relatively small amplitude of
the cis-halfyear in all variables as compared to the prominence of a putative signature of solar
wind speed, a far-transyear of ~1.3-year length. For comparison, the characteristics of a coexisting
component with a τ of precisely 1 year are also tabulated.
In SBP, the cis-half-year is statistically highly significant in nearly all intervals, each of
about 4 years, displaced for consecutive analyses by increments of 1 week. The third to fifth rows
of Figures 1-3 show results of detrended data (by the fit of a straight line for SBP and DBP and a
second-order polynomial for HR). When fitted as such only, rather than with other components,
the cis-half-year is prominent and statistically highly significant in SBP (Figure 1), as seen from
the penultimate row of P-values in which a dashed horizontal line represents 5%; practically all
values hug the 0.01 bottom line. Statistical significance is equally apparent from the fact that in the
fourth row after detrending, the acrophase (double) plot shows three lines, the middle one for the
acrophase as such, while the bracketing two lines document the 95% confidence limits of the SBP
acrophase, with very few interruptions in spots where in the row of P-values below, there are
peaklets or peaks that penetrate above the 5% level, the latter indicated by a dashed line. There is
still a majority of bracketed acrophases in Figure 2 for DBP, but very few intervals have bracketed
acrophases for HR in Figure 3.
214
Discussion
Many differences in the time structures or chronomes of BP versus HR were reviewed earlier
elsewhere (Schwartzkopff et al. 1998). Figures 1-3 and Table 1 show new differences concerning
the far-transyear and cis-halfyear in SBP and a lesser extent in DBP vs. a much less consistent
component in HR, all here demonstrated during human childhood and adolescence.
In monitoring oneself, there is much to learn; some of it, in the case of YW, FW's
cardiologist father has been communicated in 152 publications noted in order to stimulate the
interest of others to follow in his steps for their own and others' health care (Watanabe et al. this
issue). Monitoring the activity of the cosmos can be done with the very same data that are useful
primarily to detect earliest alterations as vascular variability disorders, VVDs, prompting
interventions by health care (Halberg et al. 2009). In FW, notably in his BP, cycles found as
characteristics of solar wind speed and of solar flares as yet are only of basic interest, until
reference values are obtained in clinical health from many other children and adolescents. The
broad basic scope of far-transyears is apparent from the scholarship of Prof. Miroslav Mikulecky,
who has extended their scope to natality in two geographic locations (Mikulecky and Florida 2005;
Mikulecky 2006) and to epilepsy (Kovac and Mikulecky 2006) and stroke (Kovac and Mikulecky
2005) in Slovakia.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
Bai T, Sturrock PA. (1987). The 152-day periodicity of the solar flare occurrence rate. Nature 327:
601-604.
Bogart RS, Bai T. (1985). Confirmation of a 152-day periodicity in the occurrence of solar flares
inferred from microwave data. Astrophys J 299: L51-L55.
Cornélissen G, Benser M, Halberg F. (2007a). Patterns of incidence of tachyarrhythmias recorded
in implantable cardioverter-defibrillators during 2001-2005. PS-004, Proceedings, 2nd World
Congress of Chronobiology, November 4-6, 2007, Tokyo, Japan. p. 63.
Cornélissen G, Schnaiter D, Halberg F, Mitsutake G, Otsuka K, Fiser B, et al. (2007b). A cis-halfyear
characterizes the incidence of sudden cardiac death also in and near Austria. In:
215
Proceedings, International Symposium, Problems of ecological and physiological adaptation,
People's Friendship University of Russia, Moscow, 30-31 Jan 2007. Moscow: People's
Friendship University of Russia. p. 545-551.
Cornélissen G, Tarquini R, Perfetto F, Otsuka K, Gigolashvili M, Halberg F. (2008). About 5month
cycle in human circulating melatonin: signature of weather in extraterrestrial space?
Poster presentation, Fourth UN/ESA/NASA/JAXA Workshop on the International
Heliophysical Year 2007 and Basic Space Science: "First Results from the International
Heliophysical Year 2007", Sozopol, Bulgaria, June 2-6, 2008.
Dennis BR. (1985). Solar hard X-ray bursts. Solar Physics 100: 465-490.
Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, et al. (2006).
Chronobiology's progress: season's appreciations 2004-2005. Time-, frequency-, phase-,
variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 4: 1-38.
http://www.zsf.jcu.cz/vyzkum/jab/4_1/halberg.pdf
Halberg F, Cornélissen G, Otsuka K, Fiser B, Mitsutake G, Wendt HW, et al. (2005). Incidence of
sudden cardiac death, myocardial infarction and far- and near-transyears. Biomed &
Pharmacother 59 (Suppl 1): S239-S261.
Halberg F, Cornélissen G, Otsuka K, Siegelova J, Fiser B, Dusek J, et al. (2009). Extended
consensus on means and need to detect vascular variability disorders (VVDs) and vascular
variability syndromes (VVSs). Leibniz-Online Nr. 5, 2009 (http://www.leibnizsozietaet.de/journal).
35 pp.
Halberg F, Cornélissen G, Schwartzkopff O. (2008). Quo vadis chronomics 2008: Measuring
variability in us, among us and around us. In: Halberg F, Kenner T, Fiser B, Siegelova J
(Eds.) Proceedings, Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-
7, 2008. p. 16-25. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Halberg F, Engeli M, Hamburger C, Hillman D. (1965). Spectral resolution of low-frequency,
small-amplitude rhythms in excreted 17-ketosteroid; probable androgen induced circaseptan
desychronization. Acta endocrinol (Kbh) 50 (Suppl 103): 5-54.
216
Hamamatsu A, Cornélissen G, Otsuka Ku, Halberg F, Chibisov S (presenter) (2007). Linearnonlinear
rhythmometry documents a transyear and a cishalfyear in sudden cardiac death
(ICD 10, code I46.1) in Tokyo. In: Proceedings, International Symposium, Problems of
ecological and physiological adaptation, People's Friendship University of Russia, Moscow,
30-31 Jan 2007. Moscow: People's Friendship University of Russia. p. 542-545.
Katinas GS, Halberg F, Cornélissen G, Sanchez de la Peña S, Czaplicki J, Siegelova J, BIOCOS
project (2008). C-ABPM reveals solar cis-halfyear and transyear signatures in human
diastolic blood pressure. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 144-146.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Kiplinger AL, Dennis BR, Orwig LE. (1984). Detection of a 158-day periodicity in the solar hard
X-ray flare rate. Bull Am Astronom Soc 16: 891.
Kovac M, Mikulecky M. (2005). Secular rhythms and Halberg's paraseasonality in the time
occurrence of cerebral stroke. Bratisl Lek Listy 106 (2): 423-427.
Kovac M, Mikulecky M. (2006). Time sequence of epileptic attacks from the point of view of
possible lunisolar connections. International Conference on the Frontiers of Biomedical
Science: Chronobiology, Chengdu, China, September 24-26, 2006, p. 175-179.
Mikulecky M. (2006). Reanalyza natality v jizni brazilii -- opet dominuje Halbergova
parasezonalita: International Conference on the Frontiers of Biomedical Science:
Chronobiology, Chengdu, China, September 24-26, 2006, p. 188-193.
Mikulecky M, Florida PL. (2005). Daily birth numbers in Davao, Philippines, 1993-2003:
Halberg's transyear stronger than year. Abstract, 26th Seminar, Man in His Terrestrial and
Cosmic Environment, Upice, Czech Republic, May 17-19, 2005.
Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. (1984). A 154-day periodicity
in the occurrence of hard solar flares? Nature 312: 623-625.
217
Schwartzkopff O, Cornélissen G, Halberg F. (1998). Differences in the time structures
(chronomes) of blood pressure (BP) and heart rate (HR). Abstract, 6° Convegno Nazionale
de Cronobiologia, Chianciano, Italy, November 27-28, 1998. p. 31.
Sothern RB, Katinas GS, Fiser B, Siegelova J, Cornélissen G, Halberg F. (2008). A transtridecadal
cycle in human heart rate: Selective infradian, notably multidecadal solar-physiologic BEL
congruences. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive
Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 204-213.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Watanabe F, Cornélissen G, Watanabe Y, Siegelova J, Czaplicki J, Halberg F, BIOCOS project
(2008). Differing far-transyear/calendar year amplitude ratios in blood pressure vs. heart rate
in adolescence. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 177-183.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Watanabe Y, Cornélissen G, Beaty LA, Siegelova J, Fiser B, Dusek J, Homolka P, Halberg F. (this
volume). White-coat hypertension in a cardiologist: Decades of monitoring lead to transient
MESOR-hypertension in decades of monitoring absent during vacation: strain test.
Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T, et al. (2003).
Methodology: partial moving spectra of postnatal heart rate chronome. Neuroendocrinol Lett
24 (Suppl 1): 139-144.
218
Legends
Figure 1. Chronobiologic serial section of systolic blood pressure of a boy, FW, revealing a
somewhat consistent cis-half-year by values in the row of P-values (second from bottom) mostly
below the dashed 5% line and by a 95% confidence interval bracketing the acrophases shown in
the 4th
row from the top. There is only a single interruption corresponding to a single P-value
above the dashed line. © Halberg.
Figure 2. Chronobiologic serial section of diastolic blood pressure of a boy, FW, revealing
an intermittent cis-half-year by the 4th
row of P-values when the curve remains only intermittently
below the dashed line corresponding to 5%. © Halberg.
Figure 3. Chronobiologic serial section of heart rate of a boy, FW, with the demonstration of
a cis-half-year limited to a very few intervals analyzed. © Halberg.
219
Table 1: Periods detected by extended cosinor in the circulation of FW*
Variable Trial period (years) Period [95% CI] Double amplitude [95% CI]
SBP (orig) 0.400 0.384 [0.382, 0.386] 3.50 [1.38, 5.62]
DBP (orig) 0.389 [0.387, 0.390] 2.54 [1.10, 3.98]
HR (orig) 0.385 [0.382, 0.388] 1.34 [-0.12, 2.80]
SBPres 0.400 0.384 [0.382, 0.385] 3.74 [1.82, 5.66]
DBPres 0.389 [0.387, 0.390] 2.56 [1.26, 3.88]
HRres 0.385 [0.383, 0.388] 1.40 [0.14, 2.66]
SBPres 1.000 0.9998 [.9911, 1.0085] 4.04 [2.06, 6.00]
DBPres 0.9947 [.9865, 1.0030] 2.88 [1.52, 4.22]
HRres 0.9911 [.9845, 0.9977] 3.40 [2.14, 4.66]
SBPres 1.300 1.301 [1.292, 1.309] 6.86 [4.90, 8.82]
DBPres 1.340 [1.330, 1.351] 3.92 [2.60, 5.26]
HRres 1.221 [1.208, 1.234] 2.50 [1.20, 3.80]
*CI: confidence interval; orig: original data; res: residual. There is a larger peak for HR at a period
slightly shorter than the cis-half-year range. Para-annual components with amplitude larger than
that of the coexisting annual component are shown in bold, as is the tallest component in HR.
220
Table 2: Point estimates of a cis-half-year (~154-day) periodicity, sometimes given with
estimates of uncertainty and hypothesis testing
Period (in days
except where
noted)
Reference
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Wolff CL. (1983). The rotational spectrum of g-modes in the sun. Astrophys J
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154
Rieger A, Share GH, Forrest DJ, Kanbach G, Reppin C, Chupp EL. (1984). A
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158
Kiplinger AL, Dennis BR, Orwig LE. (1984). Detection of a 158-day
periodicity in the solar hard X-ray flare rate. Bull Am Astronom Soc 16: 891.
152
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L51-L55.
152-158 Dennis BR. (1985). Solar hard X-ray bursts. Solar Physics 100: 465-490.
152
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222
Figure 1
223
Figure 2
224
Figure 3
225
WHITE-COAT HYPERTENSION IN A CARDIOLOGIST:
DECADES OF MONITORING LEAD TO TRANSIENT OCCUPATIONAL MESORHYPERTENSION
ABSENT DURING VACATION: STRAIN TEST
Yoshihiko Watanabe1
, Germaine Cornélissen2
, Larry A. Beaty2
,
Jarmila Siegelova3
, Bohumil Fiser3
, Jiri Dusek3
, Pavel Homolka3
, Franz Halberg2
1
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
2
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
3
Masaryk University, Brno, Czech Republic
Corresponding author:
Franz Halberg, M.D.
Professor of Laboratory Medicine and Pathology,
Physiology, Biology, Bioengineering and Oral Medicine
Co-director, Halberg Chronobiology Center
University of Minnesota - Campus Mail Code 8609
420 Delaware St. S.E.
Minneapolis, MN 55455, USA
PHONE +1 (612) 624.6976
FAX +1 (612) 624.9989
E-MAIL halbe001@umn.edu
URL http://www.msi.umn.edu/~halberg/
Running title: MESOR-hypertension: strain test
Support: GM-13981 (National Institutes of Health) (FH),
University of Minnesota Supercomputer Institute (GC, FH)
226
Abstract
Objective. To change the recording of blood pressure (BP) and heart rate (HR) from
spotchecks to continuous electronically implemented cost-effective self-surveillance.
Design. Parametric and complementary non-parametric assessment of results from inferential
statistical approaches by cosinor.
Setting. Everyday clinical practice by a cardiologist (YW).
Results. In a busy cardiologist's circulation, systolic (S) and diastolic (D) MESORhypertension,
MH, can be transient, i.e., absent during vacation.
Main findings. The rare opportunity of following the development of transient MH, shows
that it can differ in months-long records of the same individual. Hence, continued self-surveillance
should become routine and should be implemented in the population as a whole.
Conclusion. A spotcheck evidence-based health care awaits replacement by one based on
continued inferential statistical surveillance of the individual. The P-values and 95% confidence
intervals that are currently indispensable in publications of research are applicable to the
individual, in whose care, cost-effectively by self-surveillance, they are equally indispensable.
Introduction
Half-hourly around-the-clock BP and HR values, surveilled over 7 days or preferably over
longer spans, are 24-hour synchronized in most time series. Hence, one can fit a 24-hour cosine
curve to the data to obtain (parametrically) estimates of the midline-estimating statistic of rhythm,
i.e., the MESOR, M; the amplitude, A, and acrophase, φ, measures of the extent of rhythmic
change and of its timing, respectively. The data can also be stacked along the 24-hour scale (nonparametrically)
for comparison with time-specified reference values from clinically healthy peers
matched by gender and age. Measures of the extent of abnormality, if any, are thus obtained by the
hyperbaric (or hypobaric) indices, summarizing BP excess (or deficit). These indices consist of the
integrated area between the time-varying prediction limits and any part of the BP curve where it
lies outside the limit. Parametric endpoints are also compared with those of clinically healthy peers
of the same gender and age group for the foregoing circadian (and any broader infradian as well as
ultradian) chronobiologic assessment separately of systolic (S) and diastolic (D) BP and HR.
227
YW, a clinically healthy chrono-cardiologist/scientist, 56 years of age, is in the 21st year of
continued chronobiologically-interpreted automatic half-hourly around-the-clock, ambulatory as
well as resting monitoring (with relatively few interruptions) of his BP and HR (C-ABPM). At the
age of 55 years in an about (~) 7.5-month section of his record, he had by cosine fitting (of a 2component
model, consisting of cosine curves with periods of 24 and 12 hours) and by stacking,
both compared with reference standards of clinically healthy peers matched by gender and age, a
complete (parametric and non-parametric) SBP-MESOR (M)-hypertension (S-MH) and an
incomplete (parametric, but not non-parametric) D-MH. In an immediately following ~5-month
record at the age of 56 years, he has incomplete (only parametric) S-MH and DBP MESORnormotension,
MN (D-MN).
Months-long records in everyday life can differ as a function of professional and other loads.
For YW, this assumption is in keeping with the finding that, during 4 days of vacation away from
work at home, there is complete S-MN and D-MN, due to a statistically significant lowering of the
BP-M and only a slight numeric increase in the hyperbaric index of DBP. Thus, the monitoring
during as well as before and after a vacation constituted a professional strain test. His varying
complete vs. incomplete (both parametric and nonparametric vs. only parametric) S-MH or his
incomplete (only parametric) vs. absent D-MH can be interpreted as an occupational MESORhypertension.
We are dealing with a reversible D-MH that can be readily "treated", i.e., that is
eliminated by a change in routine.
Background
A 21-year record is available for YW, whose father died of renal failure with malignant
hypertension associated with a pheochromocytoma at the age of 47 years. Apart from his other
publications, including a book in Japanese about BP for the general reader, YW's cooperation with
the Halberg Chronobiology Center at the University of Minnesota resulted in a steady list of 152
publications, many based on automatic BP and HR monitoring, some started on himself at age 35.
YW's productivity, of interest in itself, should motivate others in a preventively useful and
scientifically rewarding surveillance of oneself and of others. YW's data fully support the
recommendation that a minimal 7-day record length for the initial monitoring of BP and HR
should be only a transient substitute for continuous unobtrusive, affordable surveillance, C-ABPM,
warranted at least by a positive family and/or personal history of cardiovascular disease and/or
interest in research, or preferably both, as in the case of YW, as suggested by a long series of
international consensus meetings (e.g., Halberg et al. 1995, 2004, 2009; Chibisov, 2005). Sooner
228
rather than later, sufficient records will become available for the use of the same data for the biotic
monitoring of the cosmos.
Method
YW wears an automatic monitor from A&D (Tokyo) around the clock with few
interruptions. His most recent summary (Watanabe et al., 2008a) serves as a reference standard for
the data accumulated in the interim of ~5 months, including 4 days of vacation from work at home.
YW's chronobiologic summaries at ages 55 and 56 years include a sphygmochron carried out with
both a parametric approach, from the fit of a two-component model (consisting of cosine curves
with periods of 24 and 12 hours) and a nonparametric one by stacking, both interpreted by
comparison with clinically healthy peers matched by gender and age, Figure 1, as done routinely in
the project on The BIOsphere and the COSmos, BIOCOS (Halberg et al., 2000a).
Results
Figure 2 stacks the data along an idealized 24-hour scale from the 3 spans summarized by the
bottom halves of the three sphygmochrons in Figure 1. Thus, the first of the 48 dots in the top row
is the average of all values collected between 00:00-00:30 during 7.5 months; the next dot
summarizes all data collected between 00:30-01:00, etc. The 7.5-month recordings caught a
glimpse of an interesting time span when most SBP clock-time mean values are above the timespecified
limit of peers matched by gender and age, while, with just 3 exceptions from 48 clocktime
mean values, the DBPs are near but just below the upper 95% prediction limit.
The diagnosis made on August 8, 2008, at age 55 (top) differed, inferentially statistically but
hardly clinically, from the one made on January 15, 2009, 5 months later. At age 55 years, it was a
complete (parametric and non-parametric) S-MH and an incomplete (parametric but not
nonparametric) D-MH seen in the top parts of sphygmochrons of Figures 1 and 2. These findings
could not be confirmed parametrically for DBP in the added 5 months of data that became
available in January 2009, nor did the nonparametric approach find any abnormality in SBP or
DBP in the last ~5 months of data, Figures 1 and 2. The extent of nonparametric excess during 24
hours below 50 mm Hg x h is acceptable. Thus, the diagnosis of 2008 changed in early 2009 to an
229
incomplete parametric but not non-parametric S-MH and (complete, both parametrically and
nonparametrically) DBP MESOR-normotension.
All abnormality of BP or HR was absent during 4 recent vacation days, summarized in the
bottom third of Figures 1 and 2. Table 1 compares the parameters of the three spans, revealing
self-explanatory statistically significant differences among the 48 mean values from each span.
Means rather than original values were compared to minimize artifactual differences due to
relatively large numbers (what has been referred to as stochastic statistical significance). The
desirability to assess and compare diagnoses with their uncertainties in inferential statistical terms
cannot be overemphasized, yet a statistically significant difference in itself does not imply clinical
or scientific signification (Halberg et al., 1991; Cornélissen et al., 1994), as in this case in January
2009.
Discussion
Whether back pain which was more prominent during the first ~7.5-month span summarized
in August 2008 contributed to the high BP is in keeping with the detection of a threshold in
another physician-scientist who suffered from back pain and whose BP-MESOR did not increase
and HR-MESOR did not decrease until a certain measure of self-rated pain was reached (Katinas
et al., 2008). The role of any of the many infradian spectral components, summarized in earlier
publications, that may also have contributed to the differences between the top two versus the
bottom sections of Figures 1 and 2 remains to be evaluated. A sharp rise of HR in the morning,
when he often runs to catch the train on his way to work, seen in the last column of Figure 2 on top
and in the middle, is not seen at the bottom when he stayed at home.
Further analyses warranted in YW's and others' time series, covering decades, may answer
the question about the degree of generality with which a deviation (e.g., an elevation) in A alone or
concomitantly with M (Cugini et al., 1998) leads to MH. Consecutive sphygmochrons to pursue
the development of a VVD remain to be computed. In the laboratory, in the spontaneouslyhypertensive
stroke-prone rat (SHR-SP), an increase in A precedes the one in M (Halberg J et al.,
1980). This sequence of A elevation preceding an elevation of M also occurs for BP and other
230
telemetered variables, albeit with a lag of only a very few days, in the saline and
desoxycorticosterone-induced hypertension of the rat (unpublished). Likewise, a higher BP-A is
associated with intermediate values of the left ventricular mass index (LVMI), whereas a higher
BP-M (above 140 mmHg) is seen only for larger LVMI values in humans (Kumagai et al., 1992).
This association has now been qualified by the finding around a SBP-M of 120 mmHg of an
increase in both A and M associated with minimal change retinopathy, discovered by Cugini and
interpreted by him as constituting a pre-hypertension (Cugini et al., 1998). Similarly, pre-diabetes
has been documented by focus upon the detection of circadian VVDs (Sanchez de la Peña et al.,
2004; Gupta et al., 2008). More than single subjects will have to be longitudinally investigated by
systematic monitoring as newborns (Halberg et al., 1990; Watanabe et al., 2003) and at school age
(Halberg et al., 1973, 2000b) to explore any sequences in the development of incomplete to
complete S-MH and D-MH, started in adulthood, now in the perspective of decades in YW.
The effect of loads like pain and/or a busy professional schedule must be quantified (Halberg
et al., 2003; Maschke et al., 2003; Katinas et al., 2008). Any load consisting of dietary ingredients,
notably the effect of sodium intake (Cornélissen et al., 1993) that is circadian stage-dependent
(Itoh et al., 1996), remains to be further tested. The removal of the load of professional activity can
normalize BP in certain individuals: this should be explored further with replications in YW's
vacations and in other individuals.
Much investigation remains to be done when we focus upon the earliest infradian as well as
circadian alteration of BP and HR characteristics. There is already evidence that an ~35-year
Brückner-Egeson-Lockyer cycle and a ~21-year Hale cycle in the bipolarity of sunspots are
mirrored in the human circulation (Halberg et al., 2006). There is also evidence in YW's son FW of
an ~5-month cycle in his SBP, putatively related to solar flares, as he aged from 8 to 15 years
(Watanabe et al., this issue).
The effect of loads upon human BP has been described as bene- or maletensive (Halberg et
al., 2003), and for YW, the 4 days away from his professional work appear to have been
benetensive, i.e., normalizing. It remains to be investigated in the light of outcomes whether the
transitions from S-MN and D-MN to an incomplete or complete S-MH or D-MH, under the load of
231
professional activity may indicate if not quantify certain limits around which benetensive stimuli
become maletensive. Alternatively, pertinent limits for a change in intervention by non-drug or
drug treatment may be resolved only when days of vacation are no longer associated with a return
of MN.
An answer to these questions may place Hans Selye's (1974) distinction of "stress" vs.
"distress" on a quantifiable basis. To be sure, monitoring for a longer span away from challenging
conditions must be examined for any effect. Moreover, different individuals may react differently
to the same stimulus that is also likely to be circadian stage-dependent (Lee JY et al., 1982; Lee
MS et al., 2003). An indirect strain test, C-ABPM, comparing endpoints on vacation days with
those on weekdays at occupational activities, which is documented for YW, must be further
investigated on YW and/or others and is not generalized. A span longer than 4 days seems
desirable, preferably with alternations between at least a week without a load to be tested,
bracketed by at least week-long spans of monitoring during "everyday life" with the load. In
routine clinical practice, the length of the test span, away from the stimulus constituting a load,
may need to be individualized by sequential procedures. A CUSUM (Cornélissen et al., 1997) may
eventually find when, e.g., BP reaches the limit of a decision interval for its MESOR, circadian or
other amplitude. Sequential tests applicable to other characteristics of dynamics such as phase or
period remain to be developed.
The frequency and sequence of superficially spontaneous alternations between incomplete or
complete S-MH vs. D-MH, that probably depend on factors like grief or conflict during the daily
routine, constitute still other problems to be explored in decades-long time series like that of YW.
It will be interesting to find out from earlier long sections of the 21-year record whether loads are
associated with differences in the infradian M and/or A or φ as well (e.g., by comparing infradian
characteristics such as those of an ~5-month cis-half-year from data collected only during
weekdays vs. weekends and holidays). Also to be further explored is the question of the sequence,
if any, in which SBP vs. DBP, their A, φ and M and their non-parametric endpoints, such as the
hyperbaric index (HBI), change, if they do not alter concomitantly. The exploration of sequences
in which the foregoing changes occur in any longitudinal records of others collected systematically
232
with diaries depends on the development of affordable, unobtrusive instrumentation for continuous
automatic BP and HR monitoring.
Follow-up longitudinal studies with outcomes will be critical to assess the relative
importance of SBP vs. DBP alteration. Whether or not, as suggested from thorough albeit nonchronobiologic
epidemiologic studies, SBP shows a more important influence than does DBP
(Kannel, 2007) must be examined longitudinally with continued around-the-clock sampling. A
transverse chronobiologic study of actual hard outcomes showed the numerically greater risk of a
circadian DBP overswing (DBP-CHAT) as compared with SBP-CHAT or a conventionally
diagnosed "hypertension" (Otsuka et al., 1996). "Hypertension" was associated with a fourfold
increase in risk of ischemic stroke, whereas that risk increased six- or eight-fold with SBP-CHAT
and DBP-CHAT, respectively (Halberg et al., 1995).
Questions may also be raised whether waiting for both the occurrence of a double
(parametric and nonparametric) failure of SBP and/or DBP to return to normal after load removal,
may be warranted before instituting treatment. The institution of drug treatment may be warranted
by an abnormality not reversed by load removal restricted to one approach such as parametric MH,
in SBP or DBP alone. A work-dependent alteration detected by both approaches in either SBP or
DBP would seem to warrant treatment once it persists for spans of time yet to be determined.
In viewing the half-hourly averages for SBP on top of Figure 2, a literal (time-varying)
"borderline" BP elevation may give this term new, perhaps more solid meaning, although it may
seem arbitrary to assign a certain percentage of the 48 means as the upper acceptable limit
prompting intervention. Before setting up complicated outcome studies prompting the initiation of
treatment with both a parametric and a nonparametric limit with institution prompted by any one
of them separately, it seems reasonable to explore what happens in cases like that of YW
longitudinally. The merits of a chronobiologic surveillance are illustrated in Table 1, wherein the
absence of professional work during a vacation is the treatment.
For drug treatment, Figure 3 (Watanabe et al., 2008b) reminds us that first we must do no
harm and that this commandment requires self-surveillance leading not only to avoiding harm by
timing but also to deriving benefit thereby. Much systematic detailed work on a true personalized
233
chronotherapy of vascular variability disorders, VVDs, guided by marker rhythms in BP for
picking and validating the kind, dose and timing and the response to treatment remains to be done.
As for comparisons of groups, inferential statistics applied to the individual, can also
mislead. Half-hourly around-the-clock measurements during two consecutive spans of several
months, one of ~7.5, the other of ~5 months, respectively, reveal statistically significantly differing
diagnoses. The scientific and clinical signification of these differences may be questioned, since
they may be expected to occur naturally when analyses of longitudinal records as a whole revealed
the presence of several infra-annual components described elsewhere (Watanabe et al., 2008c).
Nonetheless, analytical statistical testing of any differences in diagnoses should become
indispensable in clinical practice, as it is already in research, and as it was recommended
specifically by Bartter (1974) for the case of BP. Ruling out chance as much as possible in
everyday care may be at least equally important, as it is in research aimed at the same care and the
same testing is now rendered possible for the case of the individual by accumulating time series
from at least 7-day and preferably longer-term monitoring. Of course, statistical significance,
albeit a sine qua non, does not imply clinical significance or scientific signification (Halberg et al.,
1973, 1991; Lee JY et al., 1982; Cornélissen et al., 1994). From those viewpoints and from that of
stress versus distress (Selye 1974), the findings in YW remain to be further evaluated in the light
of continued surveillance. The question whether occupational hypertension requires treatment
remains to be further assessed. Whether a relaxation test consisting of 10 consecutive
measurements within 10 minutes on a fully relaxed person (Scherf et al., 2006) can do the same as
ABPM did in this study should also be checked. The effect of vacations, notably when these are
associated with celebrations, such as New Year's Eve, has been associated with hypertension
(Hecht et al., 2007) with a higher cardiac mortality (Phillips et al., 2004).
