Decadal Cycles in the Human Cardiovascular System

Abstract

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 MESOR-hypertension, 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.

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 ~10-year cycle [1–3; cf. 7, 8], whether or not this cycle, as seems likely from a remove-and-replace approach, constitutes a signature of the major decadal solar cycle (Table 1).

Table 1.

Linear cosinor evaluation of circadecadal characteristics for 7 circulating hormones and 9 vital signs in 10–14 men in the Medical Chronobiology Aging Project^* and in Wolf’s relative sunspot numbers (WN) Single cosinor summary at solar cycle period of 10.17 years (89121 hours)^**

Variable	units	% rhythm	p	Degrees from Solar φ
SUNSPOTS	Monthly	77.4	<0.001
HORMONES
Cortisol	μg/dl	2.4	0.046	−49°
Insulin	μIU/ml	2.3	0.022	−27°
LH	μIU/ml	6.8	<0.001	−35°
Melatonin	ng/L	11.0	<0.001	−224°
Prolactin	ng/ml	13.8	<0.001	−2°
T3 uptake	%	3.8	0.006	−228°
T4	μg/dl	5.6	<0.001	−19
VITAL SIGNS
Body Temp	°F	1.5	0.020	−50°
Heart rate	bts/min	6.6	<0.001	−163°
Systolic BP	mmHg	8.8	<0.001	−123°
Diastolic BP	mmHg	12.3	<0.001	−161°
PulsePressure	mmHg	5.9	<0.001	−41°
Mean Art Press	mmHg	11.6	<0.001	−150°
Double Product	SBPxHR	9.6	<0.001	−149°
Ocu Press - Rt	mmHg	1.4	0.003	−33°
Ocu Press - Lft	mmHg	3.9	<0.001	−298°

^*Based on 4 sets of solidly documented observations around the clock of vital signs and blood in men, ages 23–77 years, sampled every 3 hours for 24 hours in May 1979 (n=13), 1988 (n=11), 1993 (n=11) and/or 1998 (n=11) (some men studied more than once). Vital signs also measured every 3 hours on May 14–15, 1969 (n=13). Sleep and/or rest between 22:30 and 06:30. Since the data were collected at long intervals, follow-up studies are indicated. N of values/series: 256/446. Data from the late E.L. Kanabrocki et al., Hines VA Hospital, Hines, Illinois [4–7].

^**Single cosinor applied to all individuals’ data, serving for the test of the no-decadal or other paradecadal rhythm assumption leading to candidate rhythms. A complementary nonlinear approach is indicated when denser data become available, as already done in Figures 3A and 3B for 8 other subjects.

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].

Figure 1.

Abstract scheme of congruence as a first step toward the test of equality of two or more periods (τs) or phases (φs). Congruence or similarity in characteristics such as the period or phase of a spectral component in two or more concomitantly sampled time series of the same variables or of different variables within intracellular entities, cells, tissues, organs, organ systems, individuals, populations, disciplines and, most interestingly, when they are transdisciplinary, as are transyears or trans- and cis-half-years [2]. Wobbly nature of some natural physical environmental and biospherical spectral components require an inferential statistical approach. The congruence of anticipated components can be meaningfully assessed to approximate a yet-to-be-developed test of equality of periods and/or phases (e.g., among environmental, biological and sociological variables). * ℓ1 and ℓ2 are one-sided CI length; ℓ is distance between proximal limits of non-overlapping CIs of τs (or φs). © Halberg.

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.

Figure 2.

Nomogram. Spectral resolution depends on the length of the record available for analysis. In other words, the period of a given signal cannot be determined exactly. The uncertainty of its estimation will be much larger for longer periods than for shorter periods. Intuitively, this can be understood by the fact that for a given record length, there will be more replications of short cycles than of long cycles. From the viewpoint of a spectral analysis, the uncertainty of the period can be measured by its bandwidth (δ in the nomogram). For instance, if the record spans only 2 cycles of a given signal (n=2 in the column to the right in the nomogram), the bandwidth will be about half the length of the period (or an about 5-year uncertainty for an about 10-year cycle). If the record spans 3 cycles, the bandwidth is reduced to about 30% of the period length (or about 3 years for an about 10-year cycle). Such limitations to the spectral resolution of signals in a time series apply not only to the estimation of the period of a given component, but also to the ability to distinguish between signals with close periods: the closer the periods of two signals are from each other, the longer the record needs to be in order to be able to resolve them both. © Halberg.

