Faculty of Medicine • Masaryk University • Brno • Czech Republic Department of Functional Diagnostics and Rehabilitation PROCEEDINGS SYMPOSIUM NONINVASIVE METHODS IN CARDIOLOGY Edited by: F. Ha lb erg, T. Kenner, B. Fišer, J. Siegel ová 2006 Faculty of Medicine • Masaryk University • Brno • Czech Republic Department of Functional Diagnostics and Rehabilitation f ; PROCEEDINGS SYMPOSIUM ! : i NONINVASIVE METHODS IN CARDIOLOGY ! i Edited by: F. Hal berg, T. Kenner, B. Fiser, J. Siegelova 2006 j The Symposium takes place under the auspices of Prof. Ml Dr. Jan Zaloudik, CSc, Dean of Faculty of Medicine, Masaryk University, Brno MUDr. Roman Kraus, MBA, Director of St. Anna Teaching Hospital, Brno MUDr. Marie Kosulicova, Director of National Centre of Nursing and Other Health Professions, Brno Sponsors PRO.MED.CS, Praha a.s., Kardio-Line s.r.o, Pfizer Global Pharmaceuticals ISBN 80-7013-444-5 CONTENS PERSONAL CONSIDERATIONS ON OBSERVATION AND EVIDENCE IN PRACTICAL MEDICINE Ketmer T........................................................................................4 SEVEN DAY BLOOD PRESSURE MEASUREMENT: CONTRAVERSION IN SINGLE 24-H PROFILES OF BLOOD PRESSURE AND HEART RATE Halberg F.......................10 LESSONS ABOUT "LOADS" LEARNED WHILE DETECTING AND GREATLY REDUCING RESIDUAL ME SQR-I1YPERTEN S ION AND CHAT Halberg F..................27 CHRONOTHERANOSTICS OF MESOR-NQRMOTENSION VS. ORCADIAN OVERSWING, I.E., CHAT Cornelissen G............................................................................30 OCCASIONAL TRANSIENT CHAT OCCURS IN THE MESOR-NORMOTENSIVE INDIVIDUAL SchwartzkopfFO...............................:.............................................................33 NEED TO STANDARDIZE DATA COLLECTION Hillman D...........................................36 CHRONOBIOI.OGIC SERIAL SECTIONS COMPLEMENT SPECTRA Katinnas G........39 TIME COURSE OF BLOOD PRESSURES OVER 18 YEARS Watanabe Y.......................42 BLOOD PRESSURE AND HEART RATE VARIABILITY IN PATIENTS WITH CARDIAC TRANSPLANTATION Siegelova J....................................................................47 STROKE IN THE CZECH REPUBLIC Fiser B....................................................................55 IMPACT OF EXERCISE THERAPY ON CARDIOVASCULAR AUTONOMIC FUNCTION IN OBESE PATIENTS Svačinová H...............................................................62 COMBINED TRAINING IN WOMEN WITH ISCHEMIC HEART DISEASE: EFFECTS OF EIGHT-WEEK REHABILITATION PROGRAM Chludilova V....................................67 CARDIOPULMONARY FUNCTIONS AND BARQREFLEX SENSITIVITY BEFORE AND AFTER EXERCISE TRAINING Sosikova M..............................................................71 LUNG VOLUME REDUCTION SURGERY OF EMPHYSEMA PULMONUM: LUNG FUNCTION EXAMINATIONS VIcek J................................................................................75 EXERCISE TRAINING AND SYMPATHETIC NERVOUS ACTIVITY IN PATIENTS WITH HEART FAILURE Vank P.........................................................................................80 FUNCTIONAL IMPAIRMENT IN CHILDREN WITH CEREBRAL PALSY Drlikova L. 87 3 PERSONAL CONSIDERATIONS ON OBSERVATION AND EVIDENCE IN PRACTICAL MEDICINE Thomas Kenner, Physiologisches Institut, Graz Thomas KENNER Karl-Fran ze n s - Un i vers i tä t Graz Department of Physiology Graz, Austria Thomas .Kemi.er@kfumgraz .ac.at Dedicated to Prof, MUDr. Zdenek Placheta, DrSc. The task of physicians is either to support health of persons, to try to heal those who became sick or to reduce pain and discomfort, and to console. Essential activities within the field, of medicine have been, and still are based on observation and. experience. Any patient is a unique person and not a statistical item. The modern assumption that medicine can only be based on statistical evidence, in my opinion is an arrogance. And even, where evidence seems to be obvious it also seems obvious that quite often consequences of evidence and of observations are neglected. In the following text I want to discuss some items to which I have some personal connection. My relation to Ignaz Semmeiweis results from the fact that in 1932 due to the obvious neglect of hundred years of evidence my mother died of puerperal a few days after my birth in the University clinic of Vienna. The second topic - sudden infant death syndrome (SIDS) - shows, that on one hand a wrong hypothesis can lead to useful results and on the other hand, observation-based experience has helped to establish reasonable prophylactic effects. The third topic - peptic ulcer -- is again based on personal experience. It turns out that apparently no disease can be explained by just one single cause. I. SEMMELWEIS Against tremendous opposition and against malicious critical arguments by a majority of leading specialists Ignaz Semmeiweis (1818 ~ 1865) introduced the correct prophylactic measures to prevent puerperal fever after delivery. He demanded from students and physicians to clean their hands with chlorinated water before they were touching the women in labour. The success proved that his observations and conclusions were correct. It is important to note that his proposition was made before any bacteria had been discovered. As seen from our current knowledge, at the time of Semmeiweis the theories about the cause of puerperal fever were quite absurd. Even in our days, when, the etiology of infectious diseases like puerperal fever is well known, it is still necessary to demand hand-washing of physicians to prevent the transmission of diseases from patient to patient. Not only to avoid infection in connection with labour, but also in order to avoid any kind of hospital acquired infections (HAL) it is necessary to enforce cleaning of the hands of physicians. Weiss et al. (2006) point out that 4 several studies show that the rate of hand-washing in medical staff was between a third and a half of what was objectively required. They report, furthermore, that in the United States alone, there are two million cases of hospital acquired infections per year, 90000 of which end with the patient's death. The correct measure against a disease was introduced without knowledge of the causing agent. Now, in spite of our knowledge the correct measures are in a surprisingly high percentage neglected. It seems to be urgently necessary to teach medical students not only knowledge and skill but also behaviour, including cleanliness, proper dressing and washing of hands. II. SIDS When in 1976 a cooperation started between the department of physiology and the pediatric clinic in Graz, an incredible number of theories about the etiology of the so called sudden infant death syndrome (SIDS) could be found in textbooks. Some items on this list now are unequivocally obsolete. However, the existence of such a list indicates that the real cause of the terrible phenomenon is not yet found. One recent assumption about the etiology in the seventies was, that sleep apneas observed in infants indicate a particular high risk for sudden death. A publication by A. Steinschneider (1972) about 2 cases of sudden infant death out of 5 children in a family had stimulated an incredible number of studies about apnea in infants and - consequently - also the invention of sleep monitors for infants at risk. The children described by Steinschneider showed episodes of apnea such that the author concluded that apnea is the essential risk factor, or even cause of sudden death in infants. Our group joined this international trend by recording the respiration of babies during sleep. We also performed retrospective studies about particular observations by the parents of deceased babies. The results enabled us to establish a list of possible risk indicators and, thereof a corresponding questionnaire for the mothers of newborn. More recently we have summarized our own results as well as literature in a book (Kurz et al. 2000). 20 years after Steinschneider's publication mentioned above, it was found through confession of the parents that they had murdered the two children by suffocation. Nevertheless, it is interesting that even the misinterpreted observation by Steinschneider has led by the stimulation of research to a closer proof that problems of respiration play a role in SIDS. Furthermore, it was more clearly shown which type of respiratory problem may be dangerous, and which are the limits between normal and abnormal. So far it seems clear that no single etiologic factor can be found which makes an explanation of SIDS possible. Therefore, the attempt for a more general model of interaction between three risk factors was proposed by Filiano and Kinney (1994), which is known as "triple-risk model". The three fatally interacting factors are: critical child, critical time and critical stress. The "critical child" can be summarized as the effect of its genetic and epigenetic predisposition. The "critical time" was already observed in the 19 th century by Paltauf (1889). Many further observations, including our own findings agree with the fact that the highest incidence of SIDS can be observed in the time of second and third month of life. The "critical stress" summarizes in my opinion several possible risk factors or events: prone position during sleep, overheating, cigarette smoke, neglect or unrest in the environment of the baby. (See Kurz et al. 2000). Furthermore, the influence of chronobiological factors which lead to circadian or circannual predilection, of the time of SIDS is documented. 5 The possible influence of cosmic cycles was discussed in a study by Halberg's group (Kcnner et al. 2003). Such an influence could possibly explain worldwide long time trends in the incidence of SIDS. As far as the practical results of the campaign for the prevention of SIDS is concerned which was initiated by our group in Graz, the incidence of SIDS in the Austrian province Styria decreased significantly in the years since begin of our study. The campaign consists of information for the parents (mainly mothers), a "risk" questionnaire, pediatric counselling and, in cases of suspected risk, polygraphs sleep monitoring. III. PEPTIC ULCER During my years of chairmanship of the department of Physiology I taught besides the main lecture - among other topics - also lectures on "physiology of psychosomatic reactions". Physiology of the human person includes necessarily body and psyche. Students in general -and particularly, before they receive too much one sided indoctrination - have a high sensitivity for the recognition of the human personality of patients, a capability which includes a psychosomatic access to the patient. In 1984 the work by Marshall and Warren (2) about their discovery of the presence of the helicobacter pylori (HP) in the stomach and its relation to peptic ulcer disease was published. One professor of internal medicine in Graz made - with respect to this discovery - the following remark to some students: "Now we know the real and unique cause of peptic ulcer. Therefore, we no more need mysterious psychosomatics for explanation." With such a statement he nearly triggered a political controversy with the students who regarded this remark as a provocation. Because of my own experience and reports in the literature as described below, my position with respect to this problem is the following: In the case of peptic ulcer similar to the SIDS-example, the etiology follows a "triple risk". There is on one hand ample proof that HP plays an essential role. On the other hand not everybody who has HP in his stomach will necessarily get an ulcer. A general precondition and a trigger event certainly also play a role. My own experience as a "patient" was the following: In the diary notes from my time of deanship I find the note: "On Tuesday Dec. 15, 1992, I had to chair the most unpleasant conference ever". On Dec 17 I had to be transported to a hospital because of massive gastric bleeding from an ulcer. Before this event I never had any gastric problems. I received the necessary therapy. Since that never again had I further problems with my stomach. Only 6 years later, on recommendation of a friend, an eradication of HP (which had been found in the biopsy of the mucosa) was performed. The following is a report about observations by an Austrian surgeon who was one of my teachers during my studies at the medical school in Vienna. I knew 0. Bsteh very well because in his hospital in the city of Mistelbach (Lower Austria) I had performed my first steps as a student in practical surgery and internal medicine. In 1952 O. Bsteh, published a book in which he summarized his experience on the development of peptic ulcer. The patients who were treated in this hospital came from a quite homogeneous population of farmers. Therefore his observations are important for the study of the chronopathology of occupational factors. In the years from 1936 to 1947 the number of inhabitants in the area was about 70000. In this time 1026 persons with peptic ulcer have been treated in the hospital. From the 1026 persons, 821 were treated surgically; the others received internal medical treatment. The most severe event of the peptic ulcer-disease is the perforation. Bsteh (1952) reports in his book 185 cases of perforation within 17 years. The numbers of perforations per years 6 show a minor variation between 9 and 20 cases per year. The age of the patients was between 30 and 50 years. The main reason why it appears worthwhile to present this short report about Bsteh's results is the observation of a clear circannual distribution. As can be seen in the following table, there is a unique and marked peak in the summer months of June and July. January 6 February 2 March 8 April 9 May 15 June 30 July 34 August 22 September 17 October 18 November 12 December 12 Total 185 ulcer perforations in the years 1936 to 1947 (Bsteh 1952) Bsteh's interpretation of the peak incidence of ulcer perforation in June to July is derived from the fact that the highest physical and psychological stress in farmers is connected with the time before and during the harvest season. During this time, in addition to the daily heavy workload, the time of sleep is reduced. Furthermore, during this time climatic events as heat, rain and thunder-storms, variation of barometric pressure, may have influence on the autonomic nervous system. Interestingly enough, other authors find other periods of increased incidpence of peptic ulcer. Lauda (1949), an experienced Professor for internal medicine in Vienna mentions from his observations regarding a city population, spring and fall as typical times for the outbreak of ulcer disease. More recently Savarino et al. (1996) find high, incidence in October to December and in January to March. They observed that there was no parallel circannual fluctuation of duodenal ulcer, gastric acidity and Helicobacter Pylori infections in the studied patients. In addition it seems noteworthy that, according to Halberg (1986, 1987) the circadian time course of plasma gastrin is not in phase with the acidity in the gastric fluid. In other words, there appears no synchronization between the variables ulcer, acidity, plasma gastrin, and Helicobacter infection. Svan.es et al. (1998) find a circasemiannual periodicity with peaks in May to July and November to December. They assume that exogenous environmental and/or societal factors play a significant role although they add. that the variations in ulcer perforation may also be related to endogenous biological rhythms. It seems noteworthy, that in each of the four publications mentioned here, the timing is different, which may be due to the different occupational activities of the patients. The phase of the periodicity of the ulcer disease is influenced by societal and environmental stress factors. If there are broader peaks or even two distinct peaks in the circannual frequency distribution of certain symptoms of ulcer-disease, this may be due to the mixing of different, populations, or of groups with different occupations. 