Faculty of Medicine • Masaryk University • Brno • Czech Republic
Department of Functional Diagnostics and Rehabilitation
PROCEEDINGS
SYMPOSIUM
CHRONOBIOLOGY AND NON-INVASIVE METHODS
IN CARDIOLOGY
Dedicated to the 80th Anniversary of Masaryk University Foundation
Edited by: Halberg F., Kenner T., Fišer B., Siegelová J.
May 26, 1999
The Symposium takes place under the auspices of
Prof. RNDr. Jiří Zlatuška, CSc., Rector of Masaryk University
Prof. MUDr. Jiří Vorlíček, CSc., Dean of Faculty of Medicine Masaryk
University
MUDr. Alena Štětková, CSc., Director of the St Anna Teaching Hospital in
Brno
MUDr. Petr Svačina, Director of Institute for Postgraduate Education
The Symposium is sponsored by:
AVL MEDICAL INSTRUMENTS
ASTRA
BERLIN-CHEMIE
GEROT LANNACHER
LACHEMA
NOVARTIS
SANOFI
ELI LILLY
2
Masaryk University
80th
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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CONTENTS
CHRONOBIOLOGY
Prof.Dr.Franz Halberg – 80 years of age
Halberg F., Cornélissen G., Schwartzkopff O.(Minnesota, USA): What chronobioastrology
could do on earth and in space ………………………………………………………….… 7
Otsuka K., Yamanaka T., Cornélissen G., Halberg F.(Tokyo, Japan, Minnesota, USA):
Dynamics of baroreflex sensitivity ………………………………………………………. 14
Cornélissen G., Zaslavskaya R.M., Siegelová J., Halberg F.(Minnesota, USA,Moskva, Russia,
Brno,CZ): Circadian cardiovascular changes in conventionally acceptable and elevated blood
pressure …………………………………………………………………………………… 18
Samb A., Cissé F., Halberg F., Cornélissen G., Martineaud J.P.(Dakar, Senegal,
Minnesota,USA, Paris, France): The circadian rhythm in central temperature in fasting
subjects in hot climate (Senegal) ………………………………………………………….. 22
Illnerová H., Sumová A., Trávníčková Z., Jáč M.(Prague, CZ): The biological clock as a
calendar ………………………………………….……………………………..……….. … 29
NON-INVASIVE MEASUREMENTS IN MAN
Fedor-Freybergh G. P.(Stockholm, Sweden): Prenatal and perinatal psychology and medicine:
New interdisciplinary science in the changing world ….………………………………… 31
Siegelová J., Fišer B., Dušek J., Placheta Z., Svačinová H., Jančík J., Savin E., Martineaud
J.P.(Brno, CZ, Paris, France): Spectral analysis of blood pressure and cardiac interval
fluctuations in hypertensives and normotensives ………………………………………… 44
Fišer B., Siegelová J., Dušek J., Dobšák P., Placheta Z., Savin E., Martineaud J.P.(Brno, CZ,
Paris, France): Blood pressure component of baroreflex in patients with essential
hypertension .………………………………………………………………………………. 48
Eicher J.C., Maillefert J.F., Bulté C., Walker P., Moreau D., Casillas J.M., Brunotte F., Wolf
J.E.(Dijon, France): Effects of rehabilitation in moderate congestive heart failure using
low-frequency electrical stimulation of inferior limb muscles …………….…………..…. 52
EXPERIMENTAL STUDIES
Kenner T., Schneditz D., Krisper P., Timischl S. (Graz, Austria): A simple linear model of
the cardiovascular system and its application …………………………………………….. 56
Laubriet A., Assem M., Teyssier J.R., Rochette L.(Dijon, France): Expression of cell-death
genes during the development of right ventricular hypertrophy in monocrotaline-treated rats
……………………………………………………………………………………………… 59
Courderot-Masuyer C., Dobšák P., Laubriet A., Teyssier J.R., Rochette L. (Dijon, France,
Brno, CZ): Aminoguanidine and alloxane-induced diabetes ……………………………… 61
Dobšák P., Courderot-Masuyer C., Laubriet A., Svačinová H., Jančík J., Siegelová J., Eicher
J.C., Wolf J.E., Rochette L. (Brno, CZ, Dijon, France): New perspectives in cardioprotection:
In-vitro antiischemic effect of capsaicin and calcitonin gene-related peptide ……………. 63
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CHRONOBIOLOGY
5
Prof. Dr. Franz Halberg
80 years of age
As we all are aware, Prof. Halberg has dedicated almost 50 years of his life to
chronobiological research. His 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 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. At the beginning of
the next century Prof. Halberg is full of energy directed to discovering new
laws of chronobiology. Ad multos annos!
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WHAT CHRONOBIOASTROBIOLOGY COULD DO ON EARTH AND
IN SPACE
Halberg F., Cornélissen G., Schwartzkopff O.
Chronobiology Laboratories, University of Minnesota, Minneapolis, Minnesota,
USA
Chronobiological studies enable diagnosis and testing of treatments for disease
risk syndromes, such as circadian hyper-amplitude-tension (CHAT), that
precedes or complicates the occurrence of high blood pressure or other overt
vascular disease. As an indicator of the risk of stroke, CHAT, that is circadian
blood pressure overswinging, exceeds other factors in terms of its association
with subsequent catastrophic disease. Herein, we also invite participation in a
project on "The BIOsphere and the COSmos"(BIOCOS). BIOCOS aims at
creating a system of physical and physiological monitoring and archival
organization that serves immediately for disease risk syndrome detection, while
it also provides new insights into functional integration and adaptation in health
and disease.
The world of Johannes Kepler, a Praguian from 1600, when he became the
assistant in Tycho Brahe's observatory, was extended repeatedly by physicists,
first by those in radio- and rocket astronomy and then by those in X-ray and
gamma-ray astronomy. The new astronomies revealed previously unimaginable
ways to the stars (Friedman, 1997). In the footsteps of the physician William
Gilberd, who published a classical treatise on magnetism (Gilberd, 1900) in the
same year Kepler joined Brahe, biomedicine may again serve physics and
inquire, in previously equally unimaginable ways, through ontogeny and
phylogeny, not only about where we are and perhaps about what we are, but also
about where we were in the distant past (Halberg et al., 1991). Thereby, we
may also learn about the chronomes of past environments. We ourselves are also
ever-changing structures in time (chronomes). We are learning more and more
about the chronome's three major elements, multifrequency rhythms, chaotically
appearing changes and trends in the characteristics of both rhythms and chaos
(Otsuka et al., 1997 and Otsuka et al., 1997.
An International Womb-to-Tomb Chronome Initiative (IWTCI), coordinated by
one of us (Cornélissen & Halberg,1994 and Halberg et al., 1995 and Halberg,
1997), is ongoing worldwide, albeit on a back burner.
As a first goal, the tools now offered for the diabetic should be equally
developed into a system recommended by the health care profession for a
chronodiagnosis and chronotherapy sui generis of vascular disease risk
syndromes. These new clinical entities involve blood pressure, heart rate and
their variabilities.The long term data recording requirement (for the span of a
week or longer), two companies not only reach but surpass it by producing at
this time at least an ambulatorily functioning monitor, providing a record for 14
days. One of the devices is simple to use, involving no more than the pressing of
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a button to start it, and the daily charging of the instrument costs only electricity
and can perhaps be done during the time spent in the bathroom each morning. In
the case of a diagnose delevation of the 24-hour rhythm-adjusted blood pressure
mean (MESOR), i.e., MESOR-hypertension, the continued monitoring to assess
the effects of treatment can be checked via a control chart (Halberg et al., 1995
and Siegelová et al., 1996). The use of this approach has been documented from
Brno in cooperation with the local pharmaceutical company Lachema (Siegelová
et al., 1996). Thus, Brno continues to provide leads in the change from an
expensive since ineffective, single sample medicine based on snapshots of a
roller coaster to the longitudinal chronobiologic life-strand analysis in the 1990s,
just as it led in the past with Gregor Johann Mendel in genetics and Kurt Goedel
in mathematics.
Eventually, the mathematical task to assess the genetically anchored chronomes
may be carried out fully automatically and linked to monitors of physical
variables. The disease risk assessing tools may well follow the precedent of
wristwatches and computers by becoming household items. Here lies the
industrial challenge.The development and provision in Brno by Jan Penaz of
instrumentation for the stationary beat-to-beat monitoring of human blood
pressure has been followed by implanted devices that have performed the same
beat-to-beat monitoring on ambulatory humans for a span of 15 months on the
right side of the circulation (Bennett, 1997), still awaiting its counterpart on the
left side, another challenge to industry. With such tools available, drug effects
come to the fore, such as a variance transposition in which a prominent
circadian chronome component is replaced by one of about 3.5 days. The latter
cannot be assessed, of course, by the 6-hour (Sheps & Canzanello, 1994) and the
24-hour monitoring schedules whose limitations in record length must be
overcome.
Medtronic's REVEAL, an implanted electrocardiograph, serves to determine
retrospectively the precedents of a syncope. At any time, it keeps the last 44
minutes of an electrocardiogram in its memory. This approach should be
extended by appropriate software for windowing to derive rhythm and chaos
parameters, thereby compacting the data and recycling them (Halberg et al.,
1994 and Halberg et al., 1997) for the interpretation of alterations in windows
prepared concomitantly in different spectral regions, including windows at lower
and lower frequencies, including the resolution of about 11-year cycles, once the
record length permits this endeavor. Thus, one could diagnose symptomatically
silent disease risk syndromes and, when need be, close the loop to treatment by
an automatic drug or electrical treatment device. Furthermore, the same device
may communicate with physical monitoring; it may be prompted by the latter to
save original beat-to-beat data, for instance, in the case of magnetic storms in
the interplanetary space and beyond, and, if indicated, to initiate
countermeasures (see below). There are several reasons for this seemingly farfetched
suggestion. First, the same approximate half-week is seen during 267
days in human isolation, in both the human heart rate and in the planetary
8
geomagnetic disturbance index, Kp, providing a suggestive physiological
association (Halberg et al., 1996). The physiological finding, e.g., of a
biological free-running half-week thus leads to the finding of a rhythm with the
same frequency in Kp. A near-weekly component had been found in our
physiology in health; it differed with statistical significance from the societal
week (Halberg et al., 1965 and Halberg et al., 1996). This finding had
eventually prompted us to seek and detect a component with a similar frequency
in Kp (Halberg et al., 1991). Within the ensuing years, the presence of this
component was confirmed by physicists (Roederer, 1995 and Vladimirskii et al.,
1995). There is also a stunning precedent for an association between physical
events on earth and in interplanetary space on the one hand, and human
pathology on the other hand detected first by cross- spectral coherence (Halberg
et al., 1992) and confirmed thereafter by the method of superposed epochs
(Halberg et al., 1991 and Cornélissen et al., 1994) and otherwise (Roederer,
1995). The association demonstrated by cross-spectral coherence between MI
and Kp, and between MI and Bz occurs at the same frequency to nearly the
second decimal, at one cycle in 3.16 and 3.17 days, respectively. A concomitant
interactive physical and physiological monitoring would provide an opportunity
for instituting countermeasures against undesirable triggering effects of storms
in space before a catastrophic event such as a MI occurs. The detection of
disease risk syndromes by a monitoring system would by far exceed the value of
the black box in the cockpit of an airplane, which is consulted after the fact of a
disaster.
Some changes associated with disease risk are seen first in the about-yearly
component of the chronomes of endocrine variables (Halberg et al., 1981). The
biological half-year and the biological half-week (on occasion both merely a
description of the yearly or weekly waveform, respectively) can also have an
importance in their own right. While all other pathologies studied had a yearly
component much more prominent than the half-year (Halberg et al., 1991), over
50,000 cases of epileptic emergencies show a principal half-yearly component
(Halberg et al., 1991) suggesting the search for an equivalent physical "rhythm".
In our Kp spectra, the half-year can be prominent. Armin Grafe has described an
about-half-yearly pattern in solar flares (Grafe, 1958). Before postulating any
physical effect upon the central nervous system, more than the finding of similar
frequencies is needed (Halberg et al., 1991 and Halberg et al., 1996).
One may further speculate whether, at the latitude of Florence (43.47 degrees
N), circulating human melatonin is apparently geomagnetically synchronized by
night, while the about-yearly component predominates at that latitude in
melatonin values of blood obtained during the daily light span (Tarquini et al.,
1997). When circulating human melatonin is studied at 65 degrees N in Oulu,
Finland, where the sun's energy is received at a low angle and may take second
seat to the there perhaps most prominent geomagnetics, the half-year
predominates in the melatonin of blood samples drawn at noon (Tarquini et al.,
1997 and Martikainen et al., 1985).
9
Magnetic storms reduce the standard deviation of heart rate of cosmonauts in
space (Baevsky et al., 1997) and their association with MIs on earth (Halberg et
al., 1991) is now confirmed and extended, at least at the latitudes of 55.45
degrees N (Moscow) and 59.55 degrees N (St. Petersburg) (Villoresi et al., 1994
and Villoresi et al., 1994 and Roederer, 1995).
The implementation of streamlined physical and physiological monitoring in
BIOCOS serves for shifting emphasis in health care from a dichotomy of
assumed wellness (with attention to risk factors) vs. overt illness, to a
trichotomy of chronobiologically validated wellness, disease risk syndromes,
and overt illness, with a share of the resources switched from the care of overt
disease to developing a system for disease risk syndrome detection and
treatment, and thus for arriving at a health care that achieves more for less.
There is the need for reference data bases for disease risk syndrome detection
and for ascertaining the efficacy of treatment when needed (Cornelissen &
Halberg, 1994 and Halberg et al., 1995 and Siegelová et al., 1996, 1997 and
Cornelissen & Halberg, 1996 and Otsuka et al., 1996 and Otsuka et al., 1997).
Diagnosing overswinging, CHAT, which is particularly risky for stroke when
the 24-hour average of blood pressure is below 130/80 mmHg
(systolic/diastolic), is a must simply because the alternative is a no-win
situation. There is the opportunity to develop a system for collecting and
interpreting serial blood pressure measurements to facilitate for every woman
and every man to do what leaders in medicine have done by setting an example,
just as did Johannes Evangelista von Purkinje, who advocated self-study and
whose name for a while adorned Brno's university. The disease risk syndromes
start but do not stop at blood pressure overswinging. Chronome alterations of
heart rate variability involving the recognition of rhythm alterations in endpoints
of chaos (Otsuka et al., 1997 and Otsuka et al., 1997) also represent a challenge
in the country of Purkinje and in the city of Jan Penaz. The proper study of
human beings is the human being. Each of us can self-measure, preferably with
continuously improved systems of integrated physiological and physical
monitoring, a great opportunity for device and pharmaceutical manufacturers to
provide increasingly denser and longer assessments of the chronomes of interest
in health care, until reliance on the medical history can be integrated into a
continuous self-measurement and self-interpretation of the data in a population
characterized by chronobiologic literacy.
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implanted hemodynamic analyzer. Abstracts. MEFA Congress, Brno, Czech Republic, November
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8. Cornélissen G., Halberg F.: Introduction to Chronobiology. Medtronic Chronobiology Seminar #7,
April 1994, 52 pp. Accessible on the Internet site of the Chronobiology Laboratories,
http://revilla.mac.cie.uva.es/chrono
9. Halberg F., Cornélissen G., Siegelová J., Fišer B.: Rezoluce S.I.R.M.C.E. AmireporT 2: 105-106,
1995. [In Czech.] Also Halberg F., Cornélissen G., International Womb-to-Tomb Chronome
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March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12
pp. text, 18 figures. Accessible on the Internet site of the Chronobiology Laboratories,
http://revilla.mac.cie.uva.es/chrono
10. Halberg F.: Chronobiology and adaptations to environments near and far: the Cornélissen-series,
Chizhevsky's legacy in 1997. Proc. XXXIII Int. Cong. International Union of Physiological
Sciences, St. Petersburg, Russia, June 30-July 5, 1997, L041.02.
11. Siegelová J., Cornélissen G., Halberg F., Fišer B., Dušek J., Al-Kubati M., Machát R., Kumagai
Y., Watanabe Y., Otsuka K.: Self-starting cumulative sums for the individualized assessment of
antihypertensive response and optimization by timing. 2nd
Int. Symp. of Chronobiology and
Chronomedicine, Shenyang, China, Sept. 28-Oct. 2, 1996, p. 48.
12. Sheps S.G., Canzanello V.J.: Current role of automated ambulatory blood pressure and selfmeasured
blood pressure determinations in clinical practice. Mayo Clin. Proc. 69: 1000-1005,
1994.
13. Halberg F., Tamura K., Cornélissen G.: Chronobioengineering toward a cost-effective quality
health care. Frontiers Med. Biol. Eng. 6: 83-102, 1994.
14. Halberg F., Cornélissen G., Otsuka K., Watanabe Y., Wood M.A.,Lambert C.R., Zaslavskaya R.,
Gubin D., Petukhova E.Y., Delmore P., Bakken E.: Rewards in practice from recycling heart rate,
ectopy, ischemia, and blood pressure information. J. Medical Engineering & Technology 21: 174-
184, 1997.
15. Halberg F., Cornélissen G., Montalbini M., Lanzoni C., Galvagno A., Pimenov K., Breus T.,
Kawabata Y., Shinoda M., Johnson D.: The biologic half-week (circasemiseptan) and Kp:
evolutionary and practical implications of magnetic field disturbances. Keynote #113, 2nd World
Congress of Cellular and Molecular Biology, Ottawa, Canada, September 3-7, 1996. Cell. Molec.
Biol. 42 (Suppl.): S81-S82, 1996.
16. Roederer J.G.: Are magnetic storms hazardous to your health? Eos, Transactions, American
Geophysical Union 76: 441, 444-445, 1995.