Conclusion
Under the assumption of homeostasis rather than rhythms, it may be anticipated that
diagnoses based on monitoring spans of 5 or more months will be consistent. Chronobiologically,
they can be expected to be possibly statistically significantly different in the light of a broad
spectrum of infradian rhythms that has as yet been incompletely mapped in relatively few subjects.
Rhythms with infradian as well as circadian frequencies can blur the effect of loads that may be
tested quantitatively in some subjects like YW by a comparison of vacations from work with
weekdays. The normalization of the BP during 4 days of vacation from work at home in YW is just
234
one case showing the desirability of continuous monitoring so that any changes requiring
intervention are acted upon, notably when, contrary to what happened in YW during the time span
here reported, the normalization on Sundays and during a vacation fails to occur. We must not fly
blind (Fossel, 1998) when "seeing" may enter the state of the art in terms of both affordable,
unobtrusive hardware and software on a website for automatic analysis (Halberg et al., 2009), both
planned by the Phoenix Study Group, composed of volunteering members of the Twin Cities
chapter of the Institute of Electrical and Electronics Engineers (http://www.phoenix.tc-ieee.org), to
whom this paper is dedicated.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
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Lee MS, Lee JS, Lee JY, Cornélissen G, Otsuka K, Halberg F. (2003). About 7-day (circaseptan)
and circadian changes in cold pressor test (CPT). Biomed & Pharmacother 57 (Suppl 1): 39s-
44s.
Maschke C, Harder J, Cornélissen G, Hecht K, Otsuka K, Halberg F. (2003).
Chronoecoepidemiology of "strain": infradian chronomics of urinary cortisol and
catecholamines during nightly exposure to noise. Biomed & Pharmacother 2003; 57 (Suppl
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Otsuka K, Cornélissen G, Halberg F. (1996). Predictive value of blood pressure dipping and
swinging with regard to vascular disease risk. Clinical Drug Investigation 11: 20-31.
Phillips DP, Jarvinen JR, Abramson IS, Phillips RR. (2004) Cardiac mortality is higher around
Christmas and New Year's than at any other time: the holidays as a risk factor for death.
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Sanchez de la Pena S, Gonzalez C, Cornélissen G, Halberg F. (2004). Blood pressure (BP), heart
rate (HR) and non-insulin-dependent diabetes mellitus (NIDDM) chronobiology. Int J
Cardiol 97 (Suppl 2): S14.
Scherf H-P, Hecht K, Yilmaz Y, Meffert P. (2006). Fehlgemessener oder realier Hypertoniker? J
Hypertonie 10 (4): 6-11.
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Watanabe Y, Cornélissen G, Halberg F, Beaty L, Siegelova J, Otsuka K, et al. (2008b). Harm vs.
benefit from losartan with hydrochlorothiazide at different circadian times in MESORhypertension
or CHAT. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 149-167.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Watanabe Y, Cornélissen G, Halberg F, Hillman D, Czaplicki J, Sothern RB, et al. (2008c).
Transyears, no calendar-year in blood pressure decades before MESOR-hypertension:
normal or abnormal? In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 184-188.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Watanabe Y, Cornélissen G, Otsuka K, Revilla M, Czaplicki J, Schwartzkopff O, et al. (2008a).
Time-specified norms reveal full systolic but incomplete diastolic early MESORhypertension,
MH. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 168-176.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
Watanabe Y, Cornélissen G, Watanabe F, Tarquini R, Perfetto F, Siegelova J, Fiser B, Dusek J,
Homolka P, Halberg F (this issue). Solar signatures in a boy's blood pressure and heart rate.
Watanabe Y, Nintcheu-Fata S, Katinas G, Cornélissen G, Otsuka K, Hellbrügge T, Schwartzkopff
O, Bakken E, Halberg F. (2003). Methodology: partial moving spectra of postnatal heart rate
chronome. Neuroendocrinol Lett 24 (Suppl 1): 139-144.
239
Legends
Figure 1. Sphygmochrons of a man in everyday professional life as a cardiologist at ages 55
and 56 years, summarizing first 7.5 (top) and 5 months (middle), respectively, of mostly halfhourly
around-the-clock data, stacked and averaged for 48 consecutive (half-hourly) bins of an
idealized 24-hour day. Data during 4 days at home away from everyday activity extracted from the
second record were used to derive sphygmochron shown at the bottom. The abnormal MESOR in
bold on top and in the middle is no longer seen in the sphygmochron at the bottom. The
unintentional "treatment" by a vacation at home eliminated all systolic, diastolic, parametric and
non-parametric MESOR-hypertensions. © Halberg.
Figure 2. Nonparametric summary by stacking of half-hourly around-the-clock means along
an idealized 24-hour day at ages 55 and 56 years for blood pressure (BP) and heart rate (HR)
during regular professional life (top and middle) and during a vacation of 4 days at home (bottom).
Data during all 4 days of vacation are included in the 5-month record (middle). © Halberg.
Figure 3. Harm or benefit in the same patient from the same doses of the same
antihypertensive drug combination (Hyzaar) as a function of timing its administration, with about
1 month on each of 5 administration times and half-hourly chronobiologically interpreted ABPM
during the last week of each drug timing tested (Watanabe et al., 2008b;
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf; p. 149-167). If such chronotherapeutic
surveillance is ignored, "first do no harm" is violated. © Halberg.
240
Figure 1
241
Figure 2
242
Chronotherapy Individualized by Monitoring of a Patient (Su, M, 66y) with
Circadian Overswing (CHAT*) Finds Best Treatment Times for Lowering both
MESOR (top) and an Excessive Circadian Amplitude (bottom)
100
105
110
115
120
125
130
135
140
145
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Treatment Time (hours from awakening, AW)
SBP-M(mmHg)
1-way ANOVA: F=9.225; P<0.001
Cosinor: PR=43%; P<0.001
AW +3h +6h +9h +12h
Treatment Effect
No Treatment
Upper limit of acceptability for SBP-M
based on clinically healthy peers
matched by gender and age
0
5
10
15
20
25
30
00:00 03:00 06:00 09:00 12:00 15:00 18:00 21:00 00:00
Treatment Time (hours from awakening, AW)
SBP-A(mmHg)
1-way ANOVA: F=5.666; P=0.002
Cosinor: PR=32%; P=0.002
AW +3h +6h +9h +12h
No Treatment:
CHAT diagnosed
Treatment Effect
CHAT exacerbated
CHAT eliminated
Upper limit of acceptability
for SBP-A based on
clinically healthy peers
matched by gender and age
HARM
BENEFIT
* CHAT: Circadian Hyper-Amplitude-Tension, a vascular variability disorder. Bottom: Note that a
treatment can be useful when given in the evening, but is actually harmful when taken on awakening and
later in the morning, when it exacerbates CHAT, a condition that carries a risk of morbid events greater than
an elevated mean value of blood pressure.
Figure 3
243
Table 1: Comparison of rhythm parameters among 3 spans in Figures 1 and 2*
Systolic Blood Pressure (mmHg)
Span MESOR 24h-A 24h-φ (A,φ)
1. Jan-Aug 2008 142.6 11.76 -246
2. Aug 08-Jan 09 140.1 13.56 -251
3. Holiday (2008-09) 132.1 12.54 -226
1 vs. 2 vs. 3
F 32.174 0.440 4.598 2.501
P <0.001 0.645 0.012 0.045
1 vs. 2
F 4.247 1.029 0.392 0.708
P 0.042 0.313 0.533 0.495
2 vs. 3
F 29.504 0.246 7.073 3.886
P <0.001 0.621 0.009 0.024
Diastolic Blood Pressure (mmHg)
Span MESOR 24h-A 24h-φ (A,φ)
1. Jan-Aug 2008 87.3 5.94 -236
2. Aug 08-Jan 09 86.9 8.11 -242
3. Holiday (2008-09) 81.9 9.08 -226
1 vs. 2 vs. 3
F 13.248 1.896 1.129 1.457
P <0.001 0.154 0.327 0.219
1 vs. 2
F 0.324 5.029 0.618 2.827
P 0.571 0.027 0.434 0.065
2 vs. 3
F 13.581 0.254 1.740 0.949
P 0.001 0.616 0.192 0.391
Heart Rate (beats/min)
Span MESOR 24h-A 24h-φ (A,φ)
1. Jan-Aug 2008 74.9 4.92 -246
2. Aug 08-Jan 09 75.8 5.28 -253
3. Holiday (2008-09) 69.6 7.95 -253
1 vs. 2 vs. 3
F 21.029 2.543 0.146 1.355
P <0.001 0.082 0.865 0.253
1 vs. 2
F 0.785 0.053 0.187 0.120
P 0.378 0.819 0.667 0.887
2 vs. 3
F 37.279 3.392 0.001 1.697
P <0.001 0.069 0.975 0.189
/...
244
A: Amplitude; φ: Acrophase, expressed in (negative) degrees, with 360˚ ≡ 24 hours, 0˚ = 00:00.
Results from parameter tests (Bingham C, Arbogast B, Cornélissen Guillaume G, Lee JK, Halberg
F. Inferential statistical methods for estimating and comparing cosinor parameters. Chronobiologia
1982; 9: 397-439). For this time-microscopic assessment, the data during the 4 days of vacation in
span 3 were removed from span 2 prior to analysis. Any discrepancy between estimates of M, A
and φ in this table versus in Figure 1 may stem from the fact that original data are analyzed by
means of a 2-component model in Figure 1, whereas for this analysis a single 24-hour cosine curve
was fitted to the 48 half-hourly mean values obtained by stacking in each span separately.
245
Table 2: Comparison of vascular endpoints on Sundays with weekdays reveals acceptability of blood pressure (BP) on
Sundays by contrast to weekdays in YW, a physician-scientist
Sphygmos SBP-M DBP-M HR-M SBP-2A DBP-2A HR-2A S-HBI D-HBI TCI
1. Sun 132.9 83.0 72.2 20.03 9.10 10.30 5 1 0
2. Mon 138.8 86.9 74.2 28.15 19.86 11.25 53 11 0
3. Tue 140.9 88.2 76.2 29.58 18.05 14.23 70 12 0
4. Wed 138.6 86.2 75.0 28.33 18.33 10.46 51 9 0
5. Thu 141.4 88.3 75.2 22.85 10.78 8.07 80 6 0
6. Fri 143.0 88.4 77.0 27.52 17.70 8.84 80 5 0
7. Sat 141.0 85.6 78.5 30.86 19.30 16.17 57 5 0
*S: systolic; D: diastolic; BP: blood pressure; M: MESOR, a midline-estimating statistic of rhythm; 2A: double circadian amplitude,
HR: heart rate; HBI: hyperbaric index; TCI: tachycardic index. A lower value on Sundays for BP was also found for 30 series from 25
individuals, when the data of each subject were expressed as a percentage of their mean values, examined as a group by a one-way
analysis of variance: the lower MESOR was statistically significant for DBP below the 5% and for SBP below the 10% level. In the
same 30 series, the 2A of HR was higher on Sundays and Saturdays than on other days of the week (P<0.05).
246
ACCEPTABLE CONVENTIONAL STRESS TEST OUTCOME MAY NOT DISPEL
INDICATIONS OF A SPHYGMOCHRON
Franz Halberg 1
, Paul Rosch2
, Germaine Cornélissen1
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
American Institute of Stress, Yonkers, NY, USA
Abstract. A high risk of a myocardial infarction was detected by a chronobiologicallyinterpreted
around-the-clock cost-free blood pressure (BP) profile, a sphygmochron, but not by a
conventional "stress test" that requires special equipment and provider's time (and perhaps a copayment).
Currently a sphygmochron can be carried out cost-free via a project on the BIOsphere
and the COSmos (BIOCOS; corne001@umn.edu), in exchange for the data, and, better yet,
eventually automatically via a website (http://www.sphygmochron.org/) being built by the Phoenix
Study Group, composed of volunteering members of the Twin Cities chapter of the Institute of
Electrical and Electronics Engineers (http://www.phoenix.tc-ieee.org). With proper education of all
concerned via the same website, any computer-savvy person could serve any circle of family and
friends for cost-free surveillance, until an abnormality is found and could thus prompt action by the
also-copied care provider with added monitoring, whenever chronobiologic abnormality occurs,
irrespective of the outcome of a conventional stress test. Inaction in the case here reported was
associated with a hard event. This case report should stimulate interest in chronobiology by the
public, the care provider, the health care industry and the government. The informed care recipient
should convince the other three entities that cases such as the one here reported, now almost
certainly the rule, may become the exception, both in terms of the brevity of the record and the
neglect of its warning message, neglected based on the acceptable outcome of a conventional stress
test. We propose that continuous vascular BP and heart rate (HR) monitoring, if chronobiologically
interpreted, may constitute a stress test in its own right.
Introduction and Background. A comparison of the relative diagnostic and prognostic value of
a cardiovascular stress test administered by a care provider with that of a sphygmochron, a
chronobiologic summary as a function of time of BP and HR, should have been the topic of clinical
trials on an appropriate scale long ago. More so, since there are retrospectively analyzed trials
247
originally carried out for other purposes with outcomes or proxy outcomes showing the merit of
chronobiologic diagnostics and prognostics in Table 1 on 2,354 patients, in sets of 297, 2,039 and
18 (1), 50 (2) and 12 (3) individuals. The opportunity of a prompt outcome in a special case to
assess the merits of a conventional vs. a chronobiologic approach in Table 2 (2) is hence likely both
representative and illustrative, and deserves comment further in the light of differences in BP vs.
HR and further between workdays and holidays, a comparison of the latter days during at least
several months or preferably years or rather decades constituting a stress test in its own right in
some persons (4, 5).
Case report. BR, a computer scientist who came to our center could not be persuaded to
monitor for more than one or two days. In a first short profile over a weekend, he had a circadian
overswing near 40 mmHg, which for his gender and age is too high and is hence shown in bold type
in Table 2. He was strongly advised to monitor again and did so, albeit again for a relatively short
span on barely two workdays (rather than for an entire week, as we wished, i.a., to detect transient
abnormality and to implement another workday vs. holiday comparison). The overswing that in the
first profile was limited to systolic (S) BP now involved diastolic (D) BP as well. Furthermore, the
MESOR (a rhythm-adjusted mean) of his SBP was now also deviant (elevated). The difference
between the two profiles is visualized for his SBP only in Figure 1, which presents the abnormal
values in black.
The Sunday vs. weekday difference in the MESOR and circadian double amplitude of BP (BP-M and BP-
2A) likely contributes to what otherwise appears as a rapid progression of disease. Statistically significant Sunday
or holiday vs. workday differences were found in around-the-clock surveillance for the last 5 months of a 22-yearlong
half-hourly record of a self-monitoring cardiologist (YW) (5) as a presumably first case of true professional
white-coat MESOR-hypertension. This finding prompted the analyses of a set of 30 automatically monitored
around-the-clock series each covering about 30 days that showed great inter-individual differences. While on
Sundays the BP-M is on the average lower than during weekdays, one cannot generalize, as the weekend vs.
weekday difference was neither consistently statistically significant nor always in the same direction; at least
numerically, Sunday's average BP was not invariably lower than the average BP during weekdays (in preparation).
With the qualification that in BR, both profiles were too short, in retrospect, from the follow-up history, the
diagnosis could be made of a fulminating circadian BP overswing together with workday MESOR-hypertension, a
co-occurrence of two Vascular Variability Disorders (VVDs) that made his condition a Vascular Variability
Syndrome (VVS).
248
Note in Figure 1 (top) the increase (arrow) in the BP-M and in the circadian BP-2A (a measure
of predictable extent of within-day change) from profile 1 to profile 2 (P<0.001). The increase also
occurs for both SBP and DBP in the nonparametric hyperbaric index (HBI), based on stacking data
along the 24-hour scale, Table 2, as also seen for SBP in Figure 1 (bottom).
BR was again strongly advised, first and foremost, to continue monitoring and, if the VVS
persisted, to be treated, until the VVS was eliminated. Instead of further monitoring, he went to a
care provider who gave him a stress test which proved negative. He was advised that there was no
reason for concern, in keeping with the lack of action of the profession for which a chronobiologic
diagnosis is not in the guidelines and hence can be ignored. (This status quo has been compared
with the neglect of Ignaz Semmelweis' insistence on antisepsis.) A few months later, BR called and
asked to be monitored for a week. We inquired why he changed his mind when he was previously
reluctant to monitor for more than a couple of days. He told us that in the interim he had had a
myocardial infarction.
Discussion. In the course of NIH-sponsored research, we also diagnosed a circadian BP
overswing in several pregnant women, and could usually avoid or minimize problems by bedrest,
continued monitoring and treatment. In one case, however, with a (relatively low) 48-hour SBP-M
of 115 mmHg, the obstetrician did not put the mother to bed and did not continue monitoring as in
other cases. She developed pre-eclampsia, gave birth in the 27th week of pregnancy, and her baby
boy was hospitalized off and on for several years, with his care costing about U.S. $1 million, more
than half cost-accounted, Figure 2 (6). Other evidence is summarized in Table 1, upon which the
evidence to be used in the clinic rests. More of the same approach in specially designed clinical
trials is needed. The brevity of the records in Table 2 and the figures is illustrative of the status quo,
unacceptable for drawing inferences concerning individuals (7, 8). Conventional practice is
reflected in the discussion of several recent articles (9-13), all revolving around the fiction of "the
true" BP and ignoring VVDs, including MESOR-hypertension, the topics of last year's consensus
at this conference (14).
Certainly doing something about "hypertension" is much better than doing nothing and has
saved many lives (15). This merit does not detract from the fact that very many millions of the same
249
"hypertensives", among others, remain untreated because VVDs are unknown and false positive and
false negative diagnoses based on the spotcheck of a single 24-hour profile are excused as whitecoat
or masked hypertension, respectively. But the latter diagnoses can also be false since there is
day-to-day variability in BP. Quo usque tandem?
Marcus Tullius Cicero, whose oration we just cited, took an aggressive stand and, like
Semmelweis, died under unclement circumstances. Instead, as did Oliver Wendell Holmes in his
fight for antisepsis, and we in our endeavor toward chronobiologic self-help in health care, simply
note that "medical logic ... does not seem to have been either taught or practiced in our schools" (16;
cf. 17).
Elsewhere, Larry A. Beaty makes the point that the home use of a device in a significantly
different way from that in which it is used by care providers (the vast majority of whom measure the
fiction of "a true" static BP) constitutes a hurdle to overcome in the case of home chronobiologic
ABPM 7/24. Another hurdle is "Give blood pressure drugs to all (and do not measure at all)" (18).
Hurdle, yes, but if the public is reached and awakened to the opportunity of cyber-aided cost-free
self-help before a myocardial infarction rather than thereafter, the care receiver remembering VVDs
may be the vehicle to convince the provider of the merits of not flying blind (7).
Supported by MSM0021622402
Legends
Figure 1. Weekday (left) vs. workday (right) around-the-clock profiles provide a warning of a
high risk of a hard vascular event, which in this case was not accompanied by an abnormal result of
a conventional cardiologist's stress test. © Halberg.
Figure 2. Diagnosis of CHAT (short for Circadian Hyper-Amplitude-Tension) in the profile of
the mother of the partly cost-accounted "million-dollar baby" (6); even when it is associated with an
acceptable BP MESOR, CHAT can be a useful warning in pregnant women and in very many others
of both genders. © Halberg.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
250
1. Cornélissen G, Halberg F, Otsuka K, Singh RB, Chen CH. Chronobiology predicts actual and
proxy outcomes when dipping fails. Hypertension 2007; 49: 237-239. doi: 10.1161/01.HYP.
0000250392.51418.64.
2. Cornélissen G, Halberg F, Beaty L, Kumagai Y, Halberg E, Halberg J, Lee J, Schwartzkopff
O, Otsuka K. Cugini's syndrome in statu nascendi: Oratio contra morem prevalentem et pro
chronobiologica ratione ad pressione sanguinis curandam. La Clinica Terapeutica 2009; 160
(2): e13-e24.
3. Gupta AK, Greenway FL, Cornélissen G, Pan W, Halberg F. Prediabetes is associated with
abnormal circadian blood pressure variability. J Human Hypertension 2008; 22: 627-633.
doi:10:1038/jhh.2008.32.
4. Cornélissen G, Halberg F, Gubin D, Carandente F, Halberg J, Zaslavskaya R, Syutkin V,
Kumagai Y, Watanabe Y, Otsuka K. Carpe diem mensuratem: Fulminant CHAT, its
recognition a chronobiologic path to preventing a myocardial infarction? Abstract, 4°
Convegno Nazionale, Società Italiana di Cronobiologia, Gubbio (Perugia), Italy, June 1-2,
1996. p. 35-36.
5. Watanabe Y, Cornélissen G, Beaty LA, Siegelova J, Fiser B, Dusek J, Homolka P, Halberg F.
White-coat hypertension in a cardiologist: decades of monitoring lead to transient
occupational MESOR-hypertension absent during vacation: strain test. Proceedings,
Noninvasive Methods in Cardiology, Brno, Czech Republic, July 6-10, 2009, in press.
6. Halberg F, Cornélissen G, Carandente F. Chronobiology leads toward preventive health care
for all: cost reduction with quality improvement. A challenge to education and technology via
chronobiology. Chronobiologia 1991; 18: 187-193.
7. Fossel M. Editor's Note (to Halberg F, Cornélissen G, Halberg J, Fink H, Chen C-H, Otsuka
K, Watanabe Y, Kumagai Y, Syutkina EV, Kawasaki T, Uezono K, Zhao ZY, Schwartzkopff
O. Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging
medicine. J Anti-Aging Med 1998; 1: 239-259). J Anti-Aging Med 1998; 1: 239.
8. Schaffer E, Cornélissen G, Rhodus N, Halhuber M, Watanabe Y, Halberg F. Blood pressure
outcomes of dental patients screened chronobiologically: a seven-year follow-up. JADA 2001;
132: 891-899.
251
9. Godlee F. Editor's Choice: A new era for blood pressure management. BMJ 2009; 338: b2068.
10. McManus RJ, Glasziou P, Hayen A, Mant J, Padfield P, Potter J, Bray EP, Mant D. Blood
pressure self monitoring: questions and answers from a national conference. BMJ 2008; 337:
a2732 doi:10.1136/bmj.a2732
11. Keenan K, Hayen A, Neal BC, Irwig L. Long term monitoring in patients receiving treatment
to lower blood pressure: analysis of data from placebo controlled randomised controlled trial.
BMJ 2009; 338: b1492 doi:10.1136/bmj.b1492
12. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of
cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations
from prospective epidemiological studies. BMJ 2009; 338; b1665 doi:10.1136/bmj.b1665
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evidence raises questions about current monitoring and treatment recommendations. BMJ
2009; 338: b940.
14. Halberg F, Cornélissen G, Otsuka K, Siegelova J, Fiser B, Dusek J, Homolka P, Sanchez de la
Pena S, Singh RB, BIOCOS project. Extended consensus on means and need to detect
vascular variability disorders (VVDs) and vascular variability syndromes (VVSs). LeibnizOnline
Nr. 5, 2009 (http://www.leibniz-sozietaet.de/journal). 35 pp.
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National Heart, Lung, and Blood Institute [Editorial]. Arch Intern Med 2002; 162: 131-132.
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17. Holmes OW. The contagiousness of puerperal fever. (Printed in 1843; reprinted with
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252
12/20/95 12/21/95
Figure 1
253
Figure 2
254
Table 1. Outcomes of Chronobiological Screens of Blood Pressure and Heart Rate*
N of
patients
N at follow-up Sampling N measurements:
Total (outcomes)
Finding
10 10 (up to 5
years)
5/day daily Up to 9,125 (only
partially analyzed)
Among P. Scarpelli's patients, the 4 who died with malignant
hypertension had a larger circadian BP amplitude than the 6
who were still alive (SBP: t=1.84; P=0.103; DBP: t=2.99;
P=0.017)
63 21 after
28 years
~q4h
for 2 days
756 (252) 9 of 10 subjects without CHAT are alive while 7 of 11
subjects with CHAT are dead 28 years later (chisquare=6.390;
P<0.01)
56 56: Concomitant
LVMI
q15 min
for 24 h
5,376 (5,376) Classification by Y. Kumagai of patients by LVMI (<100; 100-
130; >130 g/m2) reveals elevation of circadian amplitude at
LVMI in 100-130 range whereas MESOR elevation occurs
only at LVMI >130.
221 221 (time of
delivery)
q1 h/48 h
in each trimester
of pregnancy
(336 profiles)
16,128 (16,128) In addition to an 8 mm Hg difference in mean value between
women who will or will not develop complications
(gestational hypertension, preeclampsia) already observed
during the first trimester of pregnancy, the occurrence of
complications is also associated with BP profiles
characterized by an elevated circadian BP amplitude. In
particular, one case (JK) of CHAT where warning was not
heeded, was followed 8 weeks later by severe preeclampsia,
premature delivery and 26 months of
hospitalization of offspring at a cost of about $1 million
297 297 after 6 years q15 min
for 48 h
57,024 (57,024) CHAT or a reduced circadian standard deviation of heart
rate, or an excessive pulse pressure (>60 mm Hg) are large
risk factors (larger than hypertension) for cerebral ischemic
events, nephropathy and coronary artery disease, even
when the blood pressure is within acceptable limits.
2039 2039
Concomitant
LVMI
Hourly averages
for 24 h
48,936 (48,936) LVMI is increased in patients with CHAT, a reduced
circadian standard deviation of heart rate, or an elevated
pulse pressure. The relation between LVMI and the circadian
endpoints is nonlinear.
23 12 after 7 years q15 min
for 9 days
19,872 (10,368) 10 of 20 patients with no consistent BP abnormality are alive
and well; 2 of 3 patients with consistent BP abnormality
reported an adverse vascular event (P=0.015 by Fisher's
Exact Test).
80 80 Response to
treatment
administered 2 h
before daily BP
peak vs. control
group treated 3
times a day
q4 h for 24 h
before and on
treatment
960 (960) With smaller doses of medications, BP was lowered by R.
Zaslavskaya to a larger extent and treatment was
accompanied by fewer complications.
Treatment: propranolol, clonidine, or alpha-methyldopa
(P<0.05 for each effect)
18 18 (12 weeks) q30 min (≥24h)
on 3 regimens
≥2592 (≥2592) Treating CHAT may prevent adverse vascular events: As
compared to placebo, nifedipine (1 mg b.i.d. at 08 & 20)
increases and benidipine (4 mg/day at 08) decreases the
circadian amplitude of blood pressure. The resulting
increase vs. decrease in the incidence of CHAT on
nifedipine vs. benidipine may account for the corresponding
difference between the number of stroke events of 7.6 vs.
3.5 and the total number of cardiovascular events of 20.4 vs.
8.8 per 1,000 person-years.
Totals:
2,807 2,754 160,769 (>141,636)
*SBP and DBP: Systolic and Diastolic Blood Pressure; HR: Heart Rate; CHAT: Circadian Hyper-Amplitude-Tension, a condition
defined by a circadian amplitude exceeding the upper 95% prediction limit of acceptability (in healthy peers matched by gender and
age); LVMI: Left Ventricular Mass Index. By comparison with several classical studies, the number of measurements in
chronobiological work completed thus far is likely to be larger, and confounding by inter-subject variability smaller.
255
Table 2: Case report: A 35-year-old man (BR) was monitored for 1 day (of a weekend;
Profile 1: 12/2/1995) and (18 days later) for 2 added days (midweek; Profile 2: 12/20/1995),
4 months before a myocardial infarction in April 1996
Endpoint (units) SBP (mmHg) DBP (mmHg) HR (beats/min)
Profile 1 2 1 2 1 2
MESOR 130.3 144.0** 81.0 86.5* 70.5 82.4***
2A (amplitude) 40.5 57.5* 20.0 45.8*** 27.1 29.2
φ (hr:min) 15:39 15:06 16:34 14:52 15:25 15:33
PTE (%) 17 54.8 8.5 35.8 0 9.2
tEx (hr:min) 14:49 14:59 22:56 16:23 - 15:57
Index (HBI or TCI) 29 230 7 92 0 15
*PTE: percent time elevation (of blood pressure or heart rate above time-specified reference limit
computed as upper 95% prediction limit); tEx: timing of excess; index: extent of excess measured as
area under the curve delineated by time-specified upper reference limit (chronodesm) and profile
whenever it exceeds the limit; for SBP and DBP, HBI = hyperbaric index in mmHg x hour during
24 hours; for heart rate TCI = tachycardic index, in beats/min x hour during 24 hours.
Values in bold are outside chronodesmic (time-varying and time-specified) reference limits.
P: *<0.05, **<0.01. In BR's first profile, only the SBP-2A was deviant; 18 days later, the SBPMESOR
and both the SBP-2A and DBP-2A and HBIs were deviant. From (2).
256
A TRANSTRIDECADAL BEL CYCLE IN HUMAN BLOOD PRESSURE
AND BODY WEIGHT
Franz Halberg1
, Germaine Cornélissen1
, William R. Best2
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Hines VA Medical Center, Hines, IL, USA
Aim. To explore the presence of non-photic cycles and in particular of a BEL cycle of a length
between 30 and 40 years in the body weight and blood pressure of a MESOR-hypertensive man
using hypotensive medication, 52 years of age at start of mostly daily measurements for the ensuing
decades.