7 The opinion that by the explanation of one of the causes of a disease the complete etiology has been found, certainly, is a mistake. Even before the discovery of the Helicobacter it was clear, that the ulcer-disease must have several cooperating causes. And even, if one of the necessary conditions now can be abolished, the other set of conditions still may be of importance. The role of a vagotonic shift of the autonomic nervous system, was already well known in older literature. There is no question that acidity of the gastric secret and the presence of Helicobacter belong to essential preconditions of gastric ulcer. However, it seems that there are still many open questions about the interaction of further etiologic components. Based on my personal experience there is no question in my mind that psychosomatic factors and stress play an essential role as trigger for the generation of the disease. CONCLUSION AND SUMMARY For this report I have chosen out of my life and my development as person, teacher and scientist, three topics to which I have some specific relation. In the introduction I have shortly explained the kind of relation that make these examples especially interesting for me. Of course, there would be quite a number of other, equally ineresting examples. However, I feel that the three examples demonstrate on one hand some particular weakness of medical and on the other hand, some strength of medical practice. The weakness results from the possibility of obvious neglect of the consequences of simple and clear observations and of evidence. The strength comes from the fact that medicine is not only science but also an art. Performing medicine as an art means that simple and clear observations should, never be neglected. From all three examples one can conclude that diagnostic as well as therapeutic conclusions can be drawn from observations and not only from statistical evidence. As far as teaching is concerned there is currently a trend, which I consider as contra-productive. In order to reduce the teaching load, more and more so called "virtual teaching" is used. This means simply, that the students - far away from teacher and from patients -learn by sitting behind a computer screen where the Instructions are presented, I see the danger that more and more also patients will be considered as virtual entities. The kind of knowledge and behaviour that can be taught by such a technique is not what is essentially necessary to educate physicians. Support: MSM0021622402 LITERATURE Bsteh. O.: Die Geschwürskrankheit des Magens und ihre chirurgischen Probleme. Verlag W. Maudrich, Wien 1952 Filiano JJ, Kinney HC; A perspective on neuropathoiogic findings in victims of the sudden infant death syndrome: the triple-risk model. Biol Neonate 1994: 65, 194- 197. Kenner T, Cornelissen G, Katinas G, Schwarzkopff O, Kenner B, Halberg F: Population cycle in sudden infant death syndrome (IDS)? Neeuroendocrinology Lett 2003: 24(Suppl 1), 96 - 100. Kurz R, Kenner T, Poets C (eds): Der plötzliche Säuglingstod. 8 Springer-Verlag Wien 2000. Lauda E: Lehrbuch der Inneren Medizin (2.Band). pp.74 ff Springer Verlag, Vienna 1949. Marshall BJ, Warren JR.: Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984: 131, 1-5. Moore JG, Halberg F: Circadian rhythm of gastric acid secretion in men with active duodenal ulcer. DigDis Sei. 1986: 31,1185-91. Moore JG, Halberg F: Circadian rhythm of gastric acid secretion in active duodenal ulcer: chronobiological statistical characteristics and comparison of acid secretory and plasma gastrin patterns with healthy subjects and postvagotomy and pyloroplasty patients. Chronobiol Int. 1987: 4, 101-10. Paltauf A: Über die Beziehungen der Thymus zum plötzlichen Säuglingstode. Wien Klin Woschenschr 1889: 2, 877 - 881. Savarino V, Mela GS, Zentilin P, Lapertosa G, Cutela P, Meie MR, Mansi C, Dallorto E, Vassallo A, Celle G: Are duodenal ulcer seasonal fluctuations paralleled by seasonal changes in 24-hour gastric acidity and Helicobacter pylori infection? J Clin Gastroenterol. 1996: 22, 178-81. Svanes C, Sothern RB, Sorbye H: Rhythmic patterns in incidence of peptic ulcer perforation over 5.5 decades in Norway. Chronobiol Int. 1998: 15, 241-64. Steinschneider A: Prolonged apnea and the sudden infant death syndrome: clinicaland laboratory observations. Pediatrics 1972: 50, 646 - 654. Weiss Y, Keller N, Goldberg A: Lessons of history and challenges for tomorrow - the need to put Semmelweis' legace into practice. Proc. 40 th Internat Congr. History of Medicine, Budapest 2006, p.321 9 SEVEN DAY BLOOD PRESSURE MEASUREMENT: CONTRA VERSION IN SINGLE 24-H PROFILES OF BLOOD PRESSURE AND HEART RATE Í 1 I J 2 2 Halberg F. , Cornélissen G. , Schwartzkopff 0. , Kaunas G. , Siegelova J. , Fišer B, , Dušek J.2, Homolka P.\ Vank P.2 university of Minnesota, Minneapolis, MN, USA; 2Masaryk University Brno, CZ Halberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email halbe001@umn.edu INTRODUCTION Currently, 24 hour monitoring of BP by ambulatory functioning devices is a gold standard, reserved for special cases of high. BP, left uninterpreted in terms of its time structure. General reliance upon a single measurement (or a single 24-hour profile) of BP, however, has been dubbed "flying blind" (1) and is at variance with the documented (2, 3) need to meet requirements, stated repeatedly for over a century by opinion leaders, i.e., that we must evaluate periodic BP variations before a patient is examined. This proposition, at the turn of the 20th century, suggested by a leader at NIH as well. (5), is greatly facilitated by modern hardware and software in the new millennium (6, 7). Aim. To examine the relative merits of long-term blood pressure (BP) monitoring, analyzed time-structurally (chronomically, from chronome = time structure). Two aspects of sphygmochrons — summaries of the temporal dynamics of BP and heart rate (HR) monitoring — are examined in 4 cases with focus on the diagnosis of an elevation of the midline-estimating statistic of rhythm, ME S OR, M, and of the double circadian amplitude, 2A, of BP by the assessment of a 7-day record as a whole and separately for each day of 7 days ~ as a minimum at the outset of monitoring in health. METHODS Subjects and methods. Four medical scientists, 3 on hypotensive medications, wore an automatic ambulatorily functioning device around the clock with gaps. Data were summarized in both, daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. Disorders can occur at each, but tentative reference values in the form of prediction intervals are currently available only for the circadian, and even in this case remain to be improved by setting up lifetime follow-ups of subjects who were "clinically healthy" at the time of monitoring, a task that remains to be done. With such qualifications, we have used tentative reference limits to illustrate the tasks ahead in diagnosing, more rigorously than is now possible, circadian MESOR-hypertension and circadian hyper-amplitude-tension (CFIAT) or circadian 30 overswing. We are fully aware that the attempt to have gender and age-specified reference limits will have to be greatly improved by already-found differences as a function of ethnicity and, above all, by gradually eliminating from the reference data base all those "clinically healthy" subjects who subsequently fell ill or whose lifespan could not be assessed because of an accident, eventually keeping only those who died in their sleep at a very advanced age, still to be determined. In our classification of BP disorders according to both a 24-hour vs. a 168-hour abnormality, again according to both the MESOR and double circadian amplitude, we emphasize that the extent of abnormality in each case can and should also readily be considered and should further qualify the percentage of MESOR-hypertension per day or per week, by the corresponding average hyperbaric indices per day and per week, and should again qualify the percentage of CHAT per day and per week by the average circadian double amplitude. These added measures provide the critical estimations of the severity of the condition. The examples illustrated thus far and to a limited extent only with the % days or weeks of an abnormal MESOR and/or circadian double amplitude, suffice to demonstrate that the current gold standard of a 24-hour profile is not sufficient to reliably describe the presence or absence and the time course of the two blood pressure disorders examined, of an excessive M or an excessive A. RESULTS Subject 1: YW, a cardiologist, currently in his 19th year of monitoring, used the Colin ABPM first and an A&D instrument thereafter. Figure la shows weekly summaries of MESORs, top, initially consisting mainly of acceptable values with few exceptions over the first 13 years and greater fluctuations and more values above the acceptable MESOR thereafter. Already during an entire week in 1989, however, a week-long data summary would have supported the diagnosis of ME SOR-hy p ertension and, in current conventional (often hurried) practice, based on single measurements or at best upon 24-hour profiles, a week-long abnormality might indeed constitute a stimulus to treat. But the one-week span is followed by MESOR-normotension for weeks (and. validates the clinical custom to ask the patient to return in a month, albeit we do not recommend only another spotcheck that could be done on a roller coaster in some cases). In the lower half of the figure the circadian double amplitude exceeds only on few occasions its limit of acceptability. By contrast, in Figure lb the daily summary over the same time span, as in Figure la, shows wider swings of the MESOR as well as of the double amplitude and reveals the dangers of basing a diagnosis of CHAT in particular, but also of MESOR-hypertension, on a single 24-hour record. Many more acceptable 24-hour records can follow several abnormal consecutive records and whether either abnormality is transient or lasting must be observed before one starts possibly unwarranted treatment, perhaps for a lifetime, for a condition that persisted only for a short time. Clinical trials that show benefit from treating "spotcheck" pressures above 120 mmHg come to mind (8) but may not be applicable to the individual, e.g., to YW. In this case, there was also a change in monitors coincidental with a change in MESOR toward the end of the record and a possibly slightly increasing trend with time is confounded, by the change of instmmentati on. When incomplete records are discarded and the analysis is assessed only on a week documented, by a minimum of 224 values (/week), the abnormality appears to be rarer, perhaps because of the sparser record. Thus, there is no CHAT, when occasional CHAT was seen certainly based on daily summaries and in weekly summaries when the decimation of incomplete data is less thorough since weekly records with as few as 116 values are analyzed. Thus, CHAT can come about more frequently than in the case, for which records with fewer 11 than 224 values per week were discarded. The comparison of results in Figure la serves to emphasize the role of the density of the record in diagnosing CHAT. There is shows CFIAT above the horizontal dotted line and MESOR-hypertension. to the right of the second vertical dotted line. Thus, the coexistence of the two conditions is seen in the upper right section in 2.3% of the days investigated. Overall MESOR-hypertension is present in only 13% of the monitored days considered and CHAT overall is rarer yet, only seen in 7%. When weekly summaries are made, keeping ail records with 116 or more values or only those with 224 values/week, in Figures le and If. respectively, the incidence of MESOR-hypertension decreases to 7.5 or 3.7% and that of CHAT to G.6%>, This result can be interpreted on an individualized basis as supporting the decision not to use hypotensive medication, even if a trial on many, almost certainly including many false positives at entry and false negatives at its end (8) could be taken to constitute an indication to treat in such a case. Subject 2, OS, a pediatrician, after coronary artery bypass grafting (CABG), aortic valve replacement, and two hip replacement surgeries, taking atenolol for cardiac arrhythmia, had a history of acceptable blood pressures since she wrote her doctoral thesis in medicine on BP. Her BP M and 2A seem to be perfectly acceptable in the light of Figure 2a, which is a summary of analyses of week-long data intervals. The picture of a clean bill of BP health when 168-hour intervals are summarized does not appreciably change in Figure 2b when 24-hour data intervals are analyzed, for M on top. At the bottom of this figure, an occasional circadian blood pressure overswing is seen on a number of days as values crossing the horizontal upper limit of the 95% prediction interval during spans when no CFIAT was apparent in the corresponding weekly summaries of Figure 2a. In daily records, Figure 2c, OS is never MESOR-hypertensive, but on quite a few occasions has circadian overswing. In Figure 2d, with weekly summaries, she has 0% abnormality of either M or 2A. CHAT has sometimes been shown to be present in clinical health, but usually only for a few days at a time, presumably under emotional loads (and the 24-h record in the 7-day perspective can actually serve as a load [stress] test) (9). Circadian overswing, however, must not be diagnosed based on records of 24 hours, dubbed transient CHAT suggested that a week be a bare minimum to rule in BP health, but not to rule out either CHAT or MESOR-hypertension, when they occur on occasion, as CHAT does in OS. Figure 3 represents data from a treated MESOR-hypertensive physiologist (FH), who himself had had two sets of CABGs performed years earlier. The Figure 3a data were taken while his greatly loved daughter, herself a physician, visited for several days from out of town. The June 17 arrow shows his BP during what to him at the time appeared to be a friendly discussion of his legacy, bracketed by a prior and a succeeding day. If only the three days in row A are considered, we see an unusual BP elevation, above the time-varying upper limits shown as a wavy curve, above which a blackened area corresponds for several hours to consecutive values that exceed by far the upper limit of a chronodesm, a 95%> prediction interval. Occasional values reach or exceed. 