Clinical ReviewCircadian rhythms and cardiovascular health
Introduction
Biological processes and functions oscillate rhythmically in time. Circadian rhythms, which are of particular relevance to everyday life and clinical medicine, are controlled by an inherited master clock residing in the paired suprachiasmatic nuclei (SCN) of the hypothalamus.1 Rhythmic activities the SCN clock genes Per1, Per2, Per3, Bmal, Clock, and Cry and their gene products comprise the central time-keeping mechanism. Transcription factors CLOCK and BMAL1 drive the expression of Per1, Per2, Cry1, Cry2, plus a variety of clock-controlled genes, i.e., target genes that are not integral clock components and that do not feedback on CLOCK/BMAL1, via E-box sequences in their promoters. PER and CRY proteins negatively feedback on the transcriptional activity of CLOCK:BMAL1, which results in a circadian rhythm in expression of the CLOCK:BMAL1-driven clock and various clock-controlled genes. Precision of the period and staging of circadian rhythms is achieved via cyclic environmental time cues. The ambient light–dark cycle is the most important cue under normal conditions, with the retinohypothalamic neural projection relaying information sensed by specialized non-cone and non-rod receptors of the retina to the SCN about the timing of light onsets and offsets during each 24-h period. The biological time-keeping system also includes the multitude of peripheral cell, tissue, and organ circadian clocks that are regulated and coordinated by the master SCN clock. The output of the central and peripheral circadian clocks is mediated by various clock-controlled genes, giving rise to the body’s circadian time structure (CTS) that is appropriately staged by environmental time cues to support optimal human metabolic and performance efficiency and capability during diurnal activity and repair and rejuvenation during nighttime rest/sleep.
Circadian clocks have been identified in nearly all mammalian cells investigated, including cardiomyocytes, fibroblasts, vascular smooth muscle cells, and endothelial cells.2, 3, 4, 5, 6 Although 24-h rhythms in heart rate (HR), blood pressure (BP), and cardiac output are classically attributed to rhythms in neuroendocrine constituents, rhythms at the cellular level also play an important role.7, 8, 9 The evidence for this comes from a series of different studies. Genetic manipulation of circadian clock components, such as CLOCK and BMAL1,10 variations within a tandem repeat of the human clock gene Per3,11 and genetic ablation of the circadian clock within endothelial or vascular smooth muscle cells,12 either alter, markedly attenuate, or abolish HR and/or BP circadian rhythms. Furthermore, studies on the cardiomyocyte-specific clock mutant mouse model, in which the cardiomyocyte circadian clock is temporally locked to the commencement of the inactive/sleep phase, show the cardiomyocyte clock differentially regulates cardiac metabolism and contractile function during the 24 h.13, 14, 15, 16 Furthermore, rodent models reveal it directly modulates myocardial ischemia/reperfusion tolerance in a circadian rhythm-dependent manner.14 Recent findings also implicate the disruption (desynchronization) of circadian clocks in the pathogenesis of cardiovascular disease (CVD).8, 17 Circadian clocks are altered in numerous animal models of increased CVD risk, including aging, diet-induced obesity, diabetes mellitus, hypertension- and pressure overload-induced hypertrophy, simulated shift work, and ischemia/reperfusion.18, 19, 20, 21, 22, 23, 24 Circadian desynchrony of the organism from its environment, either in humans through rotating shift-work schedules or in rodent through light/dark cycle or genetic alteration, augments CVD development.25, 26, 27, 28 Furthermore, rodent studies show chronic desynchrony of the circadian clock results in enhancement of cardiac mass, cardiomyocyte size, and expressed hypertrophic markers, thereby suggesting it influences responsiveness to pro-hypertrophic stimuli.29
Beyond the cellular level, circadian rhythms of cardiovascular physiology and function are very well established30; moreover, clear circadian rhythmicity is found in pathophysiological mechanisms that underlie 24-h patterning of morbid and mortal CVD events. Moreover, the administration time, relative to the staging of involved circadian rhythms, of various classes of medications used to manage CVD risk may impact, sometimes quite dramatically, their pharmacokinetics (PK) and pharmacodynamics (PD).31 This infers it is necessary to tailor preventive and therapeutic interventions to circadian rhythm determinants to optimize intended outcomes.32
Recognition of the importance of circadian rhythms in cardiovascular functions and their involvement in 24-h patterns of CVD conditions and events has lead to renewed scientific interest in chronobiology, i.e., the study of biological rhythms. Indeed, investigation of the temporal structure of the sources and mechanisms of cardiovascular rhythms is a necessary preliminary step in understanding their clinical implications, especially in regard to CVD risk and its control through therapeutic interventions. The main sources of the time-dependency of cardiovascular physiology and pathophysiology are cyclic variation in external stimuli and demands, especially physical and mental activity and stress, and endogenous circadian rhythms, even though it is often impossible to clearly separate the relative contribution of each. This article discusses the relevance of circadian rhythms to the prevention and management of CVD, focusing on the three major clinical entities of arterial hypertension, myocardial ischemia (MI), and cardiac arrhythmias. Published pathophysiologic, epidemiologic, and clinico-therapeutic evidence clearly establishes the importance of a chronobiologic approach, both to uncovering new insight into the maintenance of cardiovascular health and to improving the prognostic assessment and therapeutic management of CVD patients.