Background. Chronomics, a cartography of chronomes (time structures, consisting of rhythms,
trends and chaos), has yielded a fledgling atlas of transdisciplinary rhythms that cover a wide range
of frequencies: some are photic in origin, such as circadians and circannuals, now broadly
recognized as entities in their own right; others are non-photic components of particle radiation
from the sun and the galaxy, broadly of helio-geomagnetics, gravitation, UV flux, and/or of any
other unseen yet measurable weather in extraterrestrial space. Pairs or multiple congruent periods, in
two or more time series, defined as having overlying or at least partly overlapping CIs (95%
confidence intervals) of their periods are seen when these series are analyzed with the extended
linear-nonlinear cosinor. They are found, i.a., among helio-geomagnetic activity indices themselves
and among these and vascular spectral components, notably in blood pressure and heart rate (studied
over decades) in the spectral regions of 1 cycle in I. about 7 days, the circaseptans; II. about 5
months, the cis-half-years; III. more than one year but less than two years, the transyears (longer
than [beyond = trans] a calendar year); and IV. decades, with the transtridecadal BEL of about 30-
40 years currently extensively documented (1-9).
Earlier (10-13), we had focused upon transyears -- periods longer than a year but shorter than
1.9 years. These can be far-transyears (1.2 years ≤ [τ {period} - CI] < [τ + CI] < 1.9 years) with the
CI of τ within these limits or near-transyears (1.00 year < [τ - CI] < [τ + CI] < 1.20 years) with the
CI of τ not overlapping these limits. We had also focused on cis-half-years, slightly shorter than a
257
half-year (12; cf. 14, 15). Far-transyears predicted by Wolff (14) and found by other physicists in
solar flares (15, 16) and in the solar wind (17, 18) have congruent periods detected in physiology
(11-13, 19, 20). They were discovered in sudden cardiac death in some locations and in cardiac
arrhythmia during some time spans during some solar cycle stages (12, 13). Near-transyears found
in biology, prompted their discovery in the solar wind, solar magnetism and geomagnetics (12, 21).
Subject and method. A physician (WRB) began self-monitoring body weight (BW) and
systolic (S) and diastolic (D) blood pressure (BP) when he was a few months short of 52 years of
age and continued for over 30 years. During the most recent 12 years, he also recorded his heart rate
(HR). WRB had started hypotensive therapy (chlorthalidone 50 mg/d) in June 1972 and had a good,
sustained BP response. He began recording frequent serial BP values on graph paper in April 1974,
since he planned to reduce the dosage and wanted to know the effects of such reduction. This
graphing of his data helped him to arrive at self-medication decisions. A first set of cosinor analyses
was presented earlier (10). Here, we focus on the broader spectrum, including the transtridecadal
BEL (1-9).
Results. Figure 1 displays the original data covering 3 decades for SBP, DBP and BW.
Eyeballing sees changes that differ in BW from those in BP, but objective analyses are needed.
Accordingly, Figures 2 and 3 show cosinor spectra. Figure 2 (top) shows for SBP, among other
components, a far-transyear of 1.6-year length, with an amplitude numerically larger than that of the
calendar-yearly component, which is also present in the least squares spectrum. As seen in Figure 2
(bottom), DBP also shows a far-transyear of 1.6-year length and a near-transyear of 1.13-year
length, both much larger in amplitude than the calendar-yearly component, but the most prominent
component in DBP has a period of about 16.7 years, the possible signature of a global Makarov and
Sivaraman (22) cycle. A cis-half-yearly component is further seen in SBP (Figure 2, top) with a
period of about 0.37 year as well as in DBP along with a second cis-half-year of 0.46-year length.
For HR, Figure 3 (top) shows a relatively broad band in the spectrum with a peaklet at 1.56 years,
and another component in the neighborhood of the calendar year, a near-cisyear, and further a cishalf-year
at a period of 0.45 year. BW (Figure 3, bottom) shows a far-transyear of 1.63 years and a
near-transyear of 1.03 years, along with a peaklet at 0.4 year, a cis-half-year, and no calendar-yearly
258
component. Other anticipated non-photic components seen in Figures 1 and 2 suffice to suggest that
non-photic effects were prominent in several variables in the subject investigated, awaiting
nonlinear analysis. A circadecadal Horrebow-Schwabe cycle in HR is of 11.7 years, whereas in BW
it is of 12.5 years, Figure 3.
Linear-nonlinear analyses by the extended cosinor (23-25), using 35 years as trial period,
yielded a transtridecadal spectral component only for SBP, the period [CI] being estimated as 30.56
[29.24, 31.87] years and the amplitude (A) as 9.03 [8.46, 9.60] mmHg. For BW, the period was
28.14 [26.66, 29.63] years and the amplitude was 1.79 [1.67, 1.92] lb. Analyses failed for DBP
perhaps because this variable was characterized by a decreasing trend with age, apparent in Figure
4. Using a slightly different model that includes a linear trend with the BEL cycle and a trial period
of 32.17 years, results were compatible with the presence of a BEL cycle, as shown in Table 1.
Table 1. Transtridecadal periods with the concomitatnt fit of a linear trend *
Variable (units) Period (years) [CI] A (units) [CI]
Diastolic blood pressure (mmHg) 31.68 [23.94, 39.42] 4.62 [2.63, 6.61]
Body weight (lb) 41.23 [31.25, 51.20] 3.31 [1.80, 4.81]
* Decreasing trend in DBP, increasing trend in BW (not shown).
The about 30-year component in SBP and DBP and a component also qualifying as a transtridecadal
by a CI of the period covering part of the 30-40 year range constitute an exciting new finding on a
revisited forgotten yet vindicated BEL periodicity (26; cf. 1-9).
Discussion. The yearly progression of seasons in a mid-continental climate is anticipated to
have a profound effect on our lives, and most certainly would find expression in some measures of
body function. Before doing any statistical analysis on the question of the importance of the aboutyearly
rhythm, WRB felt sure from taking many measurements over 30 years that on a cold day,
when his body felt chilled, his BP would tend to be higher than otherwise. Despite modern
heating/air conditioning systems, when it is cold outside, he often feels cold inside as well. For at
least as long as he kept records, moderate to marked winter chilling of his body resulted in
Raynaud's phenomenon, spasms of the arterioles in some or all of his fingers, leading to a dead
white appearance lasting from minutes to (rarely) hours after warming up. This never occurred
259
while he took BP readings, but is symptomatic of his autonomic nervous system's sensitivity to cold.
This seasonality notwithstanding, transyears can be present, and overall no yearly component was
detected in a global analysis of WRB's BW. In a MESOR (chronome-adjusted mean)-normotensive
younger colleague who started measurements at 20.5 years of age (RBS), the yearly component was
most prominent in SBP and DBP. In RBS, an about 33-year cycle has been documented (7; cf. 5, 6,
8, 9). In FH (12), another elderly man, a circannual component was absent in SBP, characterized
only by transyears, which are prominent in WRB's HR as well.
In WRB's series, the BEL cycle is demonstrated for SBP and DBP and for BW, the
demonstration for the latter two variables hinging on accounting for an also-present trend. The BEL
was originally documented in climate as an alternation of hot, dry and wet cold spans that was said
to have driven people to emigrate from Europe to North America, and westward within North
America (27, 28). It persists in an analysis of temperature data measured since Brückner's time to
that of this writing (9), and is thus pertinent as a background to discussions of climate change. It
relates to economics (30) and to military-political affairs (31) as well as to international battles (32)
and thus to diseases of society, as our meta-analyses (9) of invaluable data compiled by the
scholarship of Alexander Leonidovich Chizhevsky and Raymond Holder Wheeler reveal.
Before generalizing from two elderly cases, WRB and also FH (12), and a younger adult
(RBS), and considering age rather than high BP as accounting for the spectral difference between
WRB and FH on the one hand, without dominating transyears in BP versus and RBS with a
prominent circannual component on the other hand, many more time series will have to be
collected, in the footsteps of Santorio (33), who hung a scale from the ceiling of a room in his
house, on which he reportedly carried out all his activities including eating, sleeping, work,
excretion and sex, and whose data, including those on his changes of weight that led to the
discovery of insensible perspiration, could not be retrieved. RBS's, FH’s and WRB's data in turn
allow the demonstration of otherwise “insensible” effects of the cosmos in our physiology. These
results can be complemented not only by nonlinear analyses on FH's data (1987-2009) but also by a
remove-and-replace approach, as presented elsewhere (12). A major question revolves around
selective congruence. Do different physiologic variables in RBS, WRB and FH show congruence
260
with environmental cycles of differing lengths during the same multidecadal spans, and what may
putative underlying mechanisms be?
Acknowledgement and comment
This is a rare acknowledgement wherein the two senior authors thank Dr. William R. Best (WRB), a
co-author, not only because the data presented are those of the co-author, WRB. It is a pleasant task
to clarify at the outset that WRB's motivation, which has now continued for over three decades,
constitutes a model for the public at large, when some voices suggest that one need not measure
blood pressure at all and instead could be treating all comers with antihypertensive drugs regularly.
We are in the same situation as diabetology was in the middle of the 20th century, when a lonely
voice in Iowa advocated a strict control of blood sugar at one extreme, while others in New York
disregarded all control of glycemia at the other extreme, and the majority were in the middle of the
road, as is the case today once we substitute "pressure" for "glucose". The time of strict control of
vascular variability disorders is also likely to come.
The senior author is further indebted to WRB for his publication of his studies on the response to
epinephrine in 1950 wherein he documented a decrease in the count of circulating eosinophil cells
in patients who had had their adrenals removed, a finding that torpedoed the epinephrine test of
adrenal cortical function. The latter finding was in agreement with studies of the same response to
epinephrine (decrease in eosinophil count) in gonadectomized mice of both sexes, where, in
addition to a bilateral adrenalectomy, ectopic tissue next to the vertebral column and in the large
ligaments or in the scrotal fat had also been removed.
When the failure to confirm the epinephrine test was reported by the senior author to his then
department head, the late George W. Thorn, Hersey Professor of Medicine at Harvard, Thorn said
that he admired the senior author's (FH) sticking to his guns, but all the others could not be wrong.
In the case of the epinephrine test, the then majority was wrong. So are all those who fail to
recognize vascular variability disorders, VVDs. We need not repeat the maladies of the past, such as
the failure to scrub before surgery. Measuring and interpreting chronobiologically blood pressure
series may be cumbersome, like scrubbing for antisepsis. Nontheless, in a computer era selfsurveillance
could soon be implemented by everyone continuously, whether or not he has a VVD
and as a feature of universal preventive health care it may allow even the mapping of transtridecadal
cycles and perhaps some new information thereby concerning the health of individuals and
societies.
261
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
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Legends to Figures
Figure 1. Time plots of original data of WRB can be interpreted only subjectively. © Halberg
Figure 2. Linear least squares spectra of blood pressure of WRB. © Halberg
Figure 3. Linear least squares spectra of heart rate and body weight of WRB. © Halberg
Figure 4. Modeling of blood pressure and body weight of WRB reveal the presence of a BEL cycle.
© Halberg
266
Figure 1
267
Figure 2
268
Figure 3
269
Figure 4
270
DIFFERENCES IN TIME STRUCTURAL ENVIRONMENTAL CONGRUENCE
OF VASCULAR VARIABLES IN AN ELDERLY MAN
Franz Halberg1
, Germaine Cornélissen1
, Jarmila Siegelova2
, Pavel Homolka2
, Jiri Dusek2
, Bohumil
Fiser2
.
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, USA
2
Masaryk University, Brno, Czech Republic
Abstract. A wobbly about 30-year cycle in the heart rate (HR) of an elderly man (FH) measured
around the clock with interruptions during 22 years is detected and validated, along with a 15-year
(global?) cycle and a circadecadal (Horrebow-Schwabe) component characterizing the systolic (S)
and diastolic (D) blood pressure (BP) of FH.
The extended linear-nonlinear cosinor (1-3) has been used to detect cycles and to provide point and
confidence intervals for their parameters, namely their period ( ) amplitude (A) and acrophase ( ).
The periods found in a first linear step (in a linear cosinor spectrum) were the input used as initial
values into a nonlinear model that may then provide parameter estimates that can markedly differ
from the original guesstimates. With the construction of artificial time series consisting of periodic
components with known periods, amplitudes, and acrophases, one can check the output of the
program (4). Thus, we analyzed by a linear cosinor spectrum a simulated series containing two
components with close periods of 24.0 and 24.8 hours and with widely differing amplitudes over a
span much shorter than the beat period. With additions of more and more noise, the linear spectrum
finds three peaks, two of which are spurious. But when all three periods are used as input in the
nonlinear program, the procedure converges to the correct model, one of the two spurious peaks
showing as not significant and the other converging toward the correct frequency (4). The problem
is the more interesting since our approach fared well in comparisons with other methods, as shown
elsewhere (Table 1 in 3). The extended linear-nonlinear cosinor has been applied to infradian cycles
with periods longer than 30 years, which were detected and validated by the rejection of the zeroamplitude
assumption (5, 6). The minimal amount of data in terms of the number of cycles covered
by a time series has been considered for the assessment of circadian rhythms as requiring a number
of longitudinal replications, in order to reliably estimate the characteristics of the dynamics (7). In
the case of tridecadal cycles, a longitudinal approach is often not possible and transverse analyses
had to be used, replications being implemented across different similar individuals under similar
271
conditions, rather than on the same individual. As a few test pilots practice continued surveillance
of BP and HR, long enough time series have become available for the tentative scrutiny of the
tridecadal cycle in these variables on an individualized basis, relying on results from other test
pilots as prior information for the analysis on hand. Drawing a parallel with the study of circadians
indicating that a reasonable assessment of parameters could be obtained from data covering no more
than about 2/3 to 3/4 of a cycle (albeit with wide confidence limits), we here attempt to assess a
tridecadal cycle in time series of BP and HR shorter than a full cycle.
Specifically, we analyzed SBP, DBP and HR data of an elderly man (FH), 70 years of age at the
start of half-hourly around-the-clock measurements with interruptions (1987-2009, 22 years). For
all three variables, the spectra show a circadecadal cycle, Figure 1. Linearly, spectral peaks are
found at periods of about 11, 13, and 10 years for SBP, DBP, and HR, respectively. Using a trial
period of 10 years in the nonlinear analysis, periods and their 95% confidence intervals [CIs]
converge to 11.00 [10.32, 11.69], 15.31 [14.10, 16.52], and 10.14 [9.90, 10.39] years for SBP, DBP,
and HR, respectively (Figure 2). Analyses with a trial period between 30 and 35 years invariably
fail for SBP. In the case of DBP, even a trial period of 35 years converges to the 15.31-year
component of Figure 2. In the case of HR, a different component is found with a period and CI of
25.40 [24.45, 26.36] years, Figure 3 (middle). When it is fitted together with the about 10-year
cycle, both components are detected with statistical significance, but their periods are markedly
changed to 30.01 and 7.3 years, Figure 3 (bottom). Thus, another BEL cycle is very tentatively
suggested for HR from data covering only 22 years in FH. This elderly man's SBP follows a
Horrebow-Schwabe cycle, his DBP a global Makarov and Sivaraman cycle (8) and his HR
synchronizes with both a BEL and the third harmonic of the Hale cycle (9) as can be seen also by
the unaided eye in Figure 3 (bottom).
The major question revolves around selective congruence. Different physiologic variables in a
clinically healthy adult who at 20.5 years of age started self-measurements around the clock for 40
years (RBS) (5), a physician starting self-measurements mornings around 52 years of age for 3
decades (WRB) (6), and another yet older man (FH) show concurrently congruence of their SBP,
DBP and HR with environmental cycles of differing lengths during the same multidecadal spans.
Are these endocrine, neural or, as seems possible, neuroendocrine phenomena, involving i.a., the
272
differential pineal and hypothalamic responses that can be detected during a magnetic storm, Figure
4 (10)?
The transtridecadal periods here described in the circulation of three men were documented
thoroughly in climate by Brückner (11), reported a few months earlier by Egeson (12), and
associated with changes in the length of the about decadal cycle in relative sunspot numbers by
William and Norman Lockyer (13, 14), son and father, the latter the discoverer of helium and
founder of the journal Nature. Hence, this cycle of about 30 years has been named the BEL cycle to
honor its discoverers, remembered only by notable exceptions (15).
BEL cycles are found in records of environmental temperature up to today (16-18) and in our metaanalyses
of time series bearing on economics (19) and military political affairs, including
international battles (20, cf. 17).
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
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Schwartzkopff O, Stebelova K, Dulkova K, Chibisov SM, Engebretson M, Pan W, Bubenik
GA, Nagy G, Herold M, Hardeland R, Huether G, Poeggeler B, Tarquini R, Perfetto F, Salti R,
Olah A, Csokas N, Delmore P, Otsuka K, Bakken EE, Allen J, Amory-Mazaudier C.
Chronomics, neuroendocrine feedsidewards and the recording and consulting of nowcasts
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Klimaschwankungen der Diluvialzeit. Wien und Olmuetz: E. Hoelzel; 1890. 324 pp. (Penck A,
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and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
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15. Stehr N, von Storch H (Eds.) (Stehr B, Gamlin G, trans). Eduard Brückner: the sources and
consequences of climate change and climate variability in historical times. Dordrecht/Boston:
Kluwer Academic Publishers; 2000. 338 p
16. Shanahan TM, Overpeck JT, Anchukaitis KJ, Beck JW, Cole JE, Dettman DL, Peck JA,
Scholz CA, King JW. Atlantic forcing of persistent drought in East Africa. Science 2009; 324:
377-380.
17. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle in
heliogeophysics, psychophysiology, military politics, and economics. Geophysical Processes
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Geophysical Processes and the Biosphere, in press.
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Blagonravov M, Katinas GS. Economics and biology: the BEL. In: Proceedings, 14th
International Symposium, Ecologo-Physiological Problems of Adaptation, 9-10 April 2009.
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275
Figure 1. Least squares spectra of systolic blood pressure (top), diastolic blood pressure (middle)
and heart rate (HR) of FH (M, 68 years of age at start of monitoring during 22 years, with
interruptions) reveal the presence of a prominent about 11-year cycle, among other components. ©
Halberg.
276
Figure 2. Nonlinear analyses confirm the presence of a Schwabe cycle for systolic blood pressure in
the 22-year series of FH (M, 68 years of age at start of monitoring) (top). In the case of diastolic
blood pressure, the model converges toward a global cycle with a period of about 15 years (middle).
The fit of a Schwabe cycle to the heart rate data shows considerable lack of fit, suggesting the need
to modify the model in this case (bottom). © Halberg.
277
Figure 3. Modeling heart rate data collected during 22 years (with interruptions) by FH (M, 68 years
of age at start of monitoring): anticipated components with periods of about 11 and 35 years are
fitted separately (top and middle, respectively) and concomitantly (bottom). The composite model
provides a better fit, converging towards periods that differ markedly from their estimates in the
separate single-component models, including the anticipated BEL cycle of about 30 years. ©
Halberg.
278
MELATONIN DYNAMICS IN RATS’
HYPOTHALAMUS (HT, middle) AND PINEAL (PIN, below)
DURING MAGNETIC STORM (ST) AND QUIET (Q)
ST = 2 days of the second part of a moderate double magnetic storm, Q = 2 days
of magnetic quiet, gauged by the geomagnetic equatorial disturbance index Dst in
nT (plotted, top) of -115 and -80 and Kp (a planetary magnetic disturbance index of
slightly above 6 in arbitrary units in each storm (Kp not shown).
* HALO = hours after light on. Vertical lines straddling bars are 95% confidence
intervals. P < 0.05 in each comparison, except for φ in hypothalamus.
ST Q
ST Q ST Q ST Q
MESOR (M) Amplitude (A) Acrophase (φ)
DstHTPIN
Time (days of main study)
1
0
-40
-80
-120
2 3 4 5 6 7
16
8
0
22
18
14
HALO**1200
600
0
22
18
14
HALO**
Days in April
2004 3 5 8 9 13 154 6 7 12 1410 11
Figure 4. Using the equatorial geomagnetic disturbance index Dst as a gauge of magnetic storms
(top), two subspans of 2 days each at the beginning and end of a 7-day study are selected to
compare stormy (ST) and quiet (Q) conditions as they may influence hypothalamic (HT) and pineal
(PIN) melatonin of rats kept in 12 hours of light alternating with 12 hours of darkness. Whereas
geomagnetic disturbances are associated with lower melatonin concentrations and a dampened
circadian variation in pineal melatonin as expected from other studies, melatonin concentrations are
higher and the circadian rhythm is amplified in the case of hypothalamic melatonin. Data of R Jozsa.
© Halberg.
279
DEATH FROM WOLFF-PARKINSON-WHITE SYNDROME DURING MODERATE
MAGNETIC STORM: CASE REPORT WITH LITERATURE REVIEW
Germaine Cornélissen and Franz Halberg
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
A physician who died at 38 years of in Albuquerque, New Mexico, during a solar maximum,
had a congenital conductive heart disorder, Wolff-Parkinson-White syndrome (WPW), with which
he was diagnosed at 14 years of age. Putatively pertinent magnetic storm data framing the date of
his death are here noted to stimulate others to investigate whether individuals with conductive heart
disorders might be particularly and differentially susceptible to magnetic storms.
Background
Pioneering studies by Eliyahu Stoupel report on a relation of cardiac arrhythmia and
geomagnetic activity (1) and on sudden cardiac death (SCD) and daily and monthly helio- and
geomagnetic as well as cosmic ray activity (2). The detection of arrhythmias by implanted devices
served this author's team to relate arrhythmia to cosmophysical findings (3). Pearson correlation
coefficients constitute a major approach by Stoupel (4), usually without consideration of rhythms, a
circumstance that limits inferences, Figure 1. With focus upon cycles and superposed epochs,
arrhythmias triggered by implanted devices had been investigated earlier by others (5). Koukkari
and Sothern (6) deserve credit for considering non-photic environmental (as well as societal)
circaseptans (Saturday peak) with circadian and circannual rhythms in a review of cardiovascular
disease broadly, Table 1. Photic about-daily and about-yearly patterns were documented earlier (7,
8), as were circasemiseptans by 1982-1983, Figure 2 (9; cf. 10).
The multi-frequency rhythmic element in the time structure (chronome) of the incidence of
SCD (based on the code of the tenth revision of the International Classification of Diseases, ICD-10,
code 146.1) reveals, in addition to an anticipated (photic) circadian rhythm (morning peak) and a
circannual variation (winter peak) reviewed earlier (Table 1), also non-photic signatures (11-15),
including transyears with periods longer than a calendar year (by a few weeks or by several months)
and an about 0.42-year cis-half-year, detected in some but not all geographic locations examined
280
thus far (13). ICD-10 rightly separates electrical accidents of the heart from a cardiac arrest
associated with a myocardial infarction.
Before ICD-10, analyses by superposed epoch of 70,531 SCDs in Moscow, Russia, during
1979-1981 found an about 5.4% decreased incidence (P=0.012) two days after a southward turn of
the North-South component (Bz) of the interplanetary magnetic field (16). This record was also
characterized by an about 15.21-day variation validated by nonlinear least squares (95% CI: 15.14 -
15.28 days), apparently resonating with occasional frequency trapping with the about 14-day
component in the local geomagnetic disturbance index K recorded concomitantly (17, 18), Figure 3.
Chronomic analyses of a pool of 5,503 cases of SCD (ICD-10 146.1 code) from 9 geographic
locations between 1998 and 2003 corroborate a decreased incidence of SCD on days of high
geomagnetic activity (Kp>5) (p<0.05 from the fit of a parabola to the relative SCD incidence on
days -3 to +3 bracketing days when Kp>5 = day 0), Figure 4 (14, 15). This result is in keeping with
a decreasing second-order polynomial trend in the relative incidence of SCDs as a function of Kp
(R2
=0.604; P=0.040), Figure 5 (14, 15).
A smoothed (over 5 spectral lines) population-mean cosinor spectrum (across all 9 locations)
in the frequency range of one cycle in 5 years to one cycle in 3.3 days identifies peaks at trial
periods of about 1.25 years, 14.6 and 3.5 days. Prior to smoothing, the circannual (P=0.063), cishalf-year
(P=0.054), and about 14.4-day (P=0.075) components are detected with borderline
statistical significance, whereas other components related to the solar rotation, with periods of about
9, 7, 5 and 3.5 days are detected with statistical or borderline statistical significance (P<0.06) (14,
15).
Circadian, circaseptan, and circannual patterns have also been documented to characterize
different kinds of cardiac arrhythmia (19, 20). Arrhythmias that may underlie SCD have been shown
to follow patterns similar to those characterizing SCD (13-15). Paroxysmal supraventricular
tachycardia is found to peak in the evening, later than the rather broadly classified ventricular
arrhythmia but earlier than atrial fibrillation (19). Analyses of 811 cases of atrial fibrillation
recorded between 1980 and 1989 (10 years) indicate a clear circannual component peaking in
November (P=0.003). In addition, these data are also characterized by an about 1.35-year transyear
281
(P=0.050) and an about 7-year (P<0.001) component, Figure 6. During the same 10-year span, no
circannual (P>0.50) but only about 2-year (P=0.021) and 0.45-year (P=0.009) components are found
to characterize 353 cases of paroxysmal supraventricular tachycardia (P-values not corrected for
multiple testing), Figure 7 (14, 15, 21). Transyears have also been found in all longitudinal blood
pressure and heart rate series analyzed thus far (over 46), most covering 10 years or much longer
(up to 40 years), Figure 8 (15). Analyses of long-term ECG and pacemaker-cardioverterdefibrillator
records can also help assess the relative merits of different treatment modalities (5),
notably once outcome measures also become available.
There is a precedent for such outcome studies in the case of ambulatory blood pressure
monitoring. These studies have identified abnormalities in blood pressure and heart rate variability
that can be treated, such as an excessive circadian amplitude of blood pressure (CHAT), an
excessive pulse pressure, and a deficient heart rate variability, and also an odd timing of the
circadian blood pressure rhythm, but not of that in heart rate. These conditions are associated with
increased cardiovascular disease risk, even among MESOR-normotensive subjects (22-27). There is
also a precedent for a decrease in heart rate variability associated with magnetic storms, as a factor
putatively underlying myocardial infarctions (28-30). The patterns of arrhythmia are amenable to
longitudinal study by chronomics, a microscopy in time that maps endpoints of timing in data from
around as well as in us. With considerations of safeguarding privacy by using appropriate coding
rather than personal identification, open access to archival and device data may serve not only for
prediction of SCD, but also for the study of underlying mechanisms and thus for rational prevention.
Against this background (14, 15), we present the following case report.
Case report. On the morning of 31 Jan 1978, the 38-year-old patient, diagnosed 24 years
earlier with WPW, started to get out of bed and then collapsed. He was taken to the hospital by an
ambulance and pronounced dead on arrival. Time of death was estimated to be around 07:30-08:30.
The patient had been on quinidine and/or propranolol since age 14, and had a history of being able
to convert back to a normal sinus rhythm by Valsalva or eyeball pressure. His WPW was
complicated in that during his medical residency in Madison about six years earlier, he had broken
his back in a freak bicycle accident. At the time of his accident, he was 6'4". Six years later, he had
282
suffered such severe spinal compression that he was only 6' tall. As a result, he had been in
considerable physical pain just prior to his death, and his wife attributed the lateness of his getting
up to the back pain. At age 15, his granddaughter underwent cardiac catheterization for a conductive
disorder.
As seen is Figure 8 (top 2 rows), on the day of death (marked by a black dot), Bz, the northsouth
vector of the interplanetary magnetic field, turns from positive to negative, a feature
associated with a magnetic storm. A peak was also found in the planetary index of geomagnetic
disturbance Kp, and a moderate trough in the equatorial index of geomagnetic disturbance Dst, both
features in keeping with a magnetic storm. Wolf's relative sunspot numbers had sharply risen and
there was a peaklet in the electric field. Solar wind speed peaked one day earlier while proton
temperature, proton density and flow pressure were not remarkable. This set of conditions
prevailing at the time of death of this patient with WPW syndrome is reported to stimulate the
search for common denominators in the death of other patients with WPW. This pathological
condition is characterized by abnormal pathways between the upper and lower chambers of the heart
(the bundle of Kent, an accessory pathway), leading to abnormal communication between the atria
and ventricles. To our knowledge, there are no previous investigations of magnetosensitivity (or
sensitivity to other aspects of space weather) of WPW patients. Eliyahu Stoupel had previously
investigated cardiac arrhythmia in relation to many helio-geomagnetic and other non-photic factors
(1-3), whereas we have focused upon the periodicities in the incidence patterns of both cardiac
arrhythmia and SCD. Both approaches are in agreement, documenting that overall in superposed
epochs, magnetic storms may protect the patients with arrhythmia, Figure 3. But according to Figure
8, the death of at least one patient with WPW, or this syndrome itself, may be an exception. Only
follow-up studies examining the heliogeomagnetic and other non-photic environmental constellation
at the time of death of other cases of WPW syndrome can decide this question.
283
Acknowledgement Dr. David Sonntag, from the Asian Office of Aerospace R&D, Tokyo, provided
the data here analyzed and a continuing stimulus to delve further into aligning frequency-windows
related and stochastic resonances with non-photic as well as photic environmental factors.
