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ОРИГИНАЛЬНЫЕ СТАТЬИ
BLOOD PRESSURE OR, RATHER, BLOOD PRESSURE VARIABILITY DISORDERS, VVDS, DISCUSSED IN BRNO ON OCTOBER 6, 2008
F. Halberg1, G. Cornelissen1, J. Siegelova2, B. Fiser, P. Dobsak2, T. Kenner3, Z. Placheta2, J. Dusek2, P. Homolka2, M. Al-Kubati2, O. Schwartzkopff1, M.L. Blagonravov4, S.M. Chibisov4, R.K. Agarwal4
1Halberg Chronobiology Center, University of Minnesota
Minneapolis, Minnesota, USA
2Masaryk University Brno, Czech Republic
3University of Graz, Austria
4Peoples' Friendship University of Russia M-Maklaya str., 8, Moscow, Russia, 117198
Guidelines including a consensus were developed on minimal sample size and temporal placement of measurements and on terminology, such as MESOR-normotension (MN), MESOR-hypertension (MH), vascular variability disorder (VVD), and combination of VVDs, forming vascular variability syndromes (VVSs) for information and comment at other meetings.
Consensus document
The current guidelines for diagnosing high blood pressure (BP) have to be revised, according to a consensus meeting held in Brno, Czech Republic on October 6, 2008. The diagnosing does not include the states with abnormalities in the day-night ratio of BP that have been compared with alterations in circadian rhythm parameters assessed by the cosinor method. The latter invariably proved to be superior to the day-night ratio. Risk factors can be derived from chronobiologically-interpreted ambulatory BP monitoring (C-ABPM). The term «Diagnosing HYPERTENSION» is to be replaced by the term: «Diagnosing VASCULAR VARIABILITY DISORDERS».
Vascular variability disorders (VVDs) include:
(1) an elevated BP itself. We use the term MESOR-hypertension (MH) because the diagnosis is based on the least squares fit to data collected around the clock for 7 days (7/24) of a 24-hour cosine curve. Its mean value (MESOR) is compared with the MESORs of healthy peers matched by gender and age. The circadian double am-
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plitude approximates the extent of within-day BP change. In uncomplicated MH, the double amplitude (2A) and the acrophase (a measure of the timing of overall high values recurring each day) are within acceptable limits;
(2) a circadian overswing (excessive BP variability), that is a circadian BP-2A exceeding the upper 95% prediction limit in health (CHAT, brief for Circadian Hyper-Amplitude-Tension);
(3) an odd timing of the circadian rhythm of BP but not of HR (BP ecphasia), being outside the 90% prediction interval of peers matched by gender and age;
(4) an excessive pulse pressure (EPP), above a threshold of 60 mmHg (until peer-derived reference values become available;
(5) a deficient heart rate variability (DHRV) gauged by a standard deviation of heart rate (HR) below 7.5 beats/min (until peer-derived reference values become available).
Several prospective and retrospective outcome studies have shown that VVDs such as CHAT carry a vascular disease risk that can be higher than the risk of an elevated BP itself, even among normotensive subjects [1—7]. For example, the risk of normotensives with CHAT for vascular morbidity (cerebral ischemic event, coronary artery disease, nephropathy and retinopathy) is two times bigger than the risk of patients with MH. The VVDs listed above are mostly independent and additive [5]. When two or more coexist to constitute a vascular variability syndrome (VVS), the risk is usually larger than if any one of the VVDs was present alone.
Hospitals with modern technology equipped with hardware and software for self-surveillance could make a change in health care by cost-effectively revealing the earliest changes preceding severe morbidity and mortality [3—5]. With rising health care costs, any further reduction in cardiovascular disease will be extremely helpful. This approach is here illustrated by what could be gained by chronobiologically-implemented BP monitoring.
Current practice relies on one or a few measurements of BP taken in the physician's office under standardized conditions with a sphygmomanometer. These measurements are interpreted against fixed limits that apply to all adults 18 years or older [8]. Under these circumstances, treatment of an elevated BP has been related to a decline in the incidence of cardiovascular disease [9].
Several improvements are directly within reach. It is widely accepted that BP is not constant but varies predictably, notably according to a circadian rhythm of large amplitude [10]. 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 [11]. BP is also known to change as a function of age and to differ between men and women [12].
Accordingly, an international project on The BlOsphere and the COSmos (BIOCOS), studying biological and environmental interactions by chronobiological methods, has derived time-specified reference values qualified by gender and age to interpret data from ambulatory monitors, collected around-the-clock, preferably for at least 7 days. A double-barreled approach has also been developed that consists of a parametric and non-parametric assessment of the data.
Parametrically, circadian rhythm characteristics are estimated and compared with reference standards (90% prediction limits) from clinically healthy peers matched by gender and age. Non-parametrically, the data are stacked over an idealized 24-hour day and compared with the time-specified limits of healthy peers.
Using this chronobiological approach, new VVDs have been discovered that can be present in the presence or in the absence of MH. Some VVDs, such as CHAT, can also be treated — non-pharmacologically or with anti-hypertensive drugs [13, 14]. Sometimes, for iatrogenic CHAT, all it takes is to change the timing of administration of the same dose of the same treatment [15]. There is also indication that treating CHAT may reduce cardiovascular morbidity and mortality [16].