17. Vladimirskii B.M., Narmanskii V.Ya., Temuriantz N.A.: Global rhythmics of the solar system in
the terrestrial habitat. Biophysics 40: 731-736, 1995.
18. Halberg F., Cornélissen G., Hillman D.C., Bingham C., Halberg E., Guillaume F., Barnwell F.,
Wu J.Y., Wang Z.R., Halberg F.E., Holte J., Schmitt O.H., Kellogg P.J., Luyten W., Breus T.K.,
Komarov F.I., Mikulecky M., Garcia L., Lodeiro C., Iglesias T., Quadens O., Muller C., Kaada B.,
Miles L., Hayes D.K.: Chronobiology in a moon-based chemical analysis and physiologic
monitoring laboratory. In: A Lunar-Based Chemical Laboratory (LBCAL), Ponnamperuma C.,
Gehrke C.E. (eds.), A. Deepak Publishing, Hampton, VA, 1992, pp. 161-203.
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19. Cornélissen G., Wendt H.W., Guillaume F., Bingham C., Halberg F., Breus T.K., Rapoport S.,
Komarov F.: Disturbances of the interplanetary magnetic field and human pathology.
Chronobiologia 21: 151-154, 1994.
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A., Barbosa J., Goetz F., Buckley J., Mandel J., Schuman L., Haus E., Lakatua D., Sackett L.,
Berg H., Wendt H.W., Kawasaki T., Ueno M., Uezono K., Matsuoka M., Omae T., Tarquini B.,
Cagnoni M., Garcia Sainz M., Perez Vega E., Wilson D., Griffiths K., Donati L., Tatti P., Vasta
M., Locatelli I., Camagna A., Lauro R., Tritsch G., Wetterberg L.: International geographic
studies of oncological interest on chronobiological variables. In: Neoplasms: Comparative
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Baltimore 1981, pp. 553-596.
21. Grafe A.: Einige charakteristische Besonderheiten des geomagnetischen Sonneneruptionseffektes.
Geofisica Pura e Applicata 40: 172-179, 1958.
22. Tarquini B., Cornélissen G., Perfetto F., Tarquini R., Halberg F.: Chronome assessment of
circulating melatonin in humans. In vivo 11: 473-484, 1997.
23. 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 endocrinologica (Copenh) 109:
446-450, 1985.
24. Baevsky R.M., Petrov V.M., Cornélissen G., Halberg F., Orth- Gomér K., Ĺkerstedt T., Otsuka K.,
Breus T., Siegelová J., Dušek J., Fišer B.: Meta-analyzed heart rate variability, exposure to
geomagnetic storms, and the risk of ischemic heart disease. Scripta medica 70: 199-204, 1997.
25. Villoresi G., Breus T.K., Iucci N., Dorman L.I., Rapoport S.I.: The influence of geophysical and
social effects on the incidences of clinically important pathologies (Moscow 1979-1981). Physica
Medica 10: 79-91, 1994.
26. Villoresi G., Kopytenko Y.A., Ptitsyna N.G., Tyasto M.I., Kopytenko E.A., Iucci N., Voronov
P.M.: The influence of geomagnetic storms and man-made magnetic field disturbances on the
incidence of myocardial infarction in St. Petersburg (Russia). Physica Medica 10: 107-117, 1994.
27. The Sixth Report of the Joint National Committee on Detection, Evaluation, and Treatment of
High Blood Pressure (JNC VI). Arch. Intern. Med. 157: 2413-2439, 1997.
28. Cornélissen G., Halberg F.: Impeachment of casual blood pressure measurements and the fixed
limits for their interpretation and chronobiologic recommendations. Time-dependent Structure and
Control of Arterial Blood Pressure. Portaluppi F., Smolensky M.H. (eds.). Ann. N.Y. Acad. Sci.
783: 24-46, 1996.
29. Otsuka K., Cornélissen G., Halberg F.: Predictive value of blood pressure dipping and swinging
with regard to vascular disease risk. Clinical Drug Investigation 11: 20-31, 1996.
30. Otsuka K., Cornélissen G., Halberg F., Oehlert G.: Excessive circadian amplitude of blood
pressure increases risk of ischemic stroke and nephropathy. J. Medical Engineering & Technology
21: 23-30, 1997.
31. An Essay on Man: Epistle II. Alexander Pope: Twickenham Edition, Mack M. (ed.) London:
Methuen/New Haven: Yale University Press, 1950, rep. 1964, p. 53.
32. Siegelová J, Fišer B, Al-Kubati M, Dobšák P, Dušek J.: Noninvasive determination of baroreflex
sensitivity in hypertensives treated five years with enalapril. Scripta medica 70: 239-244,1997.
Support: U.S. Public Health Service (GM-13981), National Heart,
Lung, and Blood Institute, National Institutes of Health (HL-40650),
University of Minnesota Supercomputer Institute, Dr. h.c. Dr. h.c.
Earl Bakken Fund and Dr. Betty Sullivan Fund.
Dedicated to the memory of Otto H. Schmitt (+ 1998), professor of biophysics and electrical
engineering at the University of Minnesota, ”Mr. Biophysics” worldwide; inventor of the Schmitttrigger
(a key switching device in much of today as electrical equipment); advocate of life strand
analyses, an aim of chronomedicine for the quantification of health and the earliest possible detection
of disease risk syndromes; a genius with a special personality who was greatly contributory to
chronobiologic endeavors, realizing that the ”circa” in ”circa-rhythms” related variability as well as to
12
free-running, who accordingly coined the terms ”episodic time” and ”rubbery time”. All who listened,
learned from him. By the many of us whom he taught and stimulated, in Minnesota and on many
travels around the world, Otto will be missed for as long as we are around. His legacies, ranging
broadly from vector electrocardiography to radar, will withstand.
13
DYNAMICS OF BAROREFLEX SENSITIVITY
Otsuka K.1
, Yamanaka T.1
, Cornélissen G.2
, Halberg F.2
.
1
Division of Neurocardiology, Department of Medicine I, Tokyo Women's
Medical College, Daini Hospital, Tokyo, Japan
2
Chronobiology Laboratories, University of Minnesota, Minneapolis, MN, USA
ABSTRACT
Baroreflex sensitivity can be assessed non-invasively by means of spectral
analysis without the intravenous administration of pharmacological agents such
as phenylephrine. The availability of relatively cost-effective instrumentation for
the beat-to-beat non-invasive monitoring of blood pressure and R-R intervals
enables the large-scale clinical assessment of short-term changes in baroreflex
sensitivity in response to different stimuli (such as a change in blood pressure
brought about by the administration of phenylephrine), opening the door to new
cardiological applications.
INTRODUCTION
Baroreflex sensitivity (BRS), an index of autonomic nervous function,
reportedly predicts survival in cardiovascular disease (Billman et al., 1982).
Clinical applications are broadened when BRS is assessed by spectral analysis
of blood pressure (BP) values and R-R intervals (Robbe et al., 1987) (BRS-1),
allowing continuous observation. BRS-1 is here validated by comparison with
the traditional infusion of phenylephrine (BRS-2), and used to study BRS
dynamics (BRS-3) associated with an increase in BP.
SUBJECTS AND METHODS
A Holter electrocardiographic record (Fukuda Denshi, SCM280) was started at
14:00 on 10 healthy 19-47-year-old volunteers and a catheter placed while the
subject was resting supine. Non-invasively (JENTOW-7000; Colin Medical,
Komaki, Japan;) (Sato et al., 1993), the arterial BP waveform was recorded
continuously for at least 80 sec after phenylephrine was injected intravenously.
Using the JENTOW-7000 software, a target systolic (S) BP elevation of 40
mmHg served to calculate BRS-2. BP and R-R variability was analyzed by
MEM spectral analysis using MemCalc software (Suwa-Trust, Tokyo) (Saito et
al., 1994). BRS-1 was calculated as the square root of the ratio between the
~10.5-sec (0.04-0.15 Hz; "LF") power of R-R and that of BP (Robbe et al.,
1987, Siegelová et al., 1997). Dynamic changes in BRS were assessed
14
longitudinally (BRS-3, in msec/mmHg; 2) over 30-sec spans progressively
displaced by 5 sec throughout the time series of SBP, diastolic (D) BP and R-R
intervals obtained during the about-80-sec pressor response to phenylephrine,
yielding 10 sequential records.
RESULTS
BRS-2, conventionally determined by the slope of the line regressing R-R
intervals to SBP during an intravenous bolus injection of phenylephrine, is
illustrated in Figure 1 (upper left). This estimate of BRS, BRS-2, correlates
positively with the spectral estimate of BRS, denoted as BRS-1(r=0.75; P<0.02).
BRS-1 is thus validated against an old method (BRS-2), the latter limited by
drawbacks discussed below. Figure 1 (bottom) shows the time course of SBP, RR
and BRS-3, estimated at 5-sec intervals during the about 80-sec intravenous
phenylephrine injection (left). The correlation between R-R or BRS-3 (y-axes)
and SBP (x-axis) is displayed in Figure 1 (bottom; right). While BRS-3
fluctuates around 13 msec/mmHg for SBP < 135 mmHg, it abruptly increases
for SBP >138 mm Hg, suggesting the presence of a threshold (around 138 mm
Hg in this particular instance). Similar results are obtained for DBP and mean
arterial BP of this subject and for dynamic changes in BRS-3 of the other 9
volunteers, inter- and intra-individual differences in the threshold BP value
notwithstanding.
DISCUSSION
Higher BRS values during sleep and progressively lower BRS values with
increasing mental arousal (reading and arithmetic tasks) have been reported, as
well as age- and circadian-stage-dependent effects of BRS (Fišer et al., 1993,
Siegelová et al., 1997, Kawano et al.,1995, DiRienzo et al.,1997). Such studies
had to rely on the pharmacologic approach involving intravenous phenylephrine
administration until 1987 when Robbe et al (1987) introduced a new spectral
method to assess BRS non-invasively from the changes in BP and R-R intervals.
The validation in 1993 of the accuracy of the JENTOW-7000 (Sato et al., 1993)
facilitated the assessment of BRS in the clinic. The new computerized method
provides a dynamic description of fast BRS modulations that could not be
obtained by using traditional laboratory tests. The latter usually require at least
5-10 min for a single measurement (involving the application of the external
stimulus, the observation of the hemodynamic effect, and the recovery span).
Moreover, the assessment can only be repeated a few times in view of side
effects associated with repeated artificial stimulation (Kawano et al., 1995). The
non-invasive continuous monitoring of BP and R-R intervals by arterial
tonometry thus allows BRS evaluation over very short spans, rendering possible
the detailed study of changes in response to different stimuli, opening the door
to new clinical applications.
15
Support
U.S. Public Health Service (GM-13981) (FH), National Heart, Lung, and Blood Institute, National
Institutes of Health (HL-40650), University of Minnesota Supercomputer Institute, Dr. h.c. Dr. h.c.
Earl Bakken Fund and Dr. Betty Sullivan Fund (GC, FH).
REFERENCES
1. Billman G.E., Schwartz P.J., Stone H.L.: Baroreceptor reflex control of heart rate: A predictor of
sudden cardiac death. Circulation 66: 874-880, 1982.
2. Robbe H.W.J., Mulder L.J.M., Ruddel H., Langewitz W.A., Veldman J.B.P., Mulder D.:
Assessment of baroreflex sensitivity by means of spectral analysis. Hypertension 10: 538-543,
1987.
3. Sato T., Nishinaga M., Kawamoto A., Ozawa T., Takatsuji H.: Accuracy of a continuous blood
pressure monitor based on arterial tonometry. Hypertension 21: 866-874, 1993.
4. Saito K., Koyama A., Yoneyama K., Sawada Y., Ohtomo N.: A recent advance in time series
analysis by maximum entropy method. Sapporo, Hokkaido University Press, 397, 1994.
5. Fišer B., Siegelová J., Dušek J., Cornélissen G., Halberg F.: Determination of heart rate baroreflex
sensitivity in man by spectral analysis during 24-hour period. Scripta medica 66: 11-14, 1993.
6. Siegelová J., Fišer B., Al-Kubati M., Dobšák P., Dušek J.: Noninvasive determination of baroreflex
sensitivity in hypertensives treated five years with enalapril. Scripta medica 70: 239-244, 1997.
7. Kawano Y., Tochikubo O., Miyajima E., Ishii M.: Circadian variation in baroreflex sensitivity
evaluated by beat-to-beat hemodynamic change in patients with essential hypertension. J. Cardiol.
26:159-165, 1995.
8. DiRienzo M., Parati G., Mancia G., Pedotti A., Castiglioni P.: Investigating baroreflex control of
circulation using signal processing techniques. IEEE Engineering in Medicine and Biology 16: 86-
95, 1997.
16
Legend to Figure:
Spectral vs traditional assessment of the baroreflex sensitivity (BRS).
Top: BRS conventionally determined by the slope of the line regressing R-R intervals to SBP
during an intravenous bolus injection of phenylephrine (left). This estimate of BRS correlates
positively with the spectral estimate of BRS. While all data are displayed (left), the regression
lines are computed by considering data collected only during the ascending (A) or descending
(B) time courses of SBP and R-R intervals (right).
Bottom: Time course of SBP, R-R interval and BRS, estimated at 5-sec intervals during the
about-80-sec intravenous phenylephrine injection (left). A plot of BRS (y-axis) vs SBP (xaxis)
(right) indicates that BRS abruptly increases above a threshold BP value (for SBP >138
mm Hg in this instance), determined objectively by the use of a self-starting cumulative sum
control chart.
17
CIRCADIAN CARDIOVASCULAR CHANGES IN CONVENTIONALLY
ACCEPTABLE AND ELEVATED BLOOD PRESSURE
Cornélissen G. 1
, Zaslavskaya R. M. 2
, Siegelová J. 3
, Halberg F. 1
1
University of Minnesota, Minneapolis, Minnesota, USA, 2
Department of
Cardiology, Hospital No. 60, Moscow, Russia, 3
Masaryk University, Brno,
Czech Republic
INTRODUCTION
Using a 3-timepoint approach, Panza et al. (1991) reported a circadian rhythm in
vascular tone and its relation to α-sympathetic vasoconstrictor activity in
clinically healthy volunteers. Herein (and elsewhere; Otsuka et al., 1997), these
authors’ results in health are corroborated with an 8-timepoint design. The scope
of the present investigation is extended to include results on patients with an
elevated blood pressure.
SUBJECTS AND METHODS
Vascular resistance (VR), blood flow, total (TPR) and specific (SPR) peripheral
resistance, stroke (SV) and minute (MV) volume were assessed together with
blood pressure (BP) and heart rate (HR) every 3 hours for 24 hours in 55
clinically healthy subjects after a 3-day standardization in the hospital.
Similarly, three groups of 40 patients with WHO Stage II “hypertension” were
examined at 4-hour intervals. Methods include, with venous occlusion
plethysmography, the tetrapolar variant of rheography for the determination of
stroke volume (Kubicek et al., 1974). Each data series was analyzed by single
cosinor and results were summarized by population-mean cosinor (Cornélissen
et al., 1998).
RESULTS
As apparent from Table 1, on a group basis, a circadian rhythm is demonstrated
in health (P<0.05) for almost all variables. Acrophases occurred in the afternoon
between 14:30 and 16:00, except for VR and TPR, which “peaked” at night
around 03:00. The circadian variation in VR and blood flow was not statistically
significant in the patients, except for the VR of patients with a relatively low
cardiac index (averaging 3.1 l/min/m
2
). In these patients, VR was greatly
reduced by comparison with their value in health (18.7 vs. 29.7 mm
Hg/ml/min/100 ml forearm volume), and “peaked” around 10:00. A circadian
rhythm was found for all 3 groups of MESOR-hypertensive patients in the case
of TPR with acrophases at night between 23:50 and 01:40, and for HR,
“peaking” in the afternoon as it did in clinical health. Blood flow was increase
18
in the patients, averaging 7.4, 6.9 and 5.9 vs. 3.2 ml/100 cm
3
/min in health.
Predictably, patients also had an elevated MV averaging 8.7, 7.2 and 5.5 vs. 5.1
l/min in health.
DISCUSSION AND CONCLUSION
Rhythmic changes characterize many aspects of the circulation as part of a
broader time structure, the chronome, which includes with multifrequency
rhythms also chaotically appearing changes and trends in characteristics of both
rhythms and chaos (Macey, 1994). Treatment effects are also drastically timedependent,
as demonstrated for different antihypertensive drugs (Gullner et al.,
1979, Little et al., 1990, Halberg et al., 1995,Cornélissen et al., 1994) as well as
for the anti-hypertensive (Siegelová et al., 1995) and anti-clotting (Cornélissen
et al., 1991) properties of daily low doses of aspirin. Elsewhere (Zaslavskaja,
1993, 1994), the response of blood flow to treatment with nitrosorbide (10 mg
sublingually) or captopril (25 mg orally) in patients with ischemic heart disease
and cardiac failure (stage II WHO) was also shown to depend on the time of
drug administration. These results complement a difference in the extent of
vasodilation (phentolamine-associated decrease in peripheral resistance)
reported by Panza et al. (1991). Such findings should prompt the further scrutiny
of reactive as well as spontaneous responses to treatment as a function of the
stages of all assessable components of the chronomes of pertinent variables.
The scope of the present investigation is extended to include results on patients
with an elevated blood pressure.The circadian variation of vascular resistance
and blood flow is assessed in clinically healthy subjects and in MESORhypertensive
(WHO stage II) patients.
Support:
This study was supported by the U.S. Public Health Service (GM-13981) (FH), University of
Minnesota Supercomputer Institute, Dr. h.c. Dr. h.c. Earl Bakken Fund and Dr. Betty Sullivan Fund,
and Mr. Lynn Peterson, United Business Machines, Fridley, MN (GC, FH).