200 mm Hg. This seemingly most unusual behavior loses somewhat in prominence in row B when more days bracketing the discussion are displayed. The blackened area in row A becomes just one event among others obtained in everyday life, not identified by any association, but shown by arrows. There is no question that emotions can raise the BP; equally clearly, the very high values when a monitor records them beat-to-beat can be single or very few high values, without the subject being aware of any emotion. The same subject's 24-hour BP summaries are shown in Figure 3b. Under a closely (weekly) self-supervised treatment, every so often FH has MESOR-hypertension, as shown on top of the figure, and, as seen on the bottom, there are also many days with circadian hyper-amplitude-tension. If we summarize his experience, again based on 24-h profiles, he has MESOR-hypertension for 12.1% of the time. With the relatively successful 12 treatment of his M, if not otherwise, he also exhibits circadian overswing 49.9% of the time, if 36 or more measurements/day are analyzed and records with greater gaps are discarded. Figure 3c in turn shows weekly summaries, and now his percentage, MESOR-hypertension is less than half of what it was in daily summaries, and % CHAT has also been reduced from 45.9 to 26.9%. This case also shows that weekly summaries should be the routine diagnostic basis, but are best complemented by daily ones, so that daily CHAT is not altogether ignored, and. if it persists, an attempt can be made to reduce it by whatever methods, notably relaxation procedures, are available, and helpful. Figure 4 shows data of a physician-morphologist (GK), a man known to be hypertensive and treated for this condition since his 30s, monitored automatically from his 70s at half-hour intervals around the clock, with very few gaps. Figure 4a shows again, with a weekly supervision of his BP and changes in treatment made accordingly, that he can completely eliminate neither MESOR-hypertension, nor circadian overswing, but when it occurs the extent of excess pressure seems to be relatively small. When in turn, in Figure 4b, 24-hour intervals are summarized, some of the smoothing by weekly analyses is lost, and in particular a great variability in double amplitude becomes apparent, the 2A reaching high values. Each of this subject's data set is also summarized yearly, again to compare the presence in a given subject of the two conditions considered herein. Invariably, some dots lie on the right of the vertical line indicating MESOR-hypertension, and those above the horizontal dotted line indicate circadian overswing. It was not possible to eliminate abnormal Ms and 2As, weekly summaries of the data and an adjustment of treatment notwithstanding. In this subject, the fit of a polynomial to the data suggested, only after smoothing, that CHAT is more frequent at intermediate values, as found in a population (10). When daily values are summarized in this figure MESOR-hypertension is "controlled" two-thirds of the time and CHAT barely more than one-third of the time. Again, a weekly summary is the best overall interpretation, and we find, as in. the case of FH, that GK has traded some CFIAT, that is a higher 2A (and higher risk [2, 3]) for a lesser M (Figure 4c, 4d). DISCUSSION A 24-h profile corresponds to a single circadian cycle. Others have pointed out, as have we (12), that a 24-hour profile of blood pressure and heart rate is equivalent to taking the pulse for one second, i.e., for one cardiac cycle. The variability at hand from day to day has been emphasized earlier, is particularly great in so-called borderline hypertension, and overall as well, it is hardly negligible. The question now revolves around the practicality of chronomic analyses and the instrumentation for data collection, in this order of importance. Self-measurements are practical and cheap, and chronomic analyses are offered free of charge from corne001@umn.edu, until a Phoenix Project provides user-friendly software to all comers. Continuous self- or automatic monitoring gains in importance when our perspectives broaden, taking into account, alterations not only of the circadian rhythm and all their characteristics at all is mapped thus far and of trends with age. Blood pressure (BP) varies with age: we must not assume that once diagnosed as hypertensive, a given patient will continue to have high blood pressure for the rest of his/her life. A treated hypertensive with systolic values around 200 mm Hg can become an unhealed MESOR-hypotensive with systolic values under 100 mm Hg. BP changes in many patients vary greatly along the scale of hours and days and further during weeks and months (2), so that during the same monitoring span there are both hyper- and hypotensive values. BP also varies along the scale of years and decades (3). We here show that blood pressure disorders also vary, whether they are treated or untreated. We must not fly blind (1). Disorders include 13 alterations of the BP M and 2A, and other aspects of BP and HR variability; the latter can represent a risk greater than a high. BP. For the current surveillance of BP, the chronomic analysis, carried out in the Halberg Chronobiology Center, is available for all comers. Data are obtained by monitoring during very different spans (from 1 day to many weeks and longer). These data are analyzed for differing total spans; if so, however, the results are not comparable. The problem of standardizing interval lengths for analyzing BP series for CHAT detection is to be considered and standardized at international meetings, and is here proposed, for consensus discussions on such occasions. CONCLUSION 7-day monitoring and both daily and overall analyzes are recommended, with the urgent task of collecting international reference standards in health starting with medical students and including high school students, each followed up for a lifetime to retain the records for reference values only of those who remain healthy for their lifespan. The relative merits of tolerance intervals (13, 14) vs. prediction intervals (15, 16) and the need to age-qualify reference intervals (17, 18), preferably based on clinically healthy "test pilots" monitored starting at birth (19), are also major issues, as is the task to convey the sample used to replace reference values for men and women above a certain age (20). Support: MSM0021622402 REFERENCES 1. Fossel M. Editor's Note (to Halberg F et al. Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging medicine). J Anti-Aging Med 1998; 1: 239. 2. Halberg F, Cornélissen G, International Womb4o-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18 figures, http://www.msi.umn.edu/~halberg/ 3. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress: Part Í, season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: L38. http://www.zsfj cu.cz/vyzkum/jab/4_l/halberg.pdf} and Part II, chronomics for an immediately applicable biomedicine. J Applied Biomedicine 2006; 4: 73-86. http://www.zsf.jcu.cz/vyzkum/jab/4_2/haiberg2,pdf. 4. Janeway TC. The clinical study of blood pressure. New York: D. Appleton & Co., 1904, 300 pp. "... it is essential that a record of the pressure be made at frequent intervals at some time previous [presumably to an examination], to establish the normal level and the extent of the periodic variations. When this is done, it may be possible to demonstrate changes of small extent, which, lacking this standard for comparison, would be considered within the limits of normal variation," 14 5. Bartter FC. Periodicity and medicine. In: Scheving LE, Halberg F, Pauly JE, eds. Chronobiology. Tokyo: Igaku Shoin Ltd.; 1974. p. 6-13. On his patient whose blood pressure was diagnosed differently by two physicians who saw him at different times of day: "By conventional standards, this patient is clearly normotensive every morning. But the blood pressure determined each day at 6 in the afternoon provides especially convincing evidence that this patient is a hypertensive. ... My plea today is that information contained in [data curves compiled under differing circumstances, such as 24 hours a day/7 days a week] become a routine minimal amount of information accepted for the description of a patient's blood pressure. The analysis of this information by cosinor should become a routine. It is essential that enough information be collected to allow objective characterization of a periodic phenomenon, to wit, an estimate of M [the time structure or chronome-adjusted mean, or MESOR] ... an estimate of [the amplitude] A itself, and finally an estimate of acrophase, [a measure of timing]. In this way, a patient can be compared with himself at another time, or under another treatment, and the patient can be compared with a normal or with another patient." 6. Halberg F, Cornelissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other variabilities also await treatment. Am J Medicine, in press. 7. Cornelissen G, Chen CH, Halberg F. Predictive value of blood pressure variability: merits of circadian parameters versus dipping patterns. N Engl J Med 2006 [Aug 14]; 355;8:850. 8. Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006; 119: 133-141. 9. Halberg F, Cornelissen G, Spector NH, Sonkowsky RP, Otsuka K, Baciu I, Hriscu M, Schwartzkopff O, Bakken EE. Stress/strain/life revisited. Quantification by blood pressure chronomics: benetensive, transtensive or maletensive chrono-vascuio-neuro-immuno-modulation. Biomedicine & Pharmacotherapy 2003; 57 (Suppl 1): 136s-163s. 10. Cornelissen G, Halberg F, Otsuka K, Shinagawa M, Kubo Y, Ohkawa S, Fiser B, Siegelova J, Dusek J. Iatrogenic excessive blood pressure variability (CHAT): implications for chronotherapy. Scripta medica (Brno) 2003; 76: 275-278. 11. Schwartzkopff O, Cornelissen G, Syutkina EV, Breus TK, Garcia Alonso L, Mello G, Perfetto F, Tarquini R, Udaltsova N, Halberg F. Broadening rhythm spectrum in perinatology and pediatrics, where genetics and geo-helio-magnetics meet. Abstract 14, 2nd International Symposium: Workshop on Chronoastrobiology & Chronotherapy, Tokyo Kasei University, Tokyo, Japan, November 2001, unpaginated. (3 pp). 12. Halberg F, Cornelissen G, Otsuka K, Watanabe Y, Wood MA, Lambert CR, Zaslavskaya R, Gubin D, Petukhova EY, Delmore P, Bakken E. Rewards in practice from recycling heart rate, ectopy, ischemia, and blood pressure information. J Medical Engineering & Technology 1997; 21: 174-184. 13. Halberg F, Lee JK, Nelson WL. Time-qualified reference intervals—chronodesms. Experientia (Basel) 1978; 34: 713-716. 14. Hermida RC, Fernandez JR, Ayala DE, Mojön A, Alonso I, Calvo C. Circadian time-qualified tolerance intervals for ambulatory blood pressure monitoring in the diagnosis of hypertension. Chronobiology international 2004; 21: 147-160. 15. Nelson W, Cornelissen G, Hinkley D, Bingham C, Halberg F. Construction of rhythm-specified reference intervals and regions, with emphasis on "hybrid" data, illustrated for plasma Cortisol. Chronobiologia 1983; 10: 179-193. 16. Flillman DC, Cornelissen G, Scarpclli PT, Otsuka K, Tamura K, Delmore P, Bakken E, Shinoda M, Halberg F, International Womb-to-Tomb Chronome Initiative Group. 15 Chronome maps of blood pressure and heart rate. University of Minnesota/Medtronic Chronobiology Seminar Series, #2, December 1991, 3 pp. of text, 38 figures. 17. Hadtstein C, Wühl E, Soergel M, Witte K, Schaefer F, German Study Group for Pediatric Hypertension. Normative values for circadian and ultradian cardiovascular rhythms in childhood. Hypertension 2004; 43: 547-554. 18. Cornelissen G, Haus E, Halberg F. Chronobiologic blood pressure assessment from womb to tomb. In: Touitou Y, Haus E, editors. Biological Rhythms in Clinical and Laboratory Medicine. Berlin: Springer-Verlag; 1992. p. 428-452. 19. Watanabe Y, Cornelissen G, Halberg F. Thousands of blood pressure and heart rate measurements at fixed clock hours may mislead. Neuroendocrine I Lett 2003; 24: 339-340. 20. Hagen P (ed.) Mayo Clinic Guide to Self-Care: Answers for Everyday Health Problems. Rochester, MN / Jacksonville, FL / Scottsdale, AZ: Mayo Clinic; 2003. p. 180-181. 16 Fig, la CONSECUTIVE AVERAGES (above) and ORCADIAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SBP) DURING -18 YEARS ALTERNATE BETWEEN MOSTLY ACCEPTABLE and PARTLY UNACCEPTABLE* Upper 95% prediction limits [of gender-, age- and geography-matched healthy peers Double ORCADIAN Amplitude based on 168-hour intervals 1990 1995 Time (calendar years) 2000 2005 * Results from non-overlapping 168-hour intervals in serial sections on half-hourly around-the-clock data; VW (M, 35 - 53 y). Weekly records with fewer than 116 values discarded. Fig. lb CONSECUTIVE AVERAGES (above) and CIRCADIAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SBP) DURING -18 YEARS ALTERNATE BETWEEN MOSTLY ACCEPTABLE and PARTLY UNACCEPTABLE* 200 - 180 - 160 - 140 - Hz 120- E E, 100 ■ EL ca 30 - V) 60 - 40 - 20 - 0 - Upper 95% prediction limits of gender-, age- and geography-matched healthy peers Double CIRCADIAN Amplitude based on 24-hour intervals 1990 1995 Time (calendar years) 2000 2005 * Results from non-overlapping 24-hour intervals in serial sections on half-hourly around-the-clock data; YW (M, 35 - 53 y). Daily records with fewer than 36 values discarded. 17 Fig. 2a CONSECUTIVE AVERAGES (above) and CIRCADIAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SBP) DURING ~2 YEARS ARE ALL ACCEPTABLE* x E E CD GL CO 200 180 160 140 120 100 80 60 40 20 0 MESOR based on 168-hour intervals Upper 95% prediction limits of gender-, age- and geography-matched healthy peers Double CIRCADIAN Amplitude based on 168-hour intervals MH* Yes No CHAT i Yes No 2004 2005 Time (calendar years) * Results from non-overlapping 7-day intervals in serial sections on half-hourly around the clock data; OS (F, 81-82 y) on atenolol treatment. MH = MESOR-Hypertension, CHAT = Circadian Hyper-Amplitude Tension. When 1-day intervals are used, occasional unacceptable results occur. Fig. 2b CONSECUTIVE AVERAGES (above) and CIRCADIAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SBP) DURING ~2 YEARS ALTERNATE BETWEEN MOSTLY ACCEPTABLE and RARELY UNACCEPTABLE* m a. T. 120 100 so -I 60 40 20 Upper 95% prediction limits of gender-, age- and geography-matched healthy peers ■I, Double CIRCADIAN Amplitude based on 24-hour intervals 2004 2005 Time (calendar years) CHAT Yes No * Results from non-overlapping 7-day Intervals in serial sections on half-hourly around the clock data; OS (F, 81-82 y) on atenolol treatment. ** MH = MESOR-Hypertenslon, CHAT = Circadian Hyper-Amplitude Tension. 18 Fig. 2c 168h-BASED CHAT/MESOR-HYPERTENSION INDEX 0.0/0.0 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* 50 40 x £ 30 E ™ 20 Q_ CO W 10 100.0 % 0.0 % 0.0 % CIRCADIAN HYPER-AMPLITUDE TENSION (CHAT) 0.0 % 100 % NORMOTENSION 0.0 % 0.0 % CHAT + MESOR-HYPERTERSIORr 0.0 % 0.0 % 0.0 % > 100 % MESOR-HYPERTENSION -1-1--1-I-1-r 100 110 120 130 140 150 160 170 SBP-MESOR (mm Hg) * OS (F, 81-82 y in 2005-2006) on (25 mg/day, on awakening) atenolol treatment. Results from non-overlapping (fractionated) serial sections over weekly intervals on half-hourly around-the-clock measurements analyzed. Weekly records with fewer than 224 values discarded. 19 Fig. 2d 24h-BASED CHAT/MESOR-HYPERTENSION INDEX 7.0/0.0 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* 100.0% 100 80 60 40 CIRCADIAN ■ HYPFR-AMPl ITUDF ' \ CHAT MESOP- TENSION (CHAT) 7.0 % 0.0 % HYPERTENSION 0.0 % a e 1 ........ 93.0 %. <:ft){\&^ ■ 0.0 % NOR^QTE'NSJmi ' . " - - -T-;' i —1 0.0 % 'i « MESOR-■ HYPERTENSION 7.0 % ■K V93.0 % 100 110 120 130 140 150 160 170 SBP-MESOR (mm Hg) * OS (F, 81-82 y in 2005-2006) on (25 mg/day, on awakening) atenolol treatment. Results from non-overlapping (fractionated) serial sections over daily intervals on half-hourly around-the-clock measurements. Daily records with fewer than 36 values discarded. 20 Fig. 3a 15-21-FH-OSCi. I £ E 3 ® "O o o 2 o o A FATHER'S DISCUSSION WITH HIS DAUGHTER CONCERNING A PROFESSIONAL LEGACY (v )* 200 --.......... 150 - 100 - 2004/06/16 00:00 '"-12:0.0 200 - - 00:00 12:00 00:00 -......Time (clock hours) 12:00..-••' 00:00 B iv.'s:-1"i-i-»-r-—i-1-1-r——t 11 12""* 13.....H... 15 16 17 18 19 20 21 Time (days in*June 2004) 200 - 150 - 100 - Feb Mar Apr May Time (months in 2004) Jun * Record of about 30-iuinute blood pressures of an 84-ycar old man (FH) shown in an increasingly broader perspective of 3 days (A), 12 days (B) and 5 months (C). ** Time-specified limit derived from clinically healthy peers of the same gender and similar age. NOTE: "Unique" event (""sk) is not unique when the perspective is broadened (^). Diary recommended! 21 Fig. 3b 24h-BASED CHAT/MESOR-HYPERTENSION INDEX 45.9/12.1 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* 40.9 % 47.0 % 12.1 % :26.o % : CIRCADiAN JÄßER=AJMfiUXU0E- CHAT -MESOJU TENSION (CHAT) 12.3 % *« * HYPERTENSION 7.6 % 28.6 % t*\s ' i i • . ______• •« ■•• • ■ 4.5 % NORMOTENSION .•* \ '»*:'21.0 % J MESOR-HYPERTENSION 100 110 120 130 140 150 160 ^45.9 % V54.1 % 170 SBP-MESOR (mm Hg) * FH (M, 82 - 87 y in 2001-2006) on different treatments varied in dosing and timing. Results from non-overlapping (fractionated) serial sections over daily intervals on half-hourly around-the-clock measurements analyzed. Daily records with fewer than 36 values discarded. 