Section snippets
Circadian rhythms in arterial hypertension
Systolic (SBP) and diastolic (DBP) BP exhibit distinct, although different, 24-h patterning among patients. In so-called normal dippers, the sleep-time BP mean is reduced by 10–20% relative to the daytime mean.33 During the daytime, typically two daytime peaks are manifested, the first more prominent one shortly after morning awakening and the second late in the afternoon or early evening, with a small mid-afternoon nadir. In healthy young adults, the immediate morning SBP rise amounts to about
Circadian changes in the pathophysiological mechanisms of arterial hypertension
The 24-h BP variation results primarily from the cyclic exogenous alteration of physical and mental activity, stress, among others, coupled with the sleep–wake cycle. However, endogenous neurohumoral and other circadian rhythms also play a role,75 although it is impossible to clearly separate the relative influence of the former form the latter. For sure, the effects of physical and mental activity account for the predominant proportion of the day-night variation,76 as demonstrated by studies
Twenty-four-hour pattern in MI
MI is the underlying pathogenetic mechanism of multiple clinical manifestations of CVD events: transient ischemic episodes, acute myocardial infarction (AMI), and sudden cardiac death (SCD). MI may result from either restricted and insufficient oxygen supply or increased oxygen demand. A number of physiologic variables are crucial in determining mismatch between myocardial oxygen supply and demand, and predictable circadian changes are exhibited by all of them.32 Such predictable-in-time
Circadian changes in the pathophysiological mechanisms of MI
MI is thought to be triggered by several pathophysiological mechanisms, particularly the sudden morning increase of BP, HR, SNS activity, basal vascular tone, vasoconstrictive hormones, prothrombotic tendency, platelet aggregability, plasma viscosity, and hematocrit.198 Each of these variables exhibits prominent circadian rhythmicity in phase with the reported 24-h pattern of the ischemic events.
Circadian rhythms in arrhythmias
Circadian variations have been established also in the pattern of presentation of both supraventricular216, 217 and ventricular cardiac arrhythmias,218, 219, 220 irrespective of the presence or absence of concomitant medications.221 In clinical practice, many arrhythmic episodes are observed as a consequence of MI, a pathophysiologic event that exhibits profound 24-h patterning, as previously related. However, the distribution during the 24 h of malignant arrhythmias is similar in patients with
Circadian changes in the pathophysiological mechanisms of arrhythmias
Many functional, e.g., neurohumoral, electrolytic, hemodynamic, metabolic, etc., factors, aside from MI, may trigger and maintain arrhythmic episodes. Mechanisms by which these factors interact to determine an arrhythmogenic stimulus remain incompletely understood, constituting a major problem not only for the characterization of the determinants of the 24-h pattern of arrhythmias, but also for devising optimal conventional or chronotherapeutic and chronopreventive strategies. Arrhythmias are
Perspectives and conclusions
The purpose of this review has been to highlight the (chrono)epidemiology and chronobiology of CVD and potential underlying pathogenic mechanisms. Clinically significant 24-h patterns in hypertensive BP levels, MI, AMI, SCD, and various atrial and ventricular arrhythmias are known, having been established by clinical case series and population-based studies plus meta-analysis of the data of individual reports. Clinical epidemiologists initially emphasized environmental factors as triggers of
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