REFERENCES
1. Panza J.A., Epstein S.E., Quyyumi A.A.: Circadian variation in vascular tone and its relation to
α-sympathetic vasoconstrictor activity. N. Eng. J. Med. 325: 986-990, 1991.
2. Otsuka K., Nishikawa Y., Kubo Y., Cornélissen G., Halberg F.: Chronomes (rhythms, chaos,
and age trends) of human heart rate variability in both genders. Computers in Cardiology 24: 49-
52, 1997.
3. Kubicek W.G., Kottke F.J., Ramos M.U., Patterson R.P., Witsol D.A., LaBree J.W., Remole W.,
Layman T.E., Schoening H., Garamella J.T.: Minnesota impedance cardiograph: theory and
applications. Biomed. Eng. 9: 410-462, 1974.
4. Cornélissen G., Halberg F.: Chronomedicine. In: Encyclopedia of Biostatistics, Armitage P.,
Colton T. (eds.-in-chief), v. 1, John Wiley & Sons Ltd., Chichester, UK, 1998, pp. 642-649.
5. Macey S.L. (ed.).: Encyclopedia of Time. Garland Publishing, New York, 1994, 699 pp.
6. Güllner H.G., Bartter F.C., Halberg F.: Timing antihypertensive medication. The Lancet,
September 8, 1979, p. 527.
19
7. Little J., Sánchez de la Peña S., Cornélissen G., Abramowitz P., Tuna N., Halberg F.:
Longitudinal chronobiologic blood pressure monitoring for assessing the need and timing of
antihypertensive treatment. Progress in Clin. and Biol. Res. 341B: 601-611, 1990.
8. 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.
Website http://revilla.mac.cie.uva.es/chrono
9. Cornélissen G., Zaslavskaya R.M., Kumagai Y., Romanov Y., Halberg F.:
Chronopharmacologic issues in space. J. Clin. Pharmacol. 34: 543-551, 1994.
10. Siegelová J., Cornélissen G., Dušek J., Přikryl P., Fišer B., Daňková 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) 1 (2): 43-49, 1995.
11. Cornélissen G., Halberg F., Přikryl P., Daňková E., Siegelová J., Dušek J., International Wombto-Tomb
Chronome Study Group: Prophylactic aspirin treatment: the merits of timing. JAMA
266: 3128-3129, 1991.
12. Zaslavskaya R.M.: Chronodiagnosis and chronotherapy of cardiovascular diseases. 2nd ed.
Translation into English from Russian. Moscow: Medicina, 1993, 397 pp.
13. Zaslavskaya R.M.: Circadian rhythms of blood clotting system: norm and pathology and therapy
problems. Moscow: Quartet Science Publishers, 1994, 452 pp.
20
Table 1: Circadian cardiovascular changes in health and hypertension
(WHO stage II)†
Variable (unit) MESOR Amplitude Acrophase
------------------------------------ 95% confidence limits -----------------------------------
Clinical
health: 27 men, 28 women, sampled every 3 h for 24 h
VR 29.7 — 3.1 — 03:14 —
Flow (ml/100 cm3/min) 3.2 (2.9, 3.5) 0.4 (0.2, 0.6) 15:06 (13:06, 17:00)
TPR (din·sec·cm-5) 1647.5 (1516.0, 1779.0) 273.0 (224.8, 321.2) 02:36 (01:48, 03:24)
SBP (mm Hg) 116.7 (114.2, 119.2) 3.0 (2.0, 4.0) 15:54 (14:30, 17:12)
MAP (mm Hg) 94.5 (92.6, 96.4) 2.1 (1.2, 3.0) 14:24 (12:18, 16:36)
HR (beats/min) 68.1 (65.6, 70.6) 4.3 (3.1, 5.5) 15:24 (14:24, 16:18)
SV (ml) 74.8 (68.8, 80.8) 8.6 (7.0, 10.2) 14.42 (13:36, 15:36)
MV (l/min) 5.1 (4.7, 5.5) 0.9 (0.7, 1.1) 15:00 (14:12, 15:42)
40 “hyperkinetic” MESOR-hypertensives sampled every 4 h for 24 h
VR 25.8 (19.1, 32.5) — —
Flow 7.4 (5.1, 9.7) — —
TPR 1317.6 (1038.0, 1597.3) 151.3 (35.6, 266.9) 23:54 (20.42, 02:06)
SPR (din·sec·cm-5/m2) 750.6 (577.8, 923.5) 88.4 (23.0, 153.8) 23:54 (20.42, 02:06)
SBP 152.2 (138.4, 166.0) 4.4 (0.1, 8.7) 18:48 (14:24, 00:30)
HR 67.4 (62.8, 72.0) 2.1 (0.8, 3.3) 13:42 (10:54, 18:06)
MV 8.7 (7.1, 10.3) 0.7 (0.2, 1.2) 12:42 (10.48, 14:54)
CI (l/min/m2) 4.9 (4.0, 5.8) 0.4 (0.8, 0.7) 12:42 (10.48, 14:54)
40 “eukinetic” MESOR-hypertensives sampled every 4 h for 24 h
VR 25.2 (20.6, 29.9) — —
Flow 6.9 (5.6, 8.2) — —
TPR 1732.3 (1373.2, 2091.5) 151.0 (10.7, 291.2) 00:05 (19:00, 05:00)
SPR 978.7 (775.8, 1181.6) 85.3 (6.0, 164.5) 00:05 (19:00, 05:00)
SBP 171.0 (168.7, 183.4) — —
HR 69.6 (64.1, 75.1) 3.5 (1.4, 5.7) 11.48 (09:30, 15:06)
MV 7.2 (5.8, 8.6) 0.6 (0.1, 1.0) 12:07 (10:01, 16:08)
CI 4.0 (3.2, 4.8) 0.3 (0.1, 0.5) 12:07 (10:01, 16:08)
40 “hypokinetic” MESOR-hypertensives sampled every 4 h for 24 h
VR 18.7 (13.2, 24.3) 4.8 (0.5, 9.2) 10:00 (06:48, 13:00)
Flow 5.9 (3.2, 8.4) — —
TPR 2042.6 (1787.8, 2297.3) 135.1 (29.8, 240.4) 01:35 (22:03, 06:09)
SPR 1157.5 (1006.0, 1309.1) 76.9 (16.2, 137.5) 01:24 (22:00, 06:06)
SBP 170.0 (154.7, 185.2) — —
HR 65.4 (61.8, 69.1) 1.7 (0.02, 3.5) 14:18 (08:03, 19:18)
MV 5.5 (4.9, 6.0) — —
CI 3.1 (2.7, 3.4) — —
†Summary by population-mean cosinor analysis of results obtained on each individual data
series from the least-squares fit of a 24-hour cosine curve: MESOR=midline-estimating
statistic of rhythm, a rhythm-adjusted mean; amplitude=one-half of the extent of change
within a day as predicted from the fit of a single 24-hour cosine curve to the data;
acrophase=time of overall high values in relation to local midnight.
VR=vascular resistance (in mm Hg/ml/min/100 ml forearm volume); TPR=total peripheral
resistance; SBP=systolic blood pressure; MAP=mean arterial pressure; HR=heart rate;
SV=stroke volume; MV=minute volume; SPR=specific peripheral resistance; CI=cardiac
index. Methods include, with venous occlusion plethysmography, tetropolar variant of
rheography for the determination of stroke volume.
For classification as to “kinesis” see Zaslavskaya R.M. Chronodiagnosis and chronotherapy
of cardiovascular diseases. 2nd ed. Translation into English from Russian. Moscow:
Medicina, 1993, 397 pp.
21
THE CIRCADIAN RHYTHM IN CENTRAL TEMPERATURE IN
FASTING SUBJECTS IN HOT CLIMATE (SENEGAL)
Samb A., Cissé F., Halberg F.1
, Cornélissen G.1
, Martineaud J.P.2
Chaire de Physiologie - Faculté de Médecine, Université de Dakar-Fann,
Sénégal, 1
Chronobiology Laboratories, University of Minnesota, Minneapolis,
Minnesota, USA, 2
Dept. Physiologie, Hopital Lariboisiere, France
INTRODUCTION
Human beings are characterized by a stable average core temperature with
limited and regular fluctuations over 24 hours. Consequently, both core and
skin temperatures are not constant as function of time. The circadian rhythm in
core temperature appears to be mainly generated by periodic variations in heat
production and heat loss. Within some limits, the period amplitude and phase of
circadian rhythms can be influenced by cyclic variations of multiple
environmental factors. There are the alternation of day and night, changes in
environmental temperature and reactions to various external stimuli like noise
and silence (Houdas et al., 1971). For human beings regular daily activities
linked to hours of work and rest, or activities related to participation in social
life exert influence upon circadian rhythms also. All these influences are
interconnected. First, physiological response to an increase in ambient
temperature does not occur with the same speed and intensity when exposure
occurs during the day as compared to night (Houdas et al., 1971). On the other
hand, the continuous exposition to high ambient temperatures will almost
regularly induce an appreciable increase in core temperature (Halberg et al.,
1967). In effect in hot climate during the hottest hours on day (ambient
temperature higher than 35°C), core temperatures are found to be higher than
those observed in temperate climates, even in subjects highly adapted to hot
climates. The metabolic state of the organism seems to be closely linked to the
heat production and it is known that metabolic heat production increases after
feeding in both animals and humans. This metabolic response, referred to a post
prandial thermogenesis (specific dynamic action of nutrients or diet induced
thermogenesis), is thought ascribable to the energy cost of digesting and
assimilating the dietary nutrients (Kleitman et al., 1951). Food intake does not
appear to influence mainly the temperature circadian rhythm: circadian rhythms
of the core temperature were shown to persist in subjects who for 3 weeks were
on a very restricted diet (Reinberg et al., 1973). In experimental setting of
underground isolation the rhythm persisted even when changes of period and/or
acrophase would be imposed in the conditions of deprivation of light and other
indexes necessary to orientation in time. Nevertheless in these circumstances,
the circadian difference of rectal temperatures between fasting and non-fasting
periods were still found to be different (Houdas et al., 1971). However, the
exact influence of food intake on core temperature in hot environments and in
22
subjects highly adapted to high environmental temperatures has not been
described.
The aim of the present study was to determine the influence of the fasting and
usual alimentary intake on circadian variability of central body temperature and
heart rate in healthy subjects highly adapted to hot climate.
MATERIAL AND METHODS
Environmental conditions
The experimentation was carried out in a tropical area in eastern Senegal, in the
rural zone of Kedougou situated near 12°40 North latitude and 14°11 West
longitude, during a warm period of the year, the month of February. During the
time of experiments environmental temperatures in this part of the sub-sahelian
zone ranged from 21.2°C at 6.00 AM to 35.0°C at 6.00 PM. Simultaneously
relative humidity ranged from 36% to 7%
Subjects
22 healthy young men participated in this study, mean age 23.36 ± 3.49 years,
height 176 ± 6 cm. and body weight 64.87 ± 5.53 kg. All subjects came from
Senegalese army and were well-trained in physical activities. All of them were
born and lived in Senegal. Before the experiment, they had been staying in
eastern Senegal for six months at least. Consequently they were naturally
adapted to local warm or hot climate.
They were fully informed of all aspects of the study, gave their voluntary and
informed consent to participate in this experimentation, which was approved by
the appropriate institutional ethical boards. Their diet was mainly compound by
rice and millet, fish and flesh and contained approximately 3 200 kcal /day;
drinks were only water and fruit juices. (Table 1).
Experimental protocol
The soldiers were divided in two groups of eleven subjects studied during a
period of 24 hours, since 7.00 pm to 7.00 pm on the following day, with
measurements every 3 hours. For each measurement, after maintaining subjects
resting in supine position for thirty minutes, the ambient temperature (AT),
rectal (RT) and skin (ST) temperatures, heart rate (HR), systolic (SBP) and
diastolic (DBP) blood pressure were determined. One group went first through
a 24-h period with normal alimentation and very moderate activity, followed by
a 24-h period of fasting but with free access to drinking water. While the other
group had first the 24-h fasting period, a 24-h period of normal activity and
alimentation without measurements, and then the 24-h period with normal
alimentation and very moderate activity. All measurements were performed
during the first and second or the first and third experimental periods
respectively. All subjects were staying in the same room, which was well
ventilated by opening doors and windows so that the room temperature was
quite similar with ambient temperature.
23
To avoid order bias and influence of environmental temperature fluctuations, the
individual results obtained for both groups during fasting or normal alimentation
were joined and analyzed. Mean blood pressure (MBP) was expressed as:
diastolic blood pressure + (difference systolic blood pressure - diastolic blood
pressure)/3.
Precautions
Muscular exercises were forbidden during experimentation, subjects could only
do their usual activities in the day time and were supervised in order to prevent
accidental differences in activities. Fasting subjects stopped eating after the
dinner but they had free access to drinking water which upper limits was
restricted to 3 1iters per day. During feeding period times for eating were 7.00
AM for breakfast, 11.30 AM for lunch, and 6.30 PM for dinner. All subjects
were submitted to same sleep – awake periods: out of bed at 7.00 AM and
bedtime 9.00 PM.
Data analysis
Data are presented as mean values (± standard deviation) for each group and
were analyzed using the Halberg cosinor analysis (Halberg, 1969). Student's ttest
for paired samples was used to assess effects of fasting between groups.
Difference were considered significant if probability values were lower than
0.05.
RESULTS
Since the data were collected at 3-hours intervals, only trial periods of 24, 12
and 8 hours could be examined. Each component (24h, 12h or 8 hours periods)
for each variable (RT and ST, HR and MBP) were compared. Comparison of
the two groups showed highly statistically significant differences (p < 0.001) for
the circadian and circasemidian components of rectal temperature and heart rate
(except for 12-hours component of heart rate during the reference span). The 8hours
component is also statistically significant for rectal temperature (p <
0.001) and is at least of borderline statistical significance for heart rate (p =
0.053) during feeding but is present (p < 0.05) during fasting.
It can be seen that the fasting was associated with:
1. For rectal temperature:
-a decrease in the MESOR (24-h mean value) by 0.125 ± 0.026°C (p <
0.001) and a decrease in the circadian temperature amplitude (double
amplitude corresponds to the highest value at the daytime and the lowest
value at night) by 0.09 ± 0.02°C (p = 0.001),
-a slight delay of the circadian acrophase: the delay in the circadian
acrophase (the interval between midnight and the highest daytime values)
was 0.80 ± 0.27-h (p < 0.005),
-an increase in the amplitude of the circasemidian component of rectal
temperature (p < 0.05).
2. For skin thoracic temperature:
24
the values in fasting were generally lower than values in feeding but
differences were not significant.
3. For heart rate:
-a decrease in the MESOR by 3.4 ± 0.9 bpm (p < 0.002),
-no change in the circadian amplitude: 0.9 ± 0.8 bpm (p < 0.03),
-a delay in the circadian phase of heart rate: 1.67 ± 0.53 h (p < 0.01),
-an increase in the amplitude of the circasemidian component (p < 0.05).
4. For mean blood pressure:
values were between 100 and 92 mmHg, but there was no significant
difference in the two situations.
Table 1. Daily diet in Senegalese Army
Meal Food Caloric value daily intake Water
(kcal) (%) (1)
Breakfast bread, milk, coffee 580 18
7.00 AM
Lunch meat or fish and rice, 1 280 40
11.30 AM vegetables and fruit
Dinner meat or fish and
6.30 PM rice or millet, fruit 1 340 42
Total 3 500 100 2.5-3.0
DISCUSSION
Core body temperature values measured in our study were a little higher than
those usually observed in subjects who live permanently in moderate climates
(Eckburg et al., 1987, Halberg et al., 1967, Martineaud et al., 1977). Diurnal
variations of the core temperature observed in this study with usual feeding were
comparable to those measured in hot climates (Cissé et al., 1991): lowest value
36.2°C at 4.00 AM, acrophase 37.2°C at 4.00 PM, MESOR 36.8°C and
amplitude 1.1°C. Because in this study subjects were maintained at bed rest for
thirty minutes before any measurement, then in common life with physical
activities diurnal rectal temperature will be lightly higher. Indeed it was
established that in hot climate core body temperature largely exceeds value of
37°C during the hottest hours of the day (Halberg et al., 1967, Martineaud et
al., 1977).
But circadian rhythm of thermoregulatory mechanisms seems to be coordinated
for maintaining a strict control of core body temperature during the night,
25
because the same values of approximately 36°C are observed in all subjects in
any climatic conditions (Cissé et al., 1991). Nevertheless diurnal values are
partially depending on ambient temperatures: indeed rectal temperature can
physiologically increase to 37.7°C. In other words, it appears that as an adaptive
phenomenon, human beings are better able to adjust core temperatures to high
ambient temperatures during the daytime than during the night time (Cissé et al.,
1991).
In this study performed during a warm season, we found a substantial increase
in body temperatures during afternoon with normal feeding; after lunch rectal
temperature was higher by 0.2°C than during fast. Therefore it is the
thermogenesis induced by nutriments which explains this difference in body
temperatures. Indeed it has been shown in previous studies that the postprandial
thermogenesis due to the specific dynamic action of proteins is obvious
when ambient temperature is high (Krauchi et al., 1994).
Then ordinary diet induces thermogenesis which reaches at least 10% of energy
intake (Monk et al., 1996) and can last several hours after food intake. When
ambient temperature is higher than temperature of thermic confort, heat
produced by nutriments can not be used for thermoregulation and has to be
eliminated partly immediately and partly with some delay, i.e during the night
when environmental conditions are more auspicious (Cissé et al., 1991) and this
process explains some increase in day time core temperature. But during the
night thermoregulatory mechanisms are quite efficient and the period of minimal
temperature is the same with a normal diet as in the fasting. Then in our
experiment, the circadian rhythms of central temperature persisted during fasting
period without change in acrophase but with decreases in the MESOR of rectal
temperature and circadian amplitude; this feature was associated with an
increase in amplitude of the circasemidian rhythm of rectal temperature, i.e the
about half-day component. These changes are clearly induced by the food
ingestion and intestinal absorption increasing the post-prandial metabolism.
