Ruled by the clock.

Circadian Rhythms Govern Cardiac Repolarization and Arrhythmogenesis Jeyaraj et al Nature. 2012;483:96–99. The ability of organisms to respond to time allows for anticipation of cyclic changes in the environment that provide a survival advantage. The time variance of environmental influences on an organism may occur over years, months, or days. Biological clocks are ubiquitous and hierarchical in mammals and provide cell autonomous, transcriptionally mediated mechanism(s) to regulate function over several time scales.1 The master clock in mammals is in the suprachiasmatic nucleus (SCN) of the hypothalamus, which is regulated by external cues (zeitgebers), prominently light. Circadian rhythmicity is maintained by endogenous 24-hour cycle clocks that can be regulated by external signals to produce diurnal behaviors. Circadian clocks are characteristic of most mammalian tissues and are coupled to produce complex diurnal behaviors.2 The main molecular components of mammalian biological clocks include a series of transcription factors that regulate the expression of clock-controlled genes (CCG) in a negative feedback fashion. CLOCK and BMAL1 heterodimerize and bind to an E-box motif, activating transcription of the period (PER1, 2, 3) and cryptochrome (CRY1, 2) proteins. As period proteins accumulate, they complex with cryptochromes and translocate to the nucleus, suppressing CLOCK/ BMAL1 mediated transcription. Casein kinase 1 (CK1 ) phosphorylates period proteins targeting them for proteasomal degredation, derepressing CLOCK/BMAL1-mediated transcription. These core components of the clock are regulated by a number of other CCGs including arginine vasopressin and other transcription factors such as D-element– binding proteins, hepatic leukemia factor, and thyrotrophic embryonic factor. The central clock in the SCN regulates autonomic nervous system function, levels of humoral factors, and peripheral clocks to produce circadian variation in physiological function.1 Peripheral clocks exist in virtually every tissue in the body and are believed to have similar molecular mechanisms. Cardiovascular physiology and the clinical presentation of heart and vascular disease exhibit diurnal variation. Heart rate, blood pressure, vascular reactivity, inflammation, metabolism, and thrombogenicity change in a diurnal fashion. Neurohumoral regulators of the cardiovascular system that change over the course of a day may be particularly relevant to complex phenotypes such as myocardial infarction and sudden cardiac death (SCD). More directly in the case of SCD, these deaths peak in the early morning hours,3,4 and there is a corresponding temporally coordinate increase in ventricular refractoriness,5 QT interval6,7 and QT dispersion.8 In rodents, genes that encode repolarizing K currents, specifically the transient outward (Ito, KV4.2) and ultrarapid (IKur, KV1.5) currents exhibit circadian variation in transcript levels.9 The opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar and Ali J. Marian. From the Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD. Correspondence to Gordon F. Tomaselli, MD, 720 N Rutland Ave, Ross 844, Johns Hopkins University, Baltimore, MD 21205. E-mail [email protected] (Circ Res. 2012;111:14-16.) © 2012 American Heart Association, Inc.