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.

Table 2.

Characteristics of some of records analyzed^*

Subject	Gender	Start	End	Length (years)	Age at start (years)	N of data	Variables
RBS	M	May 1967	Dec 2012	45.6	20.5	75100	BP, HR, others
MIS	F	Feb 1984	Nov 2003	19.7	66.7	~13000	BP, HR
SBS	M	Feb 1984	Nov 2012	28.8	64.5	~17000	BP, HR
YW	M	Aug 1987	Jan 2011	32.4	34.7	244000	BP, HR
EH	M	Apr 1965	Feb 1981	15.8	38.6		BP, HR, others
FH	M	Jul 1987	Jan 2013	25.5	68.0	224000	BP, HR
OS	F	Jan 2005	Sep 2005	0.7	82.6	8800	BP, HR
GC	F	Jul 1987	Oct 2011	24.2	37.6	170000	BP, HR
GSK	M	Mar 1998	Jan 2013	14.8	72	210700	BP, HR
WRB	M	May 1974	Dec 2009	35.5	51.8	931	BP, HR, other
JC	M	Feb 1990	Mar 1993	3.1	23.3	26000	Sleep-wake
JF	F	Jun 2009	Mar 2011	1.7	61.3	10500	BP, HR, others

^*Detailed discussions of these data (notably those of JC and JF) also available from [2].

BP: blood pressure; HR: heart rate.

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 algorithm [16]. The chi-square test was used to examine the presence of any preferential periods in the decadal range.

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.

Figure 3.

Figure 3A. Periods of cycles detected with their uncertainties in systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) of 7 bio-medical scientists, including 5 physicians, four of them under hypotensive treatment. Note cluster around 10 years with a vertical shaded yellow band indicating Wolf numbers during the prior 100 years with their uncertainty and a vertical shaded green band giving the 95% confidence limits of the period of the equatorial geomagnetic index Dst during the past 27 years, a rough illustration of environmental periods that we happened to have computed. The environmental counterparts of the span corresponding to the span of each subject’s data are not shown. These periods in the human circulation are summarized in Figure 3B. © Halberg.

Figure 3B. Cluster of periods in the human circulation peaking putatively near the peak of the Horrebow-Schwabe cycle in relative sunspot (Wolf) numbers, summarizing the detailed results of Figure 3A. © Halberg.

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.

Figure 4.

Changes in the period length, τ, of the cycle in Wolf’s relative sunspot numbers, determined with its 95% confidence interval. © Halberg.

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 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.

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.

Figure 5.

Figure 5A. Long periods modulate development in an untreated cardiologist (YW) of a high systolic (top) and diastolic (bottom) blood pressure MESOR (scales on the right), with acceptable MESORs on weekends when he does not work (does not put on his white coat, not shown). Without long-term monitoring, spotchecks cannot detect the long physiological periods. © Halberg.

Figure 5B. Development of a high blood pressure in a pathologist (EH). Note different long periods characterizing different variables. Again, continuous monitoring seems essential to separate an increasing arm of a long cycle from the need for treatment or vice versa. © Halberg.

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-the-clock summary were in the acceptable range for over a decade (YW).

Periods Found Linearly Earlier

The late Eugene Kanabrocki and colleagues, notably RBS, studied symptom-free men at 3-hour 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 in-between.

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 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.

Discussion

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.

Figure 6.

Just as removal and replacement of a gland led to endocrinology, so biological consequences of the loss of environmental spectral components are critical to chronomics, the study of chronomes (time structures) in and around us. The time courses of the frequency structure of the speed of the solar wind (SWS) (top) and of an elderly man’s (FH) systolic and diastolic blood pressure and heart rate (SBP, DBP and HR; rows 2–4, respectively) are examined by gliding spectral windows. Human SBP selectively resonates with SWS (top 2 sections). No obvious resonance, only minor coincidence of apparent change, is apparent to some in DBP or HR (bottom 2 sections). Aeolian rhythms in gliding spectra of SWS and SBP change in frequency (smoothly [A] or abruptly [B,C,D], bifurcating [D,F] and rejoining [G]; they also change in amplitude (B) (up to disappearing [C,E] and reappearing). © Halberg.

Figure 7.

A circadecadal component characterizes the MESOR (to) and the circadian amplitude (bottom) of systolic blood pressure of neonates monitored in early extra-uterine life. Similar results are also found for diastolic blood pressure and heart rate (not shown). Different subsets of babies with a positive or negative family history of high BP differing in postnatal age are pooled. For comparison, the data are shown together with Wolf numbers gauging solar activity during the study span. © Halberg.