Then decreases in MESOR and diurnal amplitude are an adaptation to the fast
(Cissé 1986, Cissé et al., 1991), corresponding to stimulation of
neoglycogenesis and some other metabolic processes (Schonbaum et al., 1990).
But the basic circadian rhythm is unchanged as shown by the persistence of the
same acrophase.
Determination of a cutaneous temperature confirmed a well know notion : skin
temperature mainly depends on the ambient temperature varying in the same
way, minimal at night-time, maximal in daytime but the amplitude of the
variation was only 1°C. At the highest environmental temperatures, in the
afternoon, corresponded maximal cutaneous temperature almost similar in
fasting and in feeding situation. Nevertheless in this case elimination of heat
produced by post-prandial thermogenesis induced an increase in skin blood flow
(Martineaud et al., 1997) but it was not sufficient for a significant increase in
superficial temperature.
26
As expected (Krauchi et al., 1994), this study found a circadian variation of
blood pressure and heart rate: mean values in these young subjects were lower
than in normal Senegalese population, certainly because soldiers were well
trained and developed a reinforced vagal tonus due to training. In feeding as
well in fasting subjects the circadian profile of heart rate was significantly
correlated with the circadian profile of central temperature, representative itself
of heat production. Then in fasting subjects, MESOR of heart rate decreased but
acrophase was not significantly modified and amplitude of the circasemidian
component increased. Consequently these changes are representative of
metabolic and hormonal adaptations to the fast (Reinberg , 1975). Last there was
no clear relation between blood pressure and feeding.
In this study we found that, in hot climate, the circadian rhythm of central
temperature was present in two different nutritional situations but that core body
temperature during the day was increased significantly in feeding compared to
fasting without significant alteration of cutaneous temperature implying
induction of diet thermogenesis. This increase could diminish performance of
workers and sportsmen, and explain differences in seasonal performances.
Furthermore there is a know relationship between vigilance performance and
body temperature during the circadian and it is likely that diurnal temperature
can be an reliable marker of human circadian functioning (Reinaud et al., 1977).
Our findings suggest that in hot climates, the population particularly workers
and sportsmen, should favor a poor proteic diet to the advantage of
carbohydrates because these induce a low thermogenesis and a lesser increase in
core temperature.
REFERENCES
1. Cissé F.: Adaptation de la thermorégulation aux climats de la zone intertropicale. Thèse de
Biologie Humaine, Université René Descartes, Paris V. 1986.
2. Cissé F., Martineaud J P.: Circadian cycles of central temperature in hot climate in man.
Arch.Internat. Phvsiol . Bioch. Biophys. 99: 155-159, 1991.
3. Cissé F., Martineaud R., Martineaud J P.: La température centrale lors de l'exposition chronique au
climat chaud. Arch.Internat. Phvsiol . Bioch. Biophys. 99: 385-391, 1991.
4. Eckburg J.J., Bell E.F., Rios G.R., Wilmoth P.K.: Effects of formula temperature on post prandial
thermogenesis and body temperature of premature infants. J. Pediatr. 11: 588-592, 1987.
5. Halberg F., Reinberg A.: Rythmes circadiens et rythmes de basse fréquence en physiologie
humaine. J. Physiol.Paris. 59: 117-200, 1967.
6. Halberg F.: Chonobiology. Ann. Rev. Physiol. 31: 675-725, 1969.
7. Houdas Y., Sauvage A.: La réponse du thermostat humain à une entrée pente de la
charge thermique externe. J. Physiol. Paris. 63: 293-295, 1971.
8. Kleitman N., Jackson D.P.: Body temperature and performance under different routines.
J.Appl.Physiol. 3: 309-328, 1951.
9. Krauchi K., Wirz-Justice A.: Circadian rhythm of heat production, heart rate and skin and core
temperature under unmasking condition in men. Am. J. Physiol. (Regulating Integrative Comp.
Physiol. 36) 26: R 819-R 829, 1994.
10. Martineaud J.P., Mazer A., Gahem A., Valeix P., Raynaud J.: Production de chaleur, température
centrale et débit de la main après ingestion de diverses charges protéiques. Editions INSERM.
Paris. 1977, pp 365-385.
11. Martineaud J.P., Seroussi S. : Physiologie de la circulation cutanée. Masson, Paris, 1977.
27
12. Monk T.H., Buysse D.J., Reynolds C., Kupfer D.J.: Circadian determinants of the postlunch
dip in performance. Chronobiol. Int. 13: 123-133, 1996.
13. Raynaud J., Martineaud J.P., Durand J.: Body temperature and chronic heat exposure. In:
Confort Thermique, (Durand J., Raynaud J. éds.). INSERM, Paris, 1977 , pp 345-364.
14. Reinberg A., Apfelbaum M., Assan R.: Chronophysiologic effects of restricted diet (220
Cal/24h as casein) in young healthy but obese women. Int. J. Chronobiol. 1: 391-404, 1973.
15. Reinberg A.: Circadian changes in the temperature of human beings. Bull. Radiol. 6: 128-139,
1975.
16. Schonbaum F., Lomax P.: Thermoregulation : Physiology and Biochemistry. Pergamon Press,
New-York, 1990, pp 61-110.
28
BIOLOGICAL CLOCK AS CALENDAR
Illnerová H., Sumová A., Trávníčková Z., Jáč M.
Academy of Sciences, Prague, CZ
The mammalian biological clock located in the suprachiasmatic nuclei (SCN) of
the hypothalamus controls the circadian time-keeping system and drives many
overt rhythms, among them the rhythm in the pineal melatonin production.
Duration of the nocturnal melatonin signal conveys the information on day
length, i.e., on the photoperiod into organisms. In all mammals so far studied
including the man, the melatonin signal is shorter in the long summer days
than in shorter winter days. A question remains whether the seasonally
modulated rhythmic melatonin production reflects a seasonally modulated state
of the circadian clock, i.e., whether the SCN clock is itself photoperiod
dependent.
To solve this question, intrinsic SCN rhythmicity was studied in rats maintained
under artificial long summer days, with a 16-h photoperiod and in those
maintained under short winter days, with an 8-h photoperiod. Two SCN rhythms
were followed, namely the rhythm in the light-induced c-fos gene expression
which is exhibited mainly in the ventrolateral (VL) SCN, and the rhythm in the
spontaneous c-fos gene expression elevation, which is expressed mostly in the
dorsomedial (DM) SCN. Both these SCN intristic rhythms were photoperiod
dependent. Moreover, memory on the photoperiodid was stored in the SCN
intristic rhythmicity: when rats maintained in long days were transversed to
short ones, profiles of the VL-SCN as well as the DM-SCN rhythms adjusted
just gradually, i.e., in more cycles, to the change of the photoperiod. Effect of
the photoperiod on the SCN was not mediated by the melatonin signal: the SCN
rhythmicity in long days differed from that in short days even in
pinealectomized rats.
In conclusion, the circadian SCN pacemaking systém is photoperiod dependent.
Therefore, the SCN does not program and communicate just time of the day
information but also season of the year information.
29
NON-INVASIVE MEASUREMENTS IN MAN
30
PRENATAL AND PERINATAL PSYCHOLOGY AND MEDICINE: NEW
INTERDISCIPLINARY SCIENCE IN THE CHANGING WORLD
Fedor-Freybergh P. G.
Stockholm, Sweden and Prague, Czech Republic
INTRODUCTION
The encounter with the unborn is the beginning of the continuum of human life
towards self-realization. We need to extend the standard definition of life's
continuum to include the prenatal experience, which is a part of life's continuum,
helping to shape us and determining who we are and what we will become. For
the unborn it is primarily through the imprinting process that this experience is
initiated and realized. For the mother, pregnancy this encounter with the unborn
is a chance for self-realization. For a rest of us this encounter with the unborn is
the chance to extend and deepen our own understanding of this life continuum
wherein there can be found no possible separation between the physical and
psychological dimensions of our existence.
PRENATAL AND PERINATAL PSYCHOLOGY AND MEDICINE
Prenatal and perinatal psychology and medicine is a relatively new
interdisciplinary scientific field within medical and psychological research and
practice which attempts to integrate different disciplines dealing with the basic
questions of life and its disturbances.
Emphasis is placed on the interdisciplinary character, which enables different
scientific specialties such as medicine, psychology, psychoanalysis,
anthropology, human ethology, sociology, philosophy and others to meet, find a
common language and go through the process of mutually creative influence, or,
as it were a "cross fertilization".
Prenatal and perinatal psychology and medicine can also serve as a
"psychosomatic" model stressing the indivisibility of "psychological" and
"physical" processes in the continuum of human life from its very beginning and
also the indivisible development of all functions of the central nervous system
and the immunological and neuroendocrinological processes.
One of the important intentions of this new scientific field is the publication of
different methodologies, both from experimentally oriented methods and studies
and also from more introspective methods with an effort to look for and find a
common language in order to diminish semantic misunderstandings as well as to
define a scientific theory applicable to this new interdisciplinary and integrative
approach. Integration linguistically means, among other things, assimilation,
fusion, incorporation, combination, unification and harmony. The latter,
harmony, should be stressed in particular - harmony and cooperation between
31
different integrated approaches and views, methods and methodologies, theories,
ideologies and practices, rather than confrontation and disagreement.
Society at large must encourage a sense of responsibility in parents-to-be and
counsel couples long before conception about their commitment toward the new
life; it is essential that this new life be highly respected from the very beginning
and considered to be an equal partner in the dialogue. This dialogue begins at
conception and continues through the prenatal, perinatal and postnatal stages of
life. It influences the outcome of the birth and the way the individual during his
childhood, adolescence and adult life will treat other people and his ability to
love and respect others and make commitments.
PRENATAL STAGE
The prenatal stage of life represents a unique opportunity for the primary
prevention of psychological, emotional and physical disorders in later life
(Fedor-Freybergh et al., 1988, 1952). At this stage we also can develop
preventive procedures to decrease premature birth and perinatal morbidity and
mortality. In order to understand the enormous potential power of the prenatal
processes and their impact on the individual's prenatal and postnatal health, we
have to ask ourselves what does the prenatal stage of life imply.
Pregnancy can be conceived as an active dialogue between mother and child
(Fedor-Freybergh, 1983). This dialogue is not limited but is enlarged via the
dialogue between the mother and the father and the mother's psychosocial
environment. This discourse is a part of a very active and mutually
interdependent process taking place on several levels. As a minimum, these
include the psychological, emotional, biochemical and psychoneuroendocrinological
levels.
I have never heard a mother refer to the child in her womb as "my embryo", or
"my foetus". The mother says "my baby" or even calls the child by a personal
name. Generally, pregnant mothers show a high degree of sensitivity and
sensibility towards their unborn child which, by contrast, many professionals
lack. The child is a very active partner in the pregnancy, an "active passenger in
utero" (Chamberlain, 1988). The mother-child interaction, consequently, has not
only a biological but also a psychological and social character.
This mother-child dialogue begins on an unconscious level - probably from the
very beginning of the unborn child's development. From the mother's side, the
dialogue will become a reality when she, consciously or unconsciously, makes
the move to experience the unborn "it" as the unborn "you". This event initiates
her into the beginning of a conscious encounter with her child. The transition
from "it" to "you" is just one consequence of the sensitivity and sensibility of the
unborn and the enormous creative potential in the psyche of the mother. The
dialogical experience is independent of the degree of morphological
development of the child (Fedor-Freybergh, 1983, Fedor-Freybergh et al.,
1988).
32
There is a strong impact of hormonal, psychological and immunological
influences already on the whole embryonal and fetal development.
BIRTH
Birth is a part of a comprehensive human development. The circumstances
around the birth, the birth itself and the consequences for the child, the mother
and the father in the postnatal period will essentially depend on the prenatal
stage of life and its bonding impact on the child, the mother and the father. It is
wise not to separate the role of the father from the role of the mother and child
and also not to separate the labour from the continuum of the prenatal
experience.
The father should be involved and incorporated into the entire prenatal care from
the very beginning and treated as an equal partner in the process. The father's
experience will vitally influence his activity during labour and very much his
bonding abilities with the child during birth, the prenatal and postnatal periods.
Pregnancy can be considered as the first ecological position of the human being,
the womb as the first ecological environment (Fedor-Freybergh, 1983, FedorFreybergh
et al., 1988). It is surprising to see how few professionals, even
psychologists, realize this basic fact, and that there is still a large number of
obstetricians, gynecologists and other professionals who merely consider the
womb as a "baby-carrying" anatomical organ and are still unaware of the "toxic
pollution" of potential psychological and social threat to the unborn child.
The dialogue between the unborn child, mother and father creates a "primary
togetherness" (Fedor-Freibergh et al., 1988), which in turn helps to foster
strongly compelling psycho-physical predispositions. Potentially, any such
inborn predilection has the ability to orient and shape forthcoming emotional
and social responses, especially in regard to interpersonal relationships. The
consequences of these experiences of primary togetherness run along a wide
range, including love and ethical behavior.
The human life has to be considered as an indivisible continuum where each of
the developmental stages is equally important, all stages interdependent and not
separable from the whole individual's life continuum. In this continuum, the
individual represents an indivisible entity of all functions on both physiological
or physical, psychological and social levels. The physical, biochemical,
endocrinological, immunological and psychological processes represent a
whole, which cannot be divided (Fedor- Freybergh et al., 1988).
In order to understand the process during the prenatal stages of life, a new
language is required and a new scientific theory is needed. Such a language must
assist us in getting beyond the semantic problems and confusion existing in so
much medical and psychological vernacular (Fedor-Freybergh, 1990).
It is not possible to separate any stage of human development from the rest of an
individual's life continuum. The life continuum is one of the basic needs in
human life in order to maintain homeostasis and equilibrium. The disturbance of
33
the individual's life continuum on a momentous scale would lead to illness or in
extreme cases, where homeostasis cannot be regained, results in death.
Any discontinuity from outside or from inside the individual organism will
violate these basic biological and psychological needs, both in prenatal and
postnatal life. Discontinuity is increasingly becoming a more serious problem
today causing the spread of ecological, social and political disturbances
throughout the world. No group of people or any nation is wholly immune from
the upheaval of disorienting developments on ecological and social levels
(Fedor–Freybergh et al., 1988). Many in the scientific community are very
much aware of the effects of such events, and see how the discontinuity and
disequilibrium beget many of today's mental and social diseases (Tyano, 1987).
In the field of prenatal and perinatal psychology and medicine, we are very
much aware of the dangers discontinuity can generate in the unborn and in the
newborn.
PSYCHONEUROENDOCRINOLOGY
The latest development of two relatively new and innovative lines of medical
and psychological research, namely psychoneuroendocrinology and
psychoneuroimmunology are very promising. Research in these two areas is
particularly important in serving as the scientific basis for the philosophy behind
prenatal and perinatal psychology and medicine.
Various highly specific biochemical functions (hormones, neurotransmitters and
other polypeptide structures) are needed in direct connection with input
phenomena for the transformation and storage of both sensorial and mental
types of information. Crucial to the formation of the primary central nervous
system on the hypothalamic-pituitary-ad renal level, some of these functions are
already detectable in the very beginning of the development of the human being.
Thus the embryo successively develops a high sensibility and competency for
the potential ability of perception and learning (Fedor-Freybergh, 1985).
The intrauterine experience is also a learning process for the child (FedorFreybergh,
1990). This learning is a vital prerequisite for survival since it makes
it possible for the organism to adapt itself to new circumstances. Without
adaptation there would be no survival and one cannot adapt one self without
making and having had experiences upon which to base the adaptation. Such a
process requires memory, whether consciously retained or subconsciously
imprinted. The information processing which reaches the child from the very
beginning of its development will be received via different biochemical
pathways and then transformed and stored as memory traces (this could
eventually be useful to a theoretical understanding of certain
psychotherapeutical procedures, such as hypnosis, dream analysis, prenatal
memories etc.). At this stage the embryo already shows evidence of responding
to and retaining the impact or imprint of sensory experiences in a biochemical
language, which remain as a potential learning source. These prebirth memory
34
imprints may in turn be revoked as informational sources (whether negative,
positive or ambivalent in character) during later life.
The implications of these preliminary findings are far reaching. It will require
nothing less than radical rethinking the standard human-embryo development
paradigm wherein structure is presumed to precede function. To the contrary, as
we have indicated earlier, there is a strong evidence (Fedor-Freybergh, 1983) in
support of the primacy of function over structure, the morphological organ. It is
the morphological structure which develops as a result of the inborn primal
functional urge. An organ would not develop if there was no functional urge
compelling it to do so. In the same way, the mental capacity of the human being
is not posterior to the completed morphological structure of the brain, nor to its
subsequent introduction into and experiencing of a particular sociocultural
environment after birth. The unborn already has its psychological processes
functioning long before birth; no child is tabula rasa.
We must reaffirm that the mother is not just a "receptacle" for the child's
growth, but an active initiator and participator. Today it is imperative to
reestablish the woman as the primary choice maker in this powerfully creative
process. Indeed, she is involved in a procreative process with great creative
powers of her own. The future mother needs to be aware of these powers and
how to be in touch with them in order to be better equipped to guide and
augment this creative undertaking. Pregnancy can also enable the mother to
withdraw into a kind of "creative regression" in order to enter into an intimate
dialogue with her unborn child.
In order to make an informed and stress-free choice, family planning education
must begin well before conception. Responsible parenting is not necessarily an
automatically bestowed gift from "Nature" or even an easily acquired talent, but
very often needs to be taught. That requires research concerning appropriate
socio-pedagogical implementation within the family and in our educational
system. It is vital that an integration of prenatal and perinatal studies into
medical and psychological curricula at the universities is provided.
