, Germaine Cornelissen2 and Franz Halberg2
(1)
Department of Chronomics & Gerontology, Tokyo Women’s Medical University Medical Center East, Arakawa-ku, Tokyo, Japan
(2)
Halberg Chronobiology Center, University of Minnesota, Minneapolis, MN, USA
Abstract
Currently, 24-hour monitoring of blood pressure (BP) by ambulatory functioning devices is a gold standard, reserved for special cases of high BP, left uninterpreted in terms of its time structure. General reliance upon a single measurement (or a single 24-hour profile) of BP, however, has been dubbed “flying blind.” Long-term BP monitoring, analyzed time-structurally (chronomically, from chronome = time structure), detects physiological-physical interactions. The chronobiological and chronomicinterpretation of ambulatory blood pressure monitoring (C-ABPM) records in the light of time-specified reference values derived from healthy peers matched by gender and age identifies vascular variability anomalies (VVAs) for an assessment of cardio-cerebro-reno-vascular disease risk. Even within the conventionally accepted normal range, VVAs have been associated with a statistically significant increase in risk. Long-term C-ABPM records help to “know ourselves,” serving for relief of psychological and other strain once transient VVAs are linked to the source of a load, prompting adjustment of one’s lifestyle for strain reduction.
Keywords
Chronobiologically interpreted 24-hour/7-day BP and HR monitoringVascular variability anomaliesVascular variability disordersVascular variability syndromes16.1 Preamble
The current guidelines for diagnosing abnormal, notably high BP in a substantial segment of the population, have to be revised, according to a consensus meeting held at St. Anna Hospital, Masaryk University, Brno, Czech Republic, on October 6, 2008 (in the setting where instrumentation for beat-to-beat measurements of BP was developed) [1–3]. Specifications are needed for the minimal number of measurements, for how long and how often they should be taken, including their temporal placement. Methods are also needed for the assessment of dynamics, in keeping with a document originally prepared for this meeting by Dr. Germaine Cornélissen, Professor of Integrative Biology and Physiology at the University of Minnesota, revised in Brno by those undersigned. The terms “normotension” and “hypertension” can be replaced by the terms “MESOR-normotension” (MN) and “MESOR-hypertension” (MH), respectively, whenever the conditions for a chronobiologically interpreted 24-hour/7-day BP and HR monitoring (C-ABPM) are met. The term MH indicates only one of several vascular variability disorders (VVDs) that can combine to form sets of 2, 3, and n-component vascular variability syndromes (VVSs). For current health-care practice, the foregoing diagnoses do not include changes in day-night ratios (DNRs). DNRs and their alterations are routinely computed for research. Thus far for predicting outcomes, DNRs were all inferior to the parametric and nonparametric assessment of VVDs, including some that carry a risk higher than MH itself. In diagnosing MESOR-prehypertension, correctly identified with a chronobiologic approach, the DNR misled: the DNR was normal in patients with minimal change retinopathy and abnormal in the normal controls without any retinal involvement. Prediabetes was diagnosed chronobiologically, while the DNR failed to detect it. Any chronobiologically assessed consequences of MESOR-hypotension have yet to be assessed in terms of outcomes and remain beyond the scope of this consensus.
VVDs and VVSs derived from C-ABPM gauge an increased vascular disease risk, including conditions unnoticed in current practice, some of which may be treated. When the conditions for C-ABPM 24/7 are met, the term “diagnosing hypertension” can be replaced by the wider scope of the terms “diagnosis of VVDs and of VVSs.”
16.2 Vascular Variability Disorders
Complementing other indices of risk studied, e.g., after a myocardial infarction [4, 5], the search for vascular variability disorders (VVDs) and vascular variability syndromes (VVSs), albeit aimed in particular at healthy subjects [3, 6–12] to detect earliest alterations, concerns a very large number of patients diagnosed conventionally as “hypertensive” [13–25] (about 72 million in the USA) [26]. The following diagnoses can be based upon a summary called a “sphygmochron,” provided with accompanying materials [27–30] (Fig. 16.1).
Fig. 16.1
Illustrative parametric (left) and nonparametric (right) approach brackets a sphygmochron (middle) from a MESOR-normotensive man with CHAT, a first tentative diagnosis requiring additional monitoring.