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 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].

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].

Figure 8.

Original data collected by Ignaz Zadek on one of his patients. A composite model consisting of cosine curves with periods of 24 and 84 hours fitted to the data is also shown (left). All three components with periods of 24, 84, and 168 hours are statistically significant by population-mean cosinor, the small number of 4 subjects notwithstanding (right). This cosinor demonstration in meta-analyses of Zadek’s data [30], the latter available by Janeway’s time [29], indicating that more than one periodicity was documentable in the variability of blood pressure, remains pertinent today. Circadians were dismissed as “Halberg’s paranoia” when the term was coined in the late 1950s, but are documented today by well over 67,000 articles in the PubMed database alone. The importance and ubiquity of decadals, and of infradians more generally, may well approach those of circadians as they are mapped and understood. For example, we may die preferentially in the morning from cardiac or other diseases, but the actual day of death also follows extra-circadian, notably infradian patterns, the latter constituting indispensable control information pertinent to all we do in time. © Halberg.

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-inflation events. This act affects all light motor vehicles sold after September 1, 2007.

“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?

“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.

Figure 9.

In a 6-year prospective outcome study, 34.7% of the whole study population of 297 patients had uncomplicated MESOR-Hypertension (MH), 55 (18.5%) had MH complicated by one additional Vascular Variability Anomaly (VVA) [or if it persists, Disorder (VVD)] (excessive pulse pressure, circadian blood pressure overswing, or deficient heart rate variability), 15 (5.1%) and 3 (1.0%) had MH complicated by two or three additional VVDs. In the latter group, all 3 patients had a morbid outcome within 6 years of the blood pressure (BP) monitoring. Ambulatory BP monitoring over only 48 hours, used for diagnosis, is much better than a diagnosis based on casual clinic measurements, yet its results apply only to groups. With this qualification, of the 176 patients with MH, 73 (42.2%) have additional VVDs that further increase their vascular disease risk, and that are not considered in the treatment plan of these patients since current practice does not assess these VVDs. This proportion may be smaller in a 7-day record. © Halberg.

Figure 10.

Among the 63 patients available to follow-up after 42 years, 6 of 11 (54.5%) subjects without a circadian blood pressure (BP) overswing (CHAT, Circadian Hyper-Amplitude-Tension) are alive, while all 7 with CHAT are dead (P=0.025 from Fisher’s exact test; one cell is zero). Unassessed interactions with age and with hypertension, another Vascular Variability Disorder (VVD), are unassessed in this study but are assessed in others. In them, the risk of cardiovascular disease associated with CHAT exceeds that of high BP. © Halberg.

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 self-surveillance, 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].

Figure 11.

An illustrative oversight occurred when long cycles were ignored, in the case of the urinary excretion of steroidal metabolites in a male physician, leading to an erroneous diagnosis, which in turn prompted actual (and in retrospect unwarranted) androgen replacement therapy [33]. © Halberg.

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 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<0.05 from a sign test, as well as the χ² test in Figure 3B, we here note that in 7 out of 7 human adults, a decadal and/or multidecadal spectral component was isolated in 3 circulatory variables: SBP, DBP, and HR. The conservative approach by the nonlinearly extended cosinor, according to Marquardt, provides the uncertainties of the τs found in the circulation of blood.