PRENATAL CARE
We need to establish a new educational system which would prepare people for
conscious parenthood. There is a need for a radical change of prenatal care,
where not only medical but also very much psychological and social life
circumstances of both parents would be taken into serious consideration. The
prenatal care should consider the child as an active partner in a psycho-social
dialogue with his parents who are given the opportunity to have their encounter
with their unborn child in a free and non-violent society.
The ideal child should already be loved prenatally. There should not be
unwanted children. Unwanted children are morally threatened and a moral threat
to society. Unless we can achieve these mental and social conditions concerning
the prenatal stage of life, all positive changes in the world would be superficial
and there would also be the danger of a threat to basic human needs and rights,
35
to cultural and traditional values, and to civilization and freedom itself (FedorFreybergh,
1992, David et al., 1988, Matějíček et al.,1987, 1994).
Pregnancy can sometimes be experienced by both the mother and the father as a
life crisis, which does not necessarily imply a negatively charged situation. Any
crisis may be envisioned as a challenge, which can bring about creative and
positive solutions or alternatives. We can quite often see that during pregnancy,
old, latent and unsolved conflicts become manifest. Frequently these can be
worked through during the course of the pregnancy in a very constructive way.
Indeed, it should be pointed out that many of the conflicts and problems that a
pregnant woman may experience are not the direct result of her pregnancy or her
baby. Unresolved issues may re-evoke psychological conflicts within her own
personal psyche. In this way the pregnancy often gives the mother and father a
unique opportunity to further their own inner psychological development,
sometimes within psychotherapeutical settings (Fedor-Freybergh et al., 1988).
PSYCHOTHERAPEUTIC RESEARCH
Psychotherapeutic research and practice has again shown how decisive negative
emotional influences and disturbances in the prenatal dialogue are for mental
conditions and diseases in later life. Dr. Janus has observed that psychological
traumas and prenatal and perinatal problems have largely been shown in about
two thirds of psychotherapeutic adult patients. It becomes exceedingly evident
how important the emotional maturity, mental health and social awareness of the
parents of the unborn child are. The need for psychotherapeutic intervention on
both the pregnant mother and father-to-be is becoming more relevant.
No guilt or inferiority feelings should be imposed upon the pregnant parents nor
any moral judgement placed upon them. We need to be aware that not all
pregnant women have the opportunity or possibility to provide their unborn
child with optimal nurturing conditions either economically or emotionally or
within their social structures. Pregnancy is always a dynamic process of
constantly fluctuating emotions, attitudes and even intellectual discourse. The
mother-child dialogue is almost always characterized by a mixture of positive,
negative and ambivalent emotions. The society has a responsibility to ensure
that the mother-father-child unit can not only survive but develop and grow in
the best possible circumstances.
Moreover, it must be added that a living organism has a strong propensity to
adapt and even to repair damage, or to compensate for some failure from a
previous developmental stage of the life continuum. What is unfulfilled in one
stage of experience can be applied to the next and, eventually, worked out to the
inner satisfaction of the human being.
RISK PREGNANCY
36
The term "risk pregnancy" is still used almost exclusively in its biological sense.
This means it is reserved for somatic disturbances, physical diseases or
handicaps experienced by the mother during pregnancy, which could have a
bearing on the biological health of the baby. Here we can see again how firmly
institutionalized medicine and medical philosophy, with its static terminology
and categorizations, results in the body-mind division and in continued
promulgation of psychophysical parallelism. In a holistic and comprehensive
view of human life we cannot make divisions between so-called “somatic” and
"psychological" phenomena. Psychologically, medically and anthropologically
considered, all life events are experienced as indivisible phenomenological
situations wherein body and mind (soma and psyche) represent an entity of
mutual influence and interdependence within a particular socio-cultural
environment. In this way, all events of either a so-called "somatic" or
"psychological" character, which could adversely affect the well-being and
health of the mother or her unborn child, are seen as potential or real risks. It is
therefore necessary to create a new kind of prenatal care whereby all risks can
be screened in good time, and where parents would be given the opportunity for
comprehensive care, including access to psychotherapeutic counseling (FedorFreybergh,
1983, Fedor-Freybergh et al., 1988).
Pregnancy and delivery are not diseases per se, only very exceptionally, but they
sometimes can become a disease due to a doctor's intervention. We have to give
credit to the inner wisdom of the pregnant woman and help her with our
knowledge, our empathy and the scientific information to cope with her
problems and with the potential or real risks if and when they occur.
This brings us to the topic of health. What was said before about the holistic and
comprehensive view of all human functions will be true also in considering the
issues of health and disease. The last definition of health by the World Health
Organization is "a state of complete physical and mental well-being which
results when disease-free people live in harmony with their environment and
with one another" (WHO, 1986). As Zikmund (1993) points out, this definition,
though including all three dimensions of life manifestations of man - biological,
psychological and social, has several shortcomings. In his analysis of the
dimensions of health and disease he accentuates the functional aspect of health
and disease and defines health as functional optimum of all of life processes,
biological, psychological and social.
The psycho-physical organism tries constantly to maintain its health. It strives
toward recovery, away from destruction; it strives toward homeostasis, away
from disorganization and chaos. Health has clearly a very strong dynamic and
creative dimension and in 1976 (Fedor-Freybergh) I described health as "the
dynamic movement along the creative path towards self-realization".
Self-realization has to be understood as containing biological, psychological and
social dimensions. Self-realization with regard to (a) the constructive integration
of the dialectically changing, individually depending conditions with a
simultaneous maintenance of the homeostasis of the "milieu intérieur", and (b)
37
the balance in the striving for satisfaction of the individual during the continuous
confrontation and adaptation of the psychoendocrine system with and to the
"milieu extérieur" of ordinary day-to-day life situations. By adaptation is meant
not just the adaptation of the individual to the environment, but also the
possibility to transform the environment to suit oneself.
We must abandon the restrictive, positivistic objective approach to the
individual and to the society. These approaches ignore the subjective
specificities of each individual and each society with their own soul and
spirituality, their own needs, feelings and thoughts. We have to strive after the
renaissance of individual human uniqueness in a world where the individual and
his environment should represent a spiritual unity in ecological and ethnic peace.
That is even more true for such a subtle situation as the prenatal stage of human
development. But is it not so that, from a subtle and delicate process, large and
important movements in philosophy, practice and global change can result?
According to the "butterfly effect", events are interdependent to that degree that
the very subtle and seemingly insignificant movements of a butterfly's wing are
able to set off, somewhere far away, a large typhoon. This butterfly effect can be
likened to the prenatal stage of human development. With this in mind, therein
lies the unique opportunity to prevent the world from evil.
THE NEEDS OF HUMAN BEING
The next topic I wish to stress are the basic needs of the human being. Invariably
these needs are described as eating, sleeping and sex. But I feel that there is one
more, very basic need which has never been addressed and that is the need for
taking care of someone and the need of being taken care of. The being for whom
we care becomes the most important being in our life and has also become a part
of our lives. It is irrelevant whether the one we care for is an adult, a child, a
prenatal child, a dog, a cat or a small bird - in other words all living things.
This being cared for and being taken care of is one of the prerequisites of our
survival and provides the homeostasis and equilibrium between us and our
environment. When we are being taken care of we can be healed and cured and
when taking care for someone we can heal and cure as well.
Another wonderful way to express this is with the words of Antoine de SaintExupéry
(1946): “On ne connait que les choses que l’on apprivoise", . ."Tu
deviens responsable pour toujours de ce que tu as apprivoisé."
In this way the bonding process is created and feelings of reassurance and wellbeing
are established.
In order to predict how successful the bonding process between mother, father
and child will be, we need to have a good knowledge of the personalities of the
father and mother, their past, their expectations and visions, their fears and
ambivalences. The importance of individual family history is becoming
increasingly more apparent. The individual's life starts at the latest in the house
of its grandparents, who do or do not pass on to their children (the present
38
parents-to-be), the basic values of morality, ethics and respect for life, who then
will or will not pass on these values to their unborn child.
An interdisciplinary approach invites interdisciplinary discussions where the
same topic can be viewed from different aspects. It should serve as a unique
opportunity for the cross-fertilization between the different sciences and
practices, rather than the more traditional multidisciplinary approach. It was
expressed in the leading article of Lancet (1985) “Psychiatrists and
immunologists do not meet much, and when they do they tend to speak in
different tongues". (Leading article, Lancet, 1985)
An interdisciplinary dialogue is not only possible but even extremely creative
and vitally necessary, and the possibility of common understanding and thought
within the language of different disciplines, primarily between the "humanistic"
and "natural" sciences, is reachable. In this journal there has been an
interdisciplinary (not to be confused with multidisciplinary) dialogue from the
very beginning, which has contributed to tearing down many established
barriers.
In an issue of the Universitas (Robert Schurz: "Ist Interdisziplinarität möglich?"
Universitas 11, 1995, 1070-1089), a distinguished German journal for
interdisciplinary sciences, a paper was published questioning whether
interdisciplinary communication is possible at all. It was a paper with a very
careful methodology which concluded that interdisciplinary communication is a
difficult task, probably not attainable but certainly worth aiming for.
PRENATAL SCIENCE
I believe that we have succeeded so far because of the use of "prenatal science"
as a model for the indivisibility of the “psychological” and “somatic” processes
in the continuum of human life, and that the phenomena and processes of the
central nervous system and the immuno- and neuroendocrine processes are
inseparable has also been put into the praxis. In our journal, the International
Journal of Prenatal and Perinatal Psychology and Medicine, psychoanalysis,
endocrinology, immunology, developmental psychology, obstetrics and
midwifery, just to mention a few, have crossed each other's paths and today we
are able to talk together at our congresses and read each others thoughts in the
journal without interpreters.
In order to undertake such a challenge, a common language is required, a
language that would be understood across disciplines and also would be able to
assist in getting beyond semantic problems. One of those confusions is due to
the reductionism still so very much inherent in the medical and psychological
vernacular and represents one of the major epistemological problems in the
science of prenatal and perinatal life.
There is a contradiction in the major tendencies in society at large as well as in
the family and in individuals. On one hand there are increasing tendencies
towards integrative processes within politics, economics, etc. on a world scale
39
while, on the other hand, there is a disintegration of the family and of
microsocial structures with the consequent alienation of the individual.
There is enormous progress being made in information processing and
communication with internet, e-mail and with cellular telephones in everyone's
possession while, at the same time, there is a decrease in and deterioration of
communication from person to person. Fairy tales are out, CD-ROMs are in.
I certainly do not advocate nostalgia for "the good old days". When the worst
atrocities of World Wars I and II took place, internet did not exist. But there
were fairy tales and the most degenerate war criminals loved children and dogs.
That is, however, another issue. What I want to talk about here is the clandestine
decline and disappearance of tradition and cultural values, of good education
and of good manners, of sensitivity and common sense, and the ever-increasing
alienation of the individuals from the very beginning of their life.
The prenatal child has become an object of research and observation, he or she
is born as an object in alienated surroundings, brought up as an object and lives
as an object patronized by authorities. Basic values such as closeness, love,
solidarity, intimacy, intuition and natural instincts are suppressed by
technocratic and bureaucratic manners. In this world of uncertainty and
alienation, the individual is threatened by the deprivation of his or her basic
rights.
In the International Journal of Prenatal and Perinatal Psychology and Medicine
we have been very conscious of the dimensions of health and disease, both in
children and in families, and have stressed the importance of primary health and
primary prevention as early as in the prenatal stage of life (Int. J. of Prenatal
and Perinatal Psychology and Medicine, Vol. 5, No. 3).
We strongly believe that the health of the individual is determined very early in
prenatal life and that we should put emphasis on our possibilities to optimize
prenatal care for mother and child worldwide. It could be worth a thought to
propose that the United Nations devote one year to "'The Year of the Unborn
Child".
As we have said elsewhere (Int. J. Prenatal and Perinatal Studies, Vol. 4, No.
3/4, pp. 155-160), if we want to create a healthy, non-violent, creative human
being, society or economic system, we have to return to the primary urges and
functions of that human being, that society or that system. We have to guarantee
the most optimal conditions possible at the very primary stages of development,
whether in a human being or in a society. Only then can we achieve a true
primary prevention of illness, mental and physical disturbance, hate, intolerance,
violence and war, in the individual, in the family and in society.
Looking back to the UN "Year of the Family" and reviewing the atrocities
around the world done to families, children and to entire societies and ethnic
groups, we cannot but with deep sadness acknowledge that merely to make
declarations is not enough. The world can be changed only if we achieve a
change in the basic understanding of respect for life from the very beginning. It
starts with a deep respect for the unborn child in its first ecological position in
40
the womb, respect for the mother, respect for the child at birth, and welcoming it
with great dignity as an equal partner in society.
Respect for human life from the beginning will also bring about new ways of
treating prematurely born children with dignity (Marina Marcovich, Otwin
Linderkamp, Ernest W. Freud).
This also has to do with learning empathy for other human beings. We have said
that the life of the individual begins, at the latest, in the home of its
grandparents. There the parents of this individual receive all basic norms and
values of ethics, morality, empathy, respect for life and others, which they will
then transmit to their own children even before they are conceived. Thus, we
need to review the restrictive, positivistic, objective approach to the individual
and to society - an approach which ignores the subjective specificities of each
individual and of each society with their own soul and spirituality, their own
needs, feelings and thoughts.
We have to strive for the renaissance of individual human uniqueness - that the
individual and his environment should represent a spiritual unity in ecological
peace.
The great humanist, writer and philosopher, Václav Havel (1994), President of
the Czech Republic, stressed in his speech in Philadelphia, USA, on July 4,
1994, the uniqueness of the individuals, their rights, individual knowledge and
the ability to transcend, the individual's respect toward the miracle of being,
wonder of the cosmos, of nature and of their own existence. He said "'The only
reliable way towards coexistence and togetherness in peace and creative
co-operation in the multi-cultural world of today must be anchored in human
hearts and minds much deeper than any political opinions, antipathies or
sympathies, namely, in the human ability to transcend - transcendence as an
understanding hand offered to someone close as well as to a stranger, to the
human community, to all living beings, to nature, to the cosmos; transcendence
as the deep and joyfully experienced need for harmony with that which is not us,
with that which we do not understand, which seems to be distant in time and
space, but with which we are secretly in contact because this, together with us,
builds one, unique world. Transcendence as the only real alternative to
non-existence." (Translation from Czech by the Author)
In the last few decades or, even more so, in the last few years, we have
witnessed rapid changes in the world, where at great speed most positive
tendencies towards liberalization and democratization of societies have taken
place. At the same time new dangers and fears from different movements
towards new totalitarianism and fundamentalism in philosophy and practice are
growing. It is therefore of extreme importance in this time of philosophical,
political and social transitions to stress the awareness of the optimization of
human life conditions from the beginning. We are convinced that only a change
of attitude, basic philosophy and practice concerning the prenatal conditions of
human life would lead to a humanization of those societies toward non-violence
41
and common respect for life and tolerance for individual freedom and self-
realization.
Unless we can achieve those mental and social approaches concerning the
prenatal stage of life, all positive changes in the world would stay on the surface
and there would always be a danger of threat against basic human needs and
rights, against cultural and traditional values, against civilization and freedom.
The vision is of a society with high respect for life expressed by every individual
and hence of achieving a socially healthy, non-violent world.
The title of the 11th ISPPM Congress in Heidelberg, 1995, „a time to be born“,
proposed by the past president of the ISPPM, Rudi Klimek, stressed: not only
the individual freedom of mother and child to decide the term of labour as the
result of the creative dialogue they have had during the pregnancy, but also that
it is time for the birth of a new awareness by society that the prenatal and
perinatal stages are the most crucial and decisive in human life.
Awareness that the unborn child is already a personality, a psychological and
social partner to its parents, and, through them, to society as a whole must be
brought to the fore.
Indeed, the history of humanity is also the history of children and this history
begins at the very start of life, at the very latest at conception. Studies of
Psychohistory (Lloyd DeMause, Robert MacFarland, Alenka Puhar, et al.),
studies in Epidemiology (Matějíček et al., 1987) and studies in Psychotherapy
(Janus, Hau, Caruso, Benedetti, et al.) have clearly shown the impact of being
loved, wanted and respected on the individual and their ability to cope with their
own problems and with the problems in society.
CONCLUSION
There is a change in the consciousness of society concerning the vital
importance of the events from the prenatal and perinatal period for the physical,
mental and social health of human individuals. There is an increasing awareness,
interest and even involvement in both professional and political environments
for the importance of and the need to improve prenatal life and the
circumstances surrounding birth.
If we can ensure that every child is loved and wanted from the very beginning,
that it will be given respect and that respect for life is placed highest on the scale
of human values, and if we can optimize the prenatal and perinatal stages of life
without frustration of basic needs, without aggression and psychotoxic
influence, the result could be a non-violent society.
The way you treat your child is the way the child will treat the world. This
includes the unborn child, and this is also the whole truth about primary
prevention.
The prenatal stage of life represents a unique opportunity for the primary
prevention of psychological, emotional and physical disorders in later life. At
this stage we can also develop preventive procedures to decrease premature birth
and perinatal morbidity and mortality. In order to understand the enormous
42
potential power of the prenatal processes and their impact on the individual's
prenatal and postnatal health, we have to ask ourselves what the prenatal stage
of life implies.
In closing I indeed agree with what André Gide said, "Everything has been said
already, but as no one listens, we must begin again."
REFERENCES
1. Fedor-Freybergh P.G., Vogel V.: Encounter with the Unborn: Philosophical Impetus behind
Prenatal and Perinatal Psychology and Medicine. In: Fedor-Freybergh P.G., Vogel V. (eds.)