After data covering preferably at least 7 days of blood pressure (BP) and heart rate (HR) are downloaded from the e-mail into a computer for analysis, the following results are provided (since the 1990s and currently cost free from corne001@umn.edu) for the patient as well as for the care provider:
1. A list of actual measurements and the times at which they were obtained.
2. A plot of data as a function of time, shown together with the time-specified prediction intervals (PIs) of acceptability for systolic (S) and diastolic (D) BP and HR characteristics.
3. A data summary and a report of any BP and/or HR excess in consecutive 3-hour intervals. This part of the report may be accompanied by a “rhythmometric summary,” which is just a more technical form from which the information is derived to prepare the
(4.) “sphygmochron.” A sample “sphygmochron” (center) illustrates how results are being reported. First, above, the participant’s name is kept confidential; a codename is used instead. Gender and age are listed, along with the date and time at which monitoring started, and for how long data were collected. The numerical report consists of two parts labeled “Characteristics” (parametric results) and “Indices of Deviation” (nonparametric results). In each case, results are shown for SBP (when the heart contracts) on the left, DBP (when the heart relaxes) in the middle, and HR on the right. Under “parametric results,” a mathematical model of a smooth curve is fitted to the data to assess their circadian variation, which is primarily characterized by four numbers shown in the left-hand section of the graph, one of which, the period, covers with its uncertainty the precise 24 hours, so that the other 3 numbers are given from the fit of a 24-hour cosine curve. One characteristic, called the “MESOR,” is the average value around which values fluctuate. It is very similar to the mean value, but yields more reliable results when the data are not collected at precisely regular intervals and has a smaller error when the data are equally spaced. Another characteristic, called the “double amplitude,” is a measure of the predictable change occurring within a day, from the overall low values found usually during sleep to the high values during the daily active span. The third characteristic, called the “acrophase,” is a measure of the time when overall high values are likely to recur each day. For each of the three characteristics (“parameters”), the participant’s value is compared to a range of acceptable values, derived from data provided by clinically healthy people of the same gender and age group as the participant. For instance, in the example shown here in sphygmochron, the average SBP, the DBP, and all other parameters are within the rectangles, indicating the range of acceptable values except for the double amplitudes of SBP and DBP. Under “nonparametric results,” the participant’s data are compared by computer with time-specified reference values, also derived from chronobiological archives on clinically healthy subjects matched by gender and age. For this analysis, all data are stacked over an idealized 24-hour day. Whenever a given person’s profile exceeds the limits of acceptability of peers, the data are marked as being excessive or deficient. The “percentage time of elevation” reports the relative incidence of excessive values during a 24-hour day. It is common to have occasional high values, but in the example herein, there is reason for concern. The next item, the time of excess, becomes useful when drug treatment should be timed prior to the peak in excess.
Excessive values may either be barely above the limit or in turn can be very much higher than the limit. It is therefore important to express the extent of deviation by the “area under the curve,” that is, the area between the values when they exceed the limit and this limit itself. Empirically, it has been shown that excess up to about 50 (mmHg x hour during 24 hours) may still be acceptable and accountable for by daily worries and/or physical activities. In the case summarized, the HBI is 60, in bold, and if confirmed in the next 7/24 profile, a reason for treatment.
On the top right, an abstract illustration of excess and deficit is accompanied below by 2 cases that are similar in terms of percent time elevation. They are very different in terms of hyperbaric index. In patient #2, although the percent time elevation is 9 % smaller than that in patient #1, the hyperbaric index is several times larger.
The “timing of excess” can be used as a guide to time the administration of non-drug or, if need be, of drug treatment once there is BP excess above 50 (mmHg x hour during 24 hours) and/or an elevation in MESOR, taking into account the chronopharmacokinetics of the drug prescribed. When, e.g., a tentative diagnosis of MESOR-normotension with CHAT is made, with insight into information provided on the questionnaire given to the participant with the monitor, as a first step, additional analyses may be carried out. Additional monitoring is recommended to check on any abnormality detected during the first monitoring, and, if confirmed, the need for intervention is reported to the person monitored so that it can be reported to the health-care provider. In one case summarized elsewhere, the follow-up 7-day monitoring showed that CHAT persisted for both SBP and DBP, while the MESORs were again acceptable. Thus, the diagnosis of CHAT with MESOR-normotension was confirmed. Consultation with a health-care provider was strongly and urgently recommended. In two cases of CHAT without an elevation of the BP MESOR, when such recommendations were ignored, catastrophic disease and high cost occurred, a myocardial infarction in a man [29, 30] or eclampsia in a pregnant woman with pressures of 115/67 mm Hg (SBP/DBP), leading to the delivery of a very premature boy hospitalized for 26 months at a cost of US$1 million [28]. © Halberg Chronobiology Center
(1) MESOR-normotension (MN), when (a) all characteristics of a model fitted parametrically are within the limits of 90 % prediction intervals (PI) [31] and (b) all endpoints obtained nonparametrically by stacking the data are acceptable (do not exceed thresholds) computed from data of peers matched by gender and age and, preferably, when possible, ethnicity and geography.