In 7 out of 7 human adults (P<0.05 from a sign test) and with the χ² (P<0.00001) in Figure 3B, decadal and/or multidecadal spectral components and/or their harmonics and subharmonics were isolated in human adult SBP, DBP and HR, to complement those in the neonatal human circulation, in steroidal metabolite excretion [33], and in a giant eukaryotic unicell, among very many other variables [36]. The conservative approach by the nonlinearly extended cosinor, according to Marquardt [16], provides the uncertainties of the τs found in the circulation of blood. Whether or not, as seems likely from the results of remove-and-replace studies implemented by the sun, these decadals are signatures of helio- and geomagnetic cycles acquired in the development of the human blood circulation. They are pertinent to everyday diagnosis and treatment, and reference standards to assess their anomalies will eventually be needed before people are assigned to treatment by hypotensive drugs [37]. The collection of such standards systematically from womb to tomb must be planned systematically if we wish to avoid unnecessary therapy, in order to not treat those on the ascending limb of a physiological decadal cycle and treat only those who need it. Only the recognition of the need to do for ourselves what we do for our car tires stands in the way of progress with BP in the clinic and with steroidal, cellular and even microbial variables more generally. Congruences among the τs of two time series, defined by the overlap of CIs, are a first step for the study of cosmic-biospheric associations. Investigations of the biospheric consequences of the subtraction (removal) vs. addition (replacement) of an environmental frequency [38] are the next step. Supporting evidence can be no more than a statistically significant increase in the amplitude of the environmental cycle that is followed by a statistically significant increase in the biospheric cycle’s amplitude and vice versa. The (damped) persistence of a transyear in an individual’s SBP or in the extent of terrorism encountered in a population speaks for a genetically coded infradian as well as circadian auto-resonance, with the mechanisms involved alluded to in Figure 12. We advocate replicating congruence studies over decades of physiological data on populations of self-monitoring subjects: a replication on the same individual is lengthy and involves interactions with age. Congruence and addition/subtraction studies [38] are desirable on all infradian τs, preferably by womb-to-tomb monitoring, as done for their functioning life in car tires. Rather than only an echo, a genetically coded auto-resonance in mammals, including humans, triggered by magnetic storms, Figure 13 (Section A), acts on the neuroendocrine (Sections A–C), and at the level of the cell, nucleic acids, in particular. These feedsideward mechanisms [39, 40], surveillable by C-ABPM, underlie an as-one-goes stress-strain test telling us what we liked and disliked by the appearance and disappearance of VVAs. VVAs can also serve as an alerting system to predict and develop countermeasures not only against too much or too little light or heat, but also against too much or too little nonphotics, and thus against personal, societal and even natural cataclysms, Figure 14.

Figure 12.

Scheme alluding to putative mechanisms underlying an influence by the cosmos of human physiology and pathology. © Halberg.

Figure 13.

Helio-, ionosphero- and geomagnetism: a stress contributing time-varying strain. A: Observations on the equatorial geomagnetic index Dst (top), on the hypothalamus, Ht (middle) that may be activated via the storm directly and/or via the pineal, Pin (bottom). Concerning an effect of the storm (top) upon the neuroendocrine network (below), also showing adrenocortical involvement, these unplanned observations on rats can be aligned with observations of a decreased urinary excretion of melatonin during magnetic storms, in keeping with a damping of pineal function, including its dynamics, gauged by the lower circadian amplitude during the storm. This “experiment of nature” offers a putative mechanism that cannot be dissected in vivo in humans. Nonetheless, post hoc ergo propter hoc reasoning and confounding by any unassessed effects upon circaseptan rhythms cannot be excluded and will require rebuttal or confirmation. A solution may be most readily available if investigators of pineal function check the presence or absence of a magnetic storm during their studies and, if so, compare data from magnetically stormy and quiet days after the cosinor-computation of parameters. In any event, original data or circadian parameters with calendar dates can be sent to corne001@umn.edu for integration with the results summarized herein and elsewhere. B: Results are summarized on top. The second diagram from the top illustrates the effect of the suprachiasmatic nuclei (SCN) on circadian amplitude and acrophase. The finding (not shown) of a zero-circadian amplitude indicating a lacking rhythm is the result of SCN removal in the case of locomotor activity and water drinking does not apply to a vast majority of other rhythms sampled at 4-hour or shorter intervals for 24 hours or longer spans and analyzed by inferential statistical means. The consistent findings after SCN removal are changes in circadian amplitude and/or acrophase, and these are consistent with those in A. C: Lack of effect, attenuation, or amplification by aqueous pineal homogenate (APH) of corticosterone production by bisected adrenals in response to a synthetic ACTH 1–17, Synchrodyn (Sy). When magnetic storms reach an organism, their effect will depend upon the network’s stage at exposure times, in the case of a double storm. D: Chronomodulation: on the right, a modulator, representing magnetic planetary and interplanetary solar and galactic factors (their effect on geomagnetics is shown in A) are conceived as normally modulating or, as storms, altering the socio-ecological conditions in the habitat, e.g. the synchronizing effect of the lighting regimen (the actor) in the animal room, acting upon the organismic hypothalamic-pineal-adrenocortical-vascular network. © Halberg.

Figure 14.

