NIH Public Access Author Manuscript World Heart J. Author manuscript; available in PMC 2014 May 21.
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Published in final edited form as: World Heart J. 2012 ; 4(4): 263–287.
Decadal Cycles in the Human Cardiovascular System Franz Halberg1,*, Germaine Cornelissen1, Robert B. Sothern1, Dewayne Hillman1, Yoshihiko Watanabe2, Erhard Haus1, Othild Schwartzkopff1, and William R. Best3 1Halberg
Chronobiology Center, University of Minnesota, Minneapolis, MN 55455, US
2Tokyo
Women’s Medical University, Medical Center East, Tokyo, Japan
3Hines
VA Medical Center, Hines, IL 60141
Abstract NIH-PA Author Manuscript NIH-PA Author Manuscript
Seven of the eight authors of this report each performed physiologic self-surveillance, some around the clock for decades. We here document the presence of long cycles (decadals, including circaundecennians) in the time structure of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR). Because of the non-stationary nature in time and space of these and other physiologic and environmental periodic components that, like the wind, can appear and disappear in a given or other geographic location at one or another time, they have been called “Aeolian”. The nonlinear estimation of the uncertainties of the periods (τs) of two or more variables being compared has been used to determine whether these components are congruent or not, depending on whether their CIs (95% confidence intervals) overlap or not. Among others, congruence has been found for components with τs clustering around 10 years in us and around us. There is a selective assortment among individuals, variables and cycle characteristics (mean and circadian amplitude and acrophase). Apart from basic interest, like other nonphotic solar signatures such as transyears with periods slightly longer than one year or about 33-year Brückner-Egeson-Lockyer (BEL) cycles, about 10-year and longer cycles present in 7 of 7 self-monitoring individuals are of interest in the diagnosis of Vascular Variability Anomalies (VVAs), including MESORhypertension, and others. Some of the other VVAs, such as a circadian overswing, i.e., CHAT (Circadian Hyper-Aplitude-Tension), or an excessive pulse pressure, based on repeated 7-day around-the-clock records, can represent a risk of severe cardiovascular events, greater than that of a high BP. The differential diagnosis of physiologic cycles, infradians (components with a τ longer than 28 hours) as well as circadians awaits the collection of reference values for the infradian parameters of the cycles described herein. Just as in stroke-prone spontaneously hypertensive rats during the weeks after weaning CHAT precedes an elevation of the BP MESOR, a decadal overswing seems to precede the occurrence of high BP in two of the subjects here examined. Only around-the-clock monitoring in health for the collection of reference values will allow on their basis the differential diagnosis of the onsets of a circadian versus a circadecadal overswing in BP and the specification whether, and if so, when to initiate hypotensive non-drug or drug treatment.
© 2013 Nova Science Publishers, Inc. * Correspondence: Franz Halberg. Halberg Chronobiology Center University of Minnesota – MMC-8609. 420 Delaware Street SE. Minneapolis, MN 55455, USA. Tel. 612-624-6976, Fax. 612-624-9989. [email protected], Website: http://www.msi.umn.edu/ ~halberg/.
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Keywords
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blood pressure; cardiovascular system; circaundecennians; circadecadals; cosmos; heart rate
Introduction For decades, 7 of the co-authors performed self-surveillance, mostly daily, with interruptions. One (WRB) did so once in the morning, two others about (~) 6 times a day around the wakefulness span and in four cases at 30-minute intervals around-the-clock. About 10-year cycles (decadals) [1, 2] modulate their BP and HR. Using a linear analytical approach without the computation of 95% confidence intervals (CIs), ~10-year periodicities in BP and HR were reported earlier in one of the 7 subjects herein (RBS) over a 21-year span [3]. It was also reported that data on 9 vital signs and 7 circulating hormones obtained every 3 hours around the clock for a day at 5- to 10-year intervals over 34 years from men in the Medical Chronobiology Aging Project (MCAP) [4–6] might be characterized by an ~10year cycle [1–3; cf. 7, 8], whether or not this cycle, as seems likely from a remove-andreplace approach, constitutes a signature of the major decadal solar cycle (Table 1).
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While the linear approach with a fixed period (τ) [1, 3] is an important first step in asking about the presence of, e.g., solar cycle-associated periodicities in living organisms, it is best complemented by a nonlinear specification of CIs that allow an as-yet tentative decision of which τs can be distinguished from each other by the criterion of non-overlap of their CIs or vice versa, according to congruence (Figure 1). The nonlinear extended cosinor had been used earlier to identify other nonphotic solar signatures, such as transyears with periods slightly longer than one year and ~33-year Brückner-Egeson-Lockyer (BEL) cycles [9–12].
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The CIs of τs, rather than precise estimates of τs, are chosen as endpoints to account for the ever-present aeolian variability characteristic of the behavior of the sun and of its putative signatures in the biosphere. An abstract nomogram (Figure 2) introduces the fact that resolving power depends on series length, leading to the problem at hand, related to the limited length, as well as sparsity (long intervals between a few consecutive 24-hour profiles) of some of the series available to investigate long cycles (some approaching the length of half or more of a human lifespan) [2, 8–12] and hence requiring continuous surveillance, as done, with interruptions, herein.