Support: GM-13981 (FH) and University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
284
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Legends
Figure 1. The ever-present risk of different correlations on cyclic variables dependent upon
the particular time span investigated is illustrated by correlations of the urinary excretion of 17ketosteroids
with solar activity that can display a high statistical significance (as in the second
section of the display on the left) or no significant association (as in the rest of the display on the
left), notwithstanding a cross-spectral coherence and the proper time relations with a maximum 17ketosteroid
following that in solar activity, both in keeping with a possible association. © Halberg.
Figure 2. About 3.5-day (circasemiseptan) rhythmic feature of sudden human death. Original
data by Rabkin et al. (10), who examined records of 3,983 men for sudden cardiac deaths (SCD). 63
deaths occurred in the absence of information on previous ischemic heart disease (IHD) and 89 in
the presence of IHD. For the 63 deaths without IHD and for the total of SCD, the original authors
established differences by χ2 test (P<0.01). They comment on the excess of SCD on Mondays.
Meyers and Dewar (31) comment in turn on the role of a large consumption of alcohol on
Saturdays. In Rabkin et al.'s data (10), a second peak on Thursdays is apparent to the naked eye. The
frequency multiplication (doubling) of an internal circaseptan rhythm, which is merely synchronized
by the burden of returning to work on Mondays and influenced by other factors is a working
hypothesis. Note that the best-fitting period is 84 hours (1/2 week) rather than 168 hours (1 week).
We are dealing with a frequency-doubled (circasemiseptan) change. This rhythm is apparent from
the fact that the 95% confidence ellipse from the fitting of an 84-hour cosine curve does not cover
the center (pole) of the cosinor plot. This result is in keeping with much evidence on the ubiquity of
circaseptan and circasemiseptan rhythms, their free-running in human beings, their relative
temperature compensation in the springtail and their frequency multiplication, e.g., in a fatal case of
cardiac arrhythmia, studied after a triple coronary bypass operation. 7-day synchronized
circaseptan-rhythmic mortality has also been documented by autocorrelations for homicides, motorand
non-motor-vehicle accidents and suicides. © Halberg.
P: probability of null hypothesis: amplitude = 0;
no obs: number of observations;
percent rhythm: percentage of variability accounted for by cosine curve;
290
95% CL = 95% confidence limits derived from cosinor ellipse.
†: MESOR ≡ 100%;
††: from midnight Sunday to Monday (≡0˚).
Figure 3. Circadiseptan pattern of sudden cardiac death: social (the bimonthly payday),
environmental (the first harmonic of the solar relation rate at its equator) or both may contribute to
the pattern (18). © Halberg.
Figure 4. Chronomic analyses of a pool of 5,503 cases of SCD (International Classification of
Diseases, 10th
revision, code I46.1) from 9 geographic locations between 1998 and 2003 corroborate
a decreased incidence of SCD on days of high geomagnetic activity (Kp>5) (P<0.05 from the fit of a
parabola to the relative SCD incidence on days -3 to +3 bracketting days when Kp>5 = day 0) (14,
15). © Halberg.
Figure 5. A decreasing second-order polynomial trend characterizes the relative incidence of
SCDs as a function of Kp (R2
=0.604; P=0.040) (14, 15). © Halberg.
Figure 6. Least-squares spectra of atrial fibrillation (21). © Halberg.
Figure 7. Least-squares spectra of paroxysmal supraventricular tachycardia (21). © Halberg.
Figure 8. Mostly far-transyears (1.2 years ≤ [τ {period} - CI {95% confidence interval}] <
[τ + CI] < 1.9 years) in 10 physical and environmental variables and in human physiology (14). ©
Halberg.
Figure 9. A case of Wolff-Parkinson-White syndrome or the syndrome itself may be an
exception to the protective effect of magnetic storms in cardiac arrhythmia (Figure 3). © Halberg.
291
Figure 1
292
Figure 2
293
About 14-day Component Characterizes Incidence of
Sudden Cardiac Death (SCD) in Moscow, Russia
*
55
60
65
70
75
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31
Time (Day of Month)
SCD(N/day)
F=1.628; P=0.018
Payday
*
Moscow database (1979-1981)
Figure 3
294
50
60
70
80
90
100
110
120
130
140
150
-4 -3 -2 -1 0 1 2 3 4
Time (days from Max Kp > 5)
SCD(%ofmean)
Mean ± SE
R2=0.68; P=0.022
Figure 4
Overall Trend (MN, AR, NC, CR, Tbilisi)
0
20
40
60
80
100
120
140
160
180
0 1 2 3 4 5 6 7
Kp (AU)
SCDIncidence(%mean)
r=-0.700, P=0.080
R2
=0.604, P=0.040 (2nd-order term alone)
Figure 5
295
Figure 6
Figure 7
296
The Trans-year (an ~1.3-year component) in the Cosmos (top 10 rows),
Pathology (myocardial infarction, MI), and Physiology (bottom 43 rows)*
0
10
20
30
40
50
60
70
1.0 1.1 1.2 1.3 1.4 1.5 1.6
Period (years)Series(N)
Point and 95% confidence interval (CI)
MI
43 records
of blood
pressure
and heart
rate from
13 subjects
* All differing by non-overlapping 95% CIs from the precise calendar year and many differing among each
other, a putative hint of endogenicity. Similar results found for another man providing 3 additional series.
Physical
variables
Figure 8
297
Death (dot) of a 38-year old case of Wolff-Parkinson-White Syndrome occurred at an
extremum of the equatorial magnetic disturbance index Dst that is negatively related to
magnetic storms, shortly after a peak in the planetary geomagnetic disturbance index Kp,
and shortly before a peak in Wolf relative sunspot numbers; there were other extreme values
of greater magnitude during 1978.
-9.0
-6.0
-3.0
0.0
3.0
6.0
9.0
12.0
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
BzGSE
31 Jan 1978
-10.0
-5.0
0.0
5.0
10.0
15.0
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
BzGSM
31 Jan 1978
0
200000
400000
600000
800000
1000000
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
ProtonTemperature
31 Jan 1978
0.0
10.0
20.0
30.0
40.0
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79ProtonDensity
31 Jan 1978
0
200
400
600
800
1000
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
SWS
31 Jan 1978
0.00
5.00
10.00
15.00
20.00
25.00
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
FlowPressure
31 Jan 1978
-8.00
-6.00
-4.00
-2.00
0.00
2.00
4.00
6.00
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
ElectricField
31 Jan 1978
0
40
80
120
160
200
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
WolfN
31 Jan 1978
0
10
20
30
40
50
60
70
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
Time (calendar date)
Kp
31 Jan 1978
-150
-120
-90
-60
-30
0
30
1-Jan-78 2-Apr-78 2-Jul-78 1-Oct-78 1-Jan-79
Time (calendar date)
Dst
31 Jan 1978
Figure 9
298
F. CHRONOBIOETHICS
CHRONOMICS OF CHURCH MEMBERSHIPS
Franz Halberg and Germaine Cornélissen
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
A rational scientific optimization may serve in ethics to the extent to which any mechanisms
of reproducible since cyclic features of spirituality and of criminality as well as of other illnesses
become measurable and eventually understood (1-5). Should either or both the 'good' or the 'bad' be
found to be at least passively influenced by cyclic physical environmental factors, as is putatively
the case (1, 2), these aspects of behavior may eventually become actively manipulable, perhaps
utilizable for human survival. Toward this goal, chronomics, the study of aligned environmental and
biological time series, has already mapped time structures in religious behavior, like proselytism
(2). Such maps may lead to underlying geographic/geomagnetic latitude-associated mechanisms (2).
The relative brevity of the available time series for earlier maps is a hurdle, and here, with further
clearly insufficient data, we continue a plea for much longer and denser worldwide time series.
In the growth rate of membership in the Church of Jesus Christ of Latter-Day Saints (LDS),
the linear-nonlinear cosinor (6-9) finds a spectral peak at a period of about 32.2 years, with a CI
(95% confidence interval) extending from 26.8 to 37.5 years, Figure 1. The period estimate and
most of its CI lie in the 30-40 year range. This finding qualifies it as a transtridecadal peak, or BEL.
This peak is so named after Eduard Brückner, who published his extensive groundbreaking findings
of an about 33-year cycle in 1890 (10); Charles Egeson (11), who described the cycle a few months
earlier in 1889; and William J.S. Lockyer and Sir Norman Lockyer (12, 13), son and father, who
described and reviewed, respectively, the history of an about 35-year cyclic variation in the length
of the Horrebow-Schwabe cycle (14-16). Figures 2A-C show prior findings on cosmic signatures in
church membership and Figures 3A-B summarize an about-didecadal component in religious
proselytism (2). The data underlying Figures 2A-C are too short to assess any transtridecadals, but
with this qualification, they yield signatures of sunspot cycles, albeit differing for different church
memberships. Figure 2A hints at a circadecadal Horrebow-Schwabe cycle, whereas Figures 2B and
299
2C show about 19.0-year or 19.3-year cycles, respectively, with CIs overlapping both the global
Makarov-Sivaraman (17) and the Hale bipolarity cycles.
In turning to Figures 3A-B, the zero-21.0-year-amplitude assumption is rejected (P<0.05) in
86 of 104 data series, the distribution of acrophases spanning less than 180° (half a cycle), a
statistically significant finding in its own right. By population-mean cosinor, 35% of the total
variability is accounted for by the about 21.0-year Hale cycle (P<0.001). Nonlinearly, the period is
estimated at 20.39 years, its CI extending from 18.60 to 22.25 years (2). It is in keeping with a Hale
cycle, as results in Figures 2B-C, prompting the consideration that the sunspot bipolarity cycle is
mirrored in church memberships, the CI of periods overlapping 20-24 years for data analyzed in
Figures 1, 2B-C and 3A-B.
Whether the LDS membership has both a Hale and a BEL signature will have to be
scrutinized further, but the findings are compatible with at least the possibility that these periods
alternate. A chronobiologic serial section carried out at a trial period of 32.2 years validates this
period only for the last few (overlapping) 64-year intervals, Figure 4. The time course of MESORs
(lower curve in row 2 of Figure 4) reveals a single cycle of about 100 years, in keeping with the
spectral peak in Figure 1 (bottom). To the naked eye, the transtridecadal amplitude (distance
between the two curves in row 2 of Figure 4) undergoes changes recurring also every about 32.2
years (CI: 29.6 – 34.8 years, with the qualification that amplitude estimates from the serial section
were not independent).
Until geographic regions are separately documented for other church memberships, any
latitude-dependence of parameters can be examined only for the proselytism data, Figure 5 (2).
Several characteristics of the about 21.0-year Hale cycle are statistically significant related to
geomagnetic latitude. It seems pertinent that when the adjusted growth rate of the LDS church is
examined during the span from 1950 to 2008, 27.9-year and 17.0-year components (17) dominate
(Figure 6), with the CI of the former period overlapping the 30-40 year range of the transtridecadal
BEL cycle (18-21). The BEL has been validated in Brückner's original data (18, 21) and has been
shown to characterize heliogeophysics (19), notably solar flares, also solar wind speed (19) and
300
further psychophysiology (20-22), military politics and economics (23). It is extended by Figures 1,
4 and 6, to church membership dynamics, at least one aspect of religiosity.
Albert Einstein, among many others, explicitly regarded religion as a topic inappropriate for
science, if not inapproachable or unassailable (24). Other physicists and academic engineers have
addressed spirituality as intentionality (25; cf. 26). It is the more noteworthy that, in addressing
scientists in 1983 (27), Pope John Paul II "spoke therapeutically toward the historical rift between
the (Catholic) Church and science", providing more than an "apology to the memory of Galileo".
Albert Di Canzio interprets this address as a bright ray of hope (which could become) a hint of
“better things to come". First, the bright ray: "Let us think of how the results of scientific research
help us to know the universe better, to understand better the mystery of man; think of the
advantages which the new means of communications and contact among people offer to society and
to the church; let us think of the ability to produce incalculable economic and cultural wealth, and
especially to promote the education of the masses, and to cure diseases previously thought
incurable. What admirable achievements. And the hint: yes, the church appeals to your capacities
for research in order that no limit may be placed upon our common quest for knowledge" (27).
Many pertinent data could be studied in this context, starting in earliest church records providing
time series, which are still accumulating today and should become amenable to analysis.
Acknowledgement
Dr. David Sonntag, from the Asian Office of Aerospace R&D, Tokyo, provided the data here
analyzed and a continuing stimulus to delve further into aligning frequency-windows related and
stochastic resonances with nonphotic as well as photic environmental factors.
Support: GM-13981 (FH) and University of Minnesota Supercomputing Institute (GC, FH).
Supported by MSM0021622402
301
1. Halberg F, Otsuka K, Katinas G, Sonkowsky R, Regal P, Schwartzkopff O, Jozsa R, Olah A,
Zeman M, Bakken EE, Cornélissen G. A chronomic tree of life: ontogenetic and phylogenetic
'memories' of primordial cycles — keys to ethics. Biomed & Pharmacother 2004; 58 (Suppl
1): S1-S11.
2. Starbuck S, Cornélissen G, Halberg F. Is motivation influenced by geomagnetic activity?
Biomed & Pharmacother 2002; 56 (Suppl 2): 289s-297s.
3. Halberg F, Cornélissen G, Conti A, Maestroni G, Maggioni C, Perfetto F, Salti R, Tarquini R,
Katinas GS, Schwartzkopff O. The pineal gland and chronobiologic history: mind and spirit as
feedsidewards in time structures for prehabilitation. In: Bartsch C, Bartsch H, Blask DE,
Cardinali DP, Hrushesky WJM, Mecke W (Eds.) The Pineal Gland and Cancer:
Neuroimmunoendocrine Mechanisms in Malignancy. Heidelberg: Springer; 2001. p. 66-116.
4. Cornélissen G, Bingham C, Siegelova J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Halberg
F. Cardiovascular disease risk monitoring in the light of chronobioethics. Chronobiologia
1994; 21: 321-325.
5. Halberg F, Bingham C, Siegelova J, Fiser B, Dusek J, Prikryl P, Sonkowsky RP, Cornélissen
G. "Cancer marker chronomes" assessed in the light of chronobioethics. Chronobiologia 1994;
21: 327-330.
6. Halberg F, Tong YL, Johnson EA. Circadian system phase — an aspect of temporal
morphology; procedures and illustrative examples. Proc. International Congress of
Anatomists. In: Mayersbach H v (Ed.) The Cellular Aspects of Biorhythms, Symposium on
Biorhythms. New York: Springer-Verlag; 1967. p. 20-48.
7. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
8. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
302
9. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
10. Brückner E. Klimaschwankungen seit 1700 nebst Beobachtungen über die
Klimaschwankungen der Diluvialzeit. Wien und Olmütz: E. Hölzel; 1890. 324 pp. (Penck A,
Hrsg. Geographische Abhandlungen, Band IV.)
11. Egeson C. Egeson's weather system of sun-spot causality: being original researches in solar
and terrestrial meteorology. Sydney: Turner & Henderson; 1889. 63 pp.
12. Lockyer WJS. The solar activity 1833-1900. Proc Roy Soc Lond 1901; 68: 285-300.
13. Lockyer N. Simultaneous solar and terrestrial changes. Science 1903; 18: 611-623.
14. Thiele ThN. De Macularum Solis antiquioribus quibusdam observationibus Hafniae institutis.
Astronomische Nachrichten 1859; 50: 259-261.
15. Schwabe H. Über die Flecken der Sonne. Astronomische Nachrichten 1838; 15: 244-248 (no.
350).
16. Schwabe H. Sonnen-Beobachtungen im Jahre 1843. Astronomische Nachrichten 1844; 21:
254-256 (no. 495).
17. Makarov VI, Sivaraman KR. New results concerning the global solar cycle. Solar Physics
1989; 123: 367-380.
18. Halberg F, Cornélissen G, Czaplicki J, Prabhakaran Nayar SR, Siegelova J. Brückner-EgesonLockyer
(BEL) climate cycle in original Brückner's, Lockyer's and follow-up data. In: Halberg
F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology,
Brno, Czech Republic, October 4-7, 2008. p. 74-89.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
19. Cornélissen G, Prabhakaran Nayar SR, Czaplicki J, Siegelova J, Mendoza B, Halberg F.
Brückner-Egeson-Lockyer (BEL) cycle in heliogeomagnetics. In: Halberg F, Kenner T, Fiser
B, Siegelova J (Eds.) Proceedings, Noninvasive Methods in Cardiology, Brno, Czech
Republic, October 4-7, 2008. p. 106-115. http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
303
20. Sothern RB, Katinas GS, Fiser B, Siegelova J, Cornélissen G, Halberg F. A transtridecadal
cycle in human heart rate: Selective infradian, notably multidecadal solar-physiologic BEL
congruences. In: Halberg F, Kenner T, Fiser B, Siegelova J (Eds.) Proceedings, Noninvasive
Methods in Cardiology, Brno, Czech Republic, October 4-7, 2008. p. 204-213.
http://web.fnusa.cz/files/kfdr2008/sbornik_2008.pdf
21. Halberg F, Sothern RB, Cornélissen G, Czaplicki J. Chronomics, human time estimation, and
aging. Clinical Interventions in Aging 2008; 3 (4): 749-760.
http://www.dovepress.com/articles.php?article_id=2608
22. Halberg F, Cornélissen G, Sothern RB, Czaplicki J, Schwartzkopff O. 35-year climate cycle in
heliogeophysics, psychophysiology, military politics, and economics. Geophysical Processes
and the Biosphere, in press.
23. Cornélissen G, Halberg F, Schwartzkopff O, Sanchez de la Peña S, Chibisov SM, Radysh IV,
Blagonravov M, Katinas GS. Economics and biology: the BEL. In: Proceedings, 14th
International Symposium, Ecologo-Physiological Problems of Adaptation, 9-10 April 2009.
Moscow: People's Friendship University of Russia; 2009. p. 486-489.
24. Einstein A. Science and religion. Nature 1940; 3706: 605-607.
25. Tiller WA. Science and Human Transformation: Subtle Energies, Intentionality and
Consciousness. Walnut Creek, California: Pavior, 1997. 316 pp.
26. Jahn RG. Information, consciousness, and health. Alternative Therapies in Health and
Medicine 1996; 2: 32-38.
27. Di Canzio A. Galileo: his science and his significance for the future of man. Portsmouth, NH:
Adasi; 1996. 389 pp.
304
Figure 1. The growth rate of the Church of Jesus Christ of Latter-day Saints (LDS), shown on top,
is resolved by linear-nonlinear cosinors into 3 spectral peaks, each putatively approximating a
known solar cycle. The CI (95% confidence interval) of the first peak between 80 and 115 years
could correspond to a Gleissberg cycle followed by a transtridecadal 32.2-year BEL (BrücknerEgeson-Lockyer)
cycle. The peak with a 95% confidence interval reaching 23 years could
correspond to a Hale cycle. © Halberg.
305
Figure 2A. Southern Baptist church membership hints at a circadecadal (circadecennian) cycle of
about 11 years, based on limited data. The 95% confidence interval extends from 9.7 to 12.9 years.
© Halberg.
306
Figure 2B. Seventh-day Adventist church membership record hints at a much longer circadidecadal
cycle of about 19 years. The 95% confidence interval of the period from 14.2 to 23.7 years does not
overlap the corresponding estimate in Figure 2-A. © Halberg.
307
Figure 2C. Roman Catholic church membership shows a cyclic pattern of about 19 years, in
keeping with the uncertainty of the circadidecadal peak in Figure 2-B. © Halberg.
308
Figure 3A. Least squares spectrum by population-mean cosinor of the average number of hours per
month spent working for their church by Jehovah's Witnesses (JW). Results stem from 84 of 103
available sites, including all time series spanning at least 35 years, i.e. over 85% of the fundamental
period of 42 years, allowing rejection of the zero 21-year amplitude assumption. Amplitudes are
phase-weighted, determined as the vectorial average of the (amplitude, acrophase) pairs across all
84 locations at each trial period. For ordering purposes only, without correction for multiple testing,
components found to be statistically significant by the rejection of the zero-amplitude assumption
are shown with their respective 95% confidence interval. © Halberg.
309
Figure 3B. Illustration of the about 20.39-year (95% confidence interval: 18.60-22.25) component
in the average number of hours spent working for their church per month by Jehovah's Witnesses
(JW) for the grand total, including other locations in addition to the 103 sites analyzed separately.
Model fitted by non-linear least squares consists of linear trend and cosine curve with trial period of
21.0 years. Whereas a linear trend applies to the grand total, such a trend is statistically significant
in only about 50% of the individual data series, and can be negative as well as positive. © Halberg.
310
Figure 4. Original data (top) are fitted with a 32.2-year cosine curve in a 64.4-year interval (2
cycles) displaced in 1-year increments. The lower curve in the second row represents the MESOR
(M, Midline-Estimating Statistic Of Rhythm). Changes in MESOR as a function of time hint at the
presence of an about 100-year Gleissberg cycle (in keeping with the spectral peak at 98.5 years in
Figure 1). The distance between the two curves represents the circatridecadal amplitude (A), which
suggests the occurrence of about 3 cycles. Dots below the lower curve and above the upper curve
represent the standard errors of M and A, respectively. Dots bracketting acrophases in the last 15
intervals (third row) are CIs indicating the statistical significance of the 32.2-year component
during that time span, also shown by P-values (fourth row). © Halberg.
311
Figure 5. Dependence on the geomagnetic latitude of the MESOR (top left) (r = -0.236; P = 0.044)
and relative amplitude (r = -0.318; P = 0.006) of the about 21.0-year component (top right) of the
average number of hours spent working for their church per month by Jehovah's Witnesses,
resolved by nonlinear least squares for each site separately. More time is spent at lower than at
higher latitudes (top left). The about 21.0-year cycle is also more prominent at lower than at higher
latitudes (top right). The dependence on the geomagnetic latitude of the width of the CIs of the
period (r = -0.028; P = 0.052) (bottom left) is aligned with that of the relative amplitude of the about
21.0-year component (bottom right) (r = -0.436; P < 0.001). The CI’s width tends to be smaller at
higher than at lower latitudes, suggesting a higher resolution of this component at higher latitudes.
© Halberg.
312
Figure 6. By contrast to Figure 1, which shows the growth rate of the Church of Jesus Christ of
Latter-day Saints (LDS) starting 121 years earlier and not corrected for world growth rate, the data
analyzed herein during the span from 1950 to 2008 are corrected for world growth rate (top). Their
least squares spectrum (bottom) validates a BEL insofar as the CI of the 27.9-year period estimate
overlaps the range of 30-40 years, including an about 33-year period estimate. © Halberg.
313
G. ADDENDUM
CIRCADIAN AMPLITUDE OF HUMAN HEART RATE ALONG A GERIATRIC
DEPRESSION SCALE
G. Cornélissen1
, K. Otsuka2
, F. Halberg1
, G. Yamanaka2
, N. Hotta2
, S. Murakami3
, Y. Kubo2
,
O. Matsuoka2
, E. Takasugi2
, T. Yamanaka2
, M. Shinagawa2
, S. Nunoda2
, Y. Nishimura2
,
K. Shibata2
, H. Saitoh2
, M. Nishinaga4
, M. Ishine5
, T. Wada5
, K. Okumiya6
, K. Matsubayashi7
,
S. Yano8
, S. Ishizuka9
, K. Ichihara10
, J. Siegelova11
1
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
2
Tokyo Women's Medical University, Medical Center East, Tokyo, Japan
3
Department of Internal Medicine, Osaka Medical University, Osaka, Japan
4
Department of Gerontology, School of Medicine, Kochi University, Kochi, Japan
5
Department of Field Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
6
Research Institute for Humanity and Nature, Kyoto, Japan
7
Center for South-East Asian Studies, Kyoto University, Kyoto, Japan
8
Sorachi Health and Welfare Office, Sorachi-Godochosha, Iwamizawa, Hokkaido, Japan
9
A&D Co. Ltd, R&D Division, Saitama, Japan
10
School of Medicine, Yamaguchi University, Ube, Japan
11
Masaryk University, Brno, Czech Republic
Abstract
For reducing the likelihood (if not for avoiding as far as possible) of nonsense correlations
between variables undergoing deterministic variations such as a circadian and/or other cycle(s),
associations are best based on rhythm characteristics (such as the MESOR or circadian amplitude)
rather than on actual measurements. This approach is followed herein to explore any relationship
between blood pressure (BP) and heart rate (HR) on the one hand and emotional depression on the
other hand. A weak negative correlation is thereby found between the circadian amplitude of HR
and a geriatric depression score.
Background
A depressive mood was found to be independently related to stroke and cardiovascular events
in a chronoecological health watch started in April 2001 in the town of Urausu, Hokkaido, Japan
(latitude: 43.45° N, longitude: 141.85° E) (1), involving 224 subjects (88 men and 136 women;
mean age: 56.8 ± 11.2 years). Each participant underwent a 7-day/24-hour BP and HR monitoring
314
session, starting on a Thursday. Readings were taken at 30-minute intervals between 07:00 and
22:00 and at 60-minute intervals between 22:00 and 07:00. Data stored in the memory of the
monitor (TM-2430 from A&D, Tokyo, Japan) were retrieved and analyzed by sphygmochron (2).
Subjects were asked to answer a self-administered questionnaire inquiring about 15 items of a
geriatric depression scale (GDS) (3), at the start of study and again after 1-2 years. Subjects with an
initial depression score of 5 or more and with a score higher by at least two points at the second
versus first screening were classified as having an enhanced depressive mood. The other subjects
served as the control group.
The mean follow-up time was 1,064 days at the November 30, 2004 follow-up. During this
time, four subjects suffered an adverse vascular outcome (myocardial infarction: 1 man and 1
woman; stroke: 2 men). Among the variables used in the Cox proportional hazard models, a
depressive mood, assessed by the GDS, as well as the MESOR of diastolic (D) BP and the circadian
amplitude of systolic (S) BP showed a statistically significant association with the occurrence of
adverse vascular outcomes (1). In univariate analyses, the relative risk (RR) of developing outcomes
was predicted by a 3-point increase in the GDS scale (RR = 3.088, 95% CI: 1.375-6.935, P =
0.006). Increases of 5 mmHg in DBP-MESOR and of 3 mmHg in SBP-Amplitude were associated
with RRs of 2.143 (95% CI: 1.232- 3.727, P= 0.007) and 0.700 (95% CI: 0.495-0.989, P = 0.043),
respectively (1). In multivariate analyses, when both the second GDS score and the DBP-MESOR
were used as continuous variables in the same model, GDS remained statistically significantly
associated with the occurrence of cardiovascular death (1). After adjustment for DBP-MESOR, a 3point
increase in GDS score was associated with a RR of 2.172 (95% CI: 1.123-4.200). Monday
endpoints of the 7-day profile showed a statistically significant association with adverse vascular
outcomes: a 5 mmHg increase in DBP on Monday was associated with a RR of 1.576 (95% CI:
1.011-2.457, P = 0.045) (1).
Methods
Each 7-day/24-hour profile of BP and HR was analyzed by the extended cosinor method (4-6).
The circadian rhythm characteristics were assessed by means of the least squares fit of a 24-hour
315
cosine curve to the data. The MESORs and 24-hour amplitudes of SBP, DBP and HR were
correlated with the initial GDS score (GDS1).
Results
Depression scores were available from 182 subjects. The 24-hour amplitude of HR was found
to be negatively correlated with GDS1 (r = -0.215, P = 0.005), Figure 1. The correlation, although
statistically significant, is rather weak. It is submitted for the record and for eventual further study
elsewhere.
Figure 1
Discussion and Conclusion
Vascular monitoring for stroke prevention in a community allows the search for any
associations with increased disease risk. An association of hypotension with positive and negative
affect and depressive symptoms reported in the elderly by Jorm (7) could not be found in this
population. Instead, we found a relation between the extent of daily variation in HR and a geriatric
depression score in a community of mostly healthy residents. It is emphasized that the participants
surveyed herein had no known clinical problems. Depressive subjects in this population were also
reported to show a more prominent circaseptan variation in SBP and DBP as compared to the
316
controls (8). Affordable unobtrusive ambulatory monitors for continued surveillance by everybody
is needed to investigate such problems on a much larger scale.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
1. Yamanaka G, Otsuka K, Hotta N, Murakami S, Kubo Y, Matsuoka O, Takasugi E, Yamanaka
T, Shinagawa M, Nunoda S, Nishimura Y, Shibata K, Saitoh H, Nishinaga M, Ishine M, Wada
T, Okumiya K, Matsubayashi K, Yano S, Ishizuka S, Ichihara K, Cornélissen G, Halberg F.
Depressive mood is independently related to stroke and cardiovascular events in a community.
Biomed & Pharmacother 2005; 59 (Suppl 1): S31-S39.
2. Cornélissen G, Halberg F, Bakken EE, Singh RB, Otsuka K, Tomlinson B, Delcourt A,
Toussaint G, Bathina S, Schwartzkopff O, Wang ZR, Tarquini R, Perfetto F, Pantaleoni GC,
Jozsa R, Delmore PA, Nolley E. 100 or 30 years after Janeway or Bartter, Healthwatch helps
avoid "flying blind". Biomed & Pharmacother 2004; 58 (Suppl 1): S69-S86.
3. Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, Leirer VO: Development of
validation of a geriatric depression screening scale: a preliminary report. J Psychiat Res 17:37-
49, 1983.
