Circadian influences on sudden cardiac death and cardiac electrophysiology

Abstract

Cardiologists have analyzed daily patterns in the incidence of sudden cardiac death to identify environmental, behavioral, and physiological factors that trigger fatal arrhythmias. Recent studies have indicated an overall increase in sudden cardiac arrest during daytime hours when the frequency of arrhythmogenic triggers is highest. The risk of fatal arrhythmias arises from the interaction between these triggers such as elevated sympathetic signaling, catecholamine levels, heart rate, afterload, and platelet aggregation and the susceptibility of the heart (myocardial substrate) to them. A healthy myocardial substrate has structural and functional properties that protect against arrhythmias. However, individuals with cardiovascular disease often exhibit structural and electrophysiological alterations in the myocardial substrate that predispose them to sustained lethal arrhythmias. This review focuses on how day-night and circadian rhythms, both extrinsic and intrinsic, influence the protective properties of the myocardial substrate. Specifically, it explores recent advances in the temporal regulation of ion channel gene transcription, drawing on data from comprehensive bioinformatics resources (CircaDB, CircaAge, and CircaMET) and recent RNA sequencing studies. We also examine potential mechanisms underlying the temporal regulation of mRNA expression and the challenges in linking rhythmic mRNA expression to corresponding changes in protein levels. As chronobiological research in cardiology progresses, we anticipate the development of novel therapeutic strategies to enhance the protective properties of the myocardial substrate to reduce the risk of fatal arrhythmias and sudden cardiac arrest.

Keywords: Arrhythmias; Circadian clock; Ion channels; Myocardial substrate; Sudden cardiac death; Triggers.

Figure 1.. A working model for day-night patterns in arrhythmia risk.

Arrhythmogenic triggers (red line) and the overall protective properties of the myocardial substrate (blue line) are expected to vary across the 24-hour cycle. Cardiovascular disease can alter the day-night rhythm in the protective properties of the myocardial substrate to increase arrhythmogenic risk. This can include a reduction in the amplitude or average level of protection (see 1 and 2) and the relative phase alignment between the day-night rhythms in arrhythmia risk and the protective properties of the myocardial substrate (3). This review explores whether day-night rhythms in extrinsic and intrinsic circadian signaling contribute to a day-night rhythm in the protective properties of the myocardial substrate to impact arrhythmogenic risk for sudden cardiac arrest.

Figure 2.. Understanding the impact of REGs on protein expression levels.

(A) RNAseq data showing the mRNA profiles for the core clock gene Bmal1 and the ion channel REG Kcnh2 [67] in mouse hearts. (B) The phase delay and relative amplitude for the oscillating mRNA (dotted line) and protein levels (solid line) for BMAL1 (red) and Kv11.1 protein (blue) accumulation were calculated based on a simple model of translation from Mauvoisin et al [102]. The small amplitude in mRNA oscillation and longer half-life of Kv11.1 protein predict a relatively small amplitude in the circadian oscillation of protein levels. The protein half-life estimates for BMAL1 and Kv11.1 (12-hours) were based on previously published reports [106, 108]. (C) The top table shows predicted minimum (min), median (med), and maximum (max) Kv11.1 protein levels based on a half-life (τ_1/2) of 12, 6, and 3 hours. Several KCNH2 mutations linked to the long QT syndrome are predicted to shorten the half-life of the Kv11.1 channel protein. As the Kv11.1 protein half-life decreases, the median Kv11.1 protein levels decrease, and the difference between the minimum and maximum Kv11.1 protein levels increase (i.e., larger protein oscillation). For didactic purposes, we used the oversimplified assumption that Kv11.1 protein levels directly correspond to the Kv11.1-encoded I_Kr levels. This allowed us to simulate how a circadian change in Kv11.1 protein and I_Kr levels impacts a simulation of a human ventricular action potential duration (APD) paced at 1 Hz [103]. The bottom table shows that as the protein half-life decreased and Kv11.1 protein levels decreased, the corresponding changes in I_Kr caused the APD to increase. The simulations also showed that as the difference between the minimum and maximum Kv11.1 protein and I_Kr levels increased, the difference in the APD increased. Collectively, the data suggest that mutations that shorten the half-life of circadian-regulated proteins might decrease overall levels and increase time-of-day differences in protein levels that translate to time-of-day changes in physiology (APD-action potential duration at 90% repolarization, simulations were done similar to that previously reported [104].