(2) MESOR-hypertension (MH), a chronobiologically validated elevated BP (Fig. 16.2-I). This term is used only if the diagnosis is based on the MESOR, obtained by the least-squares fit of cosine curves with anticipated (24- and 12-hour) periods, for comparison with ranges (90 % PIs) of acceptable MESORs characterizing data from clinically healthy peers matched by gender and age. The minimal time series length is a 24-hour/7-day record of data collected automatically at hourly or shorter intervals (or manually for 7 days at 4-hour intervals), analyzed both daily and for the week as a whole. It serves to rule out MH, if negative when analyzed parametrically for the weeklong record as a whole, but data collection is continued when abnormality is found. MH is a condition where the BP-M is above the upper 95 % prediction limit of BP-Ms from clinically healthy peers matched by gender and age. BP elevation is noted when the hyperbaric index (extent of excess during 24 hours) exceeds the threshold of 50 mm Hg x hour during 24 hours. MH can be the sole VVD or it can coexist and/or alternate with other VVDs to constitute a VVS.
Fig. 16.2
Definitions of some vascular variability disorders (VVDs).
I. MESOR-hypertension (top, left, and middle) is an elevation of the blood pressure MESOR above the upper 95 % prediction limits of clinically healthy peers matched by gender and age.
II. CHAT (circadian hyper-amplitude-tension) (middle, left, and middle) is an elevation of the 24-hour amplitude of blood pressure above the upper 95 % prediction limit of clinically healthy peers matched by gender and age.
III. Ecphasia (bottom left) is a deviation of 24-hour acrophase from the 90 % prediction limits of clinically healthy peers matched by gender and age.
IV. Ecfrequentia (bottom middle) is a statistically significant deviation of the period from 24 hours, assessed by the nonoverlap of 24 hours by the 95 % confidence interval of the period assessed by nonlinear least squares.
V. Excessive pulse pressure (top right) is a difference of MESORs of systolic and diastolic blood pressure larger than 60 mmHg (until it can be further qualified in terms of gender and age).
VI. Deficient heart rate variability (middle right) is a (7-day) standard deviation of heart rate below 7.5 beats/min (until it can be further qualified in terms of gender and age).
VII. Excessive pulse pressure product (bottom right) is a product of the MESORs of systolic blood pressure and heart rate larger (/100) larger than 100 ((mmHg.beats/min)/100) (until it can be further qualified in terms of gender and age).
These VVAs can occur while most, if not all data lie within the conventional physiological range. Their presence has been associated with an increased risk of adverse cardiovascular events in several outcome studies. © Halberg Chronobiology Center
(3) CHAT (circadian hyper-amplitude-tension) or circadian BP overswing (excessive BP swing) is a condition characterized by a double amplitude of BP (BP-2A) derived from a 24/7 record exceeding the upper 95 % prediction limit of BP-2As from clinically healthy peers matched by gender and age (Fig. 16.2-II). CHAT can occur alone in MN and with a usual timing of the circadian BP rhythm, or it can coexist and/or alternate with other VVDs, such as complicating MH. C-ABPM is recommended to all patients with treated MH to ascertain that the elimination or reduction of MH is not a trade for the greater risk of CHAT (Fig. 16.3).
Fig. 16.3
Illustrative results supporting the need for continued surveillance and for a chronomic analysis of blood pressure series.
An excessive circadian amplitude of blood pressure (BP-A) is a risk factor for ischemic stroke independent from the 24-hour mean (MESOR). Finding that CHAT carries a very high risk even among MESOR-normotensives who do not need antihypertensive medication
A measure of the extent of predictable change in this model, approximating the within-day BP change, the 24-hour BP-2A can be grossly underestimated by the DNR that does not account for alterations in the circadian acrophase and/or waveform. The DNR neither accounts for change with age in circadian BP characteristics, notably in terms of a postprandial BP dip, nor does it have reference values for differences between genders and is limited to a few aspects of within-day change, ignoring the many rhythms with frequencies other than circadian.
