The role of the cardiomyocyte circadian clocks in ion channel regulation and cardiac electrophysiology

Abstract

Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24 h changes in the environment, behaviour and internal circadian rhythms. This article focuses on studies that use animal models to separate the impact that circadian rhythms, as well as changes in the environment and behaviour, have on 24 h rhythms in heart rate and ventricular repolarization. Circadian rhythms are initiated at the cellular level by circadian clocks, transcription–translation feedback loops that cycle with a periodicity of 24 h. Several studies now show that the circadian clock in cardiomyocytes regulates the expression of cardiac ion channels by multiple mechanisms; underlies time‐of‐day changes in sinoatrial node excitability/intrinsic heart rate; and limits the duration of the ventricular action potential waveform. However, the 24 h rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signalling. A functional role for the cardiomyocyte circadian clock appears to buffer the heart against perturbations. For example, the cardiomyocyte circadian clock limits QT‐interval prolongation (especially at slower heart rates), and it may facilitate the realignment of the 24 h rhythm in heart rate to abrupt changes in the light cycle. Additional studies show that modifying rhythmic behaviours (including feeding behaviour) can dramatically impact the 24 h rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest that targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviours, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24 h rhythms in cardiac electrophysiology.

Feeding Behavior Modifies the Circadian Variation in RR and QT intervals by Distinct Mechanisms in Mice

“…4,30,[36][37][38] These studies were supported by data showing that ablation of SCN or transgenic mice lacking the core circadian clock transcription factor Bmal1 (e.g., Bmal1 −/− ) did not have a 24-hour rhythm in HR. [39][40][41] L-RF is not thought to impact the circadian clock mechanism in the SCN; 9 therefore, it was surprising that our previous work demonstrated that L-RF caused a large phase shift in the 24-hour rhythm of the HR. 6 L-RF in mice also shifts the phase of circadian gene expression in peripheral tissues, including the heart, to align with the timing of feeding behavior.…”

“…9 Several studies implicate the cardiomyocyte circadian clock in regulating gene expression essential for cardiac excitability, cardiac electrophysiology, and HR. 18,35,40,[42][43][44][45] One might predict then that L-RF shifts the phase of cardiomyocyte gene expression to facilitate the phase shift in HR and cardiac electrophysiology. However, genetically disrupting the cardiomyocyte-specific circadian clock (by inducing the deletion of Bmal1) does not abolish the L-RF mediated phase shift in the daily HR and cardiac electrophysiological rhythms.…”

“…(17) Several studies implicate the cardiomyocyte circadian clock in regulating gene expression essential for cardiac excitability, cardiac electrophysiology, and heart rate. (8-12, 58, 60) One might predict that light cycle-restricted feeding shifts the phase of cardiomyocyte gene expression to facilitate changes in 24-hour rhythms of heart rate. However, genetically disrupting the cardiomyocyte-specific circadian clock (by inducing the deletion of Bmal1 ) did not abolish the light cycle-restricted feeding-mediated phase shift in the 24-hour rhythm in heart rate.…”

The Circadian Biology of Heart Failure

“…26 The cardiomyocyte clock seems to prevent abnormal QT-interval prolongation. 112 In hearts from patients with advanced heart failure, some genes known to be involved in electrical properties and arrhythmias showed strong circadian expression patterns. 22 There also seems to be a diurnal variation in the incidence of arrhythmias requiring implantable cardioverter defibrillator therapy in patients with heart failure.…”

Diversification of Potassium Currents in Excitable Cells via Kvβ Proteins

“…Indeed, this delayed repolarization was readily reversed upon application of pyruvate (i.e., lowering [NADH] i :[NAD + ] i ) indicating the rapid reversibility of redox effects on the cardiac action potential. Beyond regulating cardiac electrophysiology upon acute changes in the cardiac workload, it is plausible that this mechanism to some extent underlies diurnal oscillations in heart rate and ventricular repolarization [ 93 ]. Surprisingly, redox modulation of repolarization requires the presence of both β subunits [ 9 , 87 ], indicating that Kvβ1 and Kvβ2 subunits may function together to confer metabolic sensitivity of current density and action potential duration.…”