4. Halberg F. Chronobiology: methodological problems. Acta med rom 1980; 18: 399-440.
5. Cornélissen G, Halberg F. Chronomedicine. In: Armitage P, Colton T (Eds.) Encyclopedia of
Biostatistics, 2nd ed. Chichester, UK: John Wiley & Sons Ltd; 2005. p. 796-812.
6. Refinetti R, Cornélissen G, Halberg F. Procedures for numerical analysis of circadian
rhythms. Biological Rhythm Research 2007; 38 (4): 275-325.
http://dx.doi.org/10.1080/09291010600903692
7. Jorm AF. Association of hypotension with positive and negative affect and depressive
symptoms in the elderly. Br J Psychiat 2001; 178; 553-555.
8. Otsuka K, Yamanaka G, Shinagawa M, Murakami S, Yamanaka T, Shibata K, Yano S,
Ishizuka S, Singh RB, Cornélissen G, Halberg F. Chronomic community screening reveals
about 31% depression, elevated blood pressure and infradian vascular rhythm alteration.
Biomed & Pharmacother 2004; 58:48s-55s.
317
AN ESSAY ON SOME ASPECTS OF CHRONOBIOLOGY
presented by an every-day-physiologist in honour
of Franz Halberg
Thomas Kenner (Graz, Austria)
Abstract
This essay is an attempt to summarize some thoughts in a short overview about the meaning
of time and of system-time and to point out certain time dependent functions and additional
conditions, all of which belong to chronobiology and thus, play an important role in
physiology or pathology.
The headlines of the following text correspond to the key-words:
Time and System Time
Cycles, Aging, Oscillations and Variability
Variability Diseases
Synchronization
Evolution
Optimization
Similarity and Scaling
Symmetry and Asymmetry
Chronification and Chaos
Sudden and Unexpected Phenomena
Time and system-time
Life and time are essentially interdependent and can only been seen as an interacting
complex. The recent consensus paper which was initiated by Franz Halberg (1), signed in
Brno and published in Moscow is one signal of how important chronobiology is today within
the whole context of health and disease. It should be recognized, that even the latin word for
time – tempus – can be attributed to ancient medical practice as will be described in the
following.
In an article with the title “Rhythmen und Resonanzen” in a book on Viktor von Weizsäcker ,
Friedrich Cramer (2) writes the following summary on the meaning of time, starting with the
interpretation of Newtonian understanding of time.
318
“The absolute true mathematical time flows smoothly as such and according to its nature,
without any relation to external entities. This understanding of time of Newtonian physics is
ab-solute, that means it is detached from external objects. This understanding was not given
before. The latin word tempus is derived from the temple region of the head – with the same
latin name - temporal region. In the hippokratic medicine the arterial pulse was palpated on
the temporal artery. Time as tempus originally was our system time (“Eigenzeit”), the rhythm
of our heart beat, not detached from our personality. The new absolute meaning of time
permitted to establish mathematical rules to describe movements and the paths of satellites.
The Newtonian discoveries have enabled the technical epoch – even in medicine. However,
this new point of view produced the effect, that everything living was excluded from
scientific research. Apparently, this is what Viktor von Weizsäcker meant when he wrote:
Until now, a moment in a biological process cannot be localized in the objective time, in the
sense that a biological period cannot be measured by an objective clock……This means that
biological events and rhythms have to serve as a gauge for biological periods, whereas in
physics time itself is the gauge for movement, velocity and accelerations.”
The distinction between physical and biological time, which appears as the essential statement
in this text by Friedrich Cramer, can further be underlined by the following three
observations:
At least in the time of Renaissance, musical notation was used to describe the “medical
quality” of arterial pulses. Examples can be found in a respective book on music and medicine
(3). In the time of Renaissance there existed no metronomes. Therefore, the musician or the
conductor of an ensemble had to use the time sequence of his own pulse to achieve an
indicator of proper speed for a music performance.
Recently several articles on medical aspects related to chronobiology have been published,
the title of whom refer to music. A book by Friedrich Cramer has the title “Symphonie des
Lebendigen” (4). The list of similar titles also includes one article, recently published by
Moser, Fruhwirth, Kenner with the title “symphony of life” (5).
The term “system-time”, which I used in the above translation of the German word
“Eigenzeit” is more and more used. In 2002 a report on a Symposium with the title
“Selbstorganisierte Systemzeiten” (self organized system times) was published (6).
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Cycles, Aging, Oscillations and Variability
Periodic or random oscillations and variability are characteristic features of most if not all
biologic variables.
On the one hand time dependent variations of biological variables may be generated or
controlled by certain centers, like the autonomous circadian rhythm or the periodic heart beat.
On the other hand, there may exist periodic or non-periodic external influences acting on our
body. In all these phenomena synchronization of several oscillations may appear.
There is a list of characteristic time dependent functions of life with respect to chronobiology.
Most prominent are cycles and aging and, more general, oscillations and variability. The
description of the cyclic property of life and time can only be mentioned in some examples.
The important role of cycles may be particularly found in ancient Egypt and also in Christian
religion. The process of birth, growing and aging can be found in circular pictures in
churches, which describe life from birth to death and can be described as life-time clocks.
One such picture from the 16th
century can be found in the orthodox church in Arbanassi
(Bulgaria).
Recognizing the approaching end of his life, the Austrian Habsburg Emperor Karl 5th
(1500 –
1558) had retired to the monastery San Yuste in Spain. He is reported to have tried to
synchronize the many clocks, which apparently existed in different locations in this building.
Apparently this procedure did not succeed, a fact, which he commented with the words:
“clocks are as unreliable as humans”. About hundred years later Christian Huyghens (1629 –
1695) discovered the phenomenon of synchronisation when he observed in two pendulum
clocks, which were hanging on one stick of wood.
Variability Diseases
It must be distinguished between controlled oscillations and oscillations which are due to
some kind of instability. It can be assumed that any biological variable may, under certain
conditions achieve instability. Prominent examples are the loss of the control of the
equilibrium of the body, and excessive “spontaneous” variations of blood pressure or blood
glucose. As discussed in the consensus paper (1), variability of biological oscillations may be
disturbed by abnormal amplitudes, or by shift of phases, or by irregularities, which generate
unexpected outbreaks.
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Synchronization
It can be stated that more or less all oscillations have the trend to synchronize with each other
(7). The best known example is the synchronization of heart beat and respiration (8). In this
example the periods can lock in relations like e.g. 4:1, 5:1, however also 5:2. In order to
explain in detail, 4:1 means that in each respiratory cycle, there are exactly 4 heart beats. A
synchronization 5:2 means that two respiratory cycles are identically repeated: the first of the
two respiratory cycles contains two and ½ cardiac cycle. The second respiration starts with
the second ½ cardiac cycle and continues with further two cycles. During synchronization this
configuration repeats. The appearance of these synchronization phenomena has the most close
similarity to certain music rhythms. Namely the state of synchronization is characterized by
the repeat of the same pattern in the period of one breath (when 4:1) or in the period of two
breaths (when 5:2). Of course, further rhythms with longer repeats are also possible.
The consequence of an improved regularity during synchronization appears to be advantage in
energy or information transfer.
Evolution
In this year 2009 we remember the 250th
anniversary of the publication of Darwin’s famous
book “On the Origin of Species”. His idea was, that evolution is possible by variation and
consecutive selection. As one example we can observe, that the development of the
cardiovascular system from a symmetric construction (fish) towards an asymmetric heart and
an asymmetric aortic arch (mammals) apparently improves the efficiency of the system and
the ability to adjust the function to changing load.
It can be seen that the following three further key words have to be involved in the
considerations about evolution.
Optimization
Optimization of function or of the use of mass or energy in a biologic organism is as well a
precondition as a consequence of the principle of evolution. The following example is chosen
because of our special interest in the control of the cardiovascular system. In terms of the
ventricular ejection one can show, that the time course of ejection under assumption of a
certain given stroke volume and heart rate follows a path, which minimizes the energy
expenditure (9). There is a more or less long list of examples, which permit to demonstrate the
natural search for optimization of efficiency. Including the ability of adjustment to load, E.
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Weibel (10) has coined the name “Symmorphosis”. This word expresses the importance of
interaction between structure and function.
Similarity and Scaling
There exist between animal of different size so called allometric laws which describe the
relation between body mass, energy consumption and other variables (11). It is quite
interesting and important, that these laws also include what can be called individual systemtime,
and thus, permit to illustrate what the term system-time means. The larger an animal the
slower is system time passing. The allometric laws support the idea, that structure and
function of animals are optimally adjusted.
Symmetry and Asymmetry
As well in physiology as in pathology and other fields, the observation of the role of
symmetry or asymmetry is of enormous interest. It was already mentioned above that, in the
course of evolution, the asymmetric anatomy of the heart and the aorta served as a marked
advantage for the adjustment of the cardiovascular system to variable load. There are, besides
heart and aorta, several organs, which in mammals are markedly asymmetric. We have
studied the effect of the asymmetry of the aortic impedance, which most probably is involved
in the improvement of arterial blood transport (12).
Chronification and Chaos
There exists an interesting rather simple equation, the so called logistic equation, which is
based on a feedback model where automatically the output of a calculation is fed back as the
next input (13). The logistic equation describes a kind of circular process. The result of such a
calculation depends on one parameter. Depending on the value of this parameter three
characteristic types of result can be generated: A. increase from zero to a limit level, B.
periodic oscillations or C. chaotic oscillations. Although this model is extremely simple, the
processes of variability disorder (B) or chronification or chaos (C) can be explained.
Sudden and Unexpected Phenomena
Many diseases or pathologic events happen completely unexpected. The explanation or
discussion of such phenomena is the most difficult task. Many pathologic events in medicine
start unexpected, without warning. Examples are stroke, or heart attack. The so called sudden
and unexpected death of babies is another example of such an event. In the Austrian province
322
of Styria we have developed a project for the prevention of the sudden infant death (14). The
attempt to initiate such a project includes the search for possible risk factors and the education
of parents. It can be shown that there exist internal risk factors – there is a higher incidence
around 3 month of age – and external risk factors, like prone position or smoking of parents.
SUMMARY
As initially stated, the attempt is made in this short essay, to list and shortly explain a – most
probably incomplete – set of time dependent biologic (physiological or pathological)
functions. All of these functions have to be considered as one unit. It can easily be seen that
these functions or conditions interact. In any case most or all of them have to be taken into
account if a special event should be evaluated.
Support: MSM0021622402
Literature
(1) Halberg F, Corenelissen G, Siegelova J, Fiser B, et al.: Blood pressure or, rather, blood
pressure variability disorders.
Bulletin of peoples’ Friendship University of Russia, Series Medicine No. 7, 26 – 30 (2008)
(2) Cramer F : Rhythmus und Resonanz. pp. 196
In: Jacobi R-ME, Janz D. (eds.) Zur Aktualität Viktor von Weizsäckers
(3) Kümmel W F: Musik und Medizin.
Verlag Karl Alber Freiburg/München 1977
(4) Cramer F: Symphonie des Lebendigen.
Insel-Verlag, Frankfurt 1996
(5) Moser M, Fruhwirth M, Kenner T: The symphony of life.
IEEE Erg. Med. Biol. 27: 29-37 (2008)
(6) Deppert W, et al. (eds.): Selbstorganisierte Systemzeiten
Leipziger Universitätsverlag 2002
(7) Pikovsky A, Rosenblum M, Kurths J: Synchronization.
Cambridge University Press 2001
(8) Kenner T, Pessenhofer H, Schwaberger G: Method for the analysis of the
entrainment between heart rate and ventilation rate.
Pflügers Arch. 363: 263-265 (1976)
323
(9) Pfeiffer KP, Kenner T: On the optimal strategy of cardiac ejection. pp. 133- 136.
In: Kenner T, Busse R, Hinghofer-Szalkay H (eds.):
Cardiovascular System Dynamics, models and measurements.
Press, New York - London 1982
(10) Weibel ER: Symmorphosis
Harvard University Press, 2000
(11) Schmidt-Nielsen K: Scaling, why is animal size so important?
Cambridge University Press, Cambridge (1984)
(12) Moser M., Huang J. W., Schwarz G.S., Kenner T., Noordergraaf A:
Impedance defined flow, generalization of William Harvey´s concept of the circulation - 370
years later.
Internat. J. Cardiovascular Medicine and Science 1: 205 - 211 (1998)
(13) Bassingthwaighte JB. Et al.: Fractal Physiology, pp. 120
Oxford University Press, NY, Oxford 1994
(14) Kerbl R, Kurz R, Reiterer F, Einspieler C, Haidmayer R, Kenner T, et al.:
SIDS-Prävention in der Steiermark - Das Grazer Modell
Pädologie und Pädiatrie, 29: 129 - 136 (1994)
324
CHRONOBIOLOGY AND BAROREFLEX SENSITIVITY
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Fišer B., Siegelová J., Dobšák P., Dušek J.
Dept. of Physiology, Dept. of Physiotherapy end Rehabilitation, Dept. of Functional
Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University,
St. Anna Teaching Hospital, Brno, CZ
Introduction
During the second half of the twenties century an opinion prevailed in the scientific
community that role of baroreflex in hypertension is negligible despite the fact that baroreflex
is the most important regulatory mechanism of blood pressure. This opinion was supported by
the observation of baroreflex resetting. The resetting is in other words the shift of the curve of
the relationship between carotid sinus pressure and systemic arterial pressure to the higher
values of systemic arterial pressure. This opinion was not shared by all scientists; most
prominent opponent professor Slight claimed that it is clear that all forms of hypertension –
whether primary of essential or secondary to renal, hormonal, or environmental influences –
have a neurogenic component. More recent evidence suggests that neural mechanisms,
particularly impairment of arterial baroreflexes, play an important part.
In the recent years the long-term control of blood pressure was re-evaluated. The recent
opinion is based on chronic electrical stimulation of carotid baroreceptor afferent fibers, on
re-evaluation of time of chronic resetting lasting several days according the more recent
experiments. Furthermore decreased baroreflex gain appears to precede hypertension.
Years ago baroreflex sensitivity was regarded to correspond to the capability of the
parasympathetic nervous system to react to a gross stimulus and thus concerns primarily vagal
reflexes. The measurement of baroreflex heart rate sensitivity in ms/mmHg was the adequate
method. To study the blood pressure control function of baroreflex the determination of
baroreflex gain is necessary.
The founder of modern chronobiology professor Franz Halberg demonstrated many years ago
that the reliable diagnosis of blood pressure disorders can be performed on the basis of 24
hours blood pressure monitoring at least. (The recent Prof. Halberg studies suggest seven days
monitoring to obtain a reliable estimates.)
The aim of a present paper was to determine the baroreflex open-loop gain during 24 hours in
hypertensive patients and normotensive controls.
325
Methods
The blood pressure and heart rate were recorded in thirteen healthy subjects (N), mean aged
33±12.3 years, all men, body height 178±8 cm, body weight 81±6kg and 14 patients with
essential hypertension (EH), all men, mean age 40±6 years, body height 181±8 cm, body
weight 83±8kg in the supine position by means of Peňaz´s noninvasive blood pressure
measurement. In EH medical tests and examinations excluded any other diseases and
diagnosis of essential hypertension was made according to WHO criteria to rule out any form
of secondary hypertension. All patients had been followed up at least 3 years prior to the
study in clinic. All subjects gave their informed consent and the study was approved by the
institutional ethical committee. Two inflatable cuffs were placed on both thighs. The cuff
pressure was increased abruptly 180 mmHg for 5 min. the occlusion elicited the
vasodilatation of vessels in the legs. Following the abrupt change in pressure in the occluding
cuffs from 180 to 60 mmHg caused a decrease in blood pressure followed by an increase of
heart rate. The changes in the blood pressure and heart rate were used for calculation of the
BRS. (The pressure of 60 mmHg in the occluding cuffs prevented the stimulation of the low
pressure receptors by the increased venous return.) The mean systolic pressure and mean
cardiac interval were from 5 beats preceding the abrupt decrease in the cuff pressure. The
difference between the mean systolic pressure before and the minimum systolic pressure after
the change in the cuff pressure was calculated. The difference between the mean cardiac
interval before and the shortest interval after the change in the cuff pressure was also
computed. The BRS corresponded to the ration of these two differences and was expressed in
ms/mmHg. The method is described elsewhere.
The BRS determination was repeated at 4-hour intervals during a 24-hour period. We started
at 8 a. m. and finished at 8 a. m. the next day. The daily activities of the subjects between the
measurements were unchanged. The subjects were sleeping during the night but wee awake
during the measurements. The first measurement at 8 a. m. was not taken into account. Six
measurements in each subject were used for further analysis.
The calculation of open-loop gain is based on following equation. Baroreflex gain (G)
corresponds to the decrease of blood pressure elicited by 1 mmHg increase of pressure in
carotid sinus:
G = MBP (before) – MBP(after) = HR*SV*TPR – (HR-BRShr)*(SV-BRSsv)*(TPR-BRStpr),
MBP – mean blood pressure, HR – heart rate, SV – stroke volume, TPR - total peripheral
resistance, BRShr – heart rate baroreflex sensitivity [Hz/mmHg], BRSsv – stroke volume
326
baroreflex sensitivity[ml/mmHg], BRStpr – total peripheral resistance baroreflex
sensitivity[(mmHg*s/ml)/mmHg = s/ml].
By dropping the second orders terms the equation can be simplified:
G = Ghr + Gsv +Gtpr = MBP*(BRShr/HR + BRSsv/SV + BRS/TPR),
Ghr – gain of heart loop, Gsv – gain of stroke volume loop, Gtpr – gain of total peripheral
resistance loop.
Our method enables the calculation of BRShr and Ghr only. Ghr = MBP*(BRShr/HR).
The results are seen in Table I.
Baroreflex measured as BRS (ms/mmHg) increases during the night as well as duration of
cardiac interval in normal controls, SBP and DBP decrease in both groups. The changes of
baroreflex heart gain were not observed.
Discussion
Our method made not possible the calculation of the gain of TPR and SV because SV and
TPR were not measured in our experiments but we suppose that the changes of all gains were
similar. Nowadays we have possibility to use a device Task Force Monitor for measurements
in our laboratory. Estimation of baroreflex set-point of MBF, which probably correspond to
DBP night value, enables the calculation of the theoretical value of MBP without baroreflex
and thus estimates the quantitative contribution of the baroreflex to the MBP value of an
hypertensive subject.
Lower BRS in hypertension was observed by Gribbin et al. many years ago by means of
phenylephrine. This finding was several times confirmed by noninvasive spectral method in
our laboratory. This was in the past explained by the hypertension elicited remodeling of
carotid arterial wall. The remodeling is firmly established fact as the negative correlation
between intima-media thickness and BRS indicates. On the other hand our calculation
indicates that lower baroreflex gain in the range of normal range of baroreflex in healthy
people can make an important contribution to the blood pressure increase.
Second conclusion from our study indicates the necessity to re-evaluate the role of the blood
pressure decrease during the night. Because process of resetting last of about 48 hours the
night decrease of blood pressure influence the baroreflex resetting. The set point is surely
lower than the night value and in subjects with normal blood pressure values during the night
the shift of the carotid pressure-systemic pressure curve to higher values of pressure cannot
occur. The normal chronobiology of blood pressure is so a factor protecting against
hypertension.
327
This is an additional argument supporting the view that the diagnosis and treatment of
hypertension ignoring chronobiology is bad for a patient.
Table 1 Day and night differences in cardiovascular parameters in normotensives (N) and
hypertensives (EH)
N
n = 10
EH
n = 14
day night day night
I (ms) 921±181 1008±188 758±108 793±97
SBP (mmHg) 111±12 98±10 126±12 120±20
DBP (mmHg) 68±7 59±7 79±8 76±11
BRS (ms/mmHg) 11.64±4.95 20.90±21.80 8.42±6.52 8.35±5.34
Ghr 1.02±0.43 1.47±1.47 1.04±0.79 0.94±0.59
Healthy subjects (N), Patients with Essential Hypertension (EH), Cardiac Interval (I), Systolic
Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Baroreflex Heart Rate Sensitivity
(BRS), Baroreflex Heart Rate Gain (Ghr).
Supported by MSM0021622402
References
1. SLEIGHT, P. Baroreflex and Hypertension. In PETERSSON P.B., KIRCHHEIM H.R.
(Eds.) Baroreceptor Reflexes. Integrative Functions and Clinical Aspects. Berlin : SpringerVerlag,
1991. p. 271-290.
2. BROOKS, V. L., SVED, A. F. pressure to change? Re-evaluating the role of baroreceptors
in the long-term control of arterial pressure. Am J Physiol Regul Integral Comp Physiol., vol.
288, p. R815-818.
3. SCHWARTZ, P.J. VANOLI, E., STRAMBA-BADIALE, M. et al. Autonomic
mechanisms and sudden death: New insight from the analysis of baroreceptor reflexes in
conscious dogs with and without a myocardial infarction. Circulation, 1988, vol. 78, p. 816-
824.
328
4. HALBERG, F. CORNÉLISSEN, G., OTSUCA, K. et al. Cross-spectrally coherent similar
to 10.5-and 21-year biological and physical cycles, magnetic storms and myocardial
infarctions. Neuroendocrinology letters, 2000, vol. 21, p. 233-258.
5. SAVIN, E., SIEGELOVA, J., FISER, B. et al. Noninvasive determination of human aortic
compliance. Archives of physiology and Biochemistry, 1996, vol. 104, n. 3, p. 257-264.
6. SAVIN, E., SIEGELOVA, J., FISER, B. et al. Intra- and extracranial artery blood velocity
during a sudden blood pressure decrease in humans. European J of applied physiology and
occupational physiology. 1997, vol. 76, n. 3, p. 289-293.
7. GRIBBIN, B., PICKERING, E.G., SLEIGHT, P. et al. Effect of age and high blood
pressure on baroreflex sensitivity in man. Circ. Res, vol. 29, p. 48-54.
8. DUSEK, J., SIEGELOVA, J., HOFIREK I. et al. Baroreflex sensitivity and intima media
thickness (IMT) in patients with essential hypertension under therapy. Journal of
Hypertension, 2003, vol. 21, n. 4, p. S256-256.
9. LABROVA , R., HONZIKOVA, N., MADEROVA E. et al. Age-dependent relationship
between the carotid intima-media thickness, baroreflex sensitivity, and the inter-beat interval
in normotensive and hypertensive subjects. Physiological Research, 2005, vol. 54, n. 6, p.
593-600.
329
RELATIONSHIP BETWEEN CIRCADIAN BLOOD PRESSURE VARIATION AND
AGE ANALYZED FROM 7-DAY MONITORING IN HEALTHY SUBJECTS AND
PATIENTS WITH ISCHEMIC HEART DISEASE
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Jarmila Siegelová, Bohumil Fišer, Alena Havelková, Jiří Dušek, Pavel Homolka, Pavel Vank,
Michal Pohanka, Michal Mašek, Germaine Cornélissen*, Franz Halberg*
Dept. of Physiotherapy and Rehabilitation and Department of Functional Diagnostics and
Rehabilitation, Masaryk University Brno, St. Anna Faculty Hospital Brno, Czech Republic,
*University of Minnesota, USA
INTRODUCTION
Franz Halberg, Germaine Cornélissen and BIOCOS scientific group provided strong evidence
for the need to account for day-to-day changes in blood pressure and heart rate variables in
the similar way as a circadian assessment considers the hour-to-hour variability [1-5]. The
evidence led to the recommendation of around-the-clock monitoring for 7 days at the outset
[6,7], to be continued whenever needed, until monitoring for a lifetime becomes more readily
feasible.
By 1988, major findings had been summarized in a volume of annotated illustrations
[8]. Methodology had developed concomitantly under Halberg chronobiology center
leadership in Minnesota University. In particular, the "sphygmochron" [9] was introduced.
The sphygmochron is a computer summary of results from chronobiological analyses
performed on BP and HR data collected around the clock by ambulatory monitoring. Two
approaches are possible, one parametric (model-dependent), the other non-parametric (modelindependent).
The parametric approach entails the least-squares fit of a two-component model
consisting of cosine curves with periods of 24 and 12 hours. Estimates are obtained for the
MESOR (midline-estimating statistic of rhythm), a rhythm-adjusted mean, and for the
amplitude and (acro)phase of each component, measures of (half) the extent of predictable
change within a cycle, and of the timing of overall high values recurring in each cycle,
respectively.
330
The relationship between age and circadian blood pressure (BP) variation was described by us
in 2004. One hundred eight seven subjects (130 males, 57 females), 20-77 years old, were
recruited for seven-day BP monitoring. Colin medical instruments (Komaki, Japan) were used
for ambulatory BP monitoring (oscillation method, 30-minute interval between
measurements). Sinusoidal curve was fitted (least square method) and mean value and
amplitude of the curve (the value of double amplitude shows approximately the day and night
difference) were evaluated every day of monitoring. Average 7-day values of the mean
(MESOR) and of double amplitude (2A) for systolic BP (SBP), diastolic BP (DBP) and heart
rate (HR) were determined for each subject. Mean values of M (±SD) for the whole group
were: SBP- 127±8, DBP – 79±6 mmHg, HR – 70±6 bpm; of 2A: SBP – 21±7, DBP – 15±5
mmHg, HR – 15±6 bpm. 2A of SBP and DBP was increasing with age up to 35 years, then
the curve remained relatively flat up to 55 years ( maximum at 45 years) and then decreased
again (the difference between 45 and 77 years: SBP- 13mmHg, DBP-12 mmHg). Heart rate
M and 2A were age-independent.
The aim of the present study is the evaluation of blood pressure variability by 7-day
ambulatory blood pressure (BP) monitoring in healthy subjects and in patients with ischemic
heart disease.
METHODS
The set being monitored consisted of 40 patients with ischemic heart disease (IM) of the age
63 ± 6,3 years (age between 41 and 77 years) and ejection fraction (43 ± 12,3) %.
The patients were subjected to phase II of cardiovascular rehabilitation (controlled ambulatory
rehabilitation program) lasting two to three months with the frequency of three times a week
at the Department of Functional Diagnostics and Rehabilitation of St. Anna Teaching
Hospital. The duration of the training unit was 60 min and it consisted of warm-up phase (10
min), aerobic phase (25 min), toning phase (15 min) and relaxation phase (10 min).
In the course of rehabilitation the patients underwent 7-day ambulatory monitoring of blood
pressure. During blood pressure recording they did not interrupt pharmacotherapy (ACE
inhibitors, statins, betablockers, Ca antagonists).
The set of healthy subjects was composed of 44 healthy subjects (C, age between 40 and 77
years, mean age 54 years).
7-day monitoring of blood pressure was made by means of the instrument TM – 2421 of
Japanese firm A&D operating on the principle of oscillometric analysis. The instrument
331
measured blood pressure for 7 days repeatedly every 30 min from 5 to 22 o'clock and once an
hour from 22 to 5 o'clock. If a value not much probable from the point of view of the
instrument setting was recorded, another check measurement was made (Siegelová et al.
2004).
The results were processed by using Halberg cosinor analysis. The data were smoothed by a
sinusoidal curve. The mean value of the sinusoid, designated MESOR, and amplitude of
circadian fluctuation were determined. Sinusoidal curve was fitted (least square method) and
mean value and amplitude of the curve (double amplitude corresponds to the night-day
difference) were evaluated every day of monitoring. Average 7-day values of the mean (M)
and of double amplitude (2A) for systolic BP (SBP), diastolic BP (DBP) and heart rate (HR)
were determined for each subject of both sets.
The study was approved by local ethic committee and the patients signed informed consent.
RESULTS
A significant increase of systolic BP (SBP) MESOR with age was found in C (r=0.39,
p<0.01), but not in IM (r=0.23) Fig.1. Diastolic BP (DBP) MESOR was not related to age in
C (r=014) but a decrease of DBP with age in IM was observed (r=0.362, p<0.05) - Fig.2.
Mean value of SBP MESOR was higher in C than in IM (128±9 vs. 121±8 mmHg, p<0.01),
as well as DBP MESOR (81±7 vs. 74±7 mmHg, p<0.01). DA SBP decreased with age in C
(r=0.30, p<0.05) but not in IM (r=0.03) - Fig.4. Similarly DA DBP decreased with age in C
(r=0.41, p<0.01) and not in IM (r=0.08) - Fig.5. Mean values of DA were lower in IM (DA
SBP: 21±10 vs. 16±8 mmHg, p<0.01; DA DBP: 16±8 vs. 12±5 mmHg, p<0.01). Heart rate
(HR) was not age-related in both groups, difference in mean values of HR was not observed
(C: 71±10, IM: 65±8 bpm) - Fig.3. DA HR was lower in IM (15±8 vs. 9±5 b.p.m) - Fig.6.
332
Fig. 1 Relationship between MESOR of systolic blood pressure(SBP, mmHg), measured by 7 day ambulantory blood pressure monitoring, and
age (years) of patients with MI the subjects C.
333
Fig. 2 Relationship between MESOR of diastolic blood pressure (DBP, mmHg), measured by 7 day ambulantory blood pressure monitoring, and
age (years) of the MI and C subjects.
334
Fig. 3 Relationship between MESOR of heart rate (HR, bpm), measured by 7-day ambulatory blood pressure monitoring, and age (years) of the
MI and C subjects
335
Fig. 4 Relationship between circadian amplitude of systolic blood pressure (SBP, mmHg), measured by 7-day ambulantory blood pressure
monitoring, and age (years) of the MI and C subjects.