Prenatal and Perinatal Psychology and Medicine. Encounter with the Unborn: A comprehensive
Survey of Research and Practice. Parthenon Publishing, Carnforth, 1988, pp. XVIII-XXXII.
2. Fedor-Freybergh P.G.: Prenatální a perinatální psychologie a medicina: Nový přístup k primární
prevenci. Kontext 8: 6-9, 1952.
3. Fedor-Freybergh P.G. Psychophysische Gegebenheiten der Perinatalzeit als Umwelt des Kindes.
In: Schindler S., Zimprich H. (eds.) Ökologie der Perinatalzeit. Hippokrates, Stuttgart, 1983, pp.
24-49.
4. Chamberlain D.B.: The Mind of the Newborn: Increasing Evidence of Competence. In:
Fedor-Freybergh P.G., Vogel V. (eds) Prenatal and Perinatal Psychology and Medicine. Encounter
with the Unborn: A comprehensive Survey of Research and Practice. Parthenon Publishing,
Carnforth, 1988, pp. 5-22.
5. Fedor-Freybergh P.G.: Presidential Address. 9th International Congress on Prenatal and Perinatal
Psychology and Medicine. Jerusalem. Pre- and Perinatal Psychology Journal 4: 241-248, 1990.
6. Tyano S.: Personal Communication. 1987
7. Fedor-Freybergh P.C.: The Biochemistry of Bonding. 2nd International Congress of the Pre- and
Perinatal Psychology Association of North America, San Diego, 1985.
8. Fedor-Freybergh P.G.: Continuity from Prenatal to Postnatal Life. In: Papini M, Pasquinelli A,
Gidoni EA (eds) Development, Handicap, Rehabilitation: Practice and Theory. Excerpta Medica,
Amsterdam, pp. 259-263, 1990.
9. Fedor-Freybergh P.G.: The Prenatal and Perinatal Science and Practice in the Changing World.
Presidential Address. 10th International Congress on Prenatal and Perinatal Psychology and
Medicine, Cracow. Int. J. of Prenatal and Perinatal Studies 4: 155-160, 1992.
10. World Health Organization. Health Research Strategy for Health for All by the Year 2000. WHO,
Geneva, 1986.
11. Zikmund V.: Dimensions of Health and Disease: Biological, Psychological and Social. Int. J. of
Prenatal and Perinatal Psychology and Medicine 5: 265-276, 1993.
12. Fedor-Freybergh P.G.: Hormone Therapy in Psychiatry. In: Itil T.M., Laudahn G., Herrman W.M.
(eds.) Psychotropic Action of Hormones. Spectrum Publ. Inc., New York 1976, pp. 1-51.
13. David H.P., Dytrych Z., Matějíček Z., Schüller V.: Born unwanted. Springer, New York and
Avicenum, Prague, 1988.
14. Matějíček Z., Dytrych Z., Schüller V.: Kinder aus unerwünschter Schwangerschaft geboren.
Longitudinale Studie über 20 jahre. In: Fedor-Freybergh P.G. (ed.) Pränatale und Prenatale
Psychologie und Medizin. Rotation, Berlin 1987, pp. 77-92.
15. Matějíček Z., Dytrych Z.: Abgelehnte Schwangerschaften und ihre Folgen. In: Häsing H, Janus L.
(eds.) Ungewollte Kinder. rororo, Reinbek, 1994, pp. 194-199.
16. Saint-Exupéry A.: Le Petit Prince. Librairie Gallimard, Paris, 1946.
43
SPECTRAL ANALYSIS OF BLOOD PRESSURE AND CARDIAC
INTERVAL FLUCTUATIONS IN HYPERTENSIVES AND
NORMOTENSIVES
Siegelová J.1
, Fišer B.2
, Dušek J.1
, Placheta Z.1
, Svačinová H.1
, Jančík J.1
, Savin
E.3
, Martineaud J.P.3
1
Dept. of Functional Diagnostics and Rehabilitation and 2
Dept. Physiology,
Medical Faculty, Masaryk University, Brno, CZ, 3
Dept. Physiology, Hopital
Lariboisiere, Med. Faculty, Paris, France
INTRODUCTION
The assessment of cardiac autonomic status is very important in clinical
medicine and is based on investigations of heart rate variability, blood pressure
variability and baroreflex sensitivity. Spectral analysis of blood pressure and
cardiac intervals is used in determination of heart rate variability, blood
pressure variability and enables us to determine baroreflex sensitivity. The
baroreflex heart rate sensitivity (ms/mmHg, BRS) is low in patients with
essential hypertension. This fact was demonstrated by classical phenylephrine
method (Gribbin et al., 1971) and by spectral method (Siegelová et al. 1994,
1995). The mean value of the group of hypertensives is of about one half of the
mean value of the group of normotensive subjects. Because of a large scatter of
individual values in both groups there are many normotensives with a lower
BRS than the mean value of the hypertensive subjects and vice versa. On the
other hand the gain of the blood pressure component of baroreflex is normal in
essential hypertension (Grassi et al., 1998). This is a different finding than in
patients with heart failure where both the heart rate component and the blood
pressure component are decreased (Grassi et al., 1995). The aim of the present
study was to compare BRS in patients with essential hypertension and in
healthy young subjects with low BRS. It is an important question whether
young normotensives with low BRS can be at risk for development of
hypertension later and such a study can contribute to the solution of the problem.
The estimation of the blood pressure component of baroreflex in the present
study is based on the evaluation of the short-time blood pressure variability. It
was demonstrated that this variability is decreased in subjects with high BRS
(Mancia et al., 1986) because of homeostatic function of baroreflex in damping
the blood pressure oscillations.
METHODS
The blood pressure was non-invasively continuously recorded in finger arteries
by Peňáz volume-clamp method (Peňáz, 1973) for 5 minutes (Finapres,
Ohmeda) during the metronome-controlled breathing (0.33 Hz) in a group of
44
non-treated subjects with essential hypertension (EH, n=10, mean±SD: age
49±11 years, systolic/diastolic blood pressure - 155±23/99±12 mmHg). The
diagnosis of essential hypertension (EH) was established by detecting elevated
blood pressure (more than 140/90mmHg) on the basis of sphygmomanometer
measurements on three different occasions within one month. The possibility
that patients had secondary causes of hypertension was excluded by clinical
examination. The other control groups consisted of subjects selected from large
group of controls. BRS (ms/mmHg) was determined by spectral analysis of
spontaneous fluctuation of systolic blood pressure and cardiac interval. The
results were compared with a group of 10 healthy young subjects with low BRS
(<6ms/mmHg, LBRS) and with a group of subjects with high BRS (>25
ms/mmHg, HBRS). Both control groups were selected from the population of
100 healthy young adults (age 20-22 years) as subjects with the lowest,
respectively the highest baroreflex sensitivity. The method of BRS
determination is described elsewhere (Al-Kubati et al., 1997). At least 30 min
before the test the subjects were resting and adjusting to the environment (room
temperature 20 degrees centigrade). Meanwhile, a plethysmographic transducer,
Finapres Ohmeda was affixed. If the skin of the hands was cool, the subject was
asked to put the hands into warm water for several minutes. The blood pressure
was monitored for 10 min at rest. Three minutes' recording was taken at the end
of the resting period for further analysis. Then the subject was instructed to
breathe in synchronism with a metronome at 0.33 Hz for 5 min. The last 3
minutes were recorded and analyzed. The two recordings, one made during
spontaneous breathing and the second during metronome-controlled breathing
were evaluated by means of power spectral analysis. From the non-invasive
continuous blood pressure recording, beat-to-beat values of systolic and diastolic
blood pressure and pulse intervals were derived and analyzed. The values of all
three circulatory variables were linearly interpolated at 2 Hz to ensure
equidistant sampling in each time series. The baseline linear trend was removed
from all signals. The power spectral densities and cross-spectral densities were
calculated from the auto- and cross-correlation functions using Hanning's
spectral window. The value of cross-spectral power density of pulse intervals
and systolic blood pressure fluctuation [ms*mmHg] was divided by the value of
power spectral density of systolic blood pressure fluctuation [mmHg*mmHg] at
0.1 Hz. The obtained value, modulus, was considered to be the measure of BRS
[ms/mmHg]. The coherence at 0.1 Hz, i. e. the degree of linear coupling
between systolic pressure and pulse intervals fluctuation was calculated from
both recordings, for spontaneous and metronome-controlled breathing,
respectively. The study was approved by the ethics committee of the Masaryk
University in Brno and all subjects gave their written informed consent.
RESULTS
45
The variation of systolic blood pressure at 0.05 Hz (mean±SD) was 44.1±35.3
mmHg
2
/Hz in HBRS and 194.1±141.2 mmHg
2
/Hz in LBRS. The results
confirmed the former finding that the blood pressure variability is lower in
subjects with high BRS and vice versa. On the other hand in hypertensive
subjects the blood pressure variability was low despite both low heart rate
variability and low BRS. Variation of systolic blood pressure at 0.05 Hz was
61.8±26.5 mmHg
2
/Hz (EH versus LBRS: p<0.05, Wilcoxon). At 0.1 Hz the
variation of systolic blood pressure was higher in EH than in LBRS and HBRS
(EH: 52.9±26.5 mmHg
2
/Hz, HBRS:17.6±15.9 mmHg
2
/Hz, LBRS: 35.3±13.2
mmHg
2
/Hz; EH versus HBRS p<0.05).
It is concluded that the low variation of blood pressure at 0.05 Hz corresponds to
the normal blood pressure component of baroreflex in patients with essential
hypertension. The increased blood pressure variation at 0.1 Hz in this group of
patients reflects the impaired heart rate component of baroreflex.
DISCUSSION
The analysis of spontaneous beat-to-beat fluctuations of arterial pressure and
interbeat interval has several advantages, mainly the comfort during the
measurement. Two basic approaches have been proposed and validated, based
on time-domaine and frequency-domaine measurements. With time-domaine
approach, the sequence of three or more consecutive heart beats identified,
characterized by progressive increase in systolic blood pressure and progressive
lengthening of pulse interval, are characterized by a progressive reduction in
systolic blood pressure and progressive shortening of pulse interval. The
difference in spectra of normotensive subjects and patients with essential
hypertension indicates that the low BRS in both groups is caused by different
mechanisms. The low BRS in healthy subjects can be caused by low
baroreceptor sensitivity because both components of baroreflex - the blood
pressure component and the heart rate pressure component - are attenuated. This
resembles the situation in heart failure patients, where low baroreceptor
sensitivity was proved in animal experiments. The high level of aldosterone
stimulating Na/K-ATPase decreases the sensitivity of baroreceptors. This state
can be reversed by digoxin, the potent Na/K-ATPase inhibitor (Wang et al.,
1992). In humans, the low baroreflex sensitivity for both heart rate and blood
pressure components (Semrád et al., 1997) studied by various methods (AlKubati,1996)
supports this hypothesis. In patients with essential hypertension
the situation is different. In mild and moderate hypertension the resetting of
baroreceptors is responsible for the shift of the set-point to a higher level of
blood pressure, but the slope of blood pressure-cardiac interval curve which
correspond to BRS and the slope of blood pressure-muscle sympathetic activity
curve remain unchanged (Grassi, 1987). In severe hypertension the set-point
further moves to higher values of blood pressure but the decrease in slope takes
46
place (Korner et al., 1974). This was not the case of our hypertensive subjects.
Most probably the high sympathetic activity observed in essential hypertension
accompanied with low parasympathetic activity is responsible for the decrease
in BRS at intact baroreceptor sensitivity (Mancia, 1997). It is necessary to notice
that the magnitude of fluctuation of blood pressure can be different in
hypertensives and this fact can weaken our statement about normal baroreceptor
sensitivity in essential hypertension. On the other hand the results of
experiments with vasoactive drugs support this hypothesis (Grassi, 1987). The
problem whether the low BRS contributes to the development of hypertensive
disease and in which extent remains unsettled. Only a prospective study on a
large number of subjects can answer this question. The spectral method for BRS
determination is non-invasive and in our modification with controlled rate of
respiration would be suitable for such testing.
Supported by IG A MZ CR 4313-3.
REFERENCES
1. Gribbin B., Pickering E.G., Sleight P., Peto R.: Effect of age and high blood pressure on
baroreflex sensitivity in man. Circ. Res. 29: 424-431, 1971.
2. Siegelová J., Fišer B., Dušek J., Al-Kubati M.: Die Baroreflex-Sensitivitaetsmessung bei
Patienten mit essentieller Hypertonie: Einfluss von Enalapril. Nieren und Hochdruckkrankheiten
4: 20-22, 1995.
3. Siegelová J., Fišer B., Dušek J.: Baroreflex heart rate sensitivity in essential hypertension: the
effect of Isoptin SR 240 therapy. In: 22nd Congress of the Internat. Society of Internal Medicine.
(eds.) Varro V., Chatel R. de: International Proceeding, Division Monduzzi Editore, Bologna,
Italy, 1994, 99-102.
4. Grassi G., Cattaneo B.M., Seravalle G., Lanfranchi A., Mancia G.: Baroreflex control of
sympathetic nerve activity in essential and secondary hypertension. Hypertension 31: 68-72,
1998.
5. Grassi G., Seravalle G., Cattaneo B.M., Lanfranchi A., Vailati S., Giannattasio C. et al.:
Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure.
Circulation 92: 3206-3211, 1995.
6. Mancia G., Parati G., Pomidossi G., et al.: Arterial baroreflexes and blood pressure and heart rate
variabilities in human. Hypertension 8: 147-153, 1986.
7. Peňáz J.: Photoelectric measurement of blood pressure, volume and flow in the finger. In Digest
10th Int. Conf. Med. Biol. Eng, Dresden 1973, 104.
8. Al-Kubati M.A., Fišer B., Siegelová J.: Baroreflex sensitivity during psychological stress.
Physiol. Res. 46: 27-33, 1997.
9. Wang S., Mcclain J., Zucker H.: Aldosterone-reduced baroreceptor discharge in the dog.
Hypertension Dallas 19: 270-277, 1992.
10. Semrád B., Fišer B., Honzíková N.: Blood pressure control by baroreflex in patients after
myocardial infarction. Scripta Medica, 70: 3-8 1997.
11. Al-Kubati M.A.: Baroreflex sensitivity during the stimulation of low-pressure receptors. Scripta
Medica 69: 191-196, 1996.
12. Grassi G.: Role of the sympathetic nervous system in human hypertension. J. Hypertens. 16: 1979
– 1987, 1998.
13. Korner P.I., West M.J., Shaw J., Uther J.B.: "Steady state" properties of the baroreceptor-heart
rate reflex in essential hypertension in man. Clinical and Experimental Pharmacology and
Physiology 1: 65-76, 1974.
14. Mancia G.: Bjorn Folkow Award Lecture - The sympathetic nervous system in hypertension. J.
Hyperten. 15: 1553-1565, 1997.
47
BLOOD PRESSURE COMPONENT OF BAROREFLEX IN PATIENTS
WITH ESSENTIAL HYPERTENSION
Fišer B.1
, Siegelová J.2
, Dušek J.2
, Dobšák P.2
, Placheta Z.2
, Savin E.3
,
Martineaud J.P.3
1
Department of Physiology and 2
Department of Functional Diagnostics and
Rehabilitation, Medical Faculty, Masaryk University, Brno, Czech Republic,
3
Dept. Physiology, Hopital Lariboisiere, Med. Faculty, Paris, France
INTRODUCTION
The treatment of essential hypertension with ACE-inhibitor enalapril
significantly decreased blood pressure. Baroreflex sensitivity studied by spectral
method (Robbe et al., 1987) expressed in ms/mmHg (BRS) was increased
significantly in comparison with placebo therapy, but remained low in
comparison to normotensive subjects (Siegelová et al., 1995). Similarly the
treatment with verapamil (240 mg per day in slow-releasing formulation) in
monotherapy resulted in small significant increase in BRS in group of
hypertensives with very low BRS, but BRS normalization was not achieved
(Siegelová et al., 1994).
The aim of the present study was the measurements of blood pressure
component in hypertensives treated with ACE-inhibitor trandolapril together
with slow-releasing verapamil in combination. The blood pressure component of
baroreflex was evaluated by means of a technique developed in our laboratory.
METHODS AND SUBJECTS
We examined 18 patients with mild essential hypertension (men, aged 48±5
years, body weight 88±9 kg) after 3 months of the combined therapy with
trandolapril (2 mg, in one morning dose) and dilthiazem (retard, 90 mg, twice a
day, EH TD) with mean BRS (±S.D.) 8.2±3.4 ms/mmHg. The diagnosis of
essential hypertension was proved by WHO criteria and the secondary
hypertension was disclosed. The patients with EH treated in combination with
trandolapril and dilthiazem were compared with 10 normotensives with high
BRS>10 ms/mmHg (C-HBRS) and with 10 normotensives with low BRS<5
ms/mmHg (C-LBRS). Both normotensive control groups were selected from the
population of 100 healthy adults. Another group of 10 non-treated patients with
essential hypertension (EH) with BRS 4.7±1.8 ms/mmHg was examined and
compared, too.
The blood pressure component of baroreflex was examined by the following
procedure. The subjects were studied supine. Two inflatable cuffs (width 20 cm)
were placed over the thighs of the subjects. The thigh cuffs were abruptly
inflated to 180 mmHg (or over 20 mmHg above the patient´s systolic pressure)
48
after the subject had been recumbent for at least 20 min. 5 min later a rapid
decrease in cuff pressure to 60 mmHg elicited a decrease in systolic and
diastolic blood pressure. The pressure of 60 mmHg in the occluding cuffs was
chosen in order to prevent an increased venous return from legs and stimulation
of low pressure receptors. Blood pressure in digital arteries was recorded
continuously by Peňáz non-invasive technique (Peňáz, 1973) with Finapres BP
Monitor 2300 (Ohmeda, Engelwood, USA). After a decrease in blood pressure
of approximately 10-20 mmHg the blood pressure returned back to the original
level (Savin et al.,1997). The curve of systolic and diastolic blood pressure
return is S-shaped with a linear central part. The slope of the systolic blood
pressure return (SLOPE-SBP) and the slope of the diastolic blood pressure
return (SLOPE-DBP) were calculated by means of linear regression and
expressed in mmHg/s. The magnitude of SLOPE-SBP and SLOPE-DBP
corresponded to the gain of the blood pressure component of baroreflex. The
Ethics Committee of the Masaryk University Teaching Hospital approved the
study.
