Circadian heart rate and blood pressure variability considered for research and patient care

Abstract

Objectives: To review mechanisms of circadian variations in heart rate variability (HRV) and blood pressure variability (BPV) and mortality and morbidity due to cardiovascular diseases (CVD). Methods: Results from 7-day/24-h HRV and BPV are interpreted by gender and age-specified reference values in the context of a Medline search. Results: Abnormal HRV and BPV measured around the clock for 7 days provides information on the risk of subsequent morbid events in subjects without obvious heart disease and without abnormality outside the conventional (in the sense of chronobiologically unquantified) physiological range. Meditation, β-blockers, ACE inhibitors, n-3 fatty acids and estrogens may have a beneficial influence on HRV, but there is no definitive outcome-validated therapy. Low HRV has been associated with a risk of arrhythmias and arrhythmic death, unstable angina, myocardial infarction, progression of heart failure and atherosclerosis. BPV may be characterized by treatable circadian-hyper-amplitude-tension (CHAT), which can be transient ‘24-h CHAT’ or ‘7-day-CHAT’, MESOR-hypertension and/or an unusually-timed (odd) circadian acrophase (ecphasia), all associated with an increased risk of stroke, stroke death, myocardial infarction, and kidney disease. Conclusions: Precise insight into the patho-physiology in time of HRV and BPV is needed with development of a consensus on best measures of HRV for clinical purposes and to determine when a 7-day record interpreted chronobiologically suffices and when it does not, for detection within as well as outside the conventional normal range, for diagnostic clinical practice and to direct therapy of risk greater than that associated with hypertension, smoking or any other risk factor.

Introduction

The (single or a 1-min or even a 24-h) measurement of heart rate and blood pressure can be taken to ascertain whether a patient is dead or alive. In all other cases the clinician may gain from assessing chronobiologically the variability of these and other vital signs [1], [2], [3] that undergo a broad spectrum of rhythmic and other changes. Circadians account for the difference between life and death, along the scale of a day, e.g. in response to ouabain [4]. These circadian rhythms, reflected also in mortality and morbidity patterns, are modulated by rhythms with yet longer periods, e.g. of a decade, that are beyond our scope, even if they also are reflected in morbidity and mortality [5].

A circadian cell cycle resides in every cell (Fig. 1) [6], [7] and peripheral timing mechanisms are being documented in molecular biologic terms at about 24-h (circadian) [8], [9] and higher (ultradian) [10] frequencies, with coordination, in mammals, by the adrenal and the pineal–hypothalamic–pituitary network (Fig. 1). The suprachiasmatic nuclei (SCN) contribute to the coordination of the circadian rhythms’ phase and amplitude, in everyday life [11]. The SCN are influenced by the daily alternation between light and darkness directly via the eyes and by plasma melatonin concentrations secreted by the pineal gland, which is a window to both light and geomagnetics (Fig. 1) [5]. A clinical event occurs when our neuroendocrine time structures (chronomes) are not able to cope with the adverse effects of stimuli from within or from without, acting, e.g., via the sympathetic nervous system [1], [2], [3]. Triggering of the neuroendocrines by environmental factors may activate the pineal gland, pituitary functions and adrenal secretions, resulting in adverse effects on circadian variations, heart rate variability (HRV) and blood pressure variability (BPV) [1], [2], [3], [12], [13]. The role of time-adjusted drug intake, especially in the early morning, was also known to ancient Indian physicians [13], [14], [15]. In Ayurveda, drinking of large amounts of water in the early morning is advised, which appears to be in an attempt to increase vagal tone due to gastric distention [16]. Frey [17] considered the mean distribution of deaths along the scales of the day and the year. In one industrial population, Pell and D’Allonzo [18] discussed time-macroscopically the occurrence of a peak in the morning hours in a study of acute myocardial infarction (AMI), a proposition also ascertained and extended to the yearly pattern time-microscopically [19], [20]. The subsequent reports from other countries, the Soviet Union and the extensive data by WHO in the report of myocardial infarction Community Registers [19], [20], [21], [22] from 19 European centers demonstrated a peak incidence of onset of chest pain due to AMI from 08:00 to 11:00 h with a ratio of ∼2:1. In one study from India [13], in 605 AMI patients, 39% of those who had Q wave infarction (n=174) had the onset between 06:00 h and 12:00 noon. In a more recent study [1], among 202 AMI patients, the incidence of onset of chest pain was highest in the second quarter of the day (41.0%), mainly between 04:00 and 08:00 h, followed by the 4th quarter, usually after large meals (28.2%). Emotion was the second most common trigger (43.5%), which was commonest in the patients with onset of chest pain in the second quarter of the day (51.8%). Cold weather was a predisposing factor in 29.2% and hot temperature (>40 °C) was common in 24.7% of the patients. Blood pressure is usually lower during the night, starts increasing before awakening, and remains high during the daytime. Various triggers responsible for circadian rhythms and cardiovascular events are given in Table 1.

In a recent study [21], 65 angina pectoris patients, free from other diseases and drug-free, were monitored by ECG for 24 h. A total of 30 patients were also monitored on isosorbide-5-mononitrate (IS-5-MN) and on metoprolol, respectively. Matched healthy subjects served as controls. Spectral components of HRV were analyzed hourly, with special reference to the rapid changes of autonomic tone during the night and early morning hours. During the night/morning hours, healthy controls demonstrated faster high frequency maximal velocity and higher high frequency gradient than angina patients. Metoprolol and IS-5-MN increased the high frequency gradient and metoprolol tended to increase the maximal velocity. Metoprolol substantially decreased the low frequency/high frequency gradient, velocity and maximal velocity. Rapid vagal withdrawal seemed to be a sign of a healthy autonomic nervous system in the control group of healthy subjects. It was significantly lower in angina patients, however. Both drugs tended to normalize vagal withdrawal, and metoprolol slowed down the rapid increase in sympathetic predominance in the morning in angina patients.