336
Fig. 5 Relationship between circadian amplitude of diastolic blood pressure (DBP, mmHg), measured by 7-day ambulatory blood pressure
monitoring, and age (years) of the MI and C subjects.
337
Fig. 6 Relationship between circadian amplitude of heart rate (b.p.m, HR), measured by 7-day ambulatory blood pressure monitoring, and age
(years) of the MI and C subjects.
338
DISCUSSION
There is a growing body of evidence suggesting that time structures in us and around
us are intricately interwoven. Most if not all components of variation found in biota are also
found in the environment, and vice versa [10]. For instance, about daily changes are seen in
almost every biological variable under 24-hour synchronized conditions. It has also long been
known that the phase of circadian rhythms can be manipulated by changing the phase of the
environmental cycles [11]. At least for the case of circadian rhythms, their genetic inheritance
has been demonstrated on a molecular basis [12,13], suggesting that the influence from the
environment has been acquired genetically during the course of evolution.
The mapping of chronomes should benefit our understanding of human health and disease in
several ways. The study of human chronomes can serve the derivation of refined reference
values to better define health and to identify pre-disease, so that prophylactic interventions
can be instituted as early as possible, preferably before the disease sets in [14-16]. The focus
is thus put on pre-habilitation, in the hope that the need for re-habilitation will thereby be
reduced [17,18,19].
Several studies [20, 21] comparing the classification of patients based on single office
measurements with that based on ambulatory monitoring for one to seven days suggest that
the incidence of misdiagnosis is around 40%, in keeping with the 48% response to placebo in
the Australian Therapeutic Trial [22,23]. Comparison of circadian characteristics from day to
day in records spanning at least two days further indicates the shortcomings of monitoring
limited to a single 24-hour span [24, 25, 26]. Prolonging the monitoring from one to two days
reduces the uncertainty in the estimation of circadian parameters by about 35% [27], whereas
further information on the biological week [28, 29, 30, 31] requires monitoring for at least 7
days, the current recommendation of BIOCOS for everybody at the outset [32]. It is now
widely accepted that prognosis of target organ damage is by far superior when it is based on
around the clock monitoring than on single office measurements [33,34,35].
The mistaken impression that the circadian variation in blood pressure and heart rate is
sufficiently stable to be approximated by a single 24-hour profile stems in large part from the
use of statistical methods on groups of subjects rather than focusing on the individual patient.
Correlation analyses applied to large groups of subjects with a wide range of average values
emphasize similarity. Statistical analyses focusing on individual differences observed from
one profile to another, however, yield information more likely to help the patient in need of
339
the treatment [24]. Several case reports document this point [16, 36, 37, 38, 39]. Continued
monitoring is the most logical solution.
An important distinction must be made between lessons learned from large clinical trials
and their application for the individual patient. Differences and trends uncovered in studies
made on groups, even when each subject provides only one or a few measurements, cannot be
similarly assessed in medical practice when a decision must be made for treating the
individual patient. In order to be able to reach an informed decision for the given patient,
serial rather than single data should be collected. When time series are available, it becomes
possible to assess risk elevation or the response to treatment for that particular patient.
In our former study we observed the age dependence of the circadian amplitude. Mean
values of SBP and DBP were increasing with age up to 75 years, but night-day difference of
SBP and DBP reached the maximum value at 45 years and then decreased. This decline of
day-night difference was not seen in our patients with heart disease. Furthermore the daynight
difference in about 50 years old treated patients was lower than in our about 50 years of
age controls. This fact is positive because excessive day-night difference is accompanied with
an increased risk for morbidity and mortality.
Comparison of treated patients after myocardial infarction with healthy subjects revealed that
the treatment decreased the risk of high blood pressure as well as the risk of high blood
pressure variability. The differences could be influenced by the medical therapy.
Support: GM-13981 (FH), University of Minnesota Supercomputing Institute (GC, FH),
MSM0021622402
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344
Non-invasive Evaluation of Arterial Stiffness in Czech Adult Population
using the device VaSera®
1500
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Petr DOBŠÁK, Michaela SOSIKOVÁ,
a
Ladislav DUŠEK,
b
Miroslav SOUČEK,
c
Marie
NOVÁKOVÁ,
d
Tomoyuki YAMBE,
e
Jean-Eric WOLF,
f
Jiří VÍTOVEC,
f
Lenka
ŠPINAROVÁ,
g
Vladimír SOŠKA,
c
Bohumil FIŠER, Jarmila SIEGELOVÁ
Department of Functional Diagnostics and Rehabilitation, St.Anna Faculty Hospital and
Masaryk University of Brno, Czech Republic
a
Institute for Biostatistics and Analyses, Faculty of Medicine, Masaryk University of Brno,
Czech Republic
b
IInd
Department of Internal Medicine, St.Anna Faculty Hospital and Masaryk University of
Brno, Czech Republic
c
Department of Physiology, Faculty of Medicine, Masaryk University of Brno, Czech
Republic
d
Department of Medical Engineering and Cardiology, Institute of Development, Aging
and Cancer, Tohoku University of Sendai, Japan
e
Department. of Cardiology II, Hospital du Bocage and University of Burgundy, Dijon,
France
f
Ist
Department of Internal Medicine, St.Anna Faculty Hospital and Masaryk University of
Brno, Czech Republic
g
Department of Clinical Biochemistry, St.Anna Faculty Hospital and Masaryk University of
Brno, Czech Republic
345
Abstract
The traditional non-invasive method for the early detection of arteriosclerosis is the brachialankle
pulse wave velocity (PWV), however, this method is significantly influenced by the
changes of blood pressure (BP). Recently, a new non-invasive method for the arterial stiffness
assessment was developed – the cardio-ankle vascular index (CAVI). This method has been
shown to be not affected by the BP variations and so that it could be recommended for wide
clinical use, including large population studies. The aim of this paper was to evaluate the
CAVI in the population sample of Czech adult population. A group of 121 healthy subjects
(aged from 20 to >70 years) was examined using the newest type of non-invasive monitoring
system VaSera® 1500 (Fukuda Denshi Co., Tokyo, Japan). This control group was then
compared with 3 groups of patients with selected lifestyle-related diseases: coronary artery
disease (CAD; n = 74), diabetes mellitus (DM; n = 36) and hypertension (HT; n = 58). The
statistical analysis showed a significant differences of the CAVI parameter between the
healthy subjects and patients with coronary artery disease, diabetes and hypertension; the
mean CAVI value in the control group (6.9) was significantly lower compared to the patients
with CAD (CAVI = 9.2; P < 0.001 vs.control group), diabetes (CAVI = 8.5; P < 0.001
vs.control group) and hypertension (CAVI = 8.9; P < 0.001 vs. control group). These results
demontrate that CAVI should be considered as an important clinical parameter independent of
blood pressure changes, and should be recommended as a valuable indicator of the preventive
evaluation of the arteriosclerotic risk in healthy subjects and patiens with life-style related
diseases.
Keywords:
cardio-ankle vascular index - arterial stiffness – arteriosclerosis - blood pressure cardiovascular
diseases
Introduction
The World Health Organization (WHO) report estimates that around 20 million (32%) of total
deaths are resulted from the various forms of life-related diseases (including CAD), many of
which are preventable by action on the major primary risk factors. CAD and stroke are no
longer only diseases of the developed world; some 70% of all CAD death worldwide took
place in developing countries, while these countries also accounted for 80% of the global
346
CAD disease burden. The above mentioned WHO report estimates that CAD will be the
leading cause of death in developing countries by 2010. Therefore, the early detection of the
arteriosclerotic plaque development has a crucial importance. Up to the present the widely
used method is the evaluation of the brachial-ankle pulse wave velocity (PWV). However,
several studies reported the significant dependence of PWV on the blood pressure variations,
so that the value of the measuremen is seriously compromised (1). Due to this limitation, a
new and simple instrument for the early diagnosis of arteriosclerosis is of great interest.
Recently, the device VaSera® was developed as a new non-invasive screening tool in fight
against atherosclerosis that is a considerable cause of CAD. VaSera measures vascular
compliance using sophisticated new oscillometric technology termed CAVI or Cardio Ankle
Vascular Index, used for the quantitative assessment of the arterial wall stiffness. According
to some recent studies, the parameter CAVI is less influenced by the blood pressure changes
(2 and 3). The aim of this study was to investigate: 1) the influence of the changes of blood
pressure on CAVI in Czech healthy adult subjects; and 2) the differences in the value of
CAVI between the healthy subjects and patients with selected lifestyle-related diseases:
coronary artery disease (CAD), diabetes mellitus (DM) and hypertension (HT) .
Patients and Methods
Patients’ selection
A group of 121 healthy subjects (men and women) aged from 20 to >70 years was recruited in
St.Anna Faculty Hospital in Brno (Czech Republic) and examined using the newest type of
non-invasive monitoring system VaSera® 1500 (Fukuda Denshi Co., Tokyo, Japan). This
control group was then compared with 3 groups of patients with selected lifestyle-related
diseases: coronary artery disease (CAD; n = 74), diabetes mellitus (DM; n = 36) and
hypertension (HT; n = 58).
Methods
Cardio-ankle brachial index (CAVI) – according to Yambe et al. (1)
CAVI reflects the stiffness of the artery from the heart to ankles. As arteriosclerosis
progresses, the CAVI value becomes higher. CAVI is calculated based on the stiffness
parameter β which is measured by carotid echography or the like and is not affected by blood
pressure. Thus, it represents the natural vascular stiffness. The latest type of the device
347
VaSera, the VaSera 1500® adopts the oscillometric method for blood pressure measurement.
In addition, it does not simultaneously measure blood pressure at 4 limbs but at first it
measures blood pressure at the right brachial and ankle and then measures at the left brachial
and ankle. Thus, arteries at the right and left sides are alternately pressurized with the other
side open. This not only reduces burden to examinees but also enables more accurate
measurement. CAVI calculation is based on the stiffness parameter β. It is an index to
diagnose sclerotic degrees of the carotid artery, etc. from the diametrical variation and blood
pressure measured by ultrasonic echography and represents the natural vascular stiffness
independent of blood pressure. CAVI is calculated using the stiffness parameter β obtained
with the Bramwell-Hill equation (4).
The stiffness parameter β
From the Bramwell-Hill equation (here, the ratio of volumetric change, V/ΔV, is converted to
ratio of luminal change, D/ΔD)
CAVI is obtained by substituting the equation (2)' for D/ΔD in the equation (1).
The final equation of CAVI
The reference values of CAVI are as follows:
348
CAVI < 8.0 normal range
8.0 =or< CAVI < 9.0 borderline
9.0 =or< CAVI arteriosclerosis suspected
In order to limit as much as possible the influence of the diurnal variations all the subjects
were examined during stable time period, between 7:00 AM to 10:00 AM. All the subjects
were asked to avoid caffeine drinks in the morning. The examinations were conducted in a
quiet room and at a stable temperature of 21-22°C. The influence of blood pressure changes
on CAVI was evaluated only in the kontrol group (healthy subjects). The correlation
between the R-CAVI and L-CAVI, as well as the correlations between CAVI and age,
systolic and diastolic presssure were examined only in the control group.
Statistics
Visualisation of the data is based on comparative histograms and box-whisker plots. The
descriptive summary of L (left) and R (right) values of CAVI is based on robust nonparametric
statistics, i.e. median and 5th
– 95th
percentile range. The statistical significance of
difference between L and R values was tested by Wilcoxon paired test. Statistical significance
of differences in averaged values of CAVI among the different groups of examined subjects
was evaluated using one-way ANOVA followed by Tukey post-hoc test; the variables were
described using mean and its 95% confidence interval. Pearson correlation coefficient was
applied for the analysis of relationship between CAVI and other descriptors (R and L side,
age, systolic and diastolic blood pressures). The level of statistical significance was
established at P < 0.05.
Results
Statistical analysis showed that there is no singificant difference between the right (R) and left
(L) value of CAVI. The mean CAVI value in the control group without signs of
atherosclerotic diseases) was 6.9 ± 0.5. CAVI in patients with CAD was 9.2 ± 0.3 (P < 0.001
vs.control group) and in the group of diabetic subejcts was 8.5 ± 0.3 (P < 0.001 vs. control
group). Finally, in the group of patients with hypertension the CAVI was 8.9 ± 0.3 (P < 0.001
vs. control group). These results suggest that the mean CAVI value is significantly lower in
the patiens with selected life-related diseases, and thus reflects quantitatively the extent of
349
arteriosclerotic process. The results also revealed the presence of a strong correlation between
R-CAVI and L-CAVI (r = 0.963; P < 0.001) and between mean CAVI (R and L) and the age
(r = 0.756; P < 0.001). A weak correlation was found out between meanCAVI (R and L) and
systolic blood pressure (r = 0.355; P < 0.001), and mean CAVI (R and L) and diastolic blood
pressure (r=0.354; P < 0.001). These results indicate that CAVI is not dependent on the
variations of the blood pressure.
Summary statistics of CAVI values
0,5
3,7
14,1
20,9
24,1
13,6
16,2
4,7
2,1
0,5
3,1
14,1
20,9
23,6
14,1
15,2
6,8
1,6
0
5
10
15
20
25
30
<= 4 4-5 5-6 6-7 7-8 8-9 9-10 10-11 >11
Patients(%)
CAVI
L and R CAVI values are not statistically different
(p > 0.1; Wilcoxon paired test)
(5.23; 10.22)7.45(7.43; 7.91)7.67average CAVI
(5.30; 10.24)7.50(7.46; 7.94)7.70L-CAVI
(5.20; 10.30)7.50(7.39; 7.88)7.64R-CAVI
5-95% quantileMedian95%CIMeanN=191
Fig 1 shows the summary statistics of the healthy subjects and average CAVI (± SD) for each
age group.
350
L and R CAVI values in different cohorts of patiens
0
2
4
6
8
10
12
14
right side left side
Control (N=121) Diabetes (N=36) Hypertension (N=58) CAD (N=74)CAVI
0
2
4
6
8
10
12
14
right side left side
L and R CAVI values were not statistically different in any cohort of patients (Wilcoxon paired test)
0
2
4
6
8
10
12
14
right side left side
0
2
4
6
8
10
12
14
right side left side
L-CAVI
R-CAVI
median 5-95% quantile
p=0.694 p=0.474 p=0.080p=0.175
Fig 2 shows the results of the averaged R and L-CAVI values in the healthy subjects
(controls) and in the groups of patients with diabetes, hypertension and CAD.
Differentiation of diagnoses based on averaged L and R CAVI
0,8
4,2
19,3
31,9
26,9
6,7
9,2
0,8
5,6
5,6
5,6
22,2
16,7
16,7
27,8
0
5
10
15
20
25
30
35
40
<=4
4-5
5-6
6-7
7-8
8-9
9-10
10-11
>11
control (N=121) vs. diabetes (N=36)
0,8
4,2
19,3
31,9
26,9
6,7
9,2
0,8
13,8
6,9
37,9
24,1
13,8
3,4
0
5
10
15
20
25
30
35
40
<=4
4-5
5-6
6-7
7-8
8-9
9-10
10-11
>11
0,8
4,2
19,3
31,9
26,9
6,7
9,2
0,8
2,8
5,6
5,6
16,7
22,2
27,8
13,9
5,6
0
5
10
15
20
25
30
35
40
<=4
4-5
5-6
6-7
7-8
8-9
9-10
10-11
>11
Patients(%)Patients(%)Patients(%)
CAVI
Control
Disease
0
1
2
3
4
5
6
7
8
9
10
Control
Diabetes
Hypertension
CAD
CAVI
mean 95% CI
p value: statistical significance of difference between
control and given group of patients (p < 0.05).
p<0.001
p<0.001 p<0.001
control (N=121) vs. hypertension (N=58)
control (N=121) vs. CAD (N=74)
Fig 3 shows the significant differences of the averaged CAVI values in the control group and
in the patients with diabetes, hypertension and CAD.
351
Correlation diagrams based on CAVI
0
5
10
15
0 5 10 15
R-CAVI and L-CAVI Age and average CAVI
0
2
4
6
8
10
12
14
16
75 100 125 150 175
0
2
4
6
8
10
12
14
16
0 20 40 60 80 100
0
2
4
6
8
10
12
14
16
50 75 100 125
R-CAVI
L-CAVI
r=0.963
p<0.001
Age (years)
r=0.756
p<0.001
CAVI(averageL,R-CAVI)
CAVI(averageL,R-CAVI)
CAVI(averageL,R-CAVI)
Systolic blood presure (mm Hg) Diastolic blood presure (mm Hg)
Diastolic blood pressure and average CAVISystolic blood pressure and average CAVI
r=0.355
p<0.001
r=0.354
p<0.001
Fig 4 shows the correlation diagrams between the averaged values of L-CAVI and R-CAVI,
between averaged CAVI and the age, and between averaged CAVI and systolic and diastolic
BP.
Discussion
The mortality caused by the so-called life-related diseases in the developed countries has
become the highest in the world. It has been shown that these diseases are strongly associated
with the lifestyle and inactivity, favorizing plaque formation and atherosclerosis developent.
Social needs for quantitative measurement of atherosclerosis were rapidly increasing because
the arteriosclerotic process is considered as an independent risk factor for the cardiovascular
diseases. The vesell wall arteriosclerotic changes represent the main risk for the onset of
myocardial infarction and stroke; both complications vitally worsen the prognosis and the
quality of life in the populations of developed countries (5 and 6). For these reasons, a
preventive and simple quantitative method for early diagnosis of arteriosclerosis is required.
The measurement of the aortic pulse wave velocity (PWV) is calculated by measuring the
pulse transit time and the distance traveled between two selected sites (ie, arterial distance
over transit time), which is inversely related to the distensibility of the arterial walls. PWV is
352
still popularly practiced and its usefulness in early diagnosis of arteriosclerosis was
demonstrated (7 and 8) but it had a inherent limitation of blood-pressure dependency (1).
Aortic PWV is pressure dependent, and PWV must be corrected for diastolic blood pressure
(9) and carotid and femoral pulse waves are often difficult to detect, thus limiting use in daily
clinical practice. Hayashi et al. proposed the concept of an arterial stiffness β index (10),
however, stiffness β reflects only the regional (local) arterial stiffness, is expensive and
requires specialized ultrasonic equipment. Intima-media thickness (IMT), also called intimal
medial thickness, was also becoming popular. IMT is a measurement of the thickness of
artery walls, usually by external ultrasound, occasionally by internal, invasive ultrasound
catheters, to both detect the presence and to track the progression of atherosclerotic disease in
humans (11). IMT has increasingly been used in medical research since the mid 1990's and its
key advantages are the lower cost (compared with most other methods), relative comfort for
the patient and lack of need of invasive methods or any X-ray radiation. IMT can be used
repeatedly, over years, without compromising the patient's short or long term health status.
However IMT is limited to the morphological local regional measurement, and not to obtain a
representative image of functional aspect in arterial stiffness. Radiographic IMT using
advanced computed tomography (CAT) scanners is more approximated due to its ability to
use software to more slowly and carefully process the images and the examination of the
artery segments from whatever angle appears most appropriate (12) However, the major
limitation of all CAT scanners is the dose of X-ray delivered to the patient’s body and there
are also concerns about the safety of repeated doses of X-rays to track disease status over time.
It is known that lowered extensibility of the aorta causes onset of the heart disease and so
determines the prognosis. Arteriosclerosis generally progresses from the aorta to both carotid
arteries and then the cerebral and coronary arteries (13). For the accurate non-invasive
evaluation of the stiffness of the aorta, femoral artery and tibial artery, the cardio-ankle
vascular index (CAVI) which is independent of blood pressure was developed. CAVI is a
simple test, similar to PWV but the main unique diference is that CAVI is not influenced by
blood pressure fluctuations during the measurement and CAVI could be used as a reliable
index of arterial stiffness even in subjects with labile blood pressure. Also our results
indicated that CAVI is not dependent on the variations of the blood pressure and this is an
important finding opening the possibility to evaluate f.e. the proper effects of antihypertensive
drugs on the blood pressure and the arterial stiffness (2) The variation coefficient for CAVI is
3.8%, and the reproducibility seems to be enough sufficient for clinical application (2). The
353
regions measured by both CAVI and PWV include elastic and muscular vessels (aorta and
femoral–tibial arteries) and the calculation formula for CAVI is fully compatible with the
aortic PWV measured by conventional methods. Coronary artery ischemic disease, diabetes
mellitus and hypertension induce severe arteriosclerotic changes resulting in increased arterial
stiffness, and represent a major risk factor of arteriosclerosis development (14). The
significant diference of the mean CAVI values between healthy subjects and the patients with
above mentioned 3 life-related diseases in this study seems to support this fundamental idea.
It is also well known that arteriosclerosis increases with age (15) and our results showed that
CAVI increases with age too, and thus age should be regarded as a strong risk factor. In other
words, the higher value of CAVI reflects the extent of the plaque formation and this further
hihglights the predictive value of CAVI of arteriosclerotic risk (16).
Conclusion
In conclusion, CAVI assessed by the device VaSera® 1500 is simple and valuable clinical test
for the estimation of the arterial stiffness. CAVI is not influenced by blood pressure variations,
and therefore very useful for the early detection of the plaque formation in healthy subjects
and for monitoring of the arteriosclerosis progression in patients with life-related diseases.
However, the number of subjects included in this study was not sufficient (121 healthy
volunteers only) and further large population studies are needed.
Acknowledgement
This study was supported by the grant MSM 021622402 and by the grant NS 10096-4
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7. Asmar R. Pulse wave velocity principles and measurement. In: R. Asmar, M.F.
O’Rourke and M. Safar (eds.): Arterial Stiffness and Pulse Wave Velocity, Elsevier,
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brachial-ankle pulse wave velocity measurement: correlation with abdominal aortic
calcification, Hypertens Res 2003; 26: 163–7.
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482-6.
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K, Fukuoka T, Higaki J Relationship between cardio-ankle vascular index (CAVI) and
carotid atherosclerosis in patients with essential hypertension Hypertens Res 2007;
30(4): 335-40.
15. Wakabayashi I and Matsuda H. Effects of age on the relationship between cardio-ankle
vascular index and atherosclerotic progression in patients with type2 diabetes mellitus,
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355
Respiratory exchange ratio at maximum load before and after termination of controlled
ambulatory rehabilitation program in patients after acute myocardial infarction
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Mífková L.1
, Várnay F.1
, Fišer B., Havelková A., Vank P., Pochmonová J., Svačinová H.,
Siegelová J.1
1
Department of Physiotherapy and Rehabilitation, Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Faculty Hospital, Brno
INTRODUCTION
To be able to evaluate correctly peak values of oxygen intake (VO2peak) and working capacity,
we must know whether in exercise test a sufficient metabolic load (full metabolic capacity
utilization) was achieved. The peak value of respiratory exchange ratio (RERpeak; ratio of CO2
output to O2, intake, indicated also as respiratory quotient), correlating with the increased
lactate value and acidosis degree, is the criterion of the achieved level of metabolic load (full
metabolic capacity utilization) at submaximal and maximal load.
According to the Statement of the Working Group on Cardiac Rehabilitation and Prevention
of the European Society of Cardiology the full metabolic loading is achieved at RERpeak ≥
1,15 and the exercise testing is valid (1).
AIMS
To assess the influence of respiratory exchange ratio RERpeak on VO2peak validity in evaluation
of the measure of improvement of maximal aerobic capacity of patients who suffered an acute
myocardial infarction after 12-week controlled ambulatory rehabilitation program.
MATERIAL AND METHODS
Study population
We evaluated 49 men incorporated into 12-week controlled ambulatory rehabilitation
program. All patients suffered an myocardial infarction (AIM) and started rehabilitation
356
program within three months after AIM (Table 1). The acute myocardial infarction was
diagnosed at 1st
Department of Cardioangiology in St. Anna University Hospital in Brno.
The patients were divided into two groups according to the achieved RERpeak. Group A
reached RERpeak ≥ 1,05, in group N RERpeak < 1,05 (Table 1) was achieved in one or both
exercise tests.
In the course of the rehabilitation program all patients were symptomatically stable and their
medication treatment was unchanged.
The whole study was carried out in accordance with ethic principles of Helsinki convention
from 1975 in the revision from 1983. All patients signed their informed approval.
Table 1 Characteristic of the examined set of patients with myocardial infarction
Age (years)
( x ± SD)
RERpeak ( x ± SD)
input output
Group A (n = 25) 61.3 ± 9.9 1.12 ± 0.04 1.15 ± 0.07
Group N (n = 24) 57.8 ± 10.9 1.01 ± 0.06 1.10 ± 0.13
Rehabilitation program
All patients went through the supervised exercise training with combined load three times a
week for three months. The training unit consisted of warm-up phase (10 min), aerobic phase
(25 min), resistance training phase (15 min) and relaxation phase (10 min ).
Aerobic phase on bicycle ergometers (Ergoline REHA E900) consisted of warm-up phase
lasting 3 to 4 minutes at a low load, of 25-min training with the intensity at the anaerobic
threshold level given by spiroergometric examination, and 2-min cool-down phase during
which the load intensity was gradually decreasing (2). The resistance exercises made on
multifunctional machines TK-HC COMPACT included benchpress, pull down of the pulley
and leg extension, out of the machine sitting-lying was performed. The load intensity was
determined by the method 1-RM (one repetition maximum, i.e. one repetition of the given
exercise made in the full extent of the movement with maximal load) (3). Individual exercises
were made in 3 to 5 series, at 10 repetitions. During the whole training unit there were
monitored heart rate, blood pressure, degree of subjective perception of the load intensity
according to Borg scale, during the aerobic and resistance training phases also ECG was
monitored.
357
Methods of examination
Symptom limited spiroergometric examination with ventilator gas analysis was performed
before the starting and after the finishing of the cardiovascular rehabilitation program (98
examinations altogether). It was started by ECG monitoring at rest in lying and sitting
position (Schiller CS 100). It was followed by 3-min adaptation in the sitting position on
ergometer. The workload was increased in one minute intervals. The rate of the workload
increase was chosen according to the supposed fitness in such a way that the total workload
duration was 8 to 12 minutes. In the course of the exercise test ECG was monitored
continuously, heart rate was recorded every minute according to ECG, manual blood pressure
measurement and determination of the degree of subjective perception of the load according
to Borg scale were made every 2 minutes. The test can be terminated because of dyspnoea,
exhaustion, reaching of the limit heart rate value (220-age), abnormal hypertension reaction
(≥ 230/115), decrease of systolic blood pressure (> 10 mmHg), indications of ischemia on
ECG, pectoris angina, substantial dysrhythmia, loss of motion coordination, disturbances of
consciousness, pains, orthopedical or neurological reasons, technical causes, etc.
Oxygen uptake, CO2 output and ventilation were measured in each breath (breath-by-breath
analysis) and averaged values for 30 s were recorded in the printed report (device Pulmonary
Function System 1070 - MedGraphics, USA). The device determined automatically the
anaerobic threshold according to the changes of ventilation-respiratory values and, moreover,
in all of them the determined anaerobic threshold was checked according to V-slope, by
comparing the curves of ventilation equivalent VE/O2 a VE/CO2 and the curve of CO2 excess
[ExCO2=((VCO2)2
/ VO2) – VCO2].
The anaerobic threshold value was expressed as VO2 and for the need of physical training in
watts with the corresponding heart rate and degrees of Borg scale of subjective perception of
the load intensity.
Statistical processing
Statistical processing was made by using the program Microsoft Excel for Windows and the
program Statistica, version 6.1.
The distribution was evaluated by Lillefors modification of Kolmogorov-Smirnov test of
normality in the program Statistica. With regard to normal distribution, parametric tests were
used. In comparing two dependent variables two-sample paired t-test to mean value (in
program Microsoft Excel) was performed. In comparing two independent variables first of all
it was found out by two-sample F-test for variances whether the variances differ or not, and,
358
as the case may be, either two-sample t-test with equality of variances or two-sample t-test
with inequality of variances was used (all in the program Microsoft Excel).
In all tests the significance level was primarily set to 0.05. If the result on this level was
statistically significant, testing was made also on the significance level 0.01, possibly 0.001.
Always double-sided testing was used. The results are presented in the form of means ( x)
and standard deviations (SD).
RESULTS
Graph 1 shows the survey of 98 spiroergometric examinations according to the value of
RERpeak. In 25 patients RERpeak ≥ 1.05 was achieved in both tests (right upper quadrant of
graph 1). In 5 patients only RERpeak ≥ 1.15 was achieved and the value of VO2peak can be
therefore considered to be valid according to the Statement (1). In 30 examinations RERpeak <
1,05, from that in 13 patients in entrance examination (left upper quadrant of graph 1), in 5
patients in final examination (right lower quadrant of graph 1) and in 6 patients in both
examinations (left lower quadrant of graph 1). In the group with RERpeak < 1.05 low RERpeak
predominated significantly in entrance examinations (graph 2).
In these 30 exercise tests that were terminated prematurely (RERpeak < 1,05) only in one third
the symptoms indicating possible limitation of the transport system (exhaustion, dyspnoea,
pectoris angina) were the cause of the test termination.