Subjects and Methods Of 7 subjects, 2 women (OS, GC) and 2 men (FH, YW) measured their BP and HR automatically at half-hour intervals with interruptions, 2 others (EH, RBS) self-measured manually around the span of wakefulness ~6 times a day, and a man (WRB) measured in the morning, all for decades (2). Four subjects, 1 woman and 3 men (OS, FH, EH and WRB) used hypotensive medication. Sampling information is provided in Table 2. Each record was analyzed by the extended cosinor method [13–15]. Nonlinear least squares were used to obtain period estimates with a measure of uncertainty, based on Marquardt’s
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algorithm [16]. The chi-square test was used to examine the presence of any preferential periods in the decadal range.
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Results Periods Validated Nonlinearly Figure 3A shows point estimates of τs and their CIs. The τ is indicated by symbols in the key and the length of the CI is given by horizontal bars, computed according to Marquardt’s conservative approach [16; cf. 2], applied as indicated in Figure 3A to the original data and/or to time series derived there from, consisting of consecutive estimates of the 24-hour rhythm-adjusted mean (MESOR; short for Midline-Estimating Statistic Of Rhythm, usually more precise and more accurate than the arithmetic mean) and of double 24-hour (or 7-day in the case of WRB) amplitudes obtained by the least squares fit of a 24-hour (or 7-day) cosine curve to consecutive 24-hour (or 7-day) sections. The double amplitude (2A) is an approximation of the predictable change within a given cycle. Original data, MESORs and 2As can yield different novel aspects of time structure.
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The τs found range in length along the horizontal scale from years to decades. The uncertainties (CIs) of τs are great in some cases, as seen by very wide horizontal bars, notably in the presence of gaps in the data. Other CIs of τs are narrow (Figure 3A) and are seen only within the symbol as a horizontal line. Many τs and CIs cluster (Figure 3B), as validated by a χ2 test of a uniform distribution. Twenty-six of the CIs of τs fall within the vertical shaded green band representing the equatorial index of geomagnetic disturbance (Dst) analyzed over a 27-year span. It has the widest CI of all indices of geomagnetic disturbance examined over the same span, including the antipodal (aa) and planetary (Kp) indices [2]. The CIs of the τs of other geomagnetic indices are narrower (not shown). The yellow band represents the CI of the τ of Wolf’s relative sunspot numbers, analyzed over a 100-year span. The variability in Wolf numbers is shown in Figure 4.
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It is very great in the known record, so that in the much longer past, a probably even greater range of τs may have been covered. Some physiological τs and their CIs do not overlap the CIs of the environmental τs during the same span, as seen for EH [17]. Of interest is a selective assortment of CIs of some τs that do not overlap each other and differ among individuals, variables and even between two characteristics of the same variable, such as a MESOR vs. 2A, a finding compatible with the assumption that some τs may be free-running as a persisting built-in auto-resonance, documented by dampened persistence when there is no congruent environmental counterpart [2]. For instance, with regard to inter-individual differences, RBS has no τ with a CI overlapping 11 years, among the 15 periods found by the analyses of his separate series of 24-hour MESORs and 2As. In an earlier analysis of the original data on SBP, the single cosinor rejected the assumption of a 10-year rhythm, or one near that length (note “near”). By contrast to RBS, among others, YW has a τ and 95% CI that overlaps the length of precisely 11.0 years in each of the variables investigated. Intra-individual, inter-variable differences are further illustrated for FH when τs in his three variables’ 24-hour MESORs
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all have some non-overlapping CIs. Moreover, in his DBP, the τ in his 24-hour 2 As series, estimated as 10.4 [10.1, 18.8] years, differs from that in his MESOR series, estimated as 14.5 [13.5, 15.1] years, i.e., the decadal cycles detected in rhythm characteristics of the same variable in the same subject can differ. If FH were synchronized by the environment, his different variables and characteristics follow different “drummers”, perhaps only one or the other transiently, during the relatively long spans of well over two decades investigated. Differences among characteristics are also seen in RBS’s SBP and DBP, among other variables, as that individual’s series lengthened. Some decadals and multidecadals may sometimes be driven by helio- and/or geomagnetic coperiodisms, in keeping with Figure 3A. Some of them fall into the range of uncertainties (CIs) of the aeolian relative sunspot numbers (given, as noted, as a vertical yellow shaded band) and/or into the range of the geomagnetic index Dst (shown as a vertical green shaded band). Other CIs of biospheric τs do not overlap these intervals, a finding in keeping with their (possibly transient) genetically coded free-run or auto-resonance.