22 Fig. 3c 168h-BASED CHAT/MESOR-HYPERTENSiON INDEX 26.9/4.9 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* 100 T 05 I E E < a. m CO ORCADIAN 3Q J_______HYP_ER=AMELiIU[ TENSION (CHAT) 4,1 % 60 40 20 22.8 % 26.8 % NORMOTENSION CHAT + -MESOR-- HYPERTENSION 0.0 % 4.9 % 41.4% °r 1 i ——1—t 100 110 120 130 140 150 160 170 MESOR-HYPERTENSION --r-— > 26.9 % V 73.1 % SBP-MESOR(mm Hg) * FH (M, 82 - 87 y in 2001-2006) on different treatments varied in dosing and timing. Results from non-overlapping (fractionated) serial sections over weekly intervals on half-hourly around-the-clock measurements analyzed. Weekly records with fewer than 224 values discarded. 23 Fig. 4a CONSECUTIVE AVERAGES (above) and CIRC AD IAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SEP) DURING ~8 YEARS ALTERNATE BETWEEN MOSTLY ACCEPTABLE and PARTLY UNACCEPTABLE* a. to MESOR based on 168-hour intervals MH* [Upper 95% prediction limits of gender-, age- and geography-matched healthy peers Double CIRCADIAN Amplitude based on 168-hour intervals Yes No CHAT Yes No 1998 1999 2000 2001 2002 2003 Time (calendar years) 2004 2005 2006 * Results from non-overlapping 7-day intervals in serial sections on half-hourly around the clock data; GK (M, 72-80 y) on varying treatments. ** MH = MESOR-Hypertension, CHAT = Circadian Hyper-Amplitude Tension. Fig.4b CONSECUTIVE AVERAGES (above) and CIRCADIAN SWINGS (below) of SYSTOLIC BLOOD PRESSURE (SBP) DURING ~8 YEARS ALTERNATE BETWEEN MOSTLY ACCEPTABLE and PARTLY UNACCEPTABLE* Time (calendar years) " Results from non-overlapping 1-day intervals In serial sections on half-hourly around the clock data; GK (M, 72-80 y) on varying treatments. ** MH = MESOR-Hypertension, CHAT = Circadian Hyper-Amplitude Tension. 24 Fig. 4c 168h-BASED CHAT/MESOR-HYPERTENSION INDEX 59.7/30.4 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* 100 9.6 % 60.0 % 30.4 % E E < °* CL CQ 05 CIRCADIAN g0 -HYEER?AJMPXIXU.DE_ TENSION (CHAT) 3.1 % 60 38.4 %: CHAT + -MESOR- HYPERTENSION 18.2 % ■ . • s J$ *. > . • • 2.2 % NORMOTENSION ■ 21.6% r . MESOR-HYPERTENSION -1........■.■ 59.7 % V40.3% J r i s s i 100 110 120 130 140 150 160 170 SBP-MESOR (mm Hg) * GK (M, 72 - 80 y in 1998-2006) on different treatments varied in dosing and timing. Results from non-overlapping (fractionated) serial sections over weekly intervals on half-hourly around the clock measurements analyzed. Weekly records with fewer than 224 values discarded. 25 Fig.4d. 24h-BASED CHAT/MESOR-HYPERTENSION INDEX 60.8/33.7 MESOR (M) and DOUBLE AMPLITUDE (2A) OF SYSTOLIC BLOOD PRESSURE (SBP)* circ ad ian hyper-amplitude tension (chat) 6.1 % 32.6 % : . B I chat + MESOR-' .-t-W Y-PE RTENS JON- • 22.1 % normotension V .* • :. | - * -Jr?. - mesor- on * . : • ■ 19.9 % ? *«• HYPERTENSION 100 110 120 130 140 150 160 170 ^60.8% < >"39.2% SBP-MESOR (mm Hg) * GK (M, 72 - 80 y in 1998-2006) on different treatments varied in dosing and timing. Results from non-overlapping (fractionated) serial sections over daily intervals on haff-hourly around the clock measurements analyzed. Daily records with fewer than 36 values discarded. 26 LESSONS ABOUT "LOADS" LEARNED WHILE DETECTING AND GREATLY REDUCING RESIDUAL MESOR-IIYPERTENSION AND CHAT Halberg F.*, Katinas G.*, Cornelissen G,*, Otsuka K.J, Sothern R.B. *, Singh R.B. §, Schwartzkopff O.*, Siegelova J.*, Fiser B.». Dusek J.v Homolka P.», Prikryl ?.% Refmetti R.A *Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; ^Department of Medicine, Tokyo Women's Medical Center East, Tokyo, Japan; §FIalberg Hospital and Research Institute, Moradabad, India; »St, Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; IjBrno, Czech Republic; AUniversity of South Carolina, Walterboro, SC, USA Halberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email halbe001@umn.edu INTRODUCTION Chronotheranostics, a chronomic (time structural) combination of diagnosis and therapy, may eventually involve beat-to-beat monitoring and responses by a drug pump to abnormal instantaneous values, in the light of both a circadian and extracircadian history, accumulated by repeated scans, as the time series grows, and involving as-one-goes sequential analyses of all parametric and nonparametric endpoints (1-3). Aim. To examine, over nearly 16 years, the merits of adjusting the timing of medications in the treatment of coexisting vascular variability disorders on a weekly basis as a step complementing daily and longer-span-based summaries, and to search for dividends both in health care and in science. METHODS Subject. FH is a treated MESOR-hypertensive physiologist, who himself had had two sets of CABGs performed years earlier. Measurement FH wore an automatic ambulatorily functioning device around the clock with gaps. Data were summarized in both daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. RESULTS FH's 24~hour BP summaries collected under a closely (weekly) self-supervised treatment, every so often show MESOR-hypertension and, on many days over 16 years, circadian hyper- 27 amplitude-tension, CHAT. If we summarize his experience in 24-h profiles, he has MESOR-hypertension for 12.1% of the time. With the relatively successful treatment of his M, if not for other unknown reasons, he also exhibits circadian overswing, CHAT, 49.9% of the time, if 36 or more measurements/day are analyzed and records with greater gaps are discarded. In. weekly summaries, however, the percentage of MES OR-hypertens i on is less than half of what it was in daily summaries, and % CHAT has also been reduced from 45.9 to 26.9%. Treatment of FH is associated with a practically normal M and an acceptable 2A nearly 3/4 of the time, by contrast to another case monitored half-hourly for 8.5 years, whose residual CHAT was present 3/4 of the time. A completed longevity study on groups in the perspective of 28 years ascertained that when all but one who had CHAT had died, of those still alive all but the one with CHAT, had an acceptable 2A (6). Weekly summaries could be the routine diagnostic basis, but are best complemented by daily ones, so that daily CHAT is not altogether ignored, and if it persists, an attempt can be made to reduce it by whatever methods, notably relaxation procedures, are available, and helpful. Since both an excessive MESOR and an excessive circadian double amplitude are high risks of severe disease, an attempt seems warranted to eliminate most if not all residual abnormality, to whatever extent possible. This was possible in FH despite self-experimentation, but with apparent benefit. On many occasions, in addition to attempting to optimize his own treatment, e.g., by reducing both the M and 2A of BP by timing his hypotensive medication, by adjusting the timing of other treatment, such that of the antiarrhythmic sotalol or of the use of Flomax for prostatic hypertrophy, lie also attempted to ascertain both the undesired and the desired timing in FH (thereby unduly inflating the incidence of CHAT reported above). All these procedures and. his longevity are viewed in the context of the substantial gain in longevity by those without CHAT (6), indicating that self-monitoring, a long tradition in biomedical research and education as a basis for self-experimentation, can be a dividend from "not flying blind" in self-health care. Notwithstanding privacy considerations (nor, when desired, only by coding, to safeguard anonymity), it seems mandatory to make records available to the public, so that new findings such as associations with the solar wind, a dividend of FIT s endeavor (4, 5), can be tested by subtraction and addition (remove-and-replace) approaches. DISCUSSION As an aside and as a basis for a potential load (or strain, rather than "stress") test, data were analyzed from a span when FH's greatly loved daughter, herself a physician, visited for several days from out of town. His BP during what to him at the time appeared to be a friendly discussion of his professional legacy, bracketed by a prior and a succeeding day, for several hours, exceeded by far the upper limit of a chronodesm, a 95% prediction interval, and appears to be very unusual (just as it was in discussion with a dear friend, when it also exceeded the elevation during a tornado watch at a tennis match [7]). Consecutive values exceeded 200 mm Hg systolic BP. This seemingly great response already loses somewhat in prominence when more days bracketing the discussion are displayed. With bracketing by months, years or the 16-year record as a whole, the discussion-associated rise becomes just one event among others occurring in everyday life, not identified by any association. This picture of BP changes with time may be compared with effects of emotions brought about at the time of a given event that fade away as time goes by, in keeping with the adage that time has the power to heal. The point that life is made of a series of events that can all bring about non-trivial physiological changes makes it the more desirable to monitor BP in real life rather than making a decision, often for a lifetime, based on only one or a few BP measurements 28 taken in the office under standardized but artificial conditions. Most interesting is that blood pressure alone reveals subconscious changes that can be of much greater extent than conscious ones. Thus, it is documented by another self-study of FH, monitoring while undergoing sonography and a rather painful prostatic biopsy. It took a statistical tour de force, however, to validate relatively small differences in mean (8). There is no question that pain and/or emotions can raise the BP. (Equally clearly, but not shown here, instantaneous very high values, when a monitor records them beat-to-beat, can be single or very few high values, without the subject being aware of any emotion.) To support the point of a subject's unawareness of BP change, before getting off the examination table after a routine, noninvasive colonoscopy, FH was again surprised to see that the nurse had recorded a systolic BP >200 mm Hg while he was happy since on the screen he had witnessed a clean colon with no more than a few diverticuli. The use of BP monitoring to gauge known and in particular unknown loads may be pursued along lines also noted elsewhere (9). Support; MSM0021622402 REFERENCES 1. Halberg F et al. Engineering and governmental challenge: 7-day/24-hour chronobiologic blood pressure and heart rate screening: Part I. Biomedical Instrumentation & Technology 2002; 36: 89-122. 2. Halberg F et al. Engineering and governmental challenge: 7-day/24-hour chronobiologic blood pressure and heart rate screening: Part II. Biomedical Instrumentation & Technology 2002; 36: 183-197. 3. Cornélissen G et al. Individual assessment of antihypertensive response by self-starting cumulative sums. J Medical Engineering & Technology 1997; 21: 111-120. 4. Cornélissen G et al. Resonance of about-weekly human heart rate rhythm with solar activity change. Biologia (Bratislava) 1996; 51: 749-756. 5. Halberg F et al. Chronobiology's progress: Part I, season's appreciations 2004-2005, Time-, frequency-, phase-, variable-, individual-, age- and site-specific chronomics. J Applied Biomedicine 2006; 4: 1-38. http://www.zsf.jcu.cz/vyzkum/jab/4_l/halberg.pdf. 6. Halberg F et al, Messung und chronobiologische Auswertung der Variabilitäten von Blutdruck und Herzfrequenz zur Prophylaxe schwerwiegender Krankheiten. In: Sitzungsberichte der Leibniz-Sozietät, Band 54, 2002, Fleft 3, S. 127-156. 7. Halberg F, Cornélissen G, Halberg E, Halberg J, Delmore P, Shinoda M, Bakken E. Chronobiology of human blood pressure. Medtronic Continuing Medical Education Seminars, 4th ed. Minneapolis: Medtronic Inc.; 1988. 242 pp. 8. Halberg F et al. The chronobiology of prostate-specific antigen (PSA): case report and chrono-metaanalysis. Anticancer Research 1999; 19: 857-862. 9. Haiberg F et al. Stress/strain/life revisited. Quantification by blood pressure chronomics: benetensive, transtensive or maletensive chrono-vasculo-neuro-immuno-modulation. Biomedicine & Pharmacotherapy 2003; 57 (Suppl 1): 136s-163s. 29 CIIRONOTHERANOSTICS OF MESOR-NORMOTENSION VS. CIRCADIAN OVERSWING, I.E., CHAT Cornelissen G.*, Halberg F.*, Katinas G.*, Watanabc Y.«, Sothern R.B.*, Siegelova JJ, Fiser B.i, Dusek J.t, Flomolka P$, Prikryl P.«[, Singh R.B. §, Otsuka K.A, Schwartzkopff 0.*, Refinetti R.O *Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; 8 Waseda University, Saitama, Japan; $St. Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; fBrno, Czech Republic; §Halberg Hospital and Research Institute, Moradabad, India; ATokyo Women's Medical University,Tokyo, Japan; OUniversity of South Carolina, Waltcrboro, SC, USA Halberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 632-624-9989 Email halbeOO 1 @umo.edu INTRODUCTION A consensus meeting (1) recognizing that CHAT, as compared to MESOR-hypertension, can be a greater risk of stroke and nephropathy (2), advocated the treatment of both conditions. This case report illustrates the problem encountered and the lessons learned in so doing. Aim. To know whether, and if so when, we trade MESOR-normotension for more frequent circadian hyper-amplitude-tension, i.e., CHAT, so that eventually something can be done about undue residuals of both conditions, in the face of conventionally seemingly acceptable results. METHODS Subject GK, a male physician-morphologist known to be hypertensive and treated for this condition since his 30s, monitored automatically from his 70s on at half-hour intervals around the clock, with very few gaps, with a weekly analysis of his BP and changes in treatment made accordingly. GK wore an automatic ambulatory functioning device around the clock with gaps. Data were summarized in both daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. RESULTS Results over 8.5 years of around-the-clock blood pressure (BP) and heart rate (FIR) surveillance are summarized in this presentation. When they occurred, the extent of excess in BP MESOR (midline-estimating statistic of rhythm) and/or circadian amplitude (CHAT, 30 circadian hyper-amplitude-tension, or circadian. overswing) was smaller in weekly than in daily summaries. When 24-hour intervals were summarized, some of the smoothing by overall weekly analyses was lost, and in particular a great variability in double amplitude (2A) became apparent, BP-2A reaching occasional high values. Each of this subject's data set is also summarized yearly, again to compare the presence in a given subject of the two conditions considered herein. Invariably, some measurements indicate MESOR-hypertcnsion, and others indicate circadian overswing. It was not possible to eliminate abnormal MESORs (Ms) and 2As, not even from all the weekly summaries of the data, many adjustments of treatment notwithstanding (3). In this subject, the fit of a second-order polynomial to the 2As plotted as a function of the corresponding MESORs suggested, only after smoothing, that CHAT was more frequent at intermediate values, as found in a population (4). When daily summaries were examined, MESOR-hypertension was "controlled" two-thirds of the time and CHAT barely more than one-third of the time. A weekly summary was the best overall interpretation, and we find, as in the case of another subject.(FIT) (5), that GK had perhaps traded some CHAT, that is an excessive BP-2A (and higher risk [1, 2]) for a lesser M. DISCUSSION A 24-h profile corresponds to a single circadian cycle. Others have pointed out, as have we (6, 7), that a 24-hour profile of blood pressure and heart rate is equivalent to taking the pulse for one cardiac cycle, i.e., for one second. The variability at hand from day to day has been emphasized earlier, is particularly great in so-called borderline hypertension, and overall as well, it is hardly negligible. The question now revolves around the practicality of chronomic analyses and. the instrumentation for data collection, in this order of importance. Self-measurements are practical and cheap, and chronomic analyses are offered free of charge from corneOOl @umn.edu, until a Phoenix Project (8) provides user-friendly software to all comers. Continuous self- or automatic monitoring gains in importance when our perspectives broaden, taking into account alterations of not only the circadian A and (based on at least weekly and preferably longer-term - yearly and transyearly summaries) but also of the period and waveform and of the same characteristics at all extracircadian periods mapped thus far as well as of trends with age. Chaos, the third element of chronomes has also found physiologic and clinical uses, notably when used in combination with rhythmometry (9,10). Support: MSM0021622402 REFERENCES 21. Halberg F, Cornélissen G, international Womb-to-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18, 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18 figures, http://www.nisi.umn.edu/~halberg/ 22. 