Graph 1 Spiroergometric examinations according to the value of RERpeak Graph 2
359
In the group A the value of VO2peak increased by 2.4 ml.kg-1
.min-1
(p < 0.01) after 12-week
rehabilitation program and in the group N the value of VO2peak increased by 5,1 ml.kg-1
.min-1
after the completion of the rehabilitation program (table 2, graph 3). The value of the total
achieved load (Wpeak) increased in the group A by 0.24 W.kg-1
(p < 0.001) and in the group N
by 0.51 W.kg-1
(p < 0.001) (table 2, graph 4). Comparison of differences between the groups
A and N is in table 3 and graphs 4,6.
Table 2 Comparison of input and output values of VO2peak and Wpeak in individual groups of
patients with IM
VO2peak (ml.kg-1
.min-1
) Wpeak (W.kg-1
)
Input Output Statist. Input Output Statist. sign.
Group A 21.3 ± 3.9 23.7 ± 4.4 p < 0.01 1.40 ± 1.64 ± 0.36 p < 0.001
Group N 19.6 ± 3.6 24.9 ± 6.3 p < 0.001 1.21 ± 1.72 ± 0.46 p < 0.001
Table 3 Comparison of differences of VO2peak and Wpeak between the groups A and N of
patients with IM
Group A Group N Statist. sign.
VO2peak (ml.kg-1
.min-
2.4 ± 3.3 5.1 ± 5.3 p < 0.05
Wpeak (W.kg-1
) 0.24 ± 0.24 0.51 ± 0.36 p < 0.01
Graph 3 Graph 4
360
Graph 5 Graph 6
DISCUSSION
The results of our preceding studies of men and women with ICHS, included in the controlled
rehabilitation program within the framework of cardiovascular rehabilitation, showed that
from the value of RERpeak ≥ 1.05 the values of VO2peak can be considered to be acceptably
valid for the purpose of comparison of exercise tests (4,5). That is why we divided this set of
men after AIM in advance into groups A and N. If the achieved value of RERpeak < 1,05, then
VO2peak will be underestimated and thus a mistaken assessment of VO2peak differences and
distorted results in evaluation of dynamics of the changes can occur. It turned out also in the
results of this study; lower input values of VO2peak had a significant share in more than double
increase of VO2peak in the group N in comparison with the group A in the premature
termination of the exercise test with subsequent increase of the difference between the
entrance and final test. Similar changes were found out also in the analysis of Wpeak both in
the group A and in the group N.
It is apparent that the knowledge of RERpeak value is necessary for the correct interpretation of
peak values (VO2peak, Wpeak, etc.). RERpeak value is important also for the correct classification
into functional classes according to VO2peak (e.g. according to Weber). With regard to the fact
361
that the study is not a mortality one, we cannot express our opinion of VO2peak validity for
assessment of the prognosis (at RERpeak in the range of 1.05 to 1.14). The values of VO2peak
achieved at RERpeak < 1.00 have not a prognostic significance any more (6).
CONCLUSION
When comparing two and more exercise tests, achieving of the sufficient and comparable
metabolic loading in both tests is the condition of the correct evaluation of the dynamics of
changes; RERpeak value in both tests should be at least 1.05. The low value of RERpeak
indicates premature termination of the exercise test and, consecutively, the low,
underestimated value of VO2peak. In comparing two exercise tests with considerably different
RERpeak, the values of VO2peak and thus also the difference of peak values of oxygen intake
are significantly influenced. At the low input RERpeak the difference of VO2paek increases
(apparently considerable improvement), at the low output RERpeak the difference, to the
contrary, decreases (apparently small or no improvement of VO2peak). According to the results
of our study, premature termination of the symptom-limited exercise test is relatively
frequent. In men with ICHS RERpeak is lower than 1.05 (4,5) in as many as 40 %.
Supported by MSM0021622402
LITERATURE
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364
CARDIOVASCULAR EXERCISE TRAINING IN MEN AFTER ACUTE
MYOCARDIAL INFARCTION
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
HAVELKOVÁ ALENA, MÍFKOVÁ LEONA, POCHMONOVÁ JAROSLAVA, ANBAIS
F.H., ERAJHI A.A., BÁRTLOVÁ BARBORA, FIŠER BOHUMIL, VÁRNAY
FRANTIŠEK, DOBŠÁK PETR, SIEGELOVÁ JARMILA
Dept. of Physiotherapy and Rehabilitation and Department of Functional Diagnostics and
Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Teaching Hospital, Brno,
CZ
INTRODUCTION
Cardiovascular exercise trainining is very important in the complex care of patients with
cardiovascular disease. It starts already during hospitalization and after the discharge to home
care it continues in the form of controlled out-patient rehabilitation program individual
training at home (1). It increases physical fitness, improves quality of life (2-4) and decreases
cardiovascular mortality (5,6). Dynamical endurance aerobic activities are the basis of each
training unit (7-9,13,14). The best known and most widespread type of aerobic training is the
training with continuous work load. Interval training (1,10) can be an alternative training
method for persons with a low tolerance of load, with a lower contractility of left ventricle, or
for elderly people.
AIM OF THE STUDY
The aim of the present study was to evaluate the effect of 12-week controlled out-patient
rehabilitation program with continuous and interval work load on aerobic capacity and
performance on the level of anaerobic threshold in men after acute myocardial infarction
(AIM) treated by percutaneous thoracoplasty of coronary artery (PTCI with stent
implantation).
SET OF PATIENTS
44 men patients after AIM were included into the study. They were divided into two groups.
The first group with ejection fraction (EF) 52 ±7 %, group K, n=22, went in aerobic phase
365
through the training with continuous work load, the second group with EF 49 ±12 %, group I,
n=22 went in aerobic phase with the interval training.
Controlled out-patient rehabilitation was started within 12 weeks after AIM. AIM diagnosis
was identified at 1st
internal cardioangiological clinic of Faculty of Medicine, Masaryk
University, St. Anna Teaching Hospital in Brno (treated by PTCI with stent implantation).
During rehabilitation all patients were symptomatically stable and their medication was not
changed.
The groups did not differ in age and ejection fraction, their characteristic is given in Table
1.
Table 1 Characteristic of the set
Group K Group I
Number (n) 22 22
Age (years) 57 ± 12 60 ± 7
Ejection fraction (%) 52 ± 7 49 ± 12
Starting RHB (weeks after AIM) 6 ± 2.5 5 ± 3.4
METHODOLOGY
Methods of examination
Before the beginning of rehabilitation (RHB) program and after its completion we made
spiroergometric examination to symptom-limited maximum (Pulmonary Function System
1070, MedGraphics, USA). The examination was started by monitoring resting EKG in lying
and sitting position (Schiller CS 100), followed by 3-minute adaptation in sitting position on
ergometer. The work load was increased every 2 minutes by 20 W to symptom-limited
maximum. Anaerobic threshold was determined from the course of changes of ventilatoryrespiratory
parameters. For the use of RHB it was expressed in watts, heart rate and degrees
of RPE (Borg scale).
Before the beginning of resistance training (i.e. in the 3rd
week of RHB program) we made
isometric test („handgrip“, DHG-SY3, Recens) to verify blood pressure response to isometric
load. In the case of a normal response the entrance 1-RM test (one repetition maximum test)
was made in three exercises of resistance training. The test was repeated in the 6th
week and in
the 12th
week of RHB program.
366
Rehabilitation program
The controlled out-patient RHB program lasted 12 weeks altogether with frequency three
times a week. The training unit lasted 60 minutes and consisted of warm-up phase (10 min),
aerobic phase (1st
to 2nd
week 40 min; 3rd
to 12th
week 25 min), toning phase (3rd
to 12th
week
15 min) and relaxation phase (10 min). The patients in „K“ group went in aerobic phase
through continuous training, in „I“ group they went through interval training. For the interval
training the following modification was chosen: 30 s of working phase with intensity on the
level of anaerobic threshold and 60 s of relaxation phase with the minimum work load 5
watts.
The interval training was indicated by residual ischemia, low ejection fraction of left
ventricle, generally low tolerance of work load.
The warm-up phase was aimed at preparing cardiovascular and motor system to further load,
prevention of muscular-skeletal lesion. The warm-up phase was composed from dynamical
endurance exercises (simple floor gymnastic exercises, exercises with gymnastic apparatus)
and stretching of muscle groups with a tendency to shortening.
The aerobic phase was effected on a bicycle ergometer (Ergoline REHA E900) controlled
by the program ErgoSoft+ for Windows. The aerobic training intensity was determined on the
anaerobic threshold level.
The resistance training was realized on multifunctional muscle conditioning machines TKHC
COMPACT. Four exercises were done (bench press, pull down, leg extension on the
machine and sitting-lying positions). The resistance training intensity was determined by the
method 1-RM and training loads were determined in percents of maximum: 30-60 % 1-RM
each week increases by 10 %). The number of sequences was 3 - 5 with ten repetitions.
Before starting the resistance training, the patients were thoroughly informed about proper
breathing and technique of doing exercises.
Modified Schultz autogenic training was used for relaxation.
In the course of the whole training monitoring of heart rate, blood pressure and degree of
RPE, during the aerobic phase also EKG was carried out.
Statistical processing
Statistical processing was made in the programs Microsoft Excel and Statistica, version 8.
Distribution was tested by Lillefors modification of Kolmogorov-Smirnov test of normality.
According to the result either paired t-test or Wilcoxon test for dependent specimens were
used. The significance level was determined to 0,05, at the statistical significance on this level
367
the testing was made on the level 0,01 (0,001). The results are presented as means with
standard deviations.
RESULTS
After the completion of the program a statistically significant increase of the oxygen intake on
the level of anaerobic threshold in both groups was recorded (table 2). VO2ANP increased in
„K“ group by 13 %, VO2ANP/kg by 11 %. VO2ANP increased in „I“ group by 20 %,
VO2ANP/kg also by 20 %.
Table 2 Parameters of aerobic capacity on the level of anaerobic threshold
Group K Group I
Before RHB After RHB
p
Before RHB After RHB
p
VO2ANP (ml.min-1
) 1086±190 1225±291 0.001 995±209 1194±242 0.05
VO2ANP/kg(ml.min-1
.kg-1
) 12.9 ± 1.7 14.3 ± 2.5 0.01 11.6 ± 3.30 13.9 ± 3.71 0.05
VO2ANP = oxygen intake on the level of anaerobic threshold
368
Group K
VO2ANP/kg
0
2
4
6
8
10
12
14
16
18
20
Before RHB After RHB
ml.min-1
.kg-1
Fig. 1 Oxygen consumption before and after cardiovascular exercise training at the level of
anaerobic threshold in group K (p < 0.01)
VO2ANP/kg
Group I
0
2
4
6
8
10
12
14
16
18
20
Before RHB After RHB
ml.min
-1
.kg
-1
Fig. 2 Oxygen consumption before and after cardiovascular exercise training at the level of
anaerobic threshold in group I (p < 0.01)
369
Tolerance of work load on the level of anaerobic threshold also improved statistically
significantly in both groups (table 3). WANP in „K“ group increased by 15 % and WANP/kg
by 17 %. In „I“ group WANP increased by 35 % and WANP/kg by 37 %.
Table 3 Performance parameters on the level of anaerobic threshold
Group K Group I
Before RHB After RHB
P
Before RHB After RHB
p
WANP (W) 62 ± 14.2 71 ± 19.4 0.01 52 ± 10.2 70 ± 16.1 0.001
WANP/kg(W.kg-1
) 0.7 ± 0.17 0.8 ± 0.19 0.01 0.6±0.17 0.8 ± 0.26 0.001
WANP = performance on the level of anaerobic threshold
WANP/kg
Group K
0
0,2
0,4
0,6
0,8
1
1,2
Before RHB After RHB
W.kg-1
Fig. 3 Work load before and after cardiovascular exercise training at the level of anaerobic
threshold in group K (p < 0.01)
370
WANP/kg
Group I
0
0,2
0,4
0,6
0,8
1
1,2
Before RHB After RHB
W.kg-1
Fig. 4 Work load before and after cardiovascular exercise training at the level of anaerobic
threshold in group I (p < 0.01)
DISCUSSION
The training with continuous work load and the interval training are used widely not only
in sports activities, but also in rehabilitation. The interval training in cardiovascular
rehabilitation is often recommended and conducted individually with regard to the health and
functional state, to the age and gender of the patient. Work load intensity, duration of working
and relaxation phases in interval training and the total number of exercise intervals differ
according to the orientation of the training (10-12). Mífková et al. (11) used in her study the
following modification of interval training: 30 s of working phase on the level of anaerobic
threshold and 60 s of relaxation phase on the level of 5 watts. 38 men with ischemic heart
disease were monitored in the study. Both groups differed in age and ejection fraction. The
total work done by the patients in this interval training modification was 2,5 to 3 times lower
than in the group of patients for which the continuous training was prescribed. In the final
spiroergometric examination there was no statistically significant difference between the
groups with interval and continuous training either in performance parameters or in
371
parameters of aerobic capacity (evaluated on the level of the highest values achieved). Both in
interval and continuous type of the training similar results were obtained at the same training
work load intensity.
In our study we used the same modification of interval training: (30 s of working phase
with intensity on the level of anaerobic threshold and 60 s on the level of 5 W). We evaluated
selected parameters on the level of anaerobic threshold. The patients in our group did not
differ in age and in ejection fraction. The benefit of interval training lies in the possibility of
obtaining improvement even in risk patients (11).
CONCLUSION
The group with interval training (I) had already before the starting of the program a lower
oxygen intake and a lower tolerance of work load than the group with continuous training (K).
After the completion of the program the oxygen intake on the level of anaerobic threshold
increased statistically significantly in both groups (VO2ANP increased in „K“ group by 13 %,
VO2ANP/kg by 11 % . VO2ANP increased in „I“ group by 20 %, VO2ANP/kg also by 20 %).
The tolerance of work load increased statistically significantly on the level of anaerobic
threshold in both groups. (WANP increased in „K“ group by 15 % and WANP/kg by 17 %. In
„I“ group WANP increased by 35 % and WANP/kg by 37 %.) In both groups we recorded
statistically significant improvement of the monitored parameters after 12-week rehabilitation
program. Both types of the training were well tolerated.
Supported by MSM0021622402
LITERATURE
1. Chaloupka V, Siegelová J, Špinarová L. a kol. Rehabilitace u nemocných
s kardiovaskulárním onemocněním. Cor Vasa 2006; 48: K 127-45.
2. Izawa K, et al. Improvement in physiological outcomes and health-related quality of life
following cardiac rehabilitation in patients with acute myocardial infarction. Circ J. 2004;
68(4):315-320.
3. McKelvie RS, Teo KK, Roberts RM. et al. Effects of exercise training in patients with
heart failure: the Exercise Rehabilitation Trial (EXERT). Am Heart J.2002; 144(1):23-30.
4. Pollock ML, Franklin BA, Balady GJ et al. Resistance exercise in individuals with and
without cardiovascular disease: benefits, rationale, safety, and prescription.
Circulation.2000;101:828-833.
372
5. Špaček R, Widimský P. Infarkt myokardu.1. vyd.Praha: Galén, 2003.
6. Špinar J, Vítovec J. a kol. Ischemická choroba srdeční.1. vyd.Praha:Grada Publishing,
2003.
7. Clausen JP.Circulatory adjustments to dynamic exercise and effect of physical training in
normal subjects and in patients with coronary artery disease. Prog Cardiovasc Dis
1976;18:456-495.
8. Thompson PD.The benefits and risks of exercise training in patients with chronic coronary
artery disease.JAMA.1988; 259:1537-1540.
9. Balady GJ, et al.Cardiac rehabilitation programs. Circulation.1994;90:1602-1610.
10. Siegelová J., Mifková L., Novák M. a kol. Interval and continuous training in
cardiovascular rehabilitation. Eur.J. Cardiovascular Prev.Rehabilitation 2006, 13,
Suppl.1., 85.
11. Mífková L, Siegelová J, Vymazalová L. a kol. Intervalový a kontinuální trénink
v kardiovaskulární rehabilitaci. Vnitř lék 2006; 52 (1): 44-50.
12. Mookerjee S. The Application of interval training for exercise prescription in cardiac
rehabilitation. J Cardiopulm Rehabil 1998; 18: 233-235.
13. Mífková L, Kožantová L, Siegelová J. a kol. Kombinovaný trénink u pacientů po akutním
infarktu myokardu. Med Sport Boh Slov 2005; 14(3): 115-123.
14. Chludilová V, Várnay F, Mífková L. a kol. Změny transportního systému kyslíku vlivem
kombinovaného tréninku u mužů s akutní a chronickou ischemickou chorobou srdeční.
XV. sjezd Společnosti rehabilitační a fyzikální medicíny,Luhačovice, ISBN 978-80-254-
1238-1, Společnost rehabilitační a fyzikální medicíny, 2008, 77.
373
THE EFFECT OF 8-WEEK REHABILITATION PROGRAM
IN MULTIPLE SCLEROSIS: COMBINATION OF AEROBIC
AND RESISTANT TRAINING
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
KONEČNÝ L., POSPÍŠIL P., VANK P., MÍFKOVÁ L., POCHMONOVÁ J.,
HAVELKOVÁ A., SIEGELOVÁ J., DOBŠÁK P.
Dept. of Physiotherapy and Rehabilitation, Dept. of Functional Diagnostics
and Rehabilitation, Faculty of Medicine, Masaryk University, St. Anna Faculty Hospital
in Brno, Czech Republic
INTRODUCTION
Multiple sclerosis (MS) is chronic system auto-immune disease that causes functional
neurological deficit on the basis of dissemination of demyelinisation focuses in central
nervous system (CNS) area (1). Probable cause of persisting neurological deficit is the axon
involvement that appears at the beginning of the disease. Maximum axon loss occurs in the
first years of the disease (period with minimal disability and clinical finding). As a result of
depletion of functional reserves of CNS, substantial deceleration in conduction of nerve
impulse develops. Further axon loss brings on an irreversible disability (2). Demyelinisation
and axon involvement are localized particularly in periventricular area, brain-stem,
cerebellum, lateral and posterior cords of spinal chord. Predominant manifestations include
therefore central pyramidal symptoms, cerebral, stem and sensitive symptoms, disorders of
autonomic regulation, urinary continence etc. (3). By demyelinisation processes, MS also
attacks basic physiological response to work load. Functional changes in skeletal muscles,
particularly reduction of the number of fibres of the type I, reduction of oxidative abilities and
prevailing anaerobic activity of skeletal extrafusal fibres, are ranked among other
pathophysiological processes (4). Increasing disability leads to secondary signs - lost of
physical condition with a gradual reduction of muscular mass, reduction of cardiorespiratory
fitness including autonomic nervous system dysfunction and finally lost of functional
independence (5, 6, 8, 9). Controlled exercise activity represents a significant element with
impact on physical condition and course of MS disease.
PURPOSE
The aim of this study was to analyze the effect of 8-week rehabilitation program consisted
of aerobic and resistant training form on the parameters of functional fitness, muscle strength,
374
cardiovascular autonomic functions, fatigue and functional independence in a group of
patients with Multiple Sclerosis (MS).
METHODOLOGY
Forty patients with verified MS disease, members of „Unie ROSKA Brno“ treated at the 1st
Clinic of Neurology, St. Anna Faculty Hospital in Brno, were recruited to the study. Twenty
of them fulfilled the entrance criteria for the study: ability of the patient to undergo entrance
and final examination, aerobic training on bicycle ergometer and resistant training on
multifunctional strenghtening machines. The patients with internal, metabolic and other
diseases which could influence validity of the exercise test were excluded. Clinically unstable
state of disease, active autonomic nervous system (ANS) dysfunction and medication with
influence of cardiorespiratory system or ANS was also a criterion of exclusion.
The study was approved by Masaryk University Ethical Comittee and all the MS patients
who participated in the study confirmed “Informed approval of the patient”.
Twenty patients were included to the examined group of patients. 2 of them were not able
to finish complete program, 3 of them were excluded because of arrhythmias. Final group of
patients consisted of 15 patients (12 women, 3 men). General characteristic of the group of
MS patients with the evaluation of disease activity (Kurtzke’s Expanded Disability Status
Scale; EDSS) are given in the table below (Table 1).
Table 1 Basic anthropometric data and MS disease activity description of the examined group
of MS patients (mean ± SD)
Women / men 12 / 3
Age (years) 50.7 ± 13.1
Height (m) 1.7 ± 0.1
Weight (kg) 69.1 ± 8.9
Body mass index (BMI) 24.9 ± 3.3
Clinical disability (EDSS) 2.8 ± 0.7
MS duration (years) 15.7 ± 14.4
Primary progressive form of MS (n) 1 (6.7%)
Secondary progressive form of MS (n) 5 (33.3%)
Relabs-remittent form of MS (n) 9 (60.0%)
Walking without aid (n) 11 (73.3%)
Walking with 1 or 2 crutches (n) 4 (26.7%)
Spastic paraparesis (Ashwoth ≤ 2; n) 2 (13.3%)
Without MS specific pharmacotherapy (n) 6 (40.0%)
Imunomodulancia (Interferon, Betaferon, Copaxon, Rebif; n) 7 (46.7%)
Cortico-therapy (Medrol, Solumedrol, Imuran, Prednison; n) 2 (13.3%)
375
The effect of 8-week rehabilitation program on the parameters of functional fitness, muscle
strength, cardiovascular autonomic functions, fatigue and functional independence in a group
of patients with MS was evaluated by comparison of the results of entrance examination
before starting rehabilitation program and final examination after completion of rehabilitation
program.
Entrance and final examination consisted of:
Kurtzke’s Expanded Disability Status Scale (EDSS) - a standard scale for evaluation of
clinical disability in patients with MS (10). It is a neurological examination that evaluates the
impact of MS on 8 basic functional systems. The scale is divided into 20 levels in the interval
from 0 (no functional disorder or impairment) to 10 (death due to MS).
Functional Independence Measure (FIM) - a scale for evaluation of independence in basic
daily activities (11). Locomotor skills, mental functions and general degree of independence
are evaluated in the range from 18 (full dependence) – 126 (full independence) points.
Modified Fatigue Impact Scale (MFIS; 12) is a questionnaire (21 items) expressing
subjective assessment of fatigue impact on physical condition (MFISp), cognitive functions
(MFISc) and psychosocial functions (MFISps). Answer to each item can score 0 (no fatigue
present) to 4 points (almost permanent fatigue). Results of evaluated scales and questionnaires
of the examined group of MS patients are given in the table below (Table 2).
Table 2 Results of evaluated scales and questionnaires of the group of patients (mean ± SD)
Scale Value Min. - max. value
Clinical disability (EDSS) 2.8 ± 0.7 0 – 10
Fatigue (MFIS) 28.5 ± 17.6 0 – 84
MFISp - physical 14. ± 8.3 0 – 36
MFISc – cognitive 11.7 ± 8.6 0 – 40
MFISps – psychosocial 2.3 ± 1.9 0 – 8
Independence (FIM) 118.5 ± 10.4 18 – 126
Symptom limited spiroergometry was carried out in standard conditions (13) on bicycle
ergometer. The twelve-lead electrocardiogram was recorded (Cardiovit CS 100 – Schiller).
Ventilation-respiration values were determined by a gas analyzer (Pulmonary Function
System 1070 – MedGraphics CPX/D, USA). The work load during exercise test was
increased every 2 minutes by 20 W to the symptom-limited maximum. The anaerobic
threshold was determined from the course of changes of ventilatory-respiratory parameters.
For the use of rehabilitation it was expressed in watts, heart rate, and degrees of RPE (Borg’s
Rate of Perceived Exertion).
376
Heart rate variability (HRV) was examined by TASK FORCE MONITOR (CNSystem,
Graz, Austria; 14). The examination was carried out by means of non-invasive continuous
recording of heart rate and beat-by-beat measurement of blood pressure. 5-minute recording
was made at rest in supine position with metronome controlled breathing (f = 0.33 Hz). The
data were processed using spectral analysis in the low-frequency component of HRV (0.05 -
0.15 Hz; LF; [ms2
]), high-frequency component of HRV (0.15 - 0.50 Hz; HF; [ms2
]), total
spectral power (TP; [ms2
]), index of sympatho-vagal balance (LF/HF). Examination was
carried out in standard conditions (exclusion of physical activity 24 hours before examination,
more than 4 hours after last meal, 8 hours without smoking and coffee or alcohol drinking,
examination between 9 and 12 a.m.).
The controlled outpatient RHB program was designed for 8 weeks with the frequency of
twice a week. The training unit lasted 60 to 90 minutes and consisted of a warm-up phase
(10 min), an aerobic phase (1st
to 2nd
week 20-40 min; 3rd
to 8th
week 25 min) and a relaxation
phase (10 min). Resistant training was added to the training unit in the 3rd
week of RHB
program (3rd
to 8th
week 15-20 min). ECG, blood pressure and RPE were monitored during
the aerobic phase for safety reasons.
The warm-up phase was aimed at preparing the cardiovascular and locomotor system for
further work load, prevention of musculoskeletal lesions. It consisted of dynamic endurance
exercises, basic gymnastic exercises and stretching of muscle groups with a tendency to
shortening.
The aerobic phase was realized on a bicycle ergometer (Ergoline REHA E900) controlled
by the program ErgoSoft+ for Windows. Interval or continuous work load training used for
the aerobic phase was chosen according to entrance spiroergometry examination (interval
training was used in cases of generally low tolerance of work-load intensity). The intensity of
training was set at the anaerobic threshold level. The interval training consisted of 30 s of
working phase with the intensity at the level of anaerobic threshold and 60 s with a minimum
work-load of 5 watts.
The resistant training was added after isometric exercise test (“handgrip”, DHG-SY3,
Recens) to verify physiological blood pressure response to isometric work load. In cases of
normal response, the entrance one repetition maximum test (1-RM test; [kg]) was made for
three exercises of resistant training (bench-press, pull-down, leg extension). The resistant
training was provided on multifunctional strenghtening machines (TK-HC COMPACT).
Three exercises were performed: bench-press, pull-down, leg extension. The intensity of
resistant training was determined by the 1-RM method. The patients started resistance
377
exercises at 30–60 % 1-RM with weekly increase of 10 %. All three exercises were repeated
10 times in 3 to 5 sets. Proper breathing and technique of exercises was checked by
physiotherapist.
Modified autogenic training was used for relaxation at the end of the training unit.
Statistical processing was made using the software Statistica (STATISTICA, StatSoft, Inc.
2008, v. 8.0). Normality of distribution was tested by the Lilliefors modification of the
Kolmogorov-Smirnov test. Wilcoxon test for dependent samples was used to compare the
entrance and final examination results. The results are presented as means ± standard
deviations (SD).
RESULTS
Comparison of mean antropometric values, clinical disability, functional independence and
self-perceived fatigue before and after training program completion is given in the table below
(Table 3). Significantly lower values of MFIS and MFISp are demonstrated.
Table 3 Comparison of antropometric values, functional independence, self-perceived fatigue
before and after training program (mean ± SD)
Parameter Before training After training P
Weight (kg) 69.1 ± 8.9 68.2 ± 8.6 NS
Body mass index (BMI) 24.9 ± 3.3 24.5 ± 3.2 NS
Clinical disability (EDSS) 2.8 ± 0.7 2.7 ± 0.7 NS
Fatigue (MFIS) 28.5 ± 17.6 26.0 ± 14.9 * 0.018
MFISp – physical 14.6 ± 8.3 13.3 ± 6.9 * 0.043
MFISc – cognitive 11.7 ± 8.6 10.8 ± 7.4 NS
MFISps – psychosocial 2.3 ± 1.9 2.1 ± 1.6 NS
Independence (FIM) 118.5 ± 10.4 119.2 ± 8.4 NS
* P < 0.05, NS – without statistical relevance
Comparison of mean values of cardio-respiratory tolerance before and after training
program completion is given in the table below (Table 4). Significantly higher values of
maximal symptom-limited work load and oxygen consumption are demonstrated.
378
Table 4 Comparison of cardio-respiratory values before and after training program (mean ±
SD)
Parameter Before training After training P
WSL (W) 94.4 ± 25.0 102.7 ± 27.9 * 0.042
WSL. kg-1
(Watt. kg-1
) 1.4 ± 0.3 1.5 ± 0.4 * 0.026
WANP (Watt) 53.5 ± 14.0 57.2 ± 13.6 NS
WANP. kg-1
(Watt.kg-1
) 0.8 ± 0.2 0.8 ± 0.2 NS
VO2SL (ml O2) 1463.1 ± 359.2 1578.4 ± 390.3 * 0.015
VO2SL . kg-1
(ml O2.kg-1
) 21.1 ± 4.4 22.8 ± 4.9 NS
VO2SL . SF-1
(ml O2.tep-1
) 10.7 ± 3.0 11.2 ± 2.5 NS
MET SL 6.0 ± 1.3 6.5 ± 1.4 NS
* P < 0.05, NS – without statistical relevance
Comparison of mean values of 1-RM before and after training program completion is
given in the table below (Table 5). Significant improvement in all of the exercises is
demonstrated.
Table 5 1-RM test values before and after training program (mean ± SD)
1- RM test Before training After training P
Bench-press (kg) 22.3 ± 9.3 28.1 ± 9.7 *** 0.0001
Pull-down (kg) 22.1 ± 11.3 28.3 ± 11.3 *** 0.0001
Leg extension (kg) 26.5 ± 8.3 30.9 ± 9.0 *** 0.001
*** P < 0.001
Evaluated values of HRV were logarithmically transformated because for the purposes of
data distribution. Comparison of mean values before and after program completion is given in
the table below (Table 6).