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The extent of within-day change (2A), predictable by the concomitant fit of 24- and 12-hour cosine curves in a sphygmochron [18, 19], has a within-decadal or -multidecadal change exceeding 27 mmHg in YW, Figure 5A [20]. The decadal extent of change in EH is seen in Figure 5B. As with other kinds of gaps [21], those in EH, when tested in several environmental variables, brought about the changes as discussed in detail elsewhere [17]. Day-to-day variability in BP measurements has been amply documented. In spotchecks by ABPM, limited to a few days around the clock, a physiologic increase at the peak of a decadal rhythm can yield on the basis of a few 24-hour profiles, the current (mistaken) platinum standard, a diagnosis of hypertension in a person whose BP values in a weekly around-theclock summary were in the acceptable range for over a decade (YW). Periods Found Linearly Earlier
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The late Eugene Kanabrocki and colleagues, notably RBS, studied symptom-free men at 3hour intervals around-the-clock for 24 hours on 6 occasions (always in May) at the Hines VA Hospital in Hines, IL every 5- to 10-years over a 34-year span (1969–2003) as part of the MCAP study of biological rhythms [4–7]. Circadian characteristics were documented for up to 187 variables measured around-the-clock, for components in blood, plasma, serum, saliva, urine and vital signs, including BP and HR, with observations summarized in nearly 100 papers, abstracts and book chapters and over 70 poster sessions at local, national and international meetings. The number of individuals investigated ranged from 14 to 18 per study and ages ranged from 22–27, 23–51, 41–60, 46–72, 52–77 and 57–81 years in studies 1–6, respectively, with 4 subjects participating in each of the 6 studies. During each 24-hour study, participants were free to move about during the day without napping, with bed rest between 23:00 and 07:00, being briefly awakened for the 01:00 and 04:00 samplings. Meals were served at 16:30, 07:30 and 13:30 and no food or liquids, except water, were allowed inbetween. Measurements (8–9 per subject/profile) were obtained at ~3-hour intervals beginning at 19:00, with subsequent sampling beginning at 22:00, 01:00, 04:00, 07:00, 10:00, 13:00, and World Heart J. Author manuscript; available in PMC 2014 May 21.
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16:00 (and again at 19:00 in study 2). At each test time, subjects voided their bladder for a urine sample, followed by the measurement of their vital signs before drawing of blood samples. Because variables were added or eliminated from the study over the years, not every variable was measured in each study or in each subject. Therefore, as few as 10 and up to 46 time series for some of the variables were available for numerical analyses for decadals, yielding the tentative results in Table 1. They stem from a pool of data from heterogeneous subjects, yet the positive result in the presence of such noise is encouraging. We refer to candidate decadal rhythms first because of the sparsity of the sampling from the viewpoint of decades. Moreover, even when dense around-the-clock sampling is available for decades, mostly daily rather than at intervals of several years, sole reliance on a linear approach for rhythm detection should only be a first step in determination of precise periodicities and uncertainties, notably when several relatively close periods are anticipated to coexist in the same time series and can be distinguished by a nonlinear analysis, as Figure 3A shows to be the case.
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Discussion
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The nonlinear approach in Figures 3A and 3B and the finding of some non-overlapping CIs of τs in physiological variables that have no known concurrent counterpart in the environment is in keeping with (but does not prove) an assumption that at least some decadals some of the time may be partly free-running. The theoretical possibility always exists that there may be an as-yet unknown environmental coperiodism. The observation that several other infradian cycles dampen in amplitude, but persist when the corresponding environmental (driving since amplifying) coperiodism is no longer demonstrable, also speaks for a degree of genetic coding of shorter-than-decadal infradians (Figure 6) [21; cf. 2]. On the basis of this prior evidence, as well as of Figures 3A and 3B, we assume that, just like ~24-hour [22] and ~7-day [23] cycles, decadals and multidecadals are also partly inherited. For the long cycles, studies using human twins, used in the case of circadian or circaseptan cycles, will be much more demanding. A start in that direction could be made on monozygotic vs. dizygotic twins, comparing the extent of congruence among their long cycles. If parents of twins cooperate in allowing neonatal monitoring of BP and HR from birth, having both infants in intensive care units, the accumulating neonatal data as a population phenomenon would allow future generations of investigators to take a first tentative look at the heritability of all infradian components by serially-independent sampling with each infant sampled just once for days or up to weeks. Decadals were thus found with serial independence, Figure 7 [24], while heritability was found for circaseptans with serial dependence as to individuals [23] for neonatal BP and HR. A near-10-year cycle was statistically significant in a meta-analysis of Horrebow’s sunspot counts during 1761–1776 and was also statistically significant in data published in 1838 by Schwabe, who reported a cycle by 1844 [25]. This sunspot cycle, for as long as it has been followed, has been rather variable, as seen in Figure 4. So are its signatures, as far as can be judged from a limited sample with uncertainties that are essential because of the solar variabilities that also characterize the latter’s putative biospheric signatures, including those
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in the circulation of blood [2]. In this context, our findings are a step beyond William Harvey’s jotting-down in 1603: “The movement of the blood occurs consistently in a circular manner and is the result of the beating of the heart” [26]. The movement of the blood may have also been consistently influenced by the long cycles of the solar system, with some of them also reflected in sudden cardiac death and myocardial infarctions [2, 12], facts attesting to their clinical, as well as basic, importance. The findings in Figures 3A, 3B, 5A and 5B are directly pertinent to everyday diagnosis and treatment, once the technologies for surveillance of pressure in vehicle tires, or those used by pharmaceutical companies to monitor rodents and develop new drugs, will be more generally, affordably available on a large scale, a possibility that has been documented by feasibility tests [27].