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 1997; 21: 23-30. 23. Katinas GS et al. Why continued surveillance? Intermittent blood pressure and heart rate abnormality under treatment. Biomedicine & Pharmacotherapy 2005; 59 (Suppl 1): S1.41-S151. 31 24. Watanabe Y et al. Incidence pattern and treatment of a clinical entity, overswinging or circadian hyperamplitudetension (CHAT). Scripta medica (Brno) 1997; 70: 245-261. 25. Halberg F et al. Detecting and reducing residual MESOR-hypertension and residual CHAT. These proceedings. 26. Cornelissen G et al. From various kinds of heart rate variability to chronocardiology. Am J Cardiol 1990; 66: 863-868. 27. Halberg F et al. Rewards in practice from recycling heart rate, ectopy, ischemia, and blood pressure information. J Medical Engineering & Technology 1997; 21: 174-184. 28. Phoenix Project, Twin Cities Chapter of IEEE, Halberg Chronobiology Center, http://www.phoenix.tc-ieee.org/ 29. Burioka N, Cornelissen G, Halberg F, Kaplan DT. Relationship between con-elation dimension and indices of linear analysis in both respiratory movement and electroencephalogram. Clin Neurophysiol 2001; 112: 1147-1153. 30. Otsuka K, Cornelissen G, Halberg F. Circadian rhythmic fractal scaling of heart rate variability in health and coronary artery disease. Clinical Cardiology 1997; 20: 631-638. 32 OCCASIONAL TRANSIENT CHAT OCCURS IN THE MESOR-NORMOTENSIVE INDIVIDUAL Schwartzkopff O.*, Hal berg F.*, Cornel issen G.*, Katinas G.*, Sothern R.B. *, Siegelova L\, Fiser B.J, Dušek Z.%, Homolka P.J, Přikryl ?.% Singh R.B.§ * Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; iSt. Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; fBrno, Czech Republic; §Halberg Hospital and Research institute, Moradabad, India Halberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email haibcOO 1 @ urnn.edu INTRODUCTION CHAT lasting for one day has been described in the context of 1-week monitoring (1) and has been followed as a transient condition for years (2, 3). It was tacitly assumed that it is a rare yet occasional occurrence when monitoring covers many weekly spans and that it occurs rarely and not for a week, an impression (1) here documented by a case report. Aim. To describe, in a case report, transient and rare circadian overswing (CHAT, circadian hyper-a mp 1 i iude- ten s ion) occurring in the absence of MESOR-hypertension, with its mildness and physiological nature being compatible with the condition that it is present only in a very few daily, not in weekly summaries in a record covering 2 years, with gaps. METHODS Subject OS, a pediatrician, after coronary artery bypass grafting (CABG), aortic valve replacement, and two hip replacement surgeries, taking atenolol because of occasional cardiac arrhythmia, had a history of acceptable blood pressures (BP) since she wrote her doctoral thesis in medicine on BP. Measurement OS wore an automatic ambulatory functioning device around the clock with gaps. Data were summarized in both daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. 33 RESULTS Subject OS BP MESOR (midline-estimating statistic of rhythm, M), a rhythm-adjusted mean, and double circadian amplitude, 2A (measure of the predictable extent of daily change), are acceptable in the light of a summary of analyses of week-long data intervals. The picture of a clean bill of BP health when 168-hour intervals are summarized does not appreciably change when 24-hour data intervals are analyzed, for M. An occasional circadian blood pressure overswing is, however, seen on a number of days as values of 2A cross the upper limit of the 95% prediction interval, during spans when no CHAT was apparent in the corresponding weekly summaries. In daily records, OS is never MESOR-hypertensive, but on a few occasions has circadian overswing. With weekly summaries, she has 0% abnormality of either M or 2A. DISCUSSION CHAT has sometimes been shown to be present in clinical health, but usually only for a few days at a time, presumably under emotional loads (and the 24-h record in the 7-day perspective can actually serve as a load [stress] test) (4). Circadian overswing, however, must not be diagnosed based on records of 24 hours, dubbed transient CHAT, In the case examined, perhaps the mildest category of transient CHAT, no treatment seems indicated. For the current surveillance of BP, the chronomic analysis, carried out in the Halberg Chronobiology Center, is available for all comers. Data are obtained by monitoring during very different spans (from 1 day to many weeks and longer). These data are analyzed for differing total spans; if so, however, the results are not comparable. The problem of standardizing interval lengths for analyzing BP series for CHAT detection is to be considered and standardized at international meetings, and is here proposed for consensus discussions on such occasions. CONCLUSION We suggest that a week be a bare minimum to rule in BP health, but not to rule out either CHAT or MESOR-hypertension, when they occur on occasion, as CHAT does in OS in a few daily data, but in no weekly summaries. Support: MSM0021622402 REFERENCES 1. Cornelissen G, Halberg F, Wall D, Siegelova J, Zaslavskaya RM. How long to screen: ice hockey game and transient circadian hyperamplitudetension, CHAT. Scripta medica (Brno) 1997; 70: 189-198. 2. Halberg F, Cornelissen G, Halpin C, Burchell H, Watanabe Y, Kumagai Y, Otsuka K, Zaslavskaya R. Fleeting "monitor-", "conflict-" or "grief-associated" blood pressure disorders: MESOR-hypertension and circadian hyperamplitudetension (CHAT). EuroRehab 1996; 6: 225-240. 3. Halberg F, Cornelissen G, Otsuka K, Katinas GS, Schwartzkopff O, Halpin C, Mikulecky M, Revilla M, Siegelova J, Homolka P, Dusek J, Fiser B, Singh RB. 34 Chronomics* (*the study of time structures, chronomes) detects altered vascular variabilities constituting risks greater than hypertension: with an illustrative case report. In: Mitro P, Pella D, Rybar R, Valocik G, editors. Proceedings, 2nd Congress on Cardiovascular Diseases, Kosice, Slovakia, 25-27 April 2002. Bologna: Monduzzi Editore; 2002. p. 223-258. Halberg F, Cornelissen G, Spector NH, Sonkowsky RP, Otsuka K, Baciu I, Hriscu M, Schwartzkopff O, Bakken EE. Stress/strain/life revisited. Quantification by blood pressure chronomics: benetensive, transtensive or maletensive chrono-vasculo-neuro-immuno-modulation. Biomedicine & Pharmacotherapy 2003; 57 (Suppl 1): 136s~163s. 35 NEED TO STANDARDIZE DATA COLLECTION AND REFERENCE VALUES Hillman D.1, Halberg F.1, Comclisscn G.1, Kaunas G.\ Sothern RB.\ Otsuka K.2, Singh R.B.3, Siegelova J4, Fiser B.4, Dusek J.4, HomolkaP.4, Prikryl P.5, Schwartzkopff O.1 !Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; department of Medicine, Tokyo Women's Medical Center East, Tokyo, Japan; 3HaIberg Hospital and Research Institute, Moradabad, India; 4St. Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; 5Brno, Czech Republic Halberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email halbcOO 1 (a)umn.edu INTRODUCTION Several cases document with measurement series covering decades that at or near the end of life, blood pressure (BP) in the presence or absence of MESOR (midline-estimating statistic of rhythm)-hypertension can gradually drop, just as it increases early in life, and that in so doing, the relative prominence of extracircadian vs. circadian rhythms changes. That BP varies with age at both extremes of life, early and late, as well as in-between, has been thus described time structurally (chronomically) (1). Once diagnosed as normotensive or as hypertensive in terms of the BP MESOR (M), a given person need not have that characteristic for the rest of his/her life. Some treated MESOR-hypertensives, in particular with systolic values around 200 mm Hg, can become untreated MESOR-hypotensives with, systolic values near 100 mm Hg within a decade. BP also varies around the scale of decades, and in most people varies greatly along the scale of hours and days and further during weeks and months (2), so that during the same monitoring span of a few weeks, there can be both hyper- and hypotensive values. BP and HR variability disorders also differ, whether they are treated or untreated (3-6). We must not fly blind (7) to these variations. Disorders include alterations of the BP M, double amplitude (2A) or aero phase, of the standard deviation (SD),circadian and other, including a number of infradian rhythms, as nonphotic aspects of BP and HR variability. Lasting CHAT (short for circadian hyper-amplitude-tension) can represent a risk greater than a high. BP (2). Aim. To plan for the long-term, care of people with blood pressure disorders by starting the systematic collection of reference values for extracircadian as well as circadian characteristics, validated by lifelong studies, while we summarize lessons from the monitoring of those who have contributed longitudinal data thus far. METHODS For the current surveillance of BP, the sphygmochron analysis carried out in the Halberg Chronobiology Center is available for all comers. RESULTS 36 Data are obtained by monitoring during very different spans, from 1 day to many weeks and longer, up to decades. These data are analyzed for differing total spans; if so, however, the results are not comparable. The problem of standardizing interval lengths for analyzing BP series for circadian hyper-amplitude-tension (CHAT) detection is to be considered and standardized at international meetings, and is here proposed for consensus discussions on such occasions. DISCUSSION 7-day monitoring and both daily and overall analyzes are recommended, with the urgent task of collecting international reference standards in health starting with medical students and including high school students, each followed up for a lifetime to retain the records for reference values only of those who remain healthy for their lifespan. The relative merits of tolerance intervals (8) vs. prediction intervals (9, 10) and the need to age-qualify reference intervals, preferably based on clinically healthy "test pilots" monitored starting at birth, are also major issues. Most difficult is the educational task of conveying the mountains of evidence on the merits of replacing conventional reference values that allow interpretations of single values and are the same for men and women above a certain age. The single values ignore variability disorders of necessity and thus fail to detect severe vascular disorder risks greater than hypertension (2), leaving them silent to both care recipient and caregiver and thus untreated, until a hard event occurs. Support: MSM0021622402 REFERENCES 31. Cornélissen G, Haus E, Halberg F. Chronobiologic blood pressure assessment from womb to tomb. In: Touhou Y, Haus E, editors. Biological Rhythms in Clinical and Laboratory Medicine. Berlin: Springer-Verlag; 1992. p. 428-452. 32. 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. URL http://www.msi.umn.edu/~halberg/ 33. Halberg F, Katinas G, Cornélissen G, Sothern RB, Otsuka K, Singh RB, Schwartzkopff 0, Siegelova J, Fiser B, Dušek J, Homolka P, Přikryl P. Residual MESOR-hypertension and residual CHAT. These proceedings. 34. Watanabe Y, Katinas G, Cornélissen G, Sothern RB, Siegelova J, Fiser B, Dušek J, Homolka P, Přikryl P, Singh RB, Schwartzkopff 0, Halberg F. Mostly half-hourly around-the-clock blood pressures for over 18 years analyzed by day and by week. These proceedings. 35. Cornélissen G, Katinas G, Watanabe Y, Sothern RB, Siegelova J, Fiser B, Dušek J, Homolka P, Přikryl P, Singh RB, Schwartzkopff O, Halberg F. MESOR-normotension vs. circadian overswing, i.e., CHAT. These proceedings. 36. Schwartzkopff O, Cornélissen G, Katinas G, Sothern RB, Siegelova J, Fiser B, Dušek J, Homolka P, Přikryl P, Singh RB, Halberg F. Occasional transient CHAT occurs in the MESOR-normotensive individual. These proceedings. 37 37. Fossel M. Editor's Note (to Halberg F et al. Orcadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging medicine). J Anti- Aging Med 1998; 1: 239. 38. Halberg F, Lee JK, Nelson WL. Time-qualified reference intervals—chronodesms. Experientia (Basel) 1978; 34: 713-716. 39. Nelson W, Cornelissen G, Hinkley D, Bingham C, Halberg F. Construction of rhythm-specified reference intervals and regions, with emphasis on "hybrid" data, illustrated for plasma Cortisol. Chronobiologia 1983; 10: 179-193. 40. Hillman DC, Cornelissen G, Scarpelli PT, Qtsuka K, Tamura K, Delmore P, Bakken E, Shinoda M, Halberg F, International Womb-to-Tomb Chronome Initiative Group. Chronome maps of blood pressure and heart rate. University of Minnesota/Medtronic Chronobiology Seminar Series, #2, December 1991, 3 pp. of text, 38 figures. 41. Hagen P (ed.). Mayo Clinic Guide to Self-Care: Answers for Everyday Health Problems. Rochester, MN / Jacksonville, FL / Scottsdale, AZ: Mayo Clinic; 2003. p. 180-181. 38 CHRONOBIOLOGIC SERIAL SECTIONS COMPLEMENT SPECTRA TO SEEK SOCIAL VS. PHYSICAL SIGNATURES IN HUMAN HEART RATE CIRCASEPTANS Katinas G.1, Halberg F.!, Cornelissen G,1, Otsuka K.2, Sothern R.B.1, Singh R.B.3, Siegelova J.4, Fiser B.4, Dusek J.4, Homolka P.4, Prikryl P.5, Schwartzkopff O.1 !Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; o -i Department of Medicine, Tokyo Women's Medical Center East, Tokyo, Japan; Halberg Hospital and Research Institute, Moradabad, India; 4St. Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; 5Brno, Czech Republic Halberg Chronobiology Center University of Minnesota Minneapolis, MM 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email halbeOO 1 (Sjurnn.edu INTRODUCTION When ordering significance of any approximation of oscillations in a man's heart rate in chronobiologic serial sections with different trial periods remains ambiguous, reference to a control serial section at a spectral minimum may be useful, yielding information on any nonstationarities and/or any violations of underlying assumptions such as serial correlation. Aim. To complement, by chronobiologic serial section analyses in the time-varying phase domain, earlier global analyses in the frequency domain. METHODS Subject GK, 72 years of age at start of half-hourly monitoring from April 1998 to August 2006, with very few gaps. Measurement GK wore an automatic ambulatory functioning device around the clock with gaps. Data were summarized in both daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. RESULTS Results from long lasting cardiovascular monitoring (Table 1) shows ordering significance at P<0.01. from serial sections with the number of intervals as a function of the fitted period. If the spectral components drift or jump, one of them can transiently have more than one tested "period length". The 14.3% incidence at P<0.001 is a control, since it corresponds to a valley in a spectral window (not here shown) and need not be all false positive. Moreover, the 99.5% 39 incidence of "significance" at P<0.05, albeit qualified by restricting focus to P<0.001, requires explanation. Could it be that a transient 7-day synchronization is missed in the global spectral window because of circaseptan heterophasing, in response to different timed single stimuli, so that varying phase relations during different subspans cancel out the corresponding differently phased 7.00-day synchronized social circaseptans, and allow resolution of a much weaker but not necessarily trivial effect of the solar wind, validated beyond congruence by subtraction and addition documented by concomitant monitoring in time of solar and. biologic near- but not precise weekly circaseptans (1, 2)? Table 1: Ordering statistical significance in chronobiologic serial sections of components investigated N Percentages of CSS of intervals intervals with: NP> (days) analyzed P<0.05 P<0.01 j P<0.001 1 6.772" 400 59.5 46.5 33.5 2 7.000** 387 99.5 53.7 33.9 3 7.011* 387 75.7 52.7 34.4 4 7,447*** 364 51.1 31.3 14.3 *Ordering significance of peaklets in global spectral windows not shown: P<0.001, 6.772 days is natural circaseptan period found in the entire record on the speed of the solar wind, available at the time of analysis (-42 years) and in the geomagnetic indices Kp and aa for longer records up to >100 years (for aa). **Ordering significance in global spectral window (in which it was not a peak) (P<0.001). This rthythm is analyzed because of possible synchronization of HR by the social week, but a linear regression line fitted to acrophases of non-overlapping yearly data intervals shows a statistically significant delaying trend in the fit of a 7.00-day rthythm, in keeping with the 7.011-day rthythm, but the same result can also be interpreted as a phase jump by attempts of the social schedule to lock-in the natural 7.011-day component. There is no statistically significant trend in acrophases with the rthythms of 6.772 and 7.011. ***which was a trough in the spectral window (P=0.980) analyzed as a "control" for spurious significance. DISCUSSION Regression diagnostic tests should be routinely carried out to check on the presence of any serial, correlation, normality of residuals, and homogeneity of variance, apart from the stationarity of the parameters of the component under investigation. Further investigation is needed to reduce any violation of underlying assumptions and thus to assess the extent to which results at different trial rthythms represent a lasting and stable circaseptan component. Data transformation prior to regression diagnostic tests may be indicated, but such transformations can alter the actual time structure. Whether one or the other component is a false positive result awaits, from a statistical viewpoint, robust tests that do not rely on assumptions underlying regression. At the time of this writing, the fact that a period of 6.77 days was found in the record of solar wind speed as a whole and that a very close period was found in a longer record of Kp, and in an even longer record of another geomagnetic index, validation within physics of the reality of the 6.77-day component, which gains 40 tremendously from the trans-disciplinary validation when it is also found in human heart rate and when such congruence is found in a given subject at other non-photic frequencies as well. CONCLUSION In the absence of robust inferential statistical procedures, the search for intra- and trans-disciplinary congruence of aeolians combined with subtraction and addition, approaches is indicated. Support: MSM0021622402 REFERENCES 1. Comelissen G, Halberg F. Introduction to Chronobiology. Medtronic Chronobiology Seminar #7, April 1994, 52 pp. (Library of Congress Catalog Card #94-060580) http: //www. ms i. umn. edu./~halber g/ 2. Comelissen G, Halberg F, Wendt HW, Bingham C, Sothern RB, Haus E, Kleitman E, Kleitman N, Revilla MA, Revilla M Jr, Breus TK, Pimenov K, Grigoriev AE, Mitish MD, Yatsyk GV, Syutkina EV. Resonance of about-weekly human heart rate rhythm with solar activity change. Biologia (Bratislava) 1996; 51: 749-756. 41 TIME COURSE OF BLOOD PRESSURES OVER 18 YEARS ANALYZED SEPARATELY BY DAY AND BY WEEK Watanabe Y.*, Katinas G.«, Cornelissen G.% Sothern R.B.% Sicgclova J.i., Fiscr B.:j:, Dusek. J.;};, Homolka P.t, Prikryl P.f, Singh R.B.§. Schwartzkopff O.*, Halbcrg F.» *Department of Sports Medicine, School of Sports Sciences, Waseda University, Saitama, Japan; ®Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA; $St. Anna Teaching Hospital, Masaryk University, Brno, Czech Republic; *[Brno, Czech Republic; §Halberg Hospital and Research Institute, Moradabad, India Flalberg Chronobiology Center University of Minnesota Minneapolis, MN 55455, USA Tel 612-624-6976, Fax 612-624-9989 Email halbeOO 1 (Sjumn.edu INTRODUCTION 24 hour monitoring of BP by ambulatory functioning devices is a gold standard, reserved for special cases of high BP, left uninterpreted in terms of its time structure. General reliance upon a single measurement (or a single 24~hour profile) of BP, however, has been dubbed "flying blind" (1) and is at variance with the documented (2, 3) need to meet requirements, stated repeatedly for over a century by opinion leaders, i.e., that we must evaluate periodic BP variations before a patient is examined. This proposition, at the turn of the 20th century, suggested by a leader at NIH as well (5), is greatly facilitated by modern hardware and software in the new millennium (6, 7). The aim of the study was to map the systolic blood pressure daily with weekly oscillations and to determined MESORs, M (a midline-estimating statistic of rhythm) and circadian double amplitudes, 2A, computed by the fit of a single 24-h cosine curve of a clinically healthy subject as a function of age and as an indication of any need for intervention. METHODS Subject YW, a cardiologist, currently in his 19th year of monitoring, used the Colin ABPM first and an A&D instrument thereafter to monitor at mostly half-hourly intervals around-the-clock. Measurement YW wore an automatic ambulatory functioning device around the clock with gaps. Data were summarized in both daily and weekly analyses. The midline-estimating statistic of rhythm, or MESOR, is determined by the fit of a cosine curve; the same fit can provide estimates of the double amplitude, 2A, gauging the extent of predictable periodic change, and of the acrophase, gauging the timing of change at each period, characterizing the data. 42 RESULTS Weekly summaries of MESORs initially consist mainly of acceptable values with few exceptions over the first 13 years. Thereafter, there are greater fluctuations and more values above the upper limit of an acceptable MESOR, in the light of reference standards from gender- and age-matched peers. In weekly summaries, YW's circadian double amplitude exceeds only on few occasions its limit of acceptability. By contrast, in the daily summary over the same time span, wider swings of the MESOR as well as of the double amplitude are seen, revealing the dangers of basing a diagnosis of CHAT in particular, but also of MliSOR-hypertension, on a single 24-hour record. DISCUSSION Many more acceptable 24-hour records can follow several abnormal consecutive records and whether either abnormality is transient or lasting must be observed with more than even 48-hour monitoring before one starts possibly unwarranted treatment, perhaps for a lifetime, for a condition that persisted, only for a relatively short time and recurred only briefly at long intervals. Thus, already early in his monitoring a week-long data summary would have supported the diagnosis of MESOR-hypertension and, in current conventional practice, based on single measurements or at best upon 24-hour profiles, a week-long abnormality might indeed constitute a finding prompting treatment. But the abnormal one-week span in YW is followed by MESOR-normotension for weeks, years and almost two decades and validates the proposition that a week-long monitoring can be transient and is an indication for continued monitoring for at least another week or longer, depending on results. This finding must not be misinterpreted as validating the conventional clinical custom to ask the patient to return in. a month; we do not recommend only another spotcheck (that unknowingly to care provider or receiver could be done on a roller coaster in some cases). Clinical trials that show benefit from treating "spotcheck." pressures above 120 mmHg come to mind (8). Necessarily, they include many false positives at entry and false negatives at their end and must not be taken to constitute an indication to treat what has been mislabeled "pre-hypertension" (9). A chronobiologic pre-hypertension, a gradual increase in amplitude prior to any lasting increase in M, was not (yet) seen in YW. Until trials are based on. at least week-long monitoring, they are not applicable to the individual, e.g., to YW, A decision whether a slightly increasing trend prompts starting hypotensive medication is the more complicated in this case, since there was also a change in monitors coincidental with a change in MESOR toward the end of the record and a possibly slightly increasing trend with time is confounded by the change of instrumentation. Relaxation treatment is indicated and practiced. For YW, when incomplete records are discarded and the analysis is assessed only based on those weeks that are documented by a minimum of 224 values (/week), the abnormality seems rarer, apart from the sparser record, of course. Artifactual CHAT can come about more frequently when records with 116 values/week were accepted than in the case when records with fewer than 224 values/week (greater decimation, fewer artifacts) were discarded. The role of the density of the record in diagnosing CHAT is emphasized. The coexistence of CHAT and MESOR-hypertension is seen in 2.3% of the days investigated. Overall MESOR-hypertension is present in 13.3% of the monitored days considered and CHAT overall is rarer yet, only seen in 7%. When weekly summaries are made, keeping all 43 records with 116 or more values or only those with 224 values/week, the incidence of MESOR-hypertension decreases to 7.5 or 3.7% and that of CHAT to 0.6%. CONCLUSION While monitoring continues and is done for health self-care it also contributes substantially to both biomedical and broader science (10-29). Support: MSM0021622402 REFERENCES 1. Fossel M. Editor's Note (to Halberg F et al. Circadian Hyper-Amplitude-Tension, CHAT: a disease risk syndrome of anti-aging medicine). J Anti-Aging Med. 1998; 1: 239. 2. Halberg F, Cornélissen G, International Womb-to-Tomb Chronome Initiative Group: Resolution from a meeting of the International Society for Research on Civilization Diseases and the Environment (New SIRMCE Confederation), Brussels, Belgium, March 17-18. 1995: Fairy tale or reality ? Medtronic Chronobiology Seminar #8, April 1995, 12 pp. text, 18 figures, http://www.msi.umn.edu/~halberg/ 3. Halberg F, Cornélissen G, Katinas G, Tvildiani L, Gigolashvili M, Janashia K, Toba T, Revilla M, Regal P, Sothern RB, Wendt HW, Wang ZR, Zeman M, Jozsa R, Singh RB, Mitsutake G, Chibisov SM, Lee J, Holley D, Holte JE, Sonkowsky RP, Schwartzkopff O, Delmore P, Otsuka K, Bakken EE, Czaplicki J, International BIOCOS Group. Chronobiology's progress: Part I, season's appreciations 2004-2005. Time-, frequency-, phase-, variable-, individual-, age- and site-specific chronomi.es. J Applied Biomedicine 2006; 4: 1-38. http://www.zsfjcu.cz/vyzkum/jab/4_l/halberg.pdf, and Part II, chronomics for an immediately applicable biomedicine. I Applied Biomedicine 2006; 4: 73-86. http://www.zsf.jcu.cz/vyzkum/jab/4_2/halberg2.pdf. 4. Janeway TC. The clinical study of blood pressure. New York: D. Appleton & Co., 1904, 300 pp. "... it is essential that a record of the pressure be made at frequent intervals at some time previous [presumably to an examination], to establish the normal level and the extent of the periodic variations. When this is done, it may be possible to demonstrate changes of small extent, which, lacking this standard for comparison, would be considered within the limits of normal variation." 5. Bartter FC. Periodicity and medicine. In: Scheving LE, Halberg F, Pauly JE, eds. Chronobiology. Tokyo: Igaku Shoin Ltd.; 1974. p. 6-13. On his patient whose blood pressure was diagnosed differently by two physicians who saw him at different times of day: "By conventional standards, this patient is clearly normotensive every morning. But the blood pressure determined each day at 6 in the afternoon provides especially convincing evidence that this patient is a hypertensive, ... My plea today is that information contained in [data curves compiled under differing circumstances, such as 24 hours a day/7 days a week] become a routine minimal amount of information accepted for the description of a patient's blood pressure. The analysis of this information by cosinor should become a routine. It is essential that enough information be collected to allow objective characterization of a periodic phenomenon, to wit, an estimate of M [the time structure or chronome-adjusted mean, or MESOR] ... an estimate of [the amplitude] A itself, and finally an estimate of acrophase, [a measure of timing]. In this way, a patient can be compared with himself at another time, or under another treatment, and the patient can be compared with a normal or with another patient." 44 6. Halberg F, Cornelissen G, Halberg J, Schwartzkopff 0. Pre-hypertensive and other variabilities also await treatment. Am J Medicine, in press. 7. Cornelissen G, Chen CH, Halberg F. Predictive value of blood pressure variability: merits of circadian parameters versus dipping patterns. N Engl J Med 2006 [Aug 14]; 355;8: 850. 8. Kshirsagar AV, Carpenter M, Bang H, Wyatt SB, Colindres RE. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006; 119: 133-141. 9. Halberg F, Cornelissen G, Halberg J, Schwartzkopff O. Pre-hypertensive and other variabilities also await treatment. Am J Medicine, in press, 10. Watanabe Y, Cornelissen G, Flalberg F, Otsuka K, Ohkawa S-I. Association by signatures and coherences between the human circulation and helio- and geomagnetic activity. Biomedicine & Pharmacotherapy 2001; 55 (Suppl 1): 76s-83s. 11. Watanabe Y, Cornelissen G, Halberg F, Thousands of blood pressure and heart rate measurements at fixed clock hours may mislead. Neuroendocrinol Lett 2003; 24: 339-340. 12. Watanabe Y, Nintcheu-Fata S, Katmas G, Cornelissen G, Otsuka K, Hellbrügge T, Schwartzkopff O, Bakken E, Halberg F. Methodology: partial moving spectra of postnatal heart rate chronome. Neuroendocrinol Lett 2003; 24 (Suppl 1): 139-144. 13. Watanabe Y, Cornelissen G, Halberg F, Bingham C, Siegelova J, Otsuka K, Kikuchi T. Incidence pattern and treatment of a clinical entity, overswinging or circadian hyp eramplitude tens ion (CHAT). Scripta medica (Brno) 1997; 70: 245-261, 14. Watanabe Y, Fujimaki S, Asakawa T, Ishii H, Sakurabayashi T, Saito Yuzo, Yoshizaki T, Tamura K, Kondo Y, Hashiguchi S, Halberg F. Chronobiologic characteristics of ventricular ectopy in cardiac diseases. Progress in Clinical and Biological Research 1990; 341B: 593-599. 15. Watanabe Y, Asahi Y, Wu JY, Hillman D, Otsuka K, Cornelissen G, Halberg F. Circadian-infradian aspects of the human adult blood pressure and heart rate chronomes assessed longitudinally, In: Halberg F, Watanabe H. (eds). Proc. Workshop on Computer Methods on Chronobiology and Chronomedicine, Tokyo, Sept, 13, 1990. Tokyo: Medical Review; 1992. p. 233-244. 16. Watanabe Y, Otsuka K, Watanabe H, Asahi Y, Sato C, Murayama M, Sugai J, Halberg F. Circannual rhythm of blood pressure and heart rate in ambulatory blood pressure monitoring. The Autonomic Nervous System 1992; 29: 17-23. (In Japanese with English summary.) 17. Watanabe Y, Hillman DC, Otsuka K, Bingham C, Breus TK, Cornelissen G, Flalberg F. Cross-spectral coherence between geomagnetic disturbance and human cardiovascular variables at non-societal frequencies. Chronobiologia 1994; 21: 265-272. 18. Watanabe Y, Cornelissen G, Halberg F, Otsuka K, Kikuchi T. Long-acting Carteolol lowers circadian and circaseptan blood pressure (BP) amplitude (A) as well as MESOR. Abstract, X National Symposium, Indian Society for Chronobiology, B.J. Medical College, Pune, India, August 21-22, 1995. p. 14-15. 