Role of the circadian system in cardiovascular disease

Abstract

All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. The day/night pattern of adverse cardiovascular events.

Epidemiological studies reveal that adverse cardiovascular events including myocardial infarction (MI), sudden cardiac death (SCD), and ischemic stroke have increased frequencies in the morning hours compared with other times of the day and night (redrawn from refs. 8, 9, 11).

Figure 2. Conceptual model showing interactions between behavioral stressors, circadian timing, and individual susceptibility to cardiovascular risk.

There is a constant interaction between behavioral stressors (e.g., exercise), circadian phases, and underlying individual risk. This results in resting physiological rhythms (e.g., blood pressure) and reactivity of those rhythms in the presence of stressors. In a healthy individual, the resting physiological rhythms are within normal limits and the reactivity to a stressor (upward-pointing arrows) is modest, such that the theoretical risk threshold for an adverse cardiovascular event is not crossed. However, in an individual susceptible to cardiovascular risk due to existing anatomical or physiological maladaptation, resting physiological rhythms may be elevated. Furthermore, in the presence of a stressor, the reactivity of physiological rhythms may be exaggerated and can cross the theoretical risk threshold for an adverse cardiovascular event such as stroke.

Figure 3. Example of a forced desynchrony protocol to separate the effects of the endogenous circadian system from the effects of daily behaviors.

(A) Over 15 days, lights are dim during wake periods and off during sleep periods to allow the circadian clock to tick at its own rate (usually slightly longer than 24 hours — shown here by the slowly drifting core body temperature minimum [CBTmin]). During the forced desynchrony portion (boxed in red), participants experience recurrent identical sleep/wake cycles evenly spread across the circadian cycle (here, each sleep episode is 6.67 hours and wake episode is 13.33 hours). Scheduled wake episodes are shown in yellow and sleep episodes are shaded gray. (B) Data are collected across the protocol. Model heart rate data are shown for one trial and plotted as a function of circadian time (left) or of time into each imposed 20-hour sleep/wake cycle (right). Note the relatively high heart rate during the wake episodes versus sleep episodes. (C) Raw data are averaged across different time scales to reveal endogenously rhythmic components and behaviorally elicited components. Here, despite identically scheduled behaviors in each wake episode, there is an overall approximately 24-hour rhythm, with low heart rate at the time of habitual sleep (left). As expected, heart rate is lower during (actual) sleep episodes than during waking episodes (right).