Circadian Mechanisms: Cardiac Ion Channel Remodeling and Arrhythmias

Abstract

Circadian rhythms are involved in many physiological and pathological processes in different tissues, including the heart. Circadian rhythms play a critical role in adverse cardiac function with implications for heart failure and sudden cardiac death, highlighting a significant contribution of circadian mechanisms to normal sinus rhythm in health and disease. Cardiac arrhythmias are a leading cause of morbidity and mortality in patients with heart failure and likely cause ∼250,000 deaths annually in the United States alone; however, the molecular mechanisms are poorly understood. This suggests the need to improve our current understanding of the underlying molecular mechanisms that increase vulnerability to arrhythmias. Obesity and its associated pathologies, including diabetes, have emerged as dangerous disease conditions that predispose to adverse cardiac electrical remodeling leading to fatal arrhythmias. The increasing epidemic of obesity and diabetes suggests vulnerability to arrhythmias will remain high in patients. An important objective would be to identify novel and unappreciated cellular mechanisms or signaling pathways that modulate obesity and/or diabetes. In this review we discuss circadian rhythms control of metabolic and environmental cues, cardiac ion channels, and mechanisms that predispose to supraventricular and ventricular arrhythmias including hormonal signaling and the autonomic nervous system, and how understanding their functional interplay may help to inform the development and optimization of effective clinical and therapeutic interventions with implications for chronotherapy.

Clock-Modulating Activities of the Anti-Arrhythmic Drug Moricizine

“…Cardiac arrhythmias are closely linked with ion channel expression and function, including that of the moricizine target Na v 1.5, encoded by Scn5a [ 22 ]. Furthermore, Scn5a and several other key ion channel or regulatory genes are under circadian control [ 19 ]. Therefore, we next investigated how moricizine modulates expression of these ion channel and regulatory genes ( Figure 3 B and Figure S3B ).…”

“…One question of great interest is the circadian mechanisms in SCD, the topic of a recent workshop, “Understanding Circadian Mechanisms of Sudden Cardiac Death”, convened by the National Institutes of Health, USA (accessed on 11 June 2021). Acquired or hereditary heart diseases are the leading cause of SCD, and the primary mechanism leading to SCD is cardiac arrhythmias, particularly ventricular arrhythmias [ 18 , 19 , 20 ]. In the heart, membrane depolarization (sodium and calcium channels) and repolarization (potassium channels) are tightly regulated to maintain normal action potential, and adverse events causing exaggerated depolarization or diminished repolarization can disrupt the balance, increasing the risk of arrhythmias and ultimately SCD [ 21 ].…”

“…Its oscillatory amplitude and expression levels were considerably reduced in iCSΔBmal1 mice, leading to attenuated Na+ current in ventricular myocytes [ 22 ]. Likewise, repolarization has also been shown to be subjected to circadian control [ 18 , 19 ]. For example, the transcription factor Krupple-like factor 15 (KLF15) is a CLOCK/BMAL1 target gene containing several E-box elements in its promoter region [ 23 ].…”

Monitoring Non-dipping Heart Rate by Consumer-Grade Wrist-Worn Devices: An Avenue for Cardiovascular Risk Assessment in Hypertension

“…Non-dipping, i.e., blunted BP or HR decline overnight (by <10% of the daytime mean), is coupled with an adverse cardiovascular prognosis (5). Although sustained relative sympathetic over-activation at night is considered to be pivotal in the pathophysiology of non-dipping HR, other factors may also participate, such as the disrupted endogenous circadian rhythmicity of the central clock in the suprachiasmatic nucleus, the cardiac clock in the sinoatrial node, or circulating neurohumoral factors, including catecholamines and glucocorticoids (6)(7)(8). Non-dipping HR is rather neglected during cardiovascular risk assessment and is thus omitted from risk management strategies (5).…”

Early Morning QT Prolongation During Hypoglycemia: Only a Matter of Glucose?

“…It is known that many cardiovascular outcomes vary in prevalence depending the time of the day. Indeed, the cardiac circadian rhythm is involved in different cardiac functions and it may contribute to HF and SCD ( 38 ). We noticed that in the study conducted by Tsujimoto et al, the QT prolongation was only assessed in patients with severe hypoglycemia.…”