Biospheric contributions to the understanding, if not prediction of earthquakes. Upper left: Locomotor activity of some of the mice telemetered around the clock was statistically significantly decreased starting 3 days prior to the magnitude 8.0 earthquake in Chengdu, China on 12 May 2008 (data of Zhengrong Wang). Upper right: Human systolic blood pressure (SBP) started increasing 2 days prior to the magnitude 9.0 earthquake in Sendai, Japan on 11 March 2011, documented on the basis of weeklong records of around-the-clock ambulatorily obtained data from 13 Japanese (data of Yoshihiko Watanabe). Similar records from longitudinal and transverse controls differ in their time course, suggesting that the trend observed before the earthquake was related to it rather than being a feature of an anticipated weekly pattern. Lower left: The monthly incidence of major earthquakes since 1900 is characterized by the presence of cycles with periods of about 49.3, 12.2, 1.44, and 0.41 year(s), given with their uncertainties in parentheses. Lower right: The prominent about–50-year cycle is also documented in physiology, pathology, societal upheavals and space weather. Nonlinearly estimated periods are displayed with their 95% confidence intervals shown as the length of corresponding horizontal bars. © Halberg.

As physiologic focus includes extra-circadians modulating the circadian system, it must be realized that components with τs longer than 28 hours detected in the spectra can differ depending on whether the original data are analyzed or circadian characteristics such as the MESOR, amplitude or acrophase, computed over consecutive spans of 24 hours or longer. As seen from Figure 15, the time courses of the circadian MESORs, amplitudes, and acrophases can be very different, all three parameters being estimated from the same data over a 2-week interval moved by 1-week increments. While the increment is shorter than the interval for a visualialization of time courses of the three parameters in Figure 15, consecutive (non-overlapping) intervals are used for spectral analyses (not shown).

Figure 15.

Differences in the time structure of the circadian MESORs (top), amplitudes (middle), and acrophases (bottom) are apparent to the naked eye from the time courses of systolic blood pressure (SBP) of a clinically healthy man (RBS) aging from about 20.5 to about 65 years of age. Each dot represents the average of about 5 to 6 self-measurements per day over a 2-week interval progressively moved by increments of 1 week throughout the 44.5-year record. © Halberg.

The differences found between results on original data and circadian MESORs tend to be small and affect primarily P-values and CIs. They relate mostly to the difference in the number of degrees of freedom available for testing and for deriving CIs, and to the fact that the variance associated with the circadian component, which is usually large as compared to other components, is greatly reduced, if not eliminated when MESORs are analyzed (MESORs are not subject to the large variability of within-day changes).

The latter approach may be preferred also from the viewpoint of violating the underlying assumption of independence of residuals to a lesser extent than an analysis based on original data. Spectral differences seen between the circadian MESORs, amplitudes and acrophases also stem from the fact that different infradian components can modulate these parameters in different ways.

Conclusion

From a multitude of earlier studies, it is well-known that BP and HR can change with age and as a function of health status, kind, dose and timing of anti-hypertensive medication. There is also mounting evidence suggesting that in addition to photic (light and temperature) effects, non-photic solar influences, including several mechanisms associated with changes in solar activity and the resulting changes in geomagnetism can affect human physiology. These environmental variables follow cycles with long periods, including the well-known about 11-year solar activity cycle. These cycles are non-stationary. Least squares have been used to test for periodicity and to estimate rhythm parameters. This (cosinor) approach remains applicable when the data are non-equidistant.

Results presented herein broaden our perspective in several ways. Secular trends in BP and HR may be in part predictable insofar as they follow cycles with long periods of about 10 years that have environmental counterparts. The characteristics of these cycles can differ among individuals, between SBP and DBP or HR, and depending on whether original data are analyzed or consecutive estimates of the mean or circadian (or circaseptan) amplitude, a feature referred to as “selective assortments”. Differences and similarities are assessed on the basis of inferential statistical terms, using nonlinear least squares to estimate the τ with a measure of uncertainty (95% confidence intervals).

To our knowledge, this is the first summary of all τs detected with statistical significance in longitudinal records from all individuals examined thus far showing a very sharp peak in their distribution around 10 years, corresponding to the length of a major cycle of solar activity. The presence of cycles with intermediate periods suggests that some free-running occurs invariably in the decadal range, as would be expected from a built-in resonant frequency. As such, it may be part of a chronome (time structure) anchored in the genome and NOT a mere echo of the Sun as Chijevskiy put it without considering genetics or as a noosphere as Vernadsky put it, building upon genetics but without consideration for cycles, assuming linearity in time. Thus, evidence presented in the paper qualifies two intellectual Russian geniuses by what computers and inferential statistics revealed in all 7 subjects investigated. This finding prompted us by implication to suggest that, like in the case of circadians, we are unraveling a novel time dimension in the cardiovascular system, heretofore dismissed as secularity, and revealing a new cosmic mechanism for it. To paraphrase Harvey, the beating of the heart depends upon its cosmos, with the latter past and present cycles coded in genomes as chronomes.