19. Watanabe Y, Cornelissen G, Halberg F, Saito Yoshiaki, Fukuda K, Otsuka K, Kikuchi T. Chronobiometric assessment of autogenic training effects upon blood pressure and heart rate. Perceptual and Motor Skills 1996; 83: 1395-1410. 20. Watanabe Y, Cornelissen G, Halberg F, Saito Yoshiaki, Fukuda K, Revilla M, Rodriguez C, Hawkins D, Otsuka K, Kikuchi T. Method and need for continued assessment of autogenic training effect upon blood pressure: case report, New Trends in Experimental and Clinical Psychiatry 1996; 12: 45-50. 21. Watanabe Y, Flalberg F, Cornelissen G, Kikuchi T, Saito Y, Fukuda K, Revilla M Sr, Revilla M Jr. Rodriguez C, Wark DM, Otsuka K. Self-hypnosis lowers blood pressure 45 swinging and overs winging in circadian hyperamplitndetension (CHAT). EuroRehab 1996; 2: 83-94. 22. Watanabe Y, Ftikuda K, Hasebe T, Yamanata T, Kubo Y, Shinagawa M, Omori K, Otsuka K, Kikuchi T, Halberg F, Cornelissen G. The incidence of new clinical entity Circadian Hyper-Amplitude-Tension (CHAT) in normotensives and hypertensives. Therapeutic Res 1997; 18; 115-119. 23. Watanabe Y, Otsuka K, Cornelissen G, Halbe rg F. Emphasis on the need for timing of autogenic training. Perceptual and Motor Skills 1997; 85: 121-122. 24. Watanabe Y, Cornelissen G, Halberg F, Otsuka K, Ohkawa S-i, Kikuchi T, Siegelova J. Need for chronobiologic reference values (chronodesms) smoothed over age: a problem awaiting a BIOCOS solution. Scripta medica (Brno) 2000; 73: 105-110. 25. Watanabe Y, Cornelissen G, Otsuka K. Ohkawa S, Siegelova J, Halberg F. Effect of alcohol intake and treatment with calcium antagonist on blood, pressure and heart rate assessed by ambulatory monitoring. Scripta medica (Brno) 2001; 74: 103-106. 26. Watanabe Y, Cornelissen G, Hellbrügge T, Watanabe F, Otsuka K, Schwartzkopff O, Hal berg F. Partial spectral element in the chronome of a human neonatal heart rate at term. Biomedicine & Pharmacotherapy 2002; 56 (Suppl 2): 374s-378s. 27. Watanabe Y, Cornelissen G, Otsuka K, Siegelova J, Jancik J, Halberg F. Longitudinal ambulatory blood pressure monitoring for a sequential chronobiologic assessment of losartan effects. Scripta medica (Brno) 2002; 75: 129-134. 28. Watanabe Y. Cornelissen G, Katinas G, Sothern RB, Halberg F, Watanabe M, Watanabe F, Otsuka K. Non-photic, non-thermic circadecadal solar cycle interaction with cardiovascular circannual and circasemiannual variation in heated air-conditioned habitat. Biomedicine & Pharmacotherapy 2003; 57 (Suppl 1): 55s-57s. 29. Watanabe Y, Cornelissen G, Watanabe M, Watanabe F, Otsuka K, Ohkawa S-i, Kikuchi T, Halberg F. Effects of autogenic training and antihypertensive agents on circadian and circaseptan variation of blood pressure. Clin Exp Hypertens 2003; 25: 405-412. 46 BLOOD PRESSURE AND HEART RATE VARIABILITY IN PATIENTS WITH CARDIAC TRANSPLANTATION Siegelova J., Fiscr B., Homolka P., Svačinová H., Varnay F., Vank P., Spinarova L., Vitovec J. Department of Functional Diagnostics and Rehabilitation and *Ist Department of Cardioangiology, St. Anna Teaching Hospital, Faculty of Medicine, Masaryk University, Brno, CZ INTRODUCTION Cardiac transplantation results in complete afferent and efferent denervation of the donor atria and ventricles. This denervation includes both sympathetic and parasympathetic division of the autonomic nervous system. Although functional reinnervation of both sympathetic and parasympathetic fibres to the heart has been demonstrated in the canine transplant model within six months after transplantation (1), only limited functional reinnervation has been demonstrated in humans (2,3). The absence of parasympathetic control of heart rate after human orthotopic cardiac transplantation was studied (4) and the authors showed, that arterial baroreflex gains for the donor sinus node were also depressed (early 0.1±0.2ms/mmHg, late 0.2+0.2 ms/mmHg) compared with controls (14.9±1.8 ms/mmHg). This data suggest that parasympathetic influences of the donor heart rate are absent in the majority of patients up to 96 months after cardiac transplantation. Mancia et al. found that baroreflex sensitivity is inversely related to blood pressure variability and positively related to heart rate variability (5). The aim of the present study was to compare low frequency blood pressure variability in patients after orthotopic cardiac transplantation (OCT) with healthy controls. METHODS Subjects We examined 7 cardiac transplant patients (age 55.7±9.7 years) after 2-8 years after cardiac transplantation. Cardiac transplant patients were without significant epicardial coronary artery disease and had normal left ejection fraction. Cardiac allograft rejection was excluded by right ventricular endomyocardial biopsy, usually obtained before the examinations started. All transplant patients were receiving cyclosporine, all vasculoactive medications were stopped 24 hours before the study. Nobody was treated with beta adrenergic blocking agents. The results were compared with the examination of the group of 7 healthy subjects (C) of similar age (50.0±2.8 years), Control subjects were free of organic heart disease as determined by history and physical examination. Measurements ECG, blood pressure (BP) and thoracic impedance were recorded beat-by-beat during 20 minutes (Task Force Monitor, CNSystem, Austria, Fig. 1) in supine position during spontaneous breathing (5 min) and breathing controlled by metronome (5 min, 0.33 Hz). Using thoracic impedance measurements we determined stroke volume index (ml/m2), in cardiac index (1/min.m2) and in total peripheral resistance index (dyn.s.m2/cm5). 47 The study protocol was approved by the local ethical committee and written informed consent was obtained from all participants. The results are reported as a mean ± standard deviation, comparison between healthy subjects and cardiac transplant patients was performed by using Wilcoxon's test. RESULTS Resting values of heart rate, systolic and diastolic blood pressure in healthy subjects and patients after cardiac transplantation are not different (Fig.2,3,4). Using thoracic impedance measurements stroke volume index (ml/m2), in cardiac index (1/min.m2) and in total peripheral resistance index (dyn.s.m2/cm5) were determined and we have not found any differences between healthy subjects and patients after cardiac transplantation (Fig.5,6,7). We analyzed heart rate variability spectra (ms2) and we have found the decrease in LF heart rate variability (ms2) in patients after cardiac transplantation in comparison with healthy subjects (p<0.01, Fig.8). Diastolic blood pressure variability is presented in Fig. 9. Low frequency diastolic blood pressure variability was not different in patients after cardiac transplantation in comparison with healthy subjects. 48 First ftasn«; date of fetrtrK vr**-v« ■Araj.tenflh: S^wrO STUDY; tTf One-page diagnostic disciosure Page 1 of 1 •d rr 7 si ■■■■■■ V liiilllliIiillliilliiiJ.il.....Ili.ili i I ihlil I. ...iiU-idiiiiii.. i! IS! 00 0.1 0.2 0.3 0.1 diagnosis of emphysema pulmonum -end stage > computer tomography of lungs > NYHA III and IV classification > 6 months without smoking > ability of physiotherapy Lung functional tests: > irreversible pulmonary obstruction. FEV( 20-35% > hyperinflation and air-trapping: RV>250% of ref. values, TLC >125% of ref. values > DLCO<50% of ref. values > blood gases pCO2 <7.3 kPa Exclusion criteria: 1. chest surgery 2. need of artificial respiration 3. asthma bronchiale 4. bronchitis chronica 5. bronchiectasia 6. ischemic heart disease 7. ejection fraction of left ventricle lower than 50% 8. pulmonary hypertension (PAP over 35 mmHg) 9. age over 75 years 10. long lasting therapy with corticoids (prednisone over 15 mg per day) The study protocol was approved by local ethical committee and patients signed informed consent. 75 Study protocol Lung function tests were carried out on MedGraphics, USA- pulmonary function system 1070 (4). Blood gases were determined using equipment AVL (4). Quality of life was analyzed using the questionnaire for determination of quality of life (SGRQ). Surgery procedure Surgery was performed using video-assisted thoraco-scopic surgical approach in 9 cases, in two patients thoracotomy was used to reduce lung volume. In 9 patients the procedure was carried out only on one side of the chest, in two cases in both sides of the chest. The amount of lung tissue was 30-98g. The histological examination of the lung tissue proved the diagnosis of emphysema pulmonum. The results of lung function tests before and six months after LVRS surgery are presented for 7 patients in Table 1 and Fig 1-5. Table 1. Lung function tests before and six months after LVRS surgery in 7 patients with emphysema pulmonum Before After FEVi % ref. values 32.7±11.7 48±9.5* TLC % ref. values 122.3±13,7 113±12.1 DLCO % ref. values 39.8±13.5 41±17.1 RV % ref. values 198.0±43.8 155±41* RV/TLC % ref. values 60.0±6.7 48±13* p<0.05, Wilcoxon FEVi 0/ 70 1 /a * 60 - 50 \ 30 -, f^i^WCH*] r^f;^fi^f^1 1o - f\i 14 0----EH™^™i:^J-.---,\L^iizldKz^Jl- Before After Fig. 1 Forced expiratory volume in one second (FEVj) before and after LVRS 76 TLC 0/ 160 /o 140 H 120 100 H 80 60 40 i 20 0 Before After Fig. 2 Total lung capacity (TLC) before and after LVRS % 70 ^ /O ! 60 50 40 ^ 30 20 -10 -0 Before After Fig. 3 DLCO before and after LVRS 0/ /o 300 250 200 150 100 50 0 Before After Fig. 4 Residual volume (RV) before and after LVRS % Before After Fig. 5 Ratio RV/TLC before and after LVRS 78 The results of lung volume reduction surgery of pulmonary emphysema in seven patients, who survived 6 months after surgery, showed increase in forced expiratory volume in one second (FEVj), decrease in residual volume (RV) and ratio RV/TLC (p<0.05, Wilcoxon). The quality of life was improved in accordance with the improvement of lung functions. From the group of 11 patients 3 patients died, the mortality was 27 %. In one patient the tumor of pancreas appeared and he leaved the study for this reason. DISCUSSION Lung volume reduction surgery of pulmonary emphysema is indicated in patients with end stage of emphysema pulmonum. Lung volume reduction surgery of pulmonary emphysema is performed to reduce the number of large bulges (vesicles, plebs) of lung tissue, to decrease residual volume of lungs, to decrease increased total lung volume capacity. Our results of lung function examinations in seven patients showed similar results. The age limitation of 75 years is not accepted in all studies (3). The progression of the disease of emphysema pulmonum is in the long time survival of patients also some limitation of the use of this therapy as well as the complication of surgical procedure. In our group, we detected pneumonia in four patients and in two cases pneumothorax. Support: MSM0021622402 REFERENCES 1. Cooper JD, Lefrak SS, et al. Is volume reduction surgery appropriate in the treatment of emphysema? Yes. Am J Resp Crit Care Medicine, 153,1996, 1201-1204. 2. Make JB, Fein AM, Is volume reduction surgery appropriate in the treatment of emphysema? No. Am J Resp Crit Care Medicine,153,1996,1205-1207. 3. Pekárek Z, Marel M. ReduktivnI plieni resekce v léčbě chronické plieni nemoci.Stud Pneumol Phthiseol 58,1998, 151-154. 4. Píacheta Z, Siegelova J, Štejfa M a kol. Zátěžová diagnostika v ambulantní a klinické praxi. Praha, Grada, 1999, 276p. 79 EXERCISE TRAINING AND SYMPATHETIC NERVOUS ACTIVITY IN PATIENTS WITH HEART FAILURE Vank P.1, Siegelová J.1, Pochmonová J., Chludilová V.!, Al-Mahmodi N.A.', Konečný L,', Pospíšil P.1, Dobšák P.1, Svačinová H.\ Fišer B.\ Dušek J.1, Balcárková P.3, Špinarová L.3, Eicher J.C.4 1 Department of Functional Diagnostics and Rehabilitation, Faculty of Medicine, Masaryk University, Brno, Czech Republic, 2 institute of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic,3 Ist Department of Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic, 4 Department of Cardiology, Hopital du Bocage and University of Burgundy, Dijon, France INTRODUCTION It was proved that a regular physical activity could modify the sympathetic nervous activity. The indicator of increased sympathetic activity is heart rate variability and low heart rate variability (HRV) correlates with increased risk of sudden cardiac death after myocardial infarction in patients with chronic heart failure (CHF) (I, 2). However, most of the training methods including the rehabilitation protocols used also in our previously published studies are based on aerobic exercise (3, 4), and until now there is a lack of valid information from actual bibliography concerning the effects of resistance or combined long-term training on the heart rate variability parameters (HRV). Classical methodology for evaluating the benefits of physical training is based on cardiopulmonary exercise testing. This examination is time-consuming and could be potentially life-threatening. The examination of HRV is comfortable for the patient and without any risk. The aim of this study was to investigate if ITRV testing can be useful for determination of the influence of 8-week combined exercise training on the heart rate variability expressed in frequency domain parameters in the group of patients with CHF. METHODS Ten patients (mean body weight 85 + 12 kg; mean age 61 + 13 years) with chronic heart failure were selected according to the inclusion criteria listed below. The treatment regimen of all selected patients was optimised to ensure that the patients were symptomatically stable. Standardised pharmacological treatment at the beginning and in the end of the 8-week period included administration of angiotensine converting enzyme inhibitors (ACEI), (3-blockers, diuretics and digitalis in varying combinations. Inclusion criteria were as follows: age over 18 years, symptomatic chronic congestive heart failure N'YHA class 11-111 determined for at least 3 months, and stable for at least 6 weeks; left ventricular ejection fraction < 40 % (assessed by 2D-echocardiography); symptom-limited spiroergometry showed symptom-limited oxygen consumption (V02sl) < 20 ml.kg.min"1. Before the inclusion to the study all the subjects signed the Informed Patient's Consent; the study was approved by the local Ethical Committee and conforms to the principles outlined in the Declaration of Helsinki and to GCP guidelines of European Community. 80 Heart rate variability was registered by the system Varia-Pulsc TF-3. A short-time evaluation of the heart rate variability was done using the beat-to-beat non-invasive monitoring of ECG, spontaneous and metronome-controlled breathing at 0.33Hz before and after the training period of 8 weeks. HRV frequency-domain parameters were determined by spectral analysis of pulse interval (PI). Combined exercise training was realized at the Department of Functional Diagnostics and Rehabilitation 3 times a week. Resistance training elements were included into the exercise protocol only after 2 weeks of aerobic training. One exercise session lasted 60 min and included the following periods: warm-up period (10 min), period of aerobic exercise on bicycle ergometer with load intensity at the level of anaerobic threshold (20 min), period of fitness (or resistance) training performed on combined training machine (20 min), and relaxation period (10 min). In the period of fitness (resistance) training all the subjects started to exercise at 30% level of 1-RM (one repetition maximum), and after 2 weeks they continued at 60% level of 1 -RM. The rehabilitation programme was performed by the patients for eight weeks. Standard exercise spiroergometry (Blood Gas Analyser, MedGraphics, USA) up to the maximum limited by symptoms was carried out before and after 8 weeks of training to assess symptom-limited oxygen consumption (V02sl), maximal workload (Wmax), metabolic equivalents (METs) and maximal heart rate (HRmaJ;). The first spiroergometry test was applied also to determine the anaerobic threshold (ANP) in order to decide the individual training intensity. Results are expressed as mean + SD; Wilcoxon paired test Statistical analysis of functional data was performed using the Wilcoxon paired test, the Chi-2 test, the Friedmann test, and analysis of variance ANOVA. The P value < 0.05 was considered as significant. RESULTS Improvement of physical performance Table 1 Results of registered functional parameters assessed by bicycle spiroergometry testing before and after 8 weeks of combined, exercise training. Results are expressed as mean ± SD; Wilcoxon paired test Functional parameters W '* max (watts) Wmax ..kg"1 (watts, min"1) vo2SL (ml02 .min"!) V02SL -kg"1 (1T1IO2 .min .kg"1) METs Before 93 (± 17) 1.0 (± 0.2) 1399 (± 284) 15.2 (+3.4) 4.3 (± 1.0) After * 110 (±20) * 1.2 (+ 0.2) * 1551 (±261) * 16.9 (± 2.8) * 4.7 (± 0.9) Wmax - maximal workload; Wmax ..kg"' - maximal workload per kg; VO2SL - symptom-limited oxygen uptake; VO?sl .kg"1- symptom-limited oxygen uptake per kg; METs -metabolic equivalents; * P < 0.05 Spiroergometry testing after 8 weeks of the training showed a significant increase of Wmax (110 + 20 W; *P < 0.05), and also a significant increase of V02Sl values (1551 ±261 ml02 .min"1; *P < 0.05); the increase of both values was approximately +20 % compared to the initial values (Fig. J and 2). 