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Automatic monitoring instrumentation has already been applied around the clock for decades by four of the authors of this report. Our results demonstrate that the current reliance on one or a few 24-hour records is an anachronism when trends should be followed along the scale of decades. Rather than utopia, the findings herein are a reality implementable by manual measurement by three of the authors, or by automatic monitoring, the latter more reliable than the former, also for studies in chronomics of association among physiological and environmental cycles [28]. Nor is our suggestion for the practitioner novel. In 1904, Theodore C. Janeway, an opinion leader at Johns Hopkins University, wrote that he would not see a patient before he had enough data to evaluate the periodicities (plural) characterizing BP [29]. By Janeway’s time, Ignaz Zadek had enough data to allow the demonstration by cosinor analysis of more than a single periodicity, Figure 8 [30].
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In addition, Frederic C. Bartter, head of the Hypertension-Endocrine Branch at the US National Institutes of Health (NIH), and later head of the NIH Clinical Center, wrote, on variability: “By conventional standards, this patient is clearly normotensive every morning. Yet the BP determined each day at 6 in the afternoon provides especially convincing evidence that this patient is a hypertensive. … My plea today [in 1974!] is that information contained in such curves [cosinor fits] becomes 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 A [the amplitude] itself, and finally an estimate of acrophase, φ [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” [31]. The time has come for the profession to apply what is available for research in practice. The precedent of legislative action is noted by Larry A. Beaty: “In the United States, the Firestone recall in the late 1990s (which was linked to more than 100 deaths from rollovers following tire tread-separation), pushed the Clinton administration to legislate the TREAD [Transportation Recall Enhancement, Accountability and Documentation] Act. The Act mandated the use of a suitable TPMS [Tire Pressure Monitoring System] technology in all light motor vehicles (under 10,000 pounds), to help alert drivers of severe under-
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inflation events. This act affects all light motor vehicles sold after September 1, 2007.
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“The issue isn’t so much a question of whether we could use the same pressure monitor in people, but rather why was it important and practical to put continuous pressure monitoring into cars before we put it into presumably more-valuable people? What can we learn from the history?
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“It would seem that the public didn’t demand tire pressure monitors from the automobile manufacturers until the ‘tragedy’ was publicized by the mass media. This suggests that one way to get people interested in chronobiological/chronomic interpretation of blood pressure is to get somebody to start counting and publishing ‘death-and-disablement-by-VVA’ statistics. That is, how many people died last year with a detectable, treatable VVA? (This is different than measuring the cost of treating people in the mainstream healthcare system and holding that number up in front of government agencies or insurance companies, or even the general public, claiming there’s a ‘savings’ to be had. Hard events, notably deaths mean more than dollars to many people.)” Figures 9 and 10 show that they deserve at least the same attention as President Clinton’s TREAD Act. Indeed, an estimated 66.9 million American adults have hypertension, defined as an average SBP of 140 mmHg or higher and an average DBP of 90 mmHg or higher. Hypertension was deemed uncontrolled in approximately 35.8 million, based on data from the National Health and Nutrition Examination Survey [32]. According to Dr. Thomas R. Frieden, director of the Centers for Disease Control, “We’re talking about $131 billion in health care costs annually and 1,000 deaths/day, today and every day this year” that can be attributed to uncontrolled hypertension. Figures 3A, 3B, 5A and 5B broaden the Zadek-Janeway-Bartter perspective. There is the precedent of unnecessary substitution treatment with androgen by an outstanding physician who at the time did not realize that he underwent a decadal cycle [33]. In his selfsurveillance, a statistically significant decrease over several years in the urinary metabolites of steroidal hormones was followed by an also-significant increase over many years (on data that excluded spans of testosterone supplementation) as the other complementary part of a long cycle, Figure 11 [33].
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Decadal cycles have been documented for the incidence (rate/thousand/month) of 6 cervical epithelial cytopathologic abnormalities from a population of nearly 1.2 million women undergoing routine screenings over a 21-y span in Holland [3]. These included microrganism infections from a fungus (Actinomyces urogenitalis), a bacterium (Chlamydia trachomatis), a parasite (Trichomonas vaginalis), and a virus (Human Papilloma Virus, HPV), and cervical epithelial carcinoma and dysplasia (pre-cancer) [3]. The aforementioned circadecadal solar, physiologic and pathophysiologic rhythms may indicate something potentially important about the physiologic and biomedical implications of our geomagnetic relationships with the internal dynamics of the Sun, and such information, if understood, could, in principle, result in better forecasting models of disease etiology and eventually treatment. The optimal timing of disease-specific screening, diagnosis, and treatment and prevention strategies within these long and predictable biological cycles holds potential
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benefit at no cost and without risk. Ignoring these time structures, on the other hand, may continue to increase unnecessary risk and cost, as documented in a series of consensus meetings, one of them guided by the late Bohumil Fiser, board member of the World Health Organization and minister of health of the Czech Republic, and by Thomas Kenner, emeritus president of the University of Graz (Austria), both physiology department heads and cardiac physiologists [19]. The basic nature of decadal cycles is illustrated by its presence in a population of single giant unicells Acetabularia acetabulum while being studied over 14 years under standardized light and darkness alternating at 12-hour intervals [34] and in microbial sectoring [35; cf. 2]. Whatever the relative roles of genetics and epigenetics may be, with a P
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Published in final edited form as: World Heart J. 2012 ; 4(4): 263–287.