(4) BP ecphasia is a condition characterized by an odd timing of the circadian acrophase (ϕ) of BP but not of the ϕ of HR (BP ecphasia with HR euphasia) (Fig. 16.2-III). ϕ is a measure of the timing of overall high values recurring each day, measured as the lag from a given reference time (e.g., local midnight) of the peak in the 24-hour cosine curve of the model approximating the data. BP ecphasia is differentiated from the consequences of shift work that can be associated with an altered timing of both BP and HR (Fig. 16.1). It is defined by the BP-ϕ derived from a 24/7 record lying outside the 90 % PI of BP-ϕs from clinically healthy subjects matched by gender and age.
(5) Ecfrequentia is a statistically significant deviation of the period from 24 hours, assessed by the nonoverlap of 24 hours by the 95 % confidence interval of the period assessed by nonlinear least squares (Fig. 16.2-IV).
(6) Excessive pulse pressure (EPP) is defined by a difference between the systolic (S) and diastolic (D) BP-Ms in a 24/7 record above 60 mm Hg (until gender- and age-matched reference standards become available) (Fig. 16.2-V).
(7) Deficient HR variability (DHRV) is defined as a standard deviation (SD) of HR from a 24/7 record below 7.5 beats/minute (until gender- and age-matched reference standards become available) (Fig. 16.2-VI).
(8) Excessive pulse pressure product is a product of the MESORs of systolic blood pressure and heart rate larger (/100) larger than 100 ((mmHg.beats/min)/100) (until it can be further qualified in terms of gender and age) (Fig. 16.2-VII).
Several prospective and also much larger retrospective outcome studies have shown that VVDs such as CHAT carry a vascular disease risk that can be higher than the risk of MH, even among normotensive subjects [32] (Fig. 16.4). For example, the risk of vascular morbidity (cerebral ischemic event, coronary artery disease, nephropathy, and retinopathy) associated with CHAT alone (in MESOR-normotensive subjects) is twice as large as that associated with uncomplicated MH. The VVDs listed above are mostly independent and additive. When two or more coexist to constitute a VVS, the risk is usually larger than that of any one of the VVDs present alone. The risk of vascular morbidity in patients with three VVDs is much higher than the risk of patients with any one VVD alone (Fig. 16.5).
Fig. 16.4
Illustrative results supporting the need for continued surveillance and for a chronomic analysis of blood pressure series.
Left: Among risk factors, an excessive circadian BP amplitude (A) raises the risk of ischemic stroke most. Right: Among risk factors, an excessive circadian BP-A raises the risk of nephropathy most. Detection of abnormal circadian pattern of blood pressure (CHAT, “overswinging”) associated with a risk of cerebral ischemia and nephropathy larger than other risks (including “hypertension”) assessed concomitantly
Fig. 16.5
Percentages of VVDs and VVSs missed in current practice.
The incidence of VVDs in this graph is assessed in a clinic population of 297 patients. BP and HR of each subject were monitored around the clock for 2 days at 15-minute intervals at the start of study. Each record was analyzed chronobiologically and results interpreted in the light of time-specified reference limits qualified by gender and age. On this basis, MH (diagnosed in 176 patients), EPP, CHAT, and DHRV were identified and their incidence related to outcomes (cerebral ischemic attack, coronary artery disease, nephropathy, and/or retinopathy). Outcomes, absent at the start of study in these nondiabetic patients, were checked every 6 months for 6 years, to estimate the relative risk associated with each VVD alone or in combination with 1, 2, or 3 additional VVDs, shown in columns complementing each circular display of incidences of variability disorders.
Earlier work showed that CHAT was associated with a risk of cerebral ischemic event and of nephropathy higher than MH (Fig. 16.4), and that the risks of CHAT, EPP, and DHRV were mostly independent and additive. It thus seemed important to determine the incidence of each VVD, present alone or in combination with one or more additional VVDs. Results from this investigation are summarized in this graph.