Statistics
The results are summarized as means ± SD. The statistical significance of
differences between EH and EH TD was determined by Wilcoxon test for
paired data, that between EH and C by Wilcoxon unpaired test. Further analysis
was then performed by analysis of variance.
RESULTS
The combined therapy with trandolapril and dilthiazem for 3 months
significantly decreased systolic and diastolic blood pressure and significantly
increased BRS in comparison with placebo therapy (ANOVA, p<0.05). The
results of the analysis of the blood pressure component of baroreflex revealed
that the gain of the whole baroreflex in EH TD and in EH (mean SBP 166±12
mmHg, DPB 102±8 mmHg) corresponded to healthy subjects with high BRS.
The following values of SLOPE-SBP and SLOPE-DBP respectively
(mean±S.D.) were found: EH TD - 0.93±1.33 and 0.55±0.65; C-LBRS -
0.48±0.18 and 0.30±0.14; C-HBRS - 1.29±0.62 and 1.18±0.58; EH - 1.04±0.64
and 0.92±0.68.
The values of SLOPE-SBP and SLOPE-DBP in C-LBRS were significantly
different from the other groups (ANOVA, p<0.05).
DISCUSSION
The mechanism which corresponds to the normalization of BRS after therapy
with ACE-inhibitor trandolapril and slow-releasing verapamil in combination is
unknown. Nevertheless, some results of other laboratories together with the
results of the present study can contribute to the elucidation of problems
49
related to two questions: Why BRS is low in essential hypertension and which
changes of baroreflex are responsible for the treatment-induced BRS increase?
The gain of baroreflex is the product of three parts of baroreflex, baroreceptor
sensitivity, the amplification of neuronal net and the effectivity of the effector
branches of the reflex modulating cardiac output and peripheral resistance.
A low baroreflex gain was found in patients with heart failure, where reduced
muscle sympathetic nerve activity (MSNA) modulation by baroreflex was
found (Grassi et al.,1995). This finding can be explained by a low sensitivity
of baroreceptors. Aldosterone, the concentration of which is increased in heart
failure, stimulates Na/K-ATPase of receptors. This results in hyperpolarization
of receptor cells and decreased frequency of efferent train of spikes (Wang,
1992). A low baroreceptor sensitivity is probably responsible for a decrease in
BRS in normotensives with low BRS. The correlation of low BRS with low
slope supports this hypothesis. On the other hand deactivation of baroreceptors
and stimulation by vasoactive drug-induced changes in blood pressure can
influence MSNA, so that it remains unchanged in essential hypertension
compared to normotension, at variance from the reduction in the heart rate
alteration (Mancia, 1997, Grassi et al., 1998).
An attractive hypothesis that a low baroreceptor sensitivity is compensated by
the increased responsiveness of smooth muscle of hypertrophic arterial wall
(Folkow, 1978) is not supported by the available evidence. A long-lasting
therapy with ACE-inhibitor enalapril decreased blood pressure and normalized
forearm blood flow after 5 min of ischaemia, which indicated regression of
hypertrophy of the resistance vessels. BRS, however, remained low in patients
treated with enalapril, reaching approximately one half of age-matched
normotensive controls (Siegelová et al.,1995).
It seems that sympathetic overactivity documented by increased MSNA in
subjects with essential hypertension (Mancia, 1997) inhibited the baroreflexmediated
vagal response. Angiotensin II activates the sympathetic nervous
system both centrally and peripherally (Zimmerman, 1981). The reverse of this
influence was not achieved by enalapril in one morning dose, probably because
of insufficient trough-to-peak ratio. The trough-to-peak ratio of trandolapril is
higher. Verapamil increased the threshold in sinoatrial pacemaker cells. The
increased variation of interbeat intervals at constant variation of the slope of
diastolic prepotential is the consequence of it. The normalization of BRS in
hypertensives after combined trandolapril-verapamil treatment can be the result
of synergistic influence of both drugs. If this explanation is correct then the
increase in BRS reflects the suppression of sympathetic activity which can be
very important for prevention of sudden cardiac death and other cardiac and
vascular alterations that lead to hypertension-related morbidity and mortality.
It is concluded that the gain of the whole baroreflex in patients with essential
hypertension with combined therapy with trandolapril and dilthiazem for 3
months (EH TD) corresponds to healthy subjects with high BRS.
Supported by IG A MZ CR 4313-3.
50
REFERENCES
1. Robbe H.W.J., Mulder L.J.M., Ruddel H., Langewiz W.A., Mulder G.: Assessment of
baroreceptor reflex sensitivity by means of spectral analysis. Hypertension 10: 538-543, 1987,.
2. Siegelová J., Fišer B., Dušek J., AL-Kubati M.: Baroreflex-Sensitivitaetsmessung bei Patienten
mit essentieler Hypertonie: Einfluss von Enalapril. Nieren und Hochdruckkrankheiten 24: 20-22,
1995.
3. Siegelová J., Fišer B., Dušek J.: Baroreflex heart rate sensitivity in essential hypertension: the
effect of Isoptin SR 240 therapy. In: 22nd
Congress of Internat. Medicine, V. Varró, R. de Chantel
(eds.) International Proceeding Div. Monduzzi Editore, Bologna 1994, pp. 99-102.
4. Al-Kubati M., Fišer B., Siegelová J.: Baroreflex sensitivity during psychological stress. Physiol
Res 46: 27-33, 1997.
5. Peňáz J.: Photoelectric measurement of blood pressure, volume and flow in the finger. In: Digest
of the 10th
Int. Conf. Med. Biol. Engineering, Dresden, 1973, p.104.
6. Savin E., Siegelová J., Fišer B., Bonnin P.: Intra- and extracranial artery blood velocity during a
sudden blood pressure decrease in humans. Eur. J. Appl. Physiol. 76: 289-293, 1997.
7. Grassi G., Seravalle G., Gattaneo B.M., Lanfranchi A., Vailati S., Giannattasio C. et al.:
Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure.
Circulation 92: 3206-3211, 1995.
8. Wang S.J., McClain J.M., Zucker H.: Aldosterone reduced baroreceptor discharge in the dog.
Hypertension 19: 270-277, 1992.
9. Mancia G.: The sympathetic nervous system in hypertension. J Hypertens 15: 1553-1565, 1997.
10. Grassi G., Gattaneo B.M., Seravalle G., Lanfranchi A., Mancia G.: Baroreflex control of
sympathetic nerve activity in essential and secondary hypertension. Hypertension 31: 68-72,
1998.
11. Folkow B.: The Fourth Volhard Lecture: Cardiovascular structural adaptation: its role in the
initiation and maintenance of primary hypertension. Clin. Sci. Mol. Med. 4: 3s-22s, 1978.
12. Zimmerman B.G.: Adrenergic facilitation by angiotensin: does it serve a physiological function?
Clin. Sci. 60: 343-348, 1981.
51
EFFECTS OF REHABILITATION IN MODERATE CONGESTIVE
HEART FAILURE USING LOW-FREQUENCY ELECTRICAL
STIMULATION OF INFERIOR LIMB MUSCLES
Eicher J.C., Maillefert J.F., Bulté C., Walker P., Moreau D., Cassillas J.M.,
Brunotte F., Wolf J.E.
University Hospital of Dijon, France
INTRODUCTION
Exercise intolerance is the most frequent complaint of patients with congestive
heart failure (CHF). An increase in pulmonary venous pressure may lead to
dyspnoea during exercise and muscle fatigue is the primary determinant of
exercise capacity. A skeletal muscle metabolic dysfunction, characterized by
depressed oxidative capacities, contributes to this fatigue. Low-frequency
electrical stimulation (LFMES) has been shown to induce an increase
in the muscular oxidative capacities and could represent a new form of mild
physical training. The aim of this study was to evaluate the effects of LFMES on
maximal and submaximal exercise capacity, skeletal muscle metabolism,
vasomotor response to exercise and autonomic tone in patients with CHF.
PATIENTS AND METHODS
26 patients (23 M and 3 F, aged 56,41±8,5) with idiopathic dilated
cardiomyopathy (n=12) or ischemic heart disease (n=14), in NYHA class II-III
and in stable condition were subjected to low-frequency (10 Hz) electrical
stimulation bilaterally applied to quadriceps and gastrocnemius muscle at a rate
of 1 hour/day, 5 days/week during 5 weeks, using 2 portative dual-channel
stimulators ELPHA 2000 (DANMETER, Odense, NV, Denmark). Initial and
final assessment included 6-minute walk test, maximal bicycle exercise testing
with VO2 measurement, 24-hour Holter ECG monitoring with spectral and non
spectral analysis of heart rate variability (HRV), plasma norepinephrine (PNE)
levels, Doppler evaluation of common femoral artery blood flow at rest and after
the exercise.
Statistical analysis was performed using the McNemar test of symmetry, the
Wilcoxon paired, the Chi2
and the Friedman tests. Statistical significance was
defined as a p value < 0.05.
52
RESULTS
initial final p
distance in 6min (m) 415.1±10.5 472±11 < 0.05
peak VO2 (ml/kg/min) 16.80±4.5 18,9±6 < 0.05
VO2AT (ml/kg/min) 11.50±2.8 14,2±3,6 < 0.05
MVFA (cm/s) rest 13.9±9.4 12.4±5.2 NS
post exercise 29.1±18.3 37.9±21.7 < 0.05
(VO2 : oxygen consumption, AT : anaerobic treshold, MVFA : mean blood
velocity in common femoral artery)
Maximal and submaximal exercise capacity and exercise-induced vasodilatation
were increased by LFMES, whereas no significant effect on HRV, PNE levels or
nuclear magnetic resonance (NMR) parameters could be demonstrated.
DISCUSSION
Many studies have been conducted on the effects of LFMES on skeletal
muscles, but the number of results in humans is limited (Maillefert, 1998).
Patients with CHF frequently have moderately reduced skeletal muscle volume,
which possibly contributes to exercise intolerance. In our study we showed that
LFMES did not induce variations in heart rate, arterial blood pressure, cardiac
output and rhythm. Chronic LFMES leads to early changes in the activity of
enzymes involved in the energy metabolism, with an increased activity of
oxidative enzymes and a decreased activity of glycolytic enzymes (Brownson,
1988). Structural changes include an increase in the capillary density (Brown,
1976) and in the volume density of mitochondria and in the volume of
sarcoplasmatic reticulum (Heilmann, 1981). Consequently, the contractile
properties are modified. The time-to-peak values of isometric twitch
contractions, half-relaxation time and resistance to fatigue are increased
(Hudlická, 1982). A classical training usually uses systemic exercises, which
require an increase in cardiac output and it has not been shown that such
exercises can be tolerated by all patients with severe heart failure or
arrhythmias. The results of our study suggest that LFMES is safe, well tolerated
and induces an increase in exercise capacity in patients with CHF. This seems to
be mainly mediated by an improvement of vasodilatation without effect on
autonomic tone.
CONCLUSION
LFMES of inferior limbs muscles induces an improvement of exercise capacity
in patients with chronic CHF. LFMES could represent an alternative to classical
training in these patients, which could be conducted easily at home without any
cardiac risk.
53
REFERENCES
1. Brownson C., Isenberg H., Brown W., Salmons S., Edward S.: Changes in skeletal muscle gene
transcription induced by chronic stimulation. Muscle Nerve 11:1183-1189, 1988.
2. Brown M.D., Cotter M.A., Hudlická O, Vrbová G.: The effects of different patterns of muscle
activity on capillary density: Mechanical properties and structure of slow and fast rabbit muscles.
Pflügers Arch. 361: 241-250, 1976.
3. Heilmann C., Müller W., Pette D.: Correlation between ultrastructural and functional changes in
sarcoplasmatic reticulum during chronic stimulation of fast muscle. J. Membrane 59: 143-149,
981.
4. Hudlická O., Brown M., Cotter M., Smith M., Vrbová G.: The effects of a long-term stimulation
of fast muscles on their blood flow, metabolism and ability to withstand fatigue. Pflügers Arch.
369: 141-149, 1988.
5. Maillefert J.F., Eicher J.C., Walker P., Dulieu V., Rouhier-Marcer I., Branly F., Cohen M.,
Brunotte F., Wolf J.E., Casillas J.M., Didier J.P.: Effects of low-frequency electrical stimulation
of quadriceps and calf muscles in patients with chronic heart failure. J. Cardiopulm. Rehabil., 18:
277-282, 1998.
EXPERIMENTAL STUDIES
55
THE SIMPLE LINEAR MODEL OF THE CARDIOVASCULAR
SYSTEM AND ITS APPLICATION
Kenner T., Schneditz D., Krisper P., Timischl S.
Physiologisches Institut, Medizinische Universitätsklinik, Institut für
Mathematik der Karl-Franzens-Universität Graz
INTRODUCTION
The fundamental features of the circulation depend on the fact that the
cardiovascular systém is a closed loop - as described by William Harvey in
1628. Since the first physical model of this system was designed by Ernst
Heinrich Weber in 1850, many more or less complex physical or mathematical
models have been described. Especially, it is necessary here to mention the
model by Guyton (as summarized in his textbook 1991). A very simple linear
model was used to calculate the expected pressure drop after experimental
occlusion of the portal vein (Kenner, 1959). In the time of the availability of
computer power, it is the question if there is any demand for a simple and linear
model. - The idea to revive the simple model (Kenner 1959) came up for three
reasons.
1) For the first rough interpretation of recorded biologic reactions a simple
model appears to be more effective than a very complex and sophisticated
model.
2) We have made some preliminary measurements in the dialysis unit of the
Department of Medicine of the University Hospital in Graz. In this case the
interpretation of blood pressure changes after the occlusion of the AV-shunt
of dialysis patients was of interest. An example will be discussed below.
3) A simple model is easy to understand and, therefore, of didactic value.
METHODS
The model
The model consists of one pump with the property H (dimension: inverse
resistance),
an arterial compartment (index a), a peripheral resistance R and a venous
compartment (index v).
The following symbols are used:
Q cardiac output
p pressure
VB blood volume
The very simple linear model is described by three equations:
56
(1) VB = pa.Ca + pv.Cv (blood volume)
(2) pa - pv = R.Q (peripheral resistance)
(3) Q = pv.H (Frank-Starling mechanism)
From these equations it is easily possible to plot Q versus pv, to demonstrate the
effect of a variation of the blood volume, a variation of the compliances and a
variation of the peripheral resistance. Furthermore, it turns out that in all
essential equations the nondimensional product or quotient
(4) H.R = pa/pv
acts as one main parameter. It may be reminded that H includes contractility and
heart rate. In order to summarize the results in compact form, two abbreviations
are introduced:
(5) VB/(Ca + Cv) = MCFP
(mean circulatory filling pressure according to Guyton 1991)
(6) Ca/(Ca + Cv) = k
(ratio of arterial and total compliance)
For our special problem the most interesting result is the effect of an increase of
the resistance on the arterial pressure. We find:
(7) pa = MCFP (1 + H.R)/(1 + k.H.R)
PARAMETERS AND EXAMPLE
The product H.R, under normal conditions, has a value of about 20. The value of
k is about 1/20. Therefore, if the experimentally induced increase of the total
peripheral resistance can be estimated, then the expected increase of the arterial
pressure (ceteris paribus) can be calculated from equation (7).
Patient G., male, 72 years. The measurements were made in the hemodialysis
unit after informed consent of the patient.
Cardiac output (indicator dilution): 6.1 l/min. The flow through the arteriovenous
access shunt was measured with ultrasound: 1.9 l/min. The blood
pressure was measured with the cuff technique and, continuously, with the
Penaz-technique. The control value was about 150/85 mmHg. Using the data
mentioned above, the increase of the total peripheral resistance due to complete
occlusion of the shunt was calculated to be 45%. From equation (7) an expected
increase of the mean blood pressure (ceteris paribus) of 19% was estimated.
During a 15 sec occlusion the mean blood pressure rose to a plateau, which was
only 10% above the control value before and after the occlusion. The difference
is primarily due to a reduction of H. However vascular reactions influencing the
actual value of R cannot be excluded.
57
The reduction of H consists of inotropic and chronotropic components and is in
part due to the myocardial sensitivity to the increased afterload and in part due
to the effect of baroreceptor control.
The baroreceptor sensitivity (BRS) was measured and was found to be about 2.5
ms/mmHg, a rather low value. This index characterizes primarily the
chronotropic mechanism. In other preliminary observations in dialysis patients
the BRS may even be zero.
CONCLUSION
A very simple linear model of the circulation can be used to interpret some basic
interrelations between fundamental parameters and variables of the system. As
an example the reaction of the system to a sudden increase of the peripheral
resistance is demonstrated.
REFERENCES
1. Guyton A.C.: Textbook of medical physiology. 8 th ed. W.B. Saunders Comp., Philadelphia,
London 1991, pp 221-233.
2. Kenner T.: Über die Ursache der Blutdrucksenkung nach Pfortaderligatur bei Ratten. Z.
Kreislauff. 48: 204-214, 1959.
3. Kenner T.: Beiträge zu einem Kreislaufmodell von E.H. Weber. Z. Biol. 111: 67-74, 1959.
58
EXPRESSION OF CELL-DEATH GENES DURING THE
DEVELOPMENT OF RIGHT VENTRICULAR HYPERTROPHY IN
MONOCROTALINE-TREATED RATS
Laubriet A., Assem M., Teyssier J.R., Rochette L.