Decadal Cycles in the Human Cardiovascular System Franz Halberg1,*, Germaine Cornelissen1, Robert B. Sothern1, Dewayne Hillman1, Yoshihiko Watanabe2, Erhard Haus1, Othild Schwartzkopff1, and William R. Best3 1Halberg
Chronobiology Center, University of Minnesota, Minneapolis, MN 55455, US
2Tokyo
Women’s Medical University, Medical Center East, Tokyo, Japan
3Hines
VA Medical Center, Hines, IL 60141
Abstract NIH-PA Author Manuscript NIH-PA Author Manuscript
Seven of the eight authors of this report each performed physiologic self-surveillance, some around the clock for decades. We here document the presence of long cycles (decadals, including circaundecennians) in the time structure of systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR). Because of the non-stationary nature in time and space of these and other physiologic and environmental periodic components that, like the wind, can appear and disappear in a given or other geographic location at one or another time, they have been called “Aeolian”. The nonlinear estimation of the uncertainties of the periods (τs) of two or more variables being compared has been used to determine whether these components are congruent or not, depending on whether their CIs (95% confidence intervals) overlap or not. Among others, congruence has been found for components with τs clustering around 10 years in us and around us. There is a selective assortment among individuals, variables and cycle characteristics (mean and circadian amplitude and acrophase). Apart from basic interest, like other nonphotic solar signatures such as transyears with periods slightly longer than one year or about 33-year Brückner-Egeson-Lockyer (BEL) cycles, about 10-year and longer cycles present in 7 of 7 self-monitoring individuals are of interest in the diagnosis of Vascular Variability Anomalies (VVAs), including MESORhypertension, and others. Some of the other VVAs, such as a circadian overswing, i.e., CHAT (Circadian Hyper-Aplitude-Tension), or an excessive pulse pressure, based on repeated 7-day around-the-clock records, can represent a risk of severe cardiovascular events, greater than that of a high BP. The differential diagnosis of physiologic cycles, infradians (components with a τ longer than 28 hours) as well as circadians awaits the collection of reference values for the infradian parameters of the cycles described herein. Just as in stroke-prone spontaneously hypertensive rats during the weeks after weaning CHAT precedes an elevation of the BP MESOR, a decadal overswing seems to precede the occurrence of high BP in two of the subjects here examined. Only around-the-clock monitoring in health for the collection of reference values will allow on their basis the differential diagnosis of the onsets of a circadian versus a circadecadal overswing in BP and the specification whether, and if so, when to initiate hypotensive non-drug or drug treatment.
© 2013 Nova Science Publishers, Inc. * Correspondence: Franz Halberg. Halberg Chronobiology Center University of Minnesota – MMC-8609. 420 Delaware Street SE. Minneapolis, MN 55455, USA. Tel. 612-624-6976, Fax. 612-624-9989. [email protected], Website: http://www.msi.umn.edu/ ~halberg/.
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Keywords
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blood pressure; cardiovascular system; circaundecennians; circadecadals; cosmos; heart rate
Introduction For decades, 7 of the co-authors performed self-surveillance, mostly daily, with interruptions. One (WRB) did so once in the morning, two others about (~) 6 times a day around the wakefulness span and in four cases at 30-minute intervals around-the-clock. About 10-year cycles (decadals) [1, 2] modulate their BP and HR. Using a linear analytical approach without the computation of 95% confidence intervals (CIs), ~10-year periodicities in BP and HR were reported earlier in one of the 7 subjects herein (RBS) over a 21-year span [3]. It was also reported that data on 9 vital signs and 7 circulating hormones obtained every 3 hours around the clock for a day at 5- to 10-year intervals over 34 years from men in the Medical Chronobiology Aging Project (MCAP) [4–6] might be characterized by an ~10year cycle [1–3; cf. 7, 8], whether or not this cycle, as seems likely from a remove-andreplace approach, constitutes a signature of the major decadal solar cycle (Table 1).
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While the linear approach with a fixed period (τ) [1, 3] is an important first step in asking about the presence of, e.g., solar cycle-associated periodicities in living organisms, it is best complemented by a nonlinear specification of CIs that allow an as-yet tentative decision of which τs can be distinguished from each other by the criterion of non-overlap of their CIs or vice versa, according to congruence (Figure 1). The nonlinear extended cosinor had been used earlier to identify other nonphotic solar signatures, such as transyears with periods slightly longer than one year and ~33-year Brückner-Egeson-Lockyer (BEL) cycles [9–12].
NIH-PA Author Manuscript
The CIs of τs, rather than precise estimates of τs, are chosen as endpoints to account for the ever-present aeolian variability characteristic of the behavior of the sun and of its putative signatures in the biosphere. An abstract nomogram (Figure 2) introduces the fact that resolving power depends on series length, leading to the problem at hand, related to the limited length, as well as sparsity (long intervals between a few consecutive 24-hour profiles) of some of the series available to investigate long cycles (some approaching the length of half or more of a human lifespan) [2, 8–12] and hence requiring continuous surveillance, as done, with interruptions, herein.
