Impact of the human circadian system, exercise, and their interaction on cardiovascular function

Abstract

The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.

Fig. 1.

Forced Desynchrony Protocol. Solid back bars, scheduled sleep (0 lux); gray bars, wakefulness in dim light [≈1.8 lux (≈0.0048 W/m²)]; green bars, baseline days and discharge day in normal room light (≈90 lux); red bars, test batteries; dashed blue line, illustration of trajectory of circadian CBTmin throughout the FD protocol (circadian period of 24.09 ± 0.06 h in these subjects).

Fig. 2.

Circadian rhythm in cardiovascular function at rest and during exercise. There were significant endogenous circadian rhythms at rest for plasma epinephrine, norepinephrine, cortisol, HF, pNN50, SBP, DBP, and HR. Platelet aggregability had two peaks across the circadian cycle. Platelet count had no significant circadian variation. Influence of exercise on cortisol could not be assessed reliably (see text) and is not displayed. The influence of the circadian system on reactivity to exercise is shown in Fig. S3. Data are expressed as a percentage of each individual's rest values across the FD protocol (left y axis) in addition to the absolute values (right y axis). Black circles, rest; red circles, exercise; error bars, SEM; gray bars, group average habitual sleep episodes; vertical dotted lines, CBTmin; curly brackets, most vulnerable period for adverse cardiovascular events observed in epidemiologic studies (≈6:00 AM–noon); P values, significance of circadian effect on resting values (rest) and in response to standardized exercise (reactivity) assessed by cosinor model; f2 (after P values), significance of second harmonic of circadian rhythm; blue upward arrow in Right Top Upper, example of reactivity to exercise at one particular circadian phase as analyzed in Fig. S3.