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Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia.Hayter, Edward A; orcid: 0000-0001-9996-7198; Wehrens, Sophie M T; orcid: 0000-0001-7523-1514; Van Dongen, Hans P A; orcid: 0000-0002-4678-2971; Stangherlin, Alessandra; orcid: 0000-0001-7296-1183; Gaddameedhi, Shobhan; Crooks, Elena; Barron, Nichola J; Venetucci, Luigi A; Neill, John S O'; orcid: 0000-0003-2204-6096; Brown, Timothy M; et al. (2021-04-30)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.