Subjects and Methods Of 7 subjects, 2 women (OS, GC) and 2 men (FH, YW) measured their BP and HR automatically at half-hour intervals with interruptions, 2 others (EH, RBS) self-measured manually around the span of wakefulness ~6 times a day, and a man (WRB) measured in the morning, all for decades (2). Four subjects, 1 woman and 3 men (OS, FH, EH and WRB) used hypotensive medication. Sampling information is provided in Table 2. Each record was analyzed by the extended cosinor method [13–15]. Nonlinear least squares were used to obtain period estimates with a measure of uncertainty, based on Marquardt’s
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algorithm [16]. The chi-square test was used to examine the presence of any preferential periods in the decadal range.
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Results Periods Validated Nonlinearly Figure 3A shows point estimates of τs and their CIs. The τ is indicated by symbols in the key and the length of the CI is given by horizontal bars, computed according to Marquardt’s conservative approach [16; cf. 2], applied as indicated in Figure 3A to the original data and/or to time series derived there from, consisting of consecutive estimates of the 24-hour rhythm-adjusted mean (MESOR; short for Midline-Estimating Statistic Of Rhythm, usually more precise and more accurate than the arithmetic mean) and of double 24-hour (or 7-day in the case of WRB) amplitudes obtained by the least squares fit of a 24-hour (or 7-day) cosine curve to consecutive 24-hour (or 7-day) sections. The double amplitude (2A) is an approximation of the predictable change within a given cycle. Original data, MESORs and 2As can yield different novel aspects of time structure.
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The τs found range in length along the horizontal scale from years to decades. The uncertainties (CIs) of τs are great in some cases, as seen by very wide horizontal bars, notably in the presence of gaps in the data. Other CIs of τs are narrow (Figure 3A) and are seen only within the symbol as a horizontal line. Many τs and CIs cluster (Figure 3B), as validated by a χ2 test of a uniform distribution. Twenty-six of the CIs of τs fall within the vertical shaded green band representing the equatorial index of geomagnetic disturbance (Dst) analyzed over a 27-year span. It has the widest CI of all indices of geomagnetic disturbance examined over the same span, including the antipodal (aa) and planetary (Kp) indices [2]. The CIs of the τs of other geomagnetic indices are narrower (not shown). The yellow band represents the CI of the τ of Wolf’s relative sunspot numbers, analyzed over a 100-year span. The variability in Wolf numbers is shown in Figure 4.
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It is very great in the known record, so that in the much longer past, a probably even greater range of τs may have been covered. Some physiological τs and their CIs do not overlap the CIs of the environmental τs during the same span, as seen for EH [17]. Of interest is a selective assortment of CIs of some τs that do not overlap each other and differ among individuals, variables and even between two characteristics of the same variable, such as a MESOR vs. 2A, a finding compatible with the assumption that some τs may be free-running as a persisting built-in auto-resonance, documented by dampened persistence when there is no congruent environmental counterpart [2]. For instance, with regard to inter-individual differences, RBS has no τ with a CI overlapping 11 years, among the 15 periods found by the analyses of his separate series of 24-hour MESORs and 2As. In an earlier analysis of the original data on SBP, the single cosinor rejected the assumption of a 10-year rhythm, or one near that length (note “near”). By contrast to RBS, among others, YW has a τ and 95% CI that overlaps the length of precisely 11.0 years in each of the variables investigated. Intra-individual, inter-variable differences are further illustrated for FH when τs in his three variables’ 24-hour MESORs
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all have some non-overlapping CIs. Moreover, in his DBP, the τ in his 24-hour 2 As series, estimated as 10.4 [10.1, 18.8] years, differs from that in his MESOR series, estimated as 14.5 [13.5, 15.1] years, i.e., the decadal cycles detected in rhythm characteristics of the same variable in the same subject can differ. If FH were synchronized by the environment, his different variables and characteristics follow different “drummers”, perhaps only one or the other transiently, during the relatively long spans of well over two decades investigated. Differences among characteristics are also seen in RBS’s SBP and DBP, among other variables, as that individual’s series lengthened. Some decadals and multidecadals may sometimes be driven by helio- and/or geomagnetic coperiodisms, in keeping with Figure 3A. Some of them fall into the range of uncertainties (CIs) of the aeolian relative sunspot numbers (given, as noted, as a vertical yellow shaded band) and/or into the range of the geomagnetic index Dst (shown as a vertical green shaded band). Other CIs of biospheric τs do not overlap these intervals, a finding in keeping with their (possibly transient) genetically coded free-run or auto-resonance.
