Heart Failure and Arrhythmias: Circadian and Epigenetic Interplay in Myocardial Electrophysiology

Abstract

Emerging evidence underscores the impact of circadian rhythms on cardiovascular processes, particularly in conditions such as hypertension, myocardial infarction, and heart failure, where circadian rhythm disruptions are linked to disease progression and adverse clinical outcomes. Circadian clock proteins are intricately linked to myocardial electrophysiological remodeling and epigenetic pathways associated with arrhythmias in heart failure. In the context of heart failure, circadian clock dysregulation leads to electrophysiological remodeling in the cardiomyocytes, which can precipitate life-threatening arrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (VF). This dysregulation may be influenced by environmental factors, such as diet and exercise, as well as genetic factors. Moreover, epigenetic modifications in heart failure have been implicated in the regulation of genes involved in cardiac hypertrophy, fibrosis, and inflammation. The interplay between circadian clock proteins, myocardial electrophysiological remodeling, and epigenetic pathways in heart failure-related arrhythmias is complex and multifaceted. Further research is needed to elucidate how these processes interact and contribute to the development of arrhythmias in heart failure patients. This review aims to explore the connections between circadian rhythms, myocardial electrophysiology, and arrhythmias related to heart failure, with the goal of identifying potential therapeutic targets and interventions that may counteract the adverse effects of circadian disruptions on cardiovascular health.

Keywords: circadian clock; circadian proteins; epigenetic regulations; heart failure.

Figure 1

Schematic representation of central and local circadian regulatory mechanisms and their influence on cardiac function. Light signals, detected by melanopsin-expressing retinal cells, travel to the suprachiasmatic nucleus (SCN) in the hypothalamus (the central clock). The SCN then entrains the local (peripheral) circadian oscillator in the heart—depicted here by the green box—via hormonal signals and autonomic nervous system pathways. This cardiac oscillator comprises key clock genes (e.g., Bmal1, Clock, Per2) and in turn regulates downstream gene expression relevant to calcium handling (e.g., SERCA2a, RyR2) and other cardiac functions. The interplay between these central and local clocks ensures synchronization of the cardiovascular system with the external light–dark cycle. The blue boxes and arrows illustrate the primary circadian pathways and flow of information, while the red boxes indicate genes and regulatory targets central to these processes.

Figure 2

The circadian rhythm in humans is regulated via core clock genes and clock-controlled genes within the positive and negative feedback loops. This figure illustrates how BMAL1 and CLOCK proteins form a heterodimer in the nucleus and bind to regulatory elements on the promoters of Per and Cry genes, activating their transcription. The protein products then form heterodimers in the cytoplasm and translocate to the nucleus to inhibit the transcriptional activity of BMAL1/CLOCK heterodimers on downstream target genes, forming a negative feedback regulatory loop. Additionally, BMAL1/CLOCK heterodimers activate the transcription of orphan nuclear receptor genes Nr1d1, Nr1d2 (Rev-erbα/β)and Rora, Rorb (RORα/β). These proteins compete for binding to ROR response elements in the BMAL1 promoter region, either activating or inhibiting BMAL1 transcription, which forms another transcriptional feedback regulatory loop governing circadian rhythm.