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaire
Expérimentales, Faculté de Médecine, Dijon, France.
INTRODUCTION
The tumor supressor gene P53 has come to be known as a master guardian
of the genome and a member of the DNA damage-response pathway. P53
can lead to either growth arrest or apoptosis in DNA damage cells. The
growth-suppressive role of P53 occurs by activating the expression of the
P21Waf1/Cip1 gene, which is a potent cyclin dependent kinase inhibitor.
Induction of P21 by P53 results in cell cycle arrest in G1 or G2 to allow
DNA to take place. If repair is not successfull, P53 may promote cell death
by apoptosis via the inhibition of BCl-2 and the activation of BAX. BCl-2
and BAX genes are key regulators of apoptosis: BCl-2 is a potential
antiapoptotic factor whereas BAX is a death-promoting factor (Hirsch, 1998,
Ko, 1996). Both genes encode protein subunits of a mitochondrial
megachannel called permeability transition pore. If the mitochondria
undergoes these transition of permeability, factors such as Apoptosis Inducer
Factor (AIF) and cytochrome c were released, which induce apoptosis
(Saini, 1998).
The purpose of this study was to investigate the expression of P53, P21,
BCl-2 and BAX mRNA during the development of pressure overload right
ventricular hypertrophy induced in rats by a single injection of
monocrotaline.
METHODS
Male Wistar rats received (i.p.) a single injection of 60mg/kg monocrotaline
(MCT rats) or saline (control rats) and were killed after 14, 21 or 31 days.
The hearts were removed and were dissected in right ventricle (RV), left
ventricle (LV) and septum (S). Total RNA were extracted and retrotranscript
in cDNA. Changes in P53, P21, BCl-2 and BAX transcript levels in the
hypertrophied ventricle and the unaltered left one were quantified by RTPCR.
Apoptosis associated chromatin-cleavage was assessed in situ by the
TUNEL assay on embedded paraffin section of the hearts.
59
RESULTS
MCT caused a progressive increase in the ratio of RV to LV+S weights from
days 21 to 31 that was significantly greater than the control values (140%
and 227,5% , respectively), indicating the development of RV hypertrophy
in the MCT rats. The results of RT-PCR showed that P53 was up-regulated
at 21 days in the MCT rats compared to the control rats (76%) and p21 was
significantly increased at 31 days (27%). The ratio of BCl-2 to BAX, which
gives evidence of the balance between death-repressor and death-activator
proteins, decreased significantly at day 21 and 31 in the MCT rats by –40%
and –70% , respectively, indicating that cells underwent apoptosis.
DISCUSSION
A cardiac hypoxia and a pressure overload on the right ventricle could
produce an oxidative stress and therefore, an overexpression of P53 (Wilson,
1992). Up-regulation of P53 can lead in one hand to cell growth arrest via
P21 and in the other hand to cell death of hypertrophied cardiomyocytes via
BCl-2 and BAX.
REFERENCES
1. Hirsch T., Prives C., Marzo I., Marchetti P., Zamzani N., Kroemer G. :
Mitochondrial permeability transition in apoptosis and necrosis. Cell Biology and
toxicology l4: 141-145, 1998.
2. Ko L.J., Prives C.: P53: Puzzle and paradigm. Genes and Development 10: 1054-
1072, 1996.
3. Saini K.S., Walker N.I. : Biochemical and molecular mechanisms regulating
apoptosis. Molecular and Cellular Biochemistry 178: 9-25, 1998.
4. Wilson D.W., Segall H.J., Pan L.C., Estep J.E., Morin D. : Mechanisms and
pathology of monocrotaline pulmonary toxicity. Critical Rewiews in Toxicology 22:
307-325, 1992.
60
AMINOGUANIDINE AND ALLOXAN-INDUCED DIABETES
Courderot-Masuyer C., Dobšák P. 1
, Laubriet A., Teissier J.R., Rochette L.
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaire
Expérimentales, Faculté de Médecine, Dijon, France, 1
Department of
Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk
University, St Anna Hospital Brno, CZ
INTRODUCTION
Diabetic patients have a significantly greater incidence and severity of
angina, acute myocardial infarctions, congestive heart failure and other
manifestations of atherosclerosis than the non-diabetic population. It has
been reported even in the absence of ischemic heart disease, impairment of
ventricular performence can occur. Firstly we decided to investigate cardiac
performance in the model of alloxan-induced diabetes in rats using isolated
working heart technique.
METHODS
Diabetes was induced by an intravenous injection of alloxan (60mg/kg)
dissolved in 0.1 M citrate buffer (pH 4,5). Control rats were injected with
citrate buffer alone. Both control and diabetic rats were used 48 hours after
vehicule or alloxan injection. Animals in the diabetic groups were excluded
if blood glucose was less than 3g/l. In addition a separate group of alloxaninjected
and control rats received orally and daily a dose of 250 mg/kg of
aminoguanidine during 2 days before the evaluation of cardiac performance.
Cardiac performance was assayed by the isolated perfused heart working
technique. After 30 min of perfusion. the main coronary artery was ligatured
and the ligature was maintained for 10 min. It was then cut and reperfusion
continued for 10 min. Aortic flow rate and heart beat were decresed in the
diabetic group whereas diabetic rats showed to be more resistant to ischemia
compared to control group. After aminoguanidine pretreatment aortic flow
rate recovered initial value in diabetic group although no change in glucose
blood level was observed. It has been demnostrated that advanced
glycosylation products inactivate nitric oxide and involve an impairment in
endothelium-dependent relaxation. It has also found that aminoguanidine is
an inhibitor of semicarbazine-sensitive amine oxidase and detoxify toxic
aldehydes. Aminoguanidine selectively inhibits the cytokine-inducible
isoform of NO synthase which appears to be responsible for the excess
production of NO linked to diabetes mellitus. In a second part we decided to
evaluate the antioxidant properties of aminoguanidine. Indeed
hyperglycemia is increasesingly regarded as the cause of diabetic
61
complications especially via its ability of reducing sugars to glycate proteins
and produce reactive oxygen species. So we investigated the protection
provided by aminoguanidine by two approaches: 1) Electron Paramagnetic
Resonance (EPR) spectroscopy using spin trapping techniques to assess the
superoxide and hydroxyl radical scavening effects of aminoguanidine and 2)
spectrofluometric methods to investigate the protection provided by
aminoguanidine against the oxidation of allophycocyanin (a fluorescent
protein) induced by a peroxyl radical generator.
RESULTS
Our results demonstrated that aminoguanidine was able to scavenge
hydroxyl and peroxyl radicals. So these radical scavening properties of
aminoguanidine may help to explain the prevention of diabetic
complications as vascular dysfunction by this compound. in addition
TUNEL techniques made on diabetic rat hearts showed apoptotic cells
surrounding the vessels. In the separate diabetic group which had received
aminoguanidine treatment no apoptotic cells were presents closed to the
vessels. Using immunohistochemistry techniques we noted that apoptotic
cells were not cardiomyocytes.
DISCUSSION
Although in vivo studies investigating the effects of diabetes on severe
ischemia are controversial. Paradoxally, in vitro studies are more consistent
in demonstrating that heart are less susceptible to injury following a severe
episode of ischemia (Norton, 1996, Yildiz, 1998). In the other hand,
aminoguanidine has been shown to be capable of blocking the formation of
advanced glycation end products (AGEs). There is accumulating evidence
that the formation of AGEs increases with aging and is implicated in the
pathogenesis of diabetic atherosclerosis. Further experiments are needed to
discover the type of cells involved in apoptotic process in alloxan-induced
diabetes (Saini, 1998). However apoptotic process in this model of diabetic
rat could explain the impairment of cardiac performance.
REFERENCES
1. Yildiz G., Demiryurek A.T., Sahin-Erdemli I., Kanzik I.: Comparison of antioxidant
activities of aminoguanidine, methylguanidine and guanidine by luminal-enhanced
chemiluminiscence. Brit. J. Pharmacol. 124: 905-910, 1998.
2. Norton G.R., Candy G., Woodiwiss A.J.: Aminoguanidine prevents the decreased
myocardial compliance produced by streptozocin-induced diabetes mellitus in rats.
Circulation 93: 1905-1912, 1996.
3. Saini K.S., Walker N.I.: Biochemical and molecular mechanisms regulating
apoptosis. Molecular and Cellular Biochemistry 178: 9-25, 1998.
62
NEW PERSPECTIVES IN CARDIOPROTECTION: IN VITRO
ANTIISCHEMIC EFFECT OF CAPSAICIN AND CALCITONIN
GENE-RELATED PEPTIDE
Dobšák P.1
, Courderot-Masuyer C., Laubriet A., Svačinová H., Jančík J.,
Siegelová J., Eicher J.C., Wolf J.E., Rochette L.
1
Department of functional diagnostics and rehabilitation, Faculty of
Medicine, Masaryk University, St Anna Hospital Brno, CZ.
Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaire
Expérimentales, Faculté de Médecine, Dijon, France
INTRODUCTION
Single or multiple brief periods of regional or global ischemia and reperfusion
prior to a prolonged ischemic insult showed cardioprotective effects. The
mechanism underlying this phenomenon, called „ischemic preconditioning“,
remains unclear. There is now an increasing amount of evidence which suggests
the involvement of endogenous myocardial protective substances such as
calcitonine gene-related peptide (CGRP) in ischemic preconditioning. It has
been also shown that capsaicin evokes CGRP release from sensory nerves. The
present study was designed to further explore the possible cardioprotective
effect of CGRP and capsaicin in the rat model of isolated and perfused working
heart.
MATERIAL AND METHODS
Male Wistar rats (b.w. = 290-320 g) were anesthesized by pentobarbital sodium.
The hearts were rapidly excised, mounted on a Langendorff apparatus and
perfused by Krebs-Henseleit buffer (KHB) at a constant temperature 37º C. The
experiment was divided in 3 groups: l. CGRP 5x10-8
M group (n=5), 2.
capsaicin 30 μmol group (n=5) and 3. control group (n=6). Study protocol: a)
preischemic period (10min in Langendorff mode and 15min in working heart
mode) , b) period of global ischemia (30min at 37º C) and c) reperfusion period
(15min in Langendorff mode and 20min in working heart mode). CGRP and
capsaicin were added to the perfusate medium in the 5th minute of the working
heart mode (for 5min in preischemic period). Coronary, aortic and cardiac
output and the heart rate were measured. All data were analyzed using a oneway
ANOVA test and all values expressed as means ± S.E.M. Significance level
is chosen as p < 0,05.
Capsaicin and CGRP were obtained from Sigma Chemical Company (St.Louis,
MO, USA).
63
RESULTS
In the preischemic period the analysis of hemodynamic parameters showed no
significant difference in all groups. During the reperfusion period we noticed a
statistically significant increase of the values of coronary, aortic and cardiac
output in the group treated with capsaicin 30 μmol compared to the group with
CGRP 5x10-8
M (p < 0.01). All hearts in the control group developed venticular
arrhythmia, both fatal ventricular fibrillation and ventricular tachycardia.
Pretreatment with capsaicin 30 μmol caused a significant improvement of
cardiac functions and a reduction in the incidence of ventricular arrhythmia.
There was an overall decrease in heart rate (p<0.05) in the groups with capsaicin
and CGRP during the reperfusion period compared to the initial values in
preischemic period.
DISCUSSION
Calcitonin gene-related peptide, a principal transmitter in capsaicin-sensitive
sensory nerves, is present in the hearts of animals and humans and has numerous
physiological properties, several of which are thought to be beneficial to the
ischemic myocardium (Li, 1996, Källner, 1998). Capsaicin is the active
ingredient causing the pungent effects of red hot peppers. Although capsaicin
has been extensively studied in the nervous system, few studies with capsaicin
have been performed in the myocardium. In the myocardium, capsaicin has been
shown to cause release of CGRP from terminal nerve endings and protects
against myocardial injury induced by ischemia-reperfusion in the isolated
perfused rat heart (D´Alonzo, 1996) . There is now an increasing amount of
evidence to suggest that the ischemic preconditioning stimulates the release of
endogenous myocardial protective substances, such as CGRP. An exogenous
administration of them could mimic a classic ischemic preconditioning. In this
study the cardioprotective effect was observed only in the group treated by
capsaicin 30 μmol, suggesting the possible involvement in preconditioning-like
cardioprotection. In contrast, no significant cardioprotective effect of CGRP
5x10-8
M was found on the cardiac recovery in this experimental model. The
mechanisms responsible for the beneficial effects of capsaicin (and CGRP) on
the ischemic myocardium remain unclear. Both - capsaicin and CGRP- are
involved in the Ca++
handling in myocytes and nerves and the intracellular Ca++
regulation needs to be explored with regard to the antiischemic properties
(Poyner, 1992).
The results presented in this study suggest that pretreatment with capsaicin
30 μmol (but not CGRP 5x10-8
M) induced a preconditioning-like
cardioprotection, further supporting the conclusion that capsaicin may play an
important role in the mediation of ischemic preconditioning.
64
REFERENCES
1. Li Y.J., Xiao Z.S., Peng C.F., Deng H.W.: Calcitonin gene-related peptide-induced
preconditioning protect against ischemia-reperfusion injury in isolated rat hearts. Eur.J.Cardiol.
311: 163-167, 1996.
2. Källner G., Gonon A.., Franco-Cereceda A.: Calcitonin gene-related peptide in myocardial
ischaemia and reperfusion. Cardiovasc. Res. 38: 493-499, 1998.
3. D´Alonzo A.J., Grover G.J., Darbenzio R.B., Hess T.A., Sleph P.G., Dzwonczyk S., Zhu J.L.,
Sewter J.C.: In vitro effects of capsaicin antiarrhythmic and antiischemic activity. Eur. J.
Pharmacol. 272: 269-278, 1996.
4. Poyner D.R.: Calcitonin gene-related peptide: Multiple actions, multiple receptors. Pharm.Ther.
56: 23-51, 1992.
65
Biological rhythms in medicine, their importance in diagnostics, therapy and preventions
J. Siegelová +, J. Dušek+, F. Halberg*, G. Cornélissen*, B. Fišer+,
+Masaryk University, Brno, CZ , *University of Minnesota, USA ,
Chronomedicine. The current disease-cure-oriented health care
system does too little too late, at too great an expense for those
few who can afford it. For instance, a beat-to-beat electrocardiogram is already available, from an
individual monitored for a year in apparent health. Blood pressure has been recorded mostly at 15-min
intervals for over a decade. We can then summarize variability along the frequency of the cardiac and
then of the respiratory cycle and can use cardiac and then respiratory rhythm characteristics as
compacted endpoints for summaries via further repeated passes for the analysis of longer and longer
data sections to assess rhythms with lower and lower frequencies. These broader and broader
spectral windows on more and more data, with more and more compacting, can fit into an affordable
memory for storage, so that the analyses can continue as a feature of recycling. Circadian
hyperamplitude-tension, briefly CHAT, as noted carries the greatest risk of stroke. It is to be avoided
as best one can, not only during space travel, but for all the many persons at risk on earth. This task is
as important for vascular disease prevention, and is as much in the public domain, as are vaccinations
for infections.The reference values collected in this practical endeavor of physiological monitoring may
also serve a basic and applied chronoastro-biology in the context of cross-spectral analyses with the
incoming stream of information gained from space-borne vehicles. We may learn where we come
from, to better attempt to choose among the directions into which we can evolve.
66
67
1.
Otsuka K., Cornélissen G., Halberg F.: Age, g6. OD ĆASOVÉ NESPECIFICKÝCH MĚŘENÍ K
CHRONOBIOLOGICKÝM PŘÍSTUPŮM JAKO „ CHRONOMEDICINA A
CHRONOASTROBIOLOGIE“: VÝZVA VÝROBCŮM
FROM TIME-UNSPECIFIED MEASUREMENTS TO CHRONOBIOLOGICAL SPECIALTIES SUCH
AS CHRONOMEDICINE AND CHRONOASTROBIOLOGY:
CHALLENGES FOR MANUFACTURING
F. Halberg*, G. Cornélissen*, Y. Watanabe€ , J. Siegelová+, B. Fišer+,
*University of Minnesota, USA , € Tokyo Women´s Medical University, Japan, +Masaryk University,
Brno, CZ
At any science fair in Brno, the home city of J. G.Mendel, best known as the founder of genetics,
biotechnology should be in the foreground. Chronobiologic data revealing that the same dose of the
same hormone can stimulate or inhibit DNA synthesis, in a rhythmically changing sequence, suggest
that chronobio-technology is more than a play on words. It is not generally known that in fact Mendel
published more on meteorology than on plant hybridization. By providing a living example for
monitoring the environment, the time structures of which are now coded in our genes, Mendel laid the
groundwork for chronoastrobiology.Brno was also the home of K. Gödel, the mathematician who
provided notes of healthy caution, e.g., for those who work on software to analyze the results of the
automatic monitoring of blood pressure, started in Brno by J. Penaz and brought to the clinic by the
team of J. Siegelova, B. Fiser, J. Dušek and B. Semrád. These investigators pioneered blood
pressure chronotherapy guided by a longitudinal analysis with an individualized control chart, with
drugs by the local pharmaceutical manufacturer Lachema.
Chronomedicine. The current disease-cure-oriented health care
system does too little too late, at too great an expense for those
few who can afford it. Engineering for concomitantly resolving the
external conditions and the internal schedules‹chronoengineering in the broad sense, in the service of
a project on the BIOsphere and the COSmos (BIOCOS)‹could change this status quo.
Chronobioastrology informs us about what happens after the fait accompli of a crash, as did the
autopsy in classical pathology. We can use the currently available software for repeated passes over a