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The extent of within-day change (2A), predictable by the concomitant fit of 24- and 12-hour cosine curves in a sphygmochron [18, 19], has a within-decadal or -multidecadal change exceeding 27 mmHg in YW, Figure 5A [20]. The decadal extent of change in EH is seen in Figure 5B. As with other kinds of gaps [21], those in EH, when tested in several environmental variables, brought about the changes as discussed in detail elsewhere [17]. Day-to-day variability in BP measurements has been amply documented. In spotchecks by ABPM, limited to a few days around the clock, a physiologic increase at the peak of a decadal rhythm can yield on the basis of a few 24-hour profiles, the current (mistaken) platinum standard, a diagnosis of hypertension in a person whose BP values in a weekly around-theclock summary were in the acceptable range for over a decade (YW). Periods Found Linearly Earlier
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The late Eugene Kanabrocki and colleagues, notably RBS, studied symptom-free men at 3hour intervals around-the-clock for 24 hours on 6 occasions (always in May) at the Hines VA Hospital in Hines, IL every 5- to 10-years over a 34-year span (1969–2003) as part of the MCAP study of biological rhythms [4–7]. Circadian characteristics were documented for up to 187 variables measured around-the-clock, for components in blood, plasma, serum, saliva, urine and vital signs, including BP and HR, with observations summarized in nearly 100 papers, abstracts and book chapters and over 70 poster sessions at local, national and international meetings. The number of individuals investigated ranged from 14 to 18 per study and ages ranged from 22–27, 23–51, 41–60, 46–72, 52–77 and 57–81 years in studies 1–6, respectively, with 4 subjects participating in each of the 6 studies. During each 24-hour study, participants were free to move about during the day without napping, with bed rest between 23:00 and 07:00, being briefly awakened for the 01:00 and 04:00 samplings. Meals were served at 16:30, 07:30 and 13:30 and no food or liquids, except water, were allowed inbetween. Measurements (8–9 per subject/profile) were obtained at ~3-hour intervals beginning at 19:00, with subsequent sampling beginning at 22:00, 01:00, 04:00, 07:00, 10:00, 13:00, and World Heart J. Author manuscript; available in PMC 2014 May 21.
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16:00 (and again at 19:00 in study 2). At each test time, subjects voided their bladder for a urine sample, followed by the measurement of their vital signs before drawing of blood samples. Because variables were added or eliminated from the study over the years, not every variable was measured in each study or in each subject. Therefore, as few as 10 and up to 46 time series for some of the variables were available for numerical analyses for decadals, yielding the tentative results in Table 1. They stem from a pool of data from heterogeneous subjects, yet the positive result in the presence of such noise is encouraging. We refer to candidate decadal rhythms first because of the sparsity of the sampling from the viewpoint of decades. Moreover, even when dense around-the-clock sampling is available for decades, mostly daily rather than at intervals of several years, sole reliance on a linear approach for rhythm detection should only be a first step in determination of precise periodicities and uncertainties, notably when several relatively close periods are anticipated to coexist in the same time series and can be distinguished by a nonlinear analysis, as Figure 3A shows to be the case.
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Discussion
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The nonlinear approach in Figures 3A and 3B and the finding of some non-overlapping CIs of τs in physiological variables that have no known concurrent counterpart in the environment is in keeping with (but does not prove) an assumption that at least some decadals some of the time may be partly free-running. The theoretical possibility always exists that there may be an as-yet unknown environmental coperiodism. The observation that several other infradian cycles dampen in amplitude, but persist when the corresponding environmental (driving since amplifying) coperiodism is no longer demonstrable, also speaks for a degree of genetic coding of shorter-than-decadal infradians (Figure 6) [21; cf. 2]. On the basis of this prior evidence, as well as of Figures 3A and 3B, we assume that, just like ~24-hour [22] and ~7-day [23] cycles, decadals and multidecadals are also partly inherited. For the long cycles, studies using human twins, used in the case of circadian or circaseptan cycles, will be much more demanding. A start in that direction could be made on monozygotic vs. dizygotic twins, comparing the extent of congruence among their long cycles. If parents of twins cooperate in allowing neonatal monitoring of BP and HR from birth, having both infants in intensive care units, the accumulating neonatal data as a population phenomenon would allow future generations of investigators to take a first tentative look at the heritability of all infradian components by serially-independent sampling with each infant sampled just once for days or up to weeks. Decadals were thus found with serial independence, Figure 7 [24], while heritability was found for circaseptans with serial dependence as to individuals [23] for neonatal BP and HR. A near-10-year cycle was statistically significant in a meta-analysis of Horrebow’s sunspot counts during 1761–1776 and was also statistically significant in data published in 1838 by Schwabe, who reported a cycle by 1844 [25]. This sunspot cycle, for as long as it has been followed, has been rather variable, as seen in Figure 4. So are its signatures, as far as can be judged from a limited sample with uncertainties that are essential because of the solar variabilities that also characterize the latter’s putative biospheric signatures, including those
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in the circulation of blood [2]. In this context, our findings are a step beyond William Harvey’s jotting-down in 1603: “The movement of the blood occurs consistently in a circular manner and is the result of the beating of the heart” [26]. The movement of the blood may have also been consistently influenced by the long cycles of the solar system, with some of them also reflected in sudden cardiac death and myocardial infarctions [2, 12], facts attesting to their clinical, as well as basic, importance. The findings in Figures 3A, 3B, 5A and 5B are directly pertinent to everyday diagnosis and treatment, once the technologies for surveillance of pressure in vehicle tires, or those used by pharmaceutical companies to monitor rodents and develop new drugs, will be more generally, affordably available on a large scale, a possibility that has been documented by feasibility tests [27].