1 able 1 summarizes the results of all evaluated functional parameters. Spectral analysis of HRV Spectral analysis of HRV parameters was evaluated and is presented in Table 2. They are pulse intervals (PI; ms), total power - TP; ms2, the power of low-frequency component (LF; 0.04-014 Hz/ms2), the power of high-frequency component (HF; 0.15-04 Hz/ms2) and ratio of LF power to HF power (LF/HF). Spectral analysis revealed a significant increase of the total power (TP) of HRV after 8 weeks of combined exercise training (2829 + 2600 ms ; * P < 0.05) as well as HF (2573+2435 ms2; * P < 0.05) in comparison with the TP and HF initial values (Fig 3). An increase of other HRV parameters was also observed, but it is without statistical significance. The results of HRV spectral analysis and the results of functional performance testing indicate that HRV parameters could be useful for the evaluation of the effectiveness of physical training. Table 2 Results of the spectral analysis of registered HRV frequency-domain parameters before and after 8 weeks of combined exercise training. Results are expressed as mean ± SD; Wilcoxon paired test Functional PI TP LF HF LF/HF parameters (ms) (ms2) (Hz/ms2) (Hz/ms2) before 1016 891 191 665 1.01 (± 137) (+ 1011) (± 178) (± 820) (±1.11) after 1046 * 2829 256 *2573 0.80 (± 124) (± 2600) (±214) (± 2435) (± 1.12) PI - pulse interval; TP - total power; LF - low-frequency component, HF - high-frequency component; LF/HF - LF to HF ratio; * P< 0.05 DISCUSSION In the last 20 years the decreased heart rate variability has been shown to be a significant sign of sudden death risk in patients after myocardial infarction (5), and the predictive value of decreased heart rate variability is comparable to the ejection fraction volume in the risk stratification of patients after myocardial infarction (6). 82 The autonomic nervous system is permanently influenced by a variety of stimuli of the inner ■ or outer origin. Age and health status belong to the inner stimuli, whereas climatic conditions, day (night) period, actual psychic and physical workload, or changes of the body position are 'he stimuli of the outer origin (7). For an easier interpretation of the results of HRV examination a test (supine - standing - supine position) was introduced in which the vagal activity increases in supine position, whereas the sympathetic tone is increased in standing position. Moreover, after repeated supine position an overshoot of the spectral power of the high-frequency component of the heart rate spectral analysis appears. Thus, in order to analyze the data of vagal activity with maximal precision, an analysis of spectral parameters after repeated supine position is recommended (8). With regard to the fact that the amplitude of respiration arrhythmia is predominantly dependent on the frequency and depth of breathing (without breathing frequency control), the variability at high frequency can be submitted to non-predictable changes. A deep and slowed respiration to 6 breath cycles per minute shifts the top of respiratory spectra in the area of 0.1 Hz and. so can imitate an increase of sympathetic tone modulation of cardiac rhythm (9). In our present study we evaluated 5min intervals of HRV using metronome-controlled breathing at 0.33Hz. The adaptation of cardiovascular system in resistance exercise training is different from the adaptation in dynamic exercise training. Heart muscle in resistance training shows signs of concentric hypertrophy, whereas the heart muscle adaptation in dynamic training is characterized by the increase of heart cavities and only a limited heart wall thickening. In that case the hypertrophy is considered as eccentric {10). In contrast to the resistance exercise the aerobic (or dynamic) training Is more efficient for the decrease of heart rate and systolic blood pressure at rest, and also for the increase of stroke volume at rest and during the exercise (11). Thus, it is possible to suppose that various types of exercise influence the HRV in a different manner. The results of our study showed statistically significant differences in TP. Up to the present the influence of combined training on the patients' performance and the autonomic nervous system has not been fully explained. Our results have shown that 8 weeks of combined training led to the increase of functional capacity in patients with chronic heart failure and to the increase of total spectral power. This study contributes to the knowledge about rehabilitation training importance in patients with chronic heart failure. Abbreviations used CHF - chronic heart failure, HF - high-frequency component, HRmax - maximal heart rate, HRV - heart rate variability, NYHA - New York Heart Association, LF - low-frequency component, PI - pulse interval; LF/HF - LF to HF ratio, V02sl - symptom-limited oxygen uptake, V02at ™ oxygen uptake at anaerobic threshold, TP - total power, Wmax - maximal workload This study was supported by the grant MSM0021622402 REFERENCES 1. La Rovere MT, Bigger JT, Marcus Fl, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 1998; 351: 478-484. 83 2. Galinier M, Pathak A, Fourcade J. et al Depressed low frequency power of heart rate variability as an independent predictor of sudden death in chronic heart failure. Eur Heart J 2000; 21: 475-482 3. Jančík J, Várnayová L, Siegelová J. et al. Heart rate variability in patients with chronic ischemic heart disease: effect of 8-week exercise training. Proceedings of Symposium: The Importance of Chronobiology in Diagnosing and Therapy of Internal Diseases. F.Halberg, T.Kenner, B.Fišer (eds.). IDVPZ Brno 2002: 179-184. 4. Jančík, J., Siegehyá,^ J., Dobšák, P. et al Baroreflex sensitivity and heart rate variability in patients with chronic ischemic heart disease and systolic dysfunction: effect of exercise training. Clin Autonom Res 2003; 13(1): 57. 5. Hohnloser SH, Klingenhebel T, Zabel M. Identification of patients after myocardial infarction at risk of life-threatening arrhythmias. Eur Heart J 1999; Suppl.l: 11-20. 6. Halámek J, Kára T, Jurák P. et al. Variability of phase shift between blood pressure and heart rate fluctuations - A marker of. short-term circulation control. Circulation 2003; 108(3): 292-297. 7. Semrád B, Fišer J, Honzíkova N. Aging and cardiac autonomic status. In: Clinical Guide to cardiac autonomic test. M. Malik (ed.). London, Kluwer Academic Publishers 1998: 285-300. 8. Opavský J. Metody vyšetřování autonomního nervového systému a spektrální analýza variability srdeční frekvence v klinické praxi. In: J.Salinger: Variabilita srdeční frekvence a její hodnocení v biomedicínských oborech - od teorie ke klinické praxi. Sborník článků a abstrakt. Univerzita Palackého v Olomouci. Olomouc, 2004. ISBN 80-244-0805-8 9. Kautzner J, Malik M. Variabilita srdečního rytmu a její klinická použitelnost. Cor Vasa, 1998: 40(5): 244-251. 10. Máček M, Macková J. Fyziologie tělesných cvičení. Sdružení pro rozvoj zdravotní a tělesné výchovy ve spolupráci s nakladatelstvím ONYX Praha, 1995. ISBN 80-85228-20-3 11. Pollock ML, Franklin BA, Balady GJ et al. Resistance exercise in individuals with and without cardiovascular disease. Benefits, rationale, safety, and prescription. An advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association. Circulation 2000; 101: 828-833. 84 in 15 x T3 CO o O TO § to 0) CO > 140 120 100 80 Z 60 40 20 H before □ after Fig. 1 Comparison of the values of maximal workload (Wmax) before and after 8 weeks of combined exercise training. Results are expressed as mean ± SD (* P < 0.05; Wilcoxon paired test). 0 o, o 0) o e CL >, H— o 3 > 2000 1800 H 1600 1400 1200 1000 800 600 - 400 200 0 Ü before □ after Fig. 2 Comparison of the values of symptom-limited oxygen uptake (VQ2sl) before and after 8 weeks of combined exercise training. Results are expressed as mean + SD (* P < 0.05; Wilcoxon paired test). 85 Ol o J5 o > o 0 > 7000 6000 5000 4000 3000 2000 1000 - ü before □ after Fig. 3 Comparison of the values of spectral analysis of HRV - Total Power (ms2) before and after 8 weeks of combined exercise training. Values are expressed as mean ± SD (* P < 0.05; Wilcoxon paired test). 86 FUNCTIONAL IMPAIRMENT IN CHILDREN WITH CEREBRAL PALSY Drlíková L.1, Pospíšil P., Konečný L., Chiudilová V,, Siegelova L, Fiser B., Pochmonova J., Erajhi A.A, Abais F.H., Hashim M.K.A, Al-Fadhli A., Al-Mahmodi N.A.I., Vank P. 'Home for Handicapped Children and Young Adults, Kocianka, CZ, Department of Functional Diagnostics and Rehabilitation, St. Anne's Teaching Hospital, Faculty of Medicine, Masaryk University, Brno, Czech Republic INTRODUCTION Several studies have already focused on groups of cerebral palsied children and assessed their functions in relation with therapy (1,2,3). Cerebral palsy (CP) is a non-progressive damage of brain in an early period of its development that is characterized by pathologies in muscle tone and coordination of movements. The brain was affected in an early stage of development in prenatal, perinatal or postnatal period. The status of disease is relatively stable, the impairment is determined by the development and plasticity of the brain (4). The aim of the study was to evaluate functional impairment: in a group of children suffering from cerebral palsy using Gross Motor Function Measure and Barthel index. METHODS Subjects We have examined a group of 10 CP children 5 to 15 years old suffering from different kinds of CP. The average age was 11.7 years. The group consists of 6 boys and 4 girls. The neurogical examinations showed mainly spastic forms of CP, one of the patients suffered from combination of ataxia and spasticity. We used classification according to Bobaths (4). The group of CP patients is presented in Table 1. Measurement The group was tested according to Gross Motor Function Measure (GMFM) that is designed for children from the age of 5. The GMFM enables quantitative assessment of their gross motor skills. 5 years old child must be able to prove all the items included in this measure. GMFM is divided in 5 parts according to the tested positions: A - lying and rolling, B -sitting, C - crawling and kneeling, D - standing, E - walking, running and jumping (5). We can calculate the score for each dimension in percents, the total score and goal total score. The GMFM were supplemented with Barthel index evaluating activities of daily living ADL (6). The test consists of 10 most important items of ADLs. The maximum score is 100 points (%), that means complete independency (6). The study protocol was approved by local ethical committee and the patient or parents signed informed consent. The results are presented as a mean ± standard deviation. 87 RESULTS The Gross Motor Function Measure (GMFM) shows the individual results in Table 2, the mean values are in Table 3. The total goal score, expressed in percentage, is presented in Tables 2 and 3. Our results show an individual variability and different impairment according the age and severity of the disease. Table 1. The age (years) and neurological examination of patients with cerebral palsy Age CP 1 7,1 spastic quadruplegia 2 7,6 spastic quadruplegia 3 5,4 ataxia with spasticity 4 11,6 spastic diplegia 5 10,3 spastic diplegia 6 13,6 spastic diplegia 7 15,75 spastic quadruplegia 8 15,25 spastic quadruplegia 9 15,6 spastic diplegia 10 14,6 spastic hemiplegia Table 2. GMFM in patients with cerebral palsy l 96 92 69 18 18 59 35 2 69 35 2 0 0 21 35 3 100 100 98 90 86 95 88 4 94 80 43 1.5 11 49 29 5 90 58 21 0 0 34 40 6 100 100 95 82 71 90 83 7 84 75 33 0 0 38 64 8 90 20 7 0 0 23 20 9 90 90 83 77 60 80 60 10 96 97 88 74 93 90 84 GMFM TOTAL Table 3. GMFM in group of patients with cerebral palsy GMFM GMFIVI A B GMFM C GMFM GMFM TOTAL GOAL E SCORE SCORE Mean 83 69 48 30 28 51 50 SD ±26 ±32 ±36 ±37 ±36 ±30 ±27 Barthel index of activities of daily living (ADL) in every individual patient is presented in Table 4 and the mean values (±SD) in Table 5. 88 Table 4. Barthel index of ADL in patients with cerebral palsy in percentages 1 45 2 20 3 85 4 35 5 35 6 95 7 35 8 25 9 70 10 100 Table 5. Barthel index of ADL in group of patients with cerebral palsy in percentages Mean 48 SD ±30 Our participants obtained 20 to 100 points in the test, mean value is 48 ± 30, The correlations between GMFM goal score and Barthel index is high (r=0,962) and is significant (p<0.01); it can be seen in Fig. 1. c CO CEREBRAL PALSY 90 100 Fig. 1 Correlations between GMFM goal score and Barthel index DISCUSSION The study showed the different functional impairment in the group of CP patients. Spastic forms are represented in the same rate as in the population of CP patients (1,4). Both results -of Gross Motor Function Measure and Barthel test - are in accordance with other studies (1,2,3). The results of therapy are controversial. The Greek study proved effects of Neurodevelopment treatment in their group (3), other studies were not successful and do not bring any evidence of effects (1,2). In our institute we treat the patients with different techniques of physiotherapy (Neurodevelopment treatment according to Bobath, the method according to Vojta and other non-neurological approaches) and the continuous evaluation of possible progress is necessary. High correlation between GMFM values and Barthel index indicates that both methods are suitable for this task. REFERENCES 1. Krigger, K. Cerebral palsy: An Overview. Am Fam Physician 2006; 73:91-102. 2. Sankar, C, Mundkur, N. Cerebral palsy - definition, classification, etiology and early diagnosis. Indian J Pediatr [serial, online] 2005 [cited 2006 Jun 21]' 72:865-868. Available from: http://www.iipediatricsindia.org/article.asp?issn=0019-5456;veai~2005;vohime=72:issiie=1.0;spage=865;epage=868;aiilast^Sankar 3. Tsorlakis, N., Evaggelinou, C, Grouios, G., Tsorbatzoudis, C. Effect of intensive neuro-developmental treatment in gross motor function of children with cerebral palsy. Dev Med Child Neurol. 2005 Apr; 47 (4):287-289. 4. Chmelová, I.: DMO. Zpráva ze semináře. Available from : http://www.mnof.web4u.cz/drs/s20030318/dmo.pbp 5. RusselfD., Rosenbaum,P., Gowland,C, Hardy, S. Lane, M., Plews, N., McGavin, H., Cadman, D., Jarvis, S. Gross Motor Function Measure Manual. Hamilton: McMaster University. Second edition 1993, 112. 6. Masur, H. Scales and Scores in Neurology. Quantification of Neurological deficits in Research and Practice. New York: Thieme. 2004. s. 392-393. 90 NÁZEV: EDITOR: VYDAL A VYTISKL: VYDANÍ: POČET STRAN: VYŠLO: VÝR. ČÍSLO: TI RÁŽNÍ ZNAK: NONINVASIVE METHODS IN CARDIOLOGY F. HALBERG, T. KENNER, B. FIŠER, J. SIEGELOVÁ NÁRODNÍ CENTRUM OŠETŘOVATELSTVÍ A NELÉKAŘSKÝCH ZDRAVOTNICKÝCH OBORŮ V BRNĚ VE SPOLUPRÁCI S MASARYKOVOU UNIVERZITOU BRNO PRVNÍ 90 BRNO 2006 70/2006 57-862-06 iSBN 80-7013-444-5 9788070134443