Current Opinion in Pharmacology: Circadian Clocks Regulate Cardiac Arrhythmia Susceptibility, Repolarization, and Ion Channels

Daily changes in the incidence of sudden cardiac death (SCD) reveal an interaction between environmental rhythms and internal circadian rhythms. Circadian rhythms are physiological rhythms that alter physiology to anticipate daily changes in the environment. They reflect coordinated activity of cellular circadian clocks that exist throughout the body. This review provides an overview of the state of the field by summarizing the results of several different transgenic mouse models that disrupt the function of circadian clocks throughout the body, in cardiomyocytes, or in adult cardiomyocytes. These studies identify important roles for circadian clocks in regulating heart rate, ventricular repolarization, arrhythmogenesis, and the functional expression of cardiac ion channels. They highlight a new dimension in the regulation of cardiac excitability and represent initial forays into understanding the complexities of how time impacts the functional regulation of ion channels, cardiac excitability, and time of day changes in the incidence of SCD. The graphic symbolizes the well-known observation that cardiac electrophysiology changes at different times of day. Clinically, sudden cardiac death is shown to have a time of day increase incidence for certain types of heart disease. To better understand how environment and gene interactions contribute to cardiac electrophysiology, several investigators have generated transgenic mouse models that disrupt circadian clocks in different tissues including the heart. These studies show a role for functional circadian clocks in regulating heart rate, the development of dilated cardiomyopathy, cardiac repolarization, and cardiac ion channels. on SCD. It underscores the need to improve our understanding of risk factors and underlying conditions, as well as, how these vary across regional populations and ethnicities. This paper is an observational study with significant public health implications. This prospective study examined incidence of sudden cardiac arrest (SCA) in 1535 individuals in Portland, Oregon. They found that SCA in their population did not follow the typical morning or Monday incidence of SCA. This data may provide evidence for impacts of new societal demands on the incidence of SCA and warrants further research. clocks in the body. It has important implications, in that lifestyle factors may lead to circadian dyssynchrony impacts on the heart. This paper is important because it demonstrated a role for the central circadian clock in the regulation of ion channel expression in the heart employing SCN ablation and adrenergic blockade. It suggests the complexity of the circadian system and the critical need to parse out the relative contribution of the central and peripheral clocks to the regulation of functional ion channels in the heart in order to better understand arrhythmogenesis. This provides a broad overview of animal models employed the study arrhythmias. suggest employing multiple models to address hypotheses and provide a comprehensive overview of different models and currently used species for arrhythmia research, as well as, providing extensive pros and cons of each model. multiple methodologies to demonstrate coregulation of transcripts ion channels that regulate excitability in Kcnh2 and Scn5a. forth a new paradigm expression both channels at the and ultimately, control electrical