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

Elizabeth A Schroder, Makoto Ono, Sidney R Johnson, Ezekiel R Rozmus, Don E Burgess, Karyn A Esser, Brian P Delisle

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Daily variations in cardiac electrophysiology and the incidence for different types of arrhythmias reflect ≈24-hour changes in the environment, behavior, 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 behavior, have on 24-hour 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-hours. Several studies now show 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-hour rhythms in heart rate and ventricular repolarization are primarily driven by autonomic signaling. 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-hour rhythm in heart rate to abrupt changes in the light cycle. Additional studies show modifying rhythmic behaviors (including feeding behavior) can dramatically impact the 24-hour rhythms in heart rate and ventricular repolarization. If these mechanisms are conserved, these studies suggest targeting endogenous circadian mechanisms in the heart, as well as modifying the timing of certain rhythmic behaviors, could emerge as therapeutic strategies to support heart function against perturbations and regulate 24-hour rhythms in cardiac electrophysiology. Abstract figure legend Time-of-day variations in cardiac electrophysiology and the incidence of arrhythmogenic events are generated by endogenous circadian rhythms, 24-hour rhythms in the environment, and 24-hour rhythms in behavior. This article focuses on studies that use animal models to separate the impact that circadian clocks (ubiquitously expressed transcription-translation feedback loops that initiate circadian rhythms), daily changes in the light cycle, and daily changes in the timing of feeding have on 24-hour rhythms in cardiac electrophysiology. Studies now show the circadian clock mechanism in the heart regulates the expression of cardiac ion channels; underlies time-of-day changes in intrinsic sinoatrial node excitability; and shapes the ventricular action potential waveform. Additional studies show modifying the light cycle and rhythmic feeding behavior can dramatically impact the 24-hour rhythms in cardiac electrophysiology. If conserved, these studies suggest targeting endogenous circadian clock mechanisms in the heart, as well as modifying 24-hours rhythms in the environment and behavior, could emerge as therapeutic strategies to support normal cardiac electrophysiology and mitigate the risk for arrhythmogenic events. This article is protected by copyright. All rights reserved.

    Original languageEnglish
    JournalJournal of Physiology
    DOIs
    StateE-pub ahead of print - Mar 17 2022

    Bibliographical note

    This article is protected by copyright. All rights reserved.

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