Table 6 HRV results (logarithmically transformed, mean ± SD)
HRV parameter (controlled breathing
0.33Hz) Before training After training P
Log LF 1,98 ± 0,44 2,07 ± 0,40 NS
Log HF 2,04 ± 0,46 2,03 ± 0,51 NS
Log TP 2,39 ± 0,36 2,45 ± 0,39 NS
LF – low frequency band, HF – high frequency band, TP - total power, NS – without
statistical relevance
DISCUSSION
Obtained results of our study concern a sample of MS patients with mild to moderate (16)
clinical disability (2.8 ± 0.7, interval 1 to 4) and with a majority of a relaps – remittent form
of disease (9 patients, 60%). The rehabilitation program influenced neither clinical status nor
functional independence measure. These findings could be caused by various factors. Only
20% of patients had major motor dysfunctions. The majority of causes of disability were
379
sphincter, sensitive, visual and cerebellar dysfunctions. These dysfunctions could not be
effectively improved by our program. The results of our training program could also be
influenced by the insufficient length of the program. The high level of functional
independence in the tested group of MS patients at the beginning of the program
approximates the maximal FIM test values (118.5 ± 10.4; max. 126 points). We suppose the
decrease from the maximal values to be caused mainly by sphincter, sensitive, visual and
cerebellar dysfunctions. These dysfunctions could be influenced by exercise training only in a
minimal extent (118.5 ± 10.4 FIM entrance examination values vs. 119.2 ± 8.4 FIM final
examination values; 17, 18).
Very important finding was a significant decrease in self-perceived fatigue questionnaire
MFIS (28.5 ± 17.6 vs. 26.0 ± 14.9, * 0.018) and its subscale evaluating physical impact of
fatigue on health condition MFISp (14.6 ± 8.3 vs. 13.3 ± 6.9, * 0.043). On the basis of
presented results we consider that fatigue could be primarily influenced by the physical
training as described in recent literature (19, 20, 21). Up to now, there are no relevant and
consistent results available concerning combined rehabilitation program for MS patients (22).
Physical fitness and cardio-respiratory tolerance
The comparison of mean values of cardio-respiratory tolerance before and after training
program demonstrated 8.7% improvement in symptom limited maximum work load and 7.8%
improvement in symptom limited oxygen consumption. Our former pilot studies (23, 24, 25)
demonstrated only 4% improvement of VO2SL.kg-1
(6 MS patients, EDSS 4.3 ± 1). Other
parameters were not influenced statistically significantly. It is surprising that Bjarnadottir et
al. (26) demonstrated in a group of 16 MS patients (EDSS ≤ 4) 14.7% improvement of peak
oxygen consumption, 18.2% improvement of peak work load and 27.3% improvement of
peak work load on the anaerobic threshold level. The training program (60 min) was designed
for 5 weeks (3 times per week). It consisted of warm up phase (3min, 33% VO2max), aerobic
phase on bicycle ergometer (15-20 min, 55-70% VO2max), resistant phase with 13 exercises
(upper, lower extremities, trunk muscles, 15 to 20 repetitions) and 5 minutes of stretching
with relaxation. The evident difference in physical fitness results could be probably explained
by different weekly frequency of the training. Similarly Petajan et al. (27) found in a group of
21 MS patients (EDSS ≤ 6) 9.1% improvement of peak work load after 5 weeks and 18.6%
improvement after 10 weeks of aerobic training (15 weeks program, 3 times/week). A similar
rehabilitation program was designed by Rampello et al. (28). They achieved 10%
improvement of Wmax (82 ± 43 W vs. 103 ± 48 W) and 20% improvement of VO2max.kg-1
380
(17,1 ± 7,1 vs. 20 ± 6,6 ml.min-1
. kg-1
) after 8 weeks (3 times / week) of training (11 MS
patients, EDSS 3,5). Mostert and Kesserling (29) refer 12% improvement of VO2max after 4
weeks of training intervention (5 times / week, 30 min bicycle ergometr).
Possible explanation of different results between lower values of our study and above
mentioned may probably be in different design of aerobic training on bicycle ergometer. We
used interval training form in 70% of patients. The interval training form is generally
considered rather an alternative form of training and is preferred in patients with lower work
load tolerance. In this kind of training, work load phase alternates with a phase without any
load or a lower intensity load. In our study, 30 seconds of the work load with the intensity at
the level of anaerobic threshold alternated with 60 seconds with the intensity at the level of 5
to 10 Watts. This type of training produces only a minimum amount of lactate. At our dept.,
continuous training is usually used for patients with higher cardiorespiratory capacity.
Differences of the results (WANP, WANP.kg-1
) of above mentioned training programs could also
be caused by the use of different exercise protocols (interval vs. continuous training).
Muscle force
The comparison of entrance and final 1-RM test values showed significant improvement in
all of the tested exercises after program completion. The highest strength was noticed in pulldown
(21.9%) and bench-press (20.6%) exercises which are predominantly focused on
shoulder muscle groups. Schwidt et al. (30) demonstrated greater effect in upper extremity
strength than in lower extremity in MS patients. Similarly in our study we found only 14%
increase of lower extremity muscle strength in comparison to upper extremity muscle strength
(pull-down 21.9%, bench-press 20.6%). In our previously reported pilot studies (23, 24, 25) in
a group of 6 MS patients (EDSS 4.3 ± 1.0) we noticed statistically significant increase of
muscle strength only in upper extremities. We suppose that MS patients should profit from a
specific lower extremity resistant training program more. This type of exercise training should
have a priority in designing a rehabilitation program. White et al. (31) even recommend
incorporating of the resistant training before an aerobic training.
In our group of patients, only 2 of them patients were able to follow the scheme of 10 %
weekly increase of 30–60 % 1-RM. The majority of them did not achieve even 60% level of
resistant training intensity increase. It probably indicates low tolerance and low capacity of
MS patients to progression in resistant training. A period of rehabilitation programs focused
on lower extremities resistant training should therefore be prolonged.
381
Autonomic cardiovascular control
There were not found any signs of autonomic nervous system dysfunctions in the life
history of examined group of patients. The comparison of HRV results with normative values
of healthy population showed a significant decrease in all of the spectral bands (14).
Nevertheless we registered statistically insignificant increase in LF and HF spectral powers
and in Total Power in comparison to the initial values. Spectral analysis of heart rate
variability is often used for monitoring and evaluation of rehabilitation therapy effect. On the
basis of our experience with similar types of training programs in patients with Ischemic
Heart Disease (32), Myocardium Infarction (34) or Hypertension (33) we consider increase in
HRV spectral powers a sign of improving adaptability of autonomic cardiovascular
regulation.
Program safety, negative symptoms and program duration
We noticed only a slight exacerbation of neurological signs (hemiparesthesis, visual
worsening) in two cases because of light asymptomatic viral infection in combination with the
exercise training load. One week of home rest without any specific pharmacotherapy was
recommended by supervising neurologist. One patient (spastic paraparesis, 2 point of Asworth
scale) reported a temporary increasing of lower extremity spasticity. It was expressed as acral
clonus and worsening of tibialis anterior muscle spasticity. No other patient was emergently
forced to interrupt the program. On contrary Rampello et al. (28) presented in their 8 weeks
study 26% loss of included patients (MS exacerbation, social status change etc.). We did not
notice any discomfort during training on ergometers but nearly 70% of patients reported
myofascial or light postural disturbances requiring simple chiropractic interventions caused
by the exercises for muscle strengthening. The similar findings reported Dodd et al. (32). The
maximal fatigue increase was reported between the 2nd
and 3rd
week of the program probably
due to adaptative physiological response to exercise work load. There were not noticed any
signs of overtraining. We decided to choose 8 weeks of training program on the basis of our
experiences with the same training design in cases of Ischemic Heart Disease, Diabetes
Mellitus, Myocardium Infarction and Obesity (36, 37). 8 weeks of exercise training program
with combination of aerobic and resistant training form realized twice a week is according to
previously reported articles (27, 29, 31, 38, 39, 41, 42, 43) the shortest rehabilitation program
to record improvement in a physical fitness of MS patients.
382
CONCLUSION
The results of our study demonstrate a possibility to influence some of the physical
fitness parameters after 8 weeks of rehabilitation program realized twice a week with
combination of aerobic and resistant training form in group of MS patients with mild to
moderate clinical disability (EDSS 2.8 ± 0.7). Selected design of exercise training load
significantly improved parameters of physical capacity (WSL, WSL . kg-1
), aerometabolic
parameters (VO2SL), extremity muscle strength (1-RM bench-press, pull-down, leg extension)
and self-perceived fatigue (MFIS, MFISp). We did not notice significant changes in clinical
disability (EDSS) and functional independence. We consider increase in HRV spectral powers
after exercise training as a sign of improving adaptability of autonomic cardiovascular
regulation.
We also consider 8-week of rehabilitation program with combination of aerobic and
resistant training form should be safe for the MS patients with mild to moderate clinical
disability. It is essentially important to prescribe an individual intensity of training work load
with a respect of an actual medical condition. The combined training program seems to be
safe for the MS patients with this level of disability.
ABSTRACT
The aim of this study was to analyze the effect of 8-week rehabilitation program consisted
of aerobic and resistant training form on the parameters of functional fitness, muscle strength,
cardiovascular autonomic functions, fatigue and functional independence in a group of
patients with Multiple Sclerosis (MS).
At the beginning and at the end of the study we examined 15 MS patients with clinically
active form of MS (age 50.7 ± 13.1 years, 12 women, 3 men, mean duration of MS 15.4 ±
14.4 years, EDSS 2.8 ± 0.7) who participated in the rehabilitation program. The diagnosis was
made in the 1st
Dept of Neurology. The patients underwent a clinical examination, MS
activity rating (EDSS), symptom-limited bicycle spiroergometry (MedGraphics), spectral
analysis of heart rate variability by Task Force Monitor (frequency band LF, HF, TP and
sympatho-vagal balance LF/HF) and the extremity muscle strength evaluation (1-RM). The
patients were also tested for fatigue (questionnaire MFIS) and functional independence (FIM).
The controlled outpatient RHB program was designed for 8 weeks with the frequency of
twice a week. The training unit lasted 60 to 90 minutes and consisted of a warm-up phase
(10 min), an aerobic phase (1st
to 2nd
week 20-40 min; 3rd
to 8th
week 25 min) and a relaxation
phase (10 min). Resistant training was added to the training unit in the 3rd
week of RHB
383
program (3rd
to 8th
week 15-20 min). ECG, blood pressure and RPE were monitored during
the aerobic phase for safety reasons. Three exercises were performed: bench-press, pull-down,
leg extension. The intensity of resistant training was determined by the 1-RM method. The
patients started resistance exercises at 30–60 % 1-RM with weekly increase of 10 %. All three
exercises were repeated 10 times in 3 to 5 sets.
The comparison of entrance and final values showed a significant improvement of
functional capacity, namely in the values of spiroergometry parameters (P<0.05, Wilcoxon
paired test) WSL (94.4 ± 25.0 vs. 102.7 ± 27.9 W, p = 0.042),WSL.kg-1
(1.4 ± 0.3 vs.1.5 ± 0.4
W.kg-1
, p = 0.026), VO2SL (1463.1 ± 359.2 vs. 1578.4 ± 390.3 mlO2, p = 0.015) and also in
the values of muscle strength in Bench-press (22.3 ± 9.3 vs. 28.1 ± 9.7 kg, p = 0.0001), Pulldown
(22.1 ± 11.3 vs. 28.3 ± 11.3 kg, p = 0.0001) and Leg extension (26.5 ± 8.3 vs. 30.9 ±
9.0 kg, p = 0.001). We found out the positive significant impact of rehabilitation program on
self-perception fatigue scale MFIS (28.5 ± 17.6 vs. 26.0 ± 14.9, p = 0.018; MFISp 14.6 ± 8.3
vs.13.3 ± 6.9, p = 0.043). The other studied parameters did not achieve the statistical
relevance. We consider increase in HRV spectral powers a sign of improving adaptability of
autonomic cardiovascular regulation. Clinical status (EDSS) and functional independence
(FIM) were not influenced by exercise training load and length of the rehabilitation program.
We can conclude that the results of our study demonstrate a possibility to influence some
of the physical fitness parameters, muscle strength and self-perceived fatigue after 8 weeks of
rehabilitation program realized twice a week with combination of aerobic and resistant
training form in group of MS patients with mild to moderate clinical disability (EDSS 2.8 ±
0.7.
ACKNOWLEDGMENT
The research was supported by MSM0021622402
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387
BAROREFLEX SENSITIVITY IN PARKINSON‘S DISEASE
Dedicated to Prof. Franz Halberg, Dr. M.D., Dr. h.c. multi
Pospíšil, P., Konečný, L., Katzer, L., Tarasová, M., Fišer, B., Siegelová, J., Dobšák, P.
Dept. of Physiotherapy and Rehabilitation, Clinic of Functional Diagnostics and
Rehabilitation, Medical Faculty, Masaryk University, St. Anna Faculty Hospital in Brno, CZ
INTRODUCTION
Symptoms of autonomic nervous system (ANS) dysfunction are inseparable part of
Parkinson’s disease (PD). These non-motor syptoms are increasingly recognized as a
significant cause of morbidity in later stages of PD (49). Recently ANS dysfunctions are
extensively studied by many authors. Most of them, in relation to the method used, declare
progression of ANS dysfunction proportionally to the progression of other motor symptoms
of PD or to the disease duration (13, 34, 35, 41, 51, 66). Some of them declare autonomic
failure even before the occurence of first motor symptoms (20, 48, 55). However hardly any
double-blind, randomized, controlled studies are available (59).
Clinical studies evaluate ANS function by standard tests which are often based on
examination of cardiovascular functions. It is substantiated by the fact that impairment of
these functions accompanies all the course of the disease and cardiovascular failure is one of
the most common causes of death in PD patients (18).
The most common ANS tests include orthostatic test (15, 35, 43, 51, 63, 70); Valsalva
maneuver (13, 15, 18, 66), isometric work load test (66); 30:15 ratio - the ratio between the
increase of heart rate (HR) at the 15th
heart action and the decrease of HR at the 30th
heart
action after standing up from supine position (8); E:I ratio - the ratio between the longest RR
interval during expiration and the shortest RR interval during inspiration (18); evaluation of
the HR and blood pressure (BP) response to a deep breathing (13, 18, 47, 66); tilt table test (8,
15, 35, 52), test of hyperventilation (11, 15, 47); cold pressor test (15), sympathetic skin
response (6, 8, 15, 19, 77), test of skin wrinkling (16) etc.
The evaluation of the degree of ANS dysfunctions is still in the forefront of research
interest (1, 8, 13, 16, 34, 42, 73). Preceding studies however do not deal with the differences
in factors like the severity of PD disability, type of dopaminergic and other pharmacotherapy
(56, 57, 66, 67). Examination of heart rate variability (HRV) and baroreflex sensitivity (BRS)
lies among non-invasive methods with high sensitivity, validity and reproducibility (29) that
388
can declare ANS dysfunction in early stages of the disease (13, 18, 20, 22, 34, 39, 54, 60).
Baroreflex is one of the most powerful short-term control mechanisms of arterial blood
pressure.
Some authors also recommend the examination of BRS for differential diagnostics of PD
and other extrapyramidal syndromes (6, 12, 15, 18).
The decrease of autonomic control of heart activity is a natural process caused by aging.
However, age is not the only factor to cause this decrease of ANS activity (21, 65).
Correlation of ANS dysfunction with the duration and especially progression of PD was
declared repeatedly in many former studies (13, 66, 18, 45, 74). On contrary, the most recent
studies based on iodine-131-meta-iodobenzylguanidine (MIBG) uptake in myocardial
scintigraphy do not support this hypothesis and find no correlation between age, disease
duration and progression (62). Furthermore, recent study by Haensch et al. (25) with the use
of MIBG give the evidence that cardiac denervation occurs also in cases of absent orthostatic
hypotension and impaired heart rate variability in PD.
The theory of antiparkinsonian pharmacotherapy as the other main factor of ANS
dysfunction cause was also disproved. ANS dysregulation was also declared in studies with
de novo PD patients before the first use of antiparkinsonian pharmacotherapy (5, 21, 25, 31,
39, 47). Nevertheless, the type of treatment should be analysed in respect to the aim of study
and interpreted correctly. There is wide evidence about modification of cardiovascular
responses by levodopa, bromocriptine, selegiline etc. (10, 14, 23, 33, 40, 56, 57, 66, 67, 72).
Another important factor with great impact on ANS function is psychosocial status and
cognitive impairment, especially depression (11, 38), dementia (30), apathy, anhedonia etc.
(53, 78).
AIM
The aim of the present paper was to study BRS and to analyze the relation between
progression of clinical impairment of PD and changes of blood presssure control by
baroreflex mechanism.
389
DESIGN AND METHODS
45 patients with idiopathic PD were recruited to the study from the Czech society
„Společnost Parkinson o. s.“ that organizes for its members regular exercise therapy with the
frequency 1-2 times a week. Their diagnosis of idiopathic Parkinson’s disease was confirmed
at the Ist
Clinic of Neurology, St. Anna Faculty Hospital in Brno according to United
Kingdom Parkinson's Disease Society Brain Bank diagnostic criteria for Parkinson’s disease
(16).
25 out of 45 patients that were recruited to the study did not fullfil the entrance criteria for
serious comorbidities (st.p. acute myocardium infarction, hypertension, diabetes mellitus),
medication (antiparkinsonian pharmacotherapy with proved affect on cardiovascular function,
antidepressives), depression or the presence of any other exclusion criteria listed above.
20 patients (12 men, 8 women) were included into the study. We evaluated Body Math
Index (BMI).
They fullfilled the entrance criteria: confirmed diagnosis of idiopathic PD according to
above mentioned criteria; stable medication without change at least 4 weeks before BRS
examination; no pharmacotherapy with proved effect on ANS or circulatory functions (4, 7,
10, 14, 23, 27, 28, 33, 40, 56, 57, 66, 67, 72); no serious comorbidities with impact on
cardiorespiratory and ANS function; non -smokers; no history of any cardiovascular diseases
or abnormal ECG; no depression according to Montgomery Asberg Depression Rating Scale
(44).
Clinical examination of Unified Parkinson’s disease rating scale (UPDRS) was used for
evaluation of motor status - UPDRS III (range from 0 points – no motor complications to 56
points maximum motor complications), late motor complications - UPDRS IV (range from 0
points – no late motor complications to 23 points maximum late motor complications) and
clinical impairment - UPDRS V (stadium from 0 – no impairment to 5 maximum
impairment). Questionnaire method was used to assess the ANS status - SCOPA AUT. BRS
was examined non-invasively as described in detail below. Basic characteristics of examined
group of patients are given in the table below ( x ± SD; Table 1):
Table 1: Basic characteristics of PD patients
PD
(n = 20)
AGE
(years)
DURATION
OF DISEASE
(years)
BMI
x 70.9 6.0 26.4
SD 6.3 3.0 2.3
390
Group of age and sex matched control subjects (CONTROL) was examined to enable
comparison of the absolute values of BRS. All the patients in this group fulfilled the entrance
criteria specified above for PD patients. Basic characteristics of the CONTROL group is
given in the table below ( x ± SD; Table 2):
Table 2: Basic characteristics of healthy patients – controls (C)
C
(n = 11)
AGE
(years)
BMI
x 69.9 28.0
SD 9.9 3.3
Assessment of BRS was based on non-invasive short term examination (5 minutes) in the
supine position at rest using sequence method of analysis by the system Task Force Monitor,
CNSystems Medizintechnic GmbH. Fallowing criteria were fulfilled: No abnormal physical
activity the day before examination; at least 6 hours of sleep during the night before
examination; good quality of sleep (score 6 or higher on the quality of sleep scale from the
worst sleep „0“ to the best sleep „10“), observance of typical schedule of daily tasks including
medication; only a light breakfast before examination without coffee, tea, alcohol (58) taking
into account the age of patients - at least 2 hours before the examination; the ideal “on“ state
during examination (18); examination on work day between 9 and 11 a.m. to minimize the
effect of circadian variations (37).
The data for the analysis are obtained from beat to beat measurement of blood pressure
and heart rate. BRS is assessed from sequences of examination where there was an increase or
decrease of systolic blood pressure (SBP) at least in 3 successive RR intervals. The treshold
value for including measured beat to beat SBP and RR interval changes in a sequence is set at
1 mmHg for SBP changes and 6 ms for RR interval changes. The slope of regressive curve
based on the relation between SBP and RR interval expresses the baroreflex heart rate, shortly
baroreflex sensitivity ([ms/mmHg]; 9, 36, 37).
Metronome controlled breathing with frequency f = 0.33 Hz (13, 24, 41, 47, 50, 54, 64, 66,
75) was used to increase reproducibility of BRS examination. Graphic example of BRS
sequence analysis examined in supine position at rest with metronome controlled breathing
(f = 0.33 Hz) is given in the graph below (Graph 1).
The measurement took place in a quite room. The subjects were examined after at least 10
minutes of resting in supine position with spontaneous breathing.
391
Graph 1: Graphic example of BRS examination results
The absolute values of baroreflex (ms/mmHg) were considered the indicator of the extent
of cardiovascular ANS regulation impairment in all the cases where the number of sequencies
was sufficient (down events ≥ 7 and up events ≥ 7) (the group of patients PD I). The patients
with insufficient number of sequencies (down events ≤ 7 and up events ≤ 7) were grouped in
the PD II.
The differences in all examined parameters were evaluated statistically. The normality of
data distribution was tested by the Kolmogorov-Smirnov test and the differences between
groups PD I. and PD II. by the T-test for independent samples (STATISTICA, StatSoft, Inc.
2008, v. 8.0).
The study was approved by the Ethical Comittee of Masaryk University. All the patients
were informed about the examination method used and their rights in relation to this study.
RESULTS
The results of the comparison of both groups of PD patients (PD I. vs. PD II.) are given in
the tables below ( x ± SD, statistical significance). In the table 3 there are values of age,
duration of the disease, BMI and frequency of spontaneous breathing ( x ± SD, statistical
significance; Table 3):
392
Table 3: Characteristics of patients PD I., PD II. and healthy subjects C
AGE
(years)
DURATION
OF DISEASE
(years)
BMI
SPONTANEOUS
BREATHING
FREQ. (Hz)
C
(n=11)
69.9±9.9 -- 28.0±3.3 0.28±0.05
PD I.
(n=11)
70.7±7.2 5.1±2.7 26.8±2.7 0.32±0.03
PD II.
(n=9)
71.0±4.9 7.2±3.0 26.0±1.4 0.32±0.04
n. s. n. s. n. s. n. s.
In the table 4 there are values of motor status UPDRS III, late motor complications UPDRS
IV, basic measure of clinical impairment UPDRS V and a questionnaire enquiry for ANS
dysfunctions status SCOPA-AUT ( x ± SD, statistical significance; Table 4):
Table 4: Results of Unified Parkinson’s disease rating scale (UPDRS): motor status - UPDRS
III, late motor complications - UPDRS IV, clinical impairment - UPDRS V, and a
questionnaire enquiry for ANS dysfunctions status SCOPA-AUT
UPDRS III UPDRS IV UPDRS V SCOPA-AUT
PD I.
(n=11)
19.8±10.0 3.7±3.2 1.7±0.5 15.0±8.1
PD II.
(n=9)
25.0±8.8 4.0±2.4 2.3±0.5 21.4±6.6
n. s. n. s. ** p ≤0.01 n. s.
Statistical comparison of values of the UPDRS V reveals significant increase in PD II.
group defined as a group with insufficient number of sequencies in BRS examination.
Comparison of the values of other parameters - UPDRS III, UPDRS IV and SCOPA-AUT
shows only insignificant increase in PD II. group.
In the following table mean values of RR interval, systolic blood pressure (SBP), diastolic
blood pressure (DBP) and BRS are presented ( x ± SD, statistical significance; Table 5):
393
Table 5: Examination results: hemodynamic parameters and BRS
Heart rate
(b.p.m.)
SBP
(mmHg)
DBP
(mmHg)
BRS
ms/mmHg
CONTROL
(n=11)
72.6±13.0 127.7±11.1 78.3±9.5 7.7±3.6
PD I.
(n=11)
69.0±9.5 127.7±10.6 83.2±8.3 4.7±1.4
PD II.
(n=9)
64.8±8.7 118.3±7.5 76.2±8.6 --
n. s. n. s. n. s. ** p ≤0.01
Statistical comparison of chosen parameters: RR interval, SBP, DBP and BRS between
groups PD I., PD II and CONTROL revealed insignificant differences in the values of RR
interval, SBP and DBP. BRS was significantly lower in PD I. group defined as a group with
sufficient number of sequencies in BRS examination in comparison to CONTROL group.
DISCUSSION
Baroreflexes are continuously activated by small deviations of arterial pressure around the
set point. Spontaneous fluctuations of arterial pressure and RR interval can therefore express
the quality of cardiovascular control mechanism (37).
BRS measurement plays an important role in the evaluation of cardiac ANS neuropathies
in cardiovascular diseases as well as in neurodegenerative diseases. The mechanism of
baroreflex is active during sudden changes of blood pressure and as well in the steady-state.
For that reason BRS activity can be evaluated also by analysis of spontaneous fluctuation of
arterial SBP and RR interval under various determined conditions in steady state (18, 36, 37).
Current research studies declare sympathetic noradrenergic dysfunction in PD patients. Its
clinical importance is based on the fact, that this dysfunction is considered to lead to
orthostatic hypotension. The incidence of orthostatic hypotension is among 20-50% of PD
patients and is of major interest for substantial participation on falls and accidental injuries
(20, 42, 63). There was 25% incidence of orthostatic hypotension among our group of PD
patients.
There are other factors besides baroreflex that have an impact on heart rate variability
during breathing. These factors influence correlation between RR interval fluctuations and
oscilations of SBP that is not caused only by baroreflex but also by respiration itself (4).
Nerve links in CNS cause excessive transfer of signal from the centre of respiration to
medullar vagal efferent neurons which results in inhibition of vagal activity during inspiration
394
(47). HR fluctuations are also dependent on local intracardial or sinnodial stretch reflex (32).
Another reflexes with the impact on HRV are Hering-Breuer reflex (stimulated by lung and
thoracic wall expansion during inspiration) and Bainbridge reflex (increase of central venous
volume causes changes in cardial filling). Both stimulate cardiopulmonary structures
mechanically and so increase HR (47). Humoral substances (e.g. angiotensin) play also an
important role in central modification of baroreceptor responses. All these factors can be
influenced by different patterns of breathing, exercise, psychological stress etc. (37). We
consider BRS examination with metronome controlled breathing at the frequency 0.33 Hz a
method that decreases the impact of above mentioned factors and increases reproducibility of
BRS examination.
The results of the present paper support the theory of progression of ANS dysfunction on
the basis of BRS examination from 5 minute recording during metronome controlled
breathing with the frequency 0.33 Hz. Decreased number of UP and DOWN events was found
in cases of advanced PD.
The same results were reported by Oka et al. (46) and Friedrich et al. (18) on the basis of
BRS examination of larger groups of PD patients (spontaneous breathing). Friedrich et al.
conclude the same results with the use of trigonometric spectral analysis of BRS.
BRS score 4.7±0.5 ms/mmHg in case of our group PD II. with initial PD with UPDRS V
1.7±0.5 is significantly lower than that of CONTROL group. The same values of BRS for
healthy controls were published by Tank et al. (94) for spontaneous breathing in supine
position and age category 60-69 years (8±3 ms/mmHg). Szili Török et al. (68) published
similar data on the basis of a study with 23 PD patients of mean age 65±9.3 years, UPDRS V
2.1±0.8, BRS 4.3±3.5 ms/mmHg and control group of age and sex matched healthy
individuals of mean age 70±6.6 years and BRS 8.9±6.9ms/mmHg.
No correlation was found in our study between any of the UPDRS subscales, SCOPA AUT
and symptoms of autonomic dysfunction. Correlation between orthostatic hypotension and
decreased values of BRS was presented by other authors (15, 18, 47). Idiaquez (30) suggest
independent involvement and variability among PD patients. The same opinion is supported
by latest studies by Shibata (62) based on MIBG myocardial scintigraphy.
ANS impairment is often less appreciated than motor impairment but is important source
of disability and handicap for many PD patients (71, 76). Management of non-motor
symptoms should definitely be a part of comprihensive rehabilitation approach to the
treatment of PD.
395
BRS examination plays an important role also in relation to the most common cause of
death in PD. Increased mortality in PD patients is mainly due to respiratory and
cardiovascular complications (2, 3). The ATRAMI study in patients after myocardium
infarction showed that depressed BRS can be considered an independent predictor for sudden
cardiac death (61).
We consider examination of BRS a valid tool for non-invasive assessment of ANS
dysfunction in PD.
CONCLUSION
Advanced stages of PD are accompanied by more pronounced ANS dysfunction that leads
to a decrease of a number of sequencies in BRS examination and to a decrease of absolute
values of BRS (4.7±1.4 ms/mmHg in PD patients vs. 7.7±3.6 ms/mmHg in healthy controls).
The study was supported by MSM0021622402.
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