Clinical studies aiming at comparing treatment modalities, including chronothe-rapy studies seeking the optimal timing of administration of a given drug, have relied on groups, all subjects in a given group receiving the same medication at the same cir-cadian stage. In view of the different risks associated with the VVDs, it is critical to optimize the timing of treatment on an individualized basis, taking into account the findings from the chronodiagnosis. Such linking of chronotherapy to the chronodiagnosis has been referred to as «chronotheranostics» [5[. The best time to administer a given anti-hypertensive agent may differ depending on whether the patient has CHAT or a small circadian BP variation. The decision to treat a patient with MH with felodipine or lercanidipine may differ depending on whether the patient has an acceptable or a deficient HR variability, only one of the two drugs being able to increase HRV [5].
The proposed approach relies on the estimation of circadian rhythm characteristics, obtained by the least squares fit of a two-component model consisting of cosine curves with periods of 24 and 12 hours. The inclusion in the model of a second harmonic with a period of 12 hours accounts for the non-sinusoidal waveform of the cir-cadian rhythm in BP (and HR). Attempts have been made to simplify the assessment of a circadian rhythm by the computation of day-time and night-time means and of day-night ratios (DNRs). Whereas some studies have linked some cardiovascular pathologies to the DNR (17), whenever the merits of the DNR have been compared with those of the circadian rhythm characteristics, the latter were shown to be superior: in a 6-year prospective study of 297 patients in Japan [1, 2, 18] and in a smaller 7-year prospective study of dental patients in Minnesota [7] based on actual outcome, and also in a much larger study of over 1,000 patients, using the left ventricular mass index as surrogate outcome measure [19]. A chronobiological approach detects pre-hypertension [20] and pre-diabetes [21, 22] when a discrimination based on the DNR fails [22]. In an Italian study of patients with minimal change retinopathy and healthy controls by Cugini et al. [23], anticipated differences were found in terms of circadian rhythm characteristics but not in terms of the DNR [24, 25].
The example in the case of BP will be followed to change a health care based on spotcheck evidence in office visits to one based on self-surveillance.
Just as inferential statistical procedures have become indispensable for research in biomedicine, they should apply to the individual's everyday care. Their implementation in the case of BP may break the proverbial ice and should be followed to a change from a health care blind to variability based on spotcheck «evidence» in office visits to one based on self-surveillance with hypothesis testing, parameter estimations and sequential
testing with parameter tests [26—31] that apply to the given individual in everyday health care.
The Russian authors join the international consensus group above. Once it is accepted that many VVDs are unrecognized and hence untreated today, Russians, who were first in extraterrestrial space, may institute governmental endeavors to be first in introducing self-surveillance with automatic monitoring via a website [32, 33]. The latter should provide free analysis in exchange for the data. The self-helper in health care would benefit by recognizing and eventually treating stroke and other severe diseases, while the same data would also be used to monitor the cosmos and gain an understanding of its undesirable effect upon aggression and thus eventually to develop countermeasures to societal diseases [34].
Conclusion
Today we have the wherewithal to implement Zadek's [35], Janeway's [36], Bartter's [37] and others' [38] wishes. We monitor garages around the clock to prevent crime and vandalism. We monitor small rodents by telemetry to develop drugs. Let us use available technology to consider those who have to be reliably diagnosed, who need the drugs, and establish the approach to the diagnosis and treatment of each patient in an individualized inferential statistical way by now-available and yet to be further extended software.
Based on chronobiologically-interpreted C-ABPM 24/7, 5 VVDs can be diagnosed (MESOR hypertension, CHAT, BP ecphasia, excessive pulse pressure, and/or deficient heart rate variability). To make the diagnosis reliable in case of a VVD, 24-hour/ 7-day ABPM should be repeated for at least 7 added days to rule out VVDs and/or should be made continuous, depending on outcomes of C-ABPM 24/7. The effect of treatment should be controlled by C-ABPM with sequential and parameter tests and accordingly modified.
Utopia. Yuri Gagarin achieved a long-time dream of humanity by exploring space in person. It is now time for nations to realize that exploring health by now-feasible self-monitoring, rather than flying blind with respect to variability, is also a dream that can be made a reality, notably in the homeland of Alexander Leonidovich Chizhevsky and Vladimir Ivanovich Vernadsky. Preventing morbid events by detecting VVDs could become a national priority in health care, and the same data may help us to understand the undesirable effects of the cosmos so that we can eventually develop countermea-sures.
ЛИТЕРАТУРА
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АРТЕРИАЛЬНОЕ ДАВЛЕНИЕ ИЛИ, ВЕРНЕЕ, СИНДРОМ НАРУШЕНИЯ ВАРИАБЕЛЬНОСТИ
АРТЕРИАЛЬНОГО ДАВЛЕНИЯ (VVDS). ДИСКУССИЯ В БРНО 6 ОКТЯБРЯ 2008 ГОДА
Ф. Халберг1, Ж. Корнелиссен1, Дж. Сиегелова2, Б. Фишер2, П. Добшак2, Т. Кеннер3, З. Плачета2, Дж. Душек2, П. Гомолка2, М. Аль-Кубати2, О. Швацкопф1, М.Л. Благонравов4, С.М. Чибисов4, Р.К. Агарвал4
'Центр хронобиологии Халберга, Университет Миннесоты Миннеаполис, Миннесота, США
2Масарикский университет Брно, Чешская республика
3Университет г. Грац, Австрия
4Российский университет дружбы народов ул. Миклухо-Маклая, 8, Москва, Россия, 117198
Для дальнейших сообщений и комментариев на других конференциях были разработаны основные принципы, включающие соглашение по минимальному объёму выборки и организации временного размещения измерений, а также по терминологии: МЕЗОР-нормотония (МН), МЕЗОР-гипертония (МГ), нарушение вариабельности сосудистого тонуса (УУБ) и сочетание УУБ с развивающимися синдромами вариабельности сосудистого тонуса (УУЯ).