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Automatic monitoring instrumentation has already been applied around the clock for decades by four of the authors of this report. Our results demonstrate that the current reliance on one or a few 24-hour records is an anachronism when trends should be followed along the scale of decades. Rather than utopia, the findings herein are a reality implementable by manual measurement by three of the authors, or by automatic monitoring, the latter more reliable than the former, also for studies in chronomics of association among physiological and environmental cycles [28]. Nor is our suggestion for the practitioner novel. In 1904, Theodore C. Janeway, an opinion leader at Johns Hopkins University, wrote that he would not see a patient before he had enough data to evaluate the periodicities (plural) characterizing BP [29]. By Janeway’s time, Ignaz Zadek had enough data to allow the demonstration by cosinor analysis of more than a single periodicity, Figure 8 [30].
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In addition, Frederic C. Bartter, head of the Hypertension-Endocrine Branch at the US National Institutes of Health (NIH), and later head of the NIH Clinical Center, wrote, on variability: “By conventional standards, this patient is clearly normotensive every morning. Yet the BP determined each day at 6 in the afternoon provides especially convincing evidence that this patient is a hypertensive. … My plea today [in 1974!] is that information contained in such curves [cosinor fits] becomes 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 A [the amplitude] itself, and finally an estimate of acrophase, φ [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” [31]. The time has come for the profession to apply what is available for research in practice. The precedent of legislative action is noted by Larry A. Beaty: “In the United States, the Firestone recall in the late 1990s (which was linked to more than 100 deaths from rollovers following tire tread-separation), pushed the Clinton administration to legislate the TREAD [Transportation Recall Enhancement, Accountability and Documentation] Act. The Act mandated the use of a suitable TPMS [Tire Pressure Monitoring System] technology in all light motor vehicles (under 10,000 pounds), to help alert drivers of severe under-
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inflation events. This act affects all light motor vehicles sold after September 1, 2007.
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“The issue isn’t so much a question of whether we could use the same pressure monitor in people, but rather why was it important and practical to put continuous pressure monitoring into cars before we put it into presumably more-valuable people? What can we learn from the history?
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“It would seem that the public didn’t demand tire pressure monitors from the automobile manufacturers until the ‘tragedy’ was publicized by the mass media. This suggests that one way to get people interested in chronobiological/chronomic interpretation of blood pressure is to get somebody to start counting and publishing ‘death-and-disablement-by-VVA’ statistics. That is, how many people died last year with a detectable, treatable VVA? (This is different than measuring the cost of treating people in the mainstream healthcare system and holding that number up in front of government agencies or insurance companies, or even the general public, claiming there’s a ‘savings’ to be had. Hard events, notably deaths mean more than dollars to many people.)” Figures 9 and 10 show that they deserve at least the same attention as President Clinton’s TREAD Act. Indeed, an estimated 66.9 million American adults have hypertension, defined as an average SBP of 140 mmHg or higher and an average DBP of 90 mmHg or higher. Hypertension was deemed uncontrolled in approximately 35.8 million, based on data from the National Health and Nutrition Examination Survey [32]. According to Dr. Thomas R. Frieden, director of the Centers for Disease Control, “We’re talking about $131 billion in health care costs annually and 1,000 deaths/day, today and every day this year” that can be attributed to uncontrolled hypertension. Figures 3A, 3B, 5A and 5B broaden the Zadek-Janeway-Bartter perspective. There is the precedent of unnecessary substitution treatment with androgen by an outstanding physician who at the time did not realize that he underwent a decadal cycle [33]. In his selfsurveillance, a statistically significant decrease over several years in the urinary metabolites of steroidal hormones was followed by an also-significant increase over many years (on data that excluded spans of testosterone supplementation) as the other complementary part of a long cycle, Figure 11 [33].
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Decadal cycles have been documented for the incidence (rate/thousand/month) of 6 cervical epithelial cytopathologic abnormalities from a population of nearly 1.2 million women undergoing routine screenings over a 21-y span in Holland [3]. These included microrganism infections from a fungus (Actinomyces urogenitalis), a bacterium (Chlamydia trachomatis), a parasite (Trichomonas vaginalis), and a virus (Human Papilloma Virus, HPV), and cervical epithelial carcinoma and dysplasia (pre-cancer) [3]. The aforementioned circadecadal solar, physiologic and pathophysiologic rhythms may indicate something potentially important about the physiologic and biomedical implications of our geomagnetic relationships with the internal dynamics of the Sun, and such information, if understood, could, in principle, result in better forecasting models of disease etiology and eventually treatment. The optimal timing of disease-specific screening, diagnosis, and treatment and prevention strategies within these long and predictable biological cycles holds potential
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benefit at no cost and without risk. Ignoring these time structures, on the other hand, may continue to increase unnecessary risk and cost, as documented in a series of consensus meetings, one of them guided by the late Bohumil Fiser, board member of the World Health Organization and minister of health of the Czech Republic, and by Thomas Kenner, emeritus president of the University of Graz (Austria), both physiology department heads and cardiac physiologists [19]. The basic nature of decadal cycles is illustrated by its presence in a population of single giant unicells Acetabularia acetabulum while being studied over 14 years under standardized light and darkness alternating at 12-hour intervals [34] and in microbial sectoring [35; cf. 2]. Whatever the relative roles of genetics and epigenetics may be, with a P
