Hayter, E.A., Wehrens, S.M.T., Van Dongen, H.P.A. et al. Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia. Nat Commun 12, 2472 (2021). https://doi.org/10.1038/s41467-021-22788-8
Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of–day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart’s conduction system and inherent susceptibility to arrhythmia.
It is clear that long-term shift work is associated with an elevated risk of cardiovascular disease, the incidence of cardiac events, and altered electrophysiological parameters15,45,46,47,48. Whether alteration of cardiac conduction parameters during mistimed sleep and shift-work routines increases susceptibility to arrhythmia or other harmful cardiac events in otherwise healthy humans is not yet clear. Nevertheless, it is likely to be of important clinical consideration in patients with pre-existing cardiac dysfunction or injury, as well as in relation to ECG-based diagnoses and pharmacological intervention, where the time of day, patient occupation, and/or sleep–wake history may significantly impact the outcome. Moreover, we show that susceptibility to VT was rarely observed upon cardiomyocyte Bmal1 deletion, indicating that the circadian clock drives increased excitability during the active period of the day at the cost of creating vulnerability to arrhythmias. This suggests that clock function within the heart contributes to the long-known temporal variation in cardiac arrhythmia propensity observed in humans. Given the widespread influence of the circadian clock and established detrimental consequences of clock disruption, any clock-directed intervention must be approached with caution. Nevertheless, our findings offer an important and logical new avenue for therapeutic investigation.