Addendum

The authors are indebted to Professsor Ramadur B. Singh, editor in chief, for refereeing the foregoing paper and for noting in his acceptance that “other factors of BP variability, such as age, BMI, alcohol, sedentary behavior need adjustment (“quite apart from the non sequitur:”) to say that these factors are due to BEL.” We here report an about 10-year peak in the histogram of periods characterizing cardiovascular variables, but have not yet collected and displayed all findings at the paratridecadal BEL (Brückner-Egeson-Lockyer) cycle [11, 12], even if we are glad to Professor Singh called attention to long and very long cycles. The evaluation of risk factors was originally beyond the scope of this paper, since we have dealt with some of the factors [18, 19] while others (very many) dealt with all of those generally considered, Professor Singh in particular, in his publications [41–43]. Moreover, we are not prepared to generalize, as many in the literature do, and prefer to focus separately on the risk of a given individual, knowing, for instance, that subjects react differently, some in opposite directions, with their BP e.g., to sodium [44–49].

In this paper, we summarize for the first time, as a histogram, a sufficient number of decadal and longer periods, to conclude with statistical significance that they characterize human BP and HR. We show that they are detected in each of seven persons with available long records, a finding significant by a sign test. The peak at about 10 years is even more significant. We wish to point out on the basis of unique records covering decades that there are many cycles to be considered, that all can be altered, and that in general the presence of these decadals bears on the early differential diagnosis of VVAs versus the current many (mis)diagnoses of high BP, a topic that we covered abundantly elsewhere [18, 19].

Advancing in age, an obvious risk factor is common to all 7 subjects. The fact that BP and HR undergo long-period cycles accounts for decreases as well as increases observed in each record, as seen in Figures 5A and 5B, rather than a steady linear increase or decrease as a function of age. In the same patient population in an outcome study in Japan [18, 19], age, MESOR-hypertension, an excessive pulse pressure, and CHAT, all are associated with a relative risk (RR) statistically significantly larger than one. By comparison, obesity (BMI>25 kg/m²) is associated with a small and non-significant increase in risk (RR = 1.19 [CI: 0.64, 2.20], P>0.50), whereas alcohol consumption increases cardiovascular disease risk significantly (RR = 1.82 [CI: 1.02, 3.25]) but to a lesser extent than the other factors in Figure 16. In this figure, RR is estimated on the basis of actual outcomes, including all cardiovascular events (coronary artery disease, cerebral ischemic event, nephropathy and retinopathy). When considering cerebral ischemic events and nephropathy as separate outcomes, CHAT has a numerically larger RR than MESOR-hypertension, as shown in Figures 17A and 17B. As for sodium intake, three independent studies [44–46, cf. 47–49] showed that some subjects respond to sodium loading with a decrease in BP. Another study further showed that the BP response to sodium intake depends on when (at which circadian stage) it is taken (with which daily meal) [50]. This is just another reason to advocate continuous monitoring, so that only interventions beneficial to the given patient are recommended and implemented, rather than assuming that salt is bad for everybody.

Figure 16.

In a 6-year prospective outcome study on 297 patients with no morbidity at the outset, the relative risk of having an ischemic cerebral event or developing within the 6-year span coronary artery disease, nephropathy and/or retinopathy associated with being overweight is not statistically significant: the 95% conficence interval (height of bar) covers the horizontal line representing equal risk between patients with or without the tested risk factor. By comparison, MESOR-hypertension carries the (numerically) largest risk, age, an excessive pulse pressure and CHAT also associated with a very large increase in cardiovascular disease risk, whereas the risk associated with alcohol consumption is relatively small and barely sttaistically significant. © Halberg.

Figure 17.

Figure 17A. An excessive circadian amplitude of diastolic blood pressure raises the risk of an ischemic event by 720% (see last column on right). Original data of Kuniaki Otsuka. © Halberg.

Figure 17B. Excessive circadian amplitude of diastolic blood pressure raises the risk of nephropathy by 590% (see last column on right). Original data of Kuniaki Otsuka. © Halberg.