Results related to MH are shown in the graph. The 176 patients with MH are broken down into 103 (34.7 % of the whole study population of 297 patients) with uncomplicated MH, 55 (18.5 %) with MH complicated by one additional VVD (EPP, CHAT, or DHRV), 15 (5.1 %) and 3 (1.0 %) with MH complicated by two or three additional VVDs. In the latter group, all 3 patients had a morbid outcome within 6 years of the 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 (available for CHAT)
VVDs and/or VVSs detect earliest risk elevations, when these may be more readily reversed as prehypertension [6–10], prediabetes [11, 12] and, possibly with a focus on pulse pressure and obesity [13], a pre-metabolic syndrome. Hospitals with modern technology, equipped with hardware and software for automatic continuous self-surveillance, could make a change in health care by cost-effectively detecting the earliest changes when they precede severe vascular disease.
A manned website, for pre-habilitation, rather than only for rehabilitation, can provide self-helpers with analyses of their data collected with devices for ABPM and data transfer, as is now done on a small scale by e-mail within the scope of the BIOCOS project (corne001@umn.edu).
16.3 Benefit of 7-Day/24-Hour ABP Monitoring
The self-helper in health care gets the needed information on his or her health status cost free, without requiring support from caregivers, unless the analyses suggest the need for a consultation. We here illustrate what can be gained by chronobiologically implemented ambulatory BP and HR self-monitoring, carried out automatically, as a start around the clock at hourly or shorter intervals for 7 days (C-ABPM 24/7 or at about 3- to 4-hour intervals manually, the ambulatory automatic instrument being much preferred).
Merits are compared with the status quo, limiting the use of ABPM to special cases, for one or a few days only, without any chronobiologic interpretation. Under such current practice, the proportion of cases that remain unrecognized and hence untreated corresponds to the darker red segments in the upper left corner of Fig. 16.5, corresponding to MH complicated by one, two, or three additional VVDs. It also corresponds to the lightest red part of Fig. 16.5, representing VVDs other than MH not complicated by any other VVD (including MH).
16.4 Background of 7-Day/24-Hour ABP Monitoring
The 7th Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7) describes a SBP <120 mmHg and DBP < 80 mmHg as normal. A SBP of 120–139 mmHg and DBP of 80–89 mmHg has been termed as prehypertension, while a SBP > 140 mmHg and/or a DBP > 90 mmHg is hypertension [33]. These guidelines are based on the (office) spot measurements of BP, which are suspect in the diagnosis of normotension, prehypertension, or hypertension. A “control” group can have many false-negative diagnoses; vice versa, a group of mild hypertensives may have false positives. There is evidence from 24/7 records of half-hourly data that “spotcheck hypertensives” (so misdiagnosed based only on a single 24-hour profile) can be MESOR-normotensive based on a 7-day/24-hour record and thus have some acceptable 7-day MESORs and vice versa. This observation may contribute to questionable results such as 48 % cures by a placebo when the false positives at entry into a clinical trial and the false negatives at its end are not assessed [27, 34].
Current practice no longer needs to rely on one or a few measurements of BP taken in the physician’s office under standardized conditions with a mercury sphygmomanometer, interpreted against fixed limits applying to all adults 18 years or older [17, 33]. Thirty home measurements without indication of their temporal placement are required by the Austrian guidelines [18] to be interpreted in the light of a time-unspecified limit, as in the international guidelines [33]. A fixed limit for a rhythmically changing variable can make the diagnosis dependent on the time of day when the measurement is made, an abstract fact [20], documented in clinical practice as checked at the US National Institutes of Health [21]. Such limitations notwithstanding, treatment of an elevated BP has been related to a decline in the incidence of cardiovascular morbidity and mortality [22], yet there are a number of people who receive treatment they do not need while others, who need treatment, do not get it [35]. With rising health-care costs, any robust reduction in cardiovascular disease will be extremely helpful for those concerned about the cost of health care for preventing incapacitation and suffering.
Several improvements are directly within reach. It is widely accepted that BP is not constant but varies predictably, among others according to the individual’s circadian rhythm usually of large amplitude [19]. Measuring BP around the clock is now readily feasible with ambulatory monitors without too much disturbance of sleep and the daily routine. Measurements from these monitors have also been shown to be superior to clinic measurements in terms of diagnosis and prognosis [24]. BP is also known to change as a function of age and to differ between men and women [25] and among individuals of the same gender, age, and ethnicity [16]. Not yet generally known is that in decades-long series, a number of newly discovered cyclicities have been mapped that all contribute to variability which has to be resolved. Their periods coexist with those of the environmental day and year or replace the calendar year, differing from a precise year. Some of the periods reflect different aspects of solar activity, including beat periods of nonradial solar rotations at different solar latitudes [36–48].
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