Circadian Variation Linked to Mechanism Underlying Sudden Cardiac Death

A molecular mechanism involved in regulating diurnal variation of potassium electrical currents in heart cells has now been directly linked to abnormal cardiac repolarization and susceptibility to arrhythmogenesis.

The incidence of sudden cardiac death from ventricular arrhythmias, the principal cause of mortality from heart disease worldwide, exhibits distinct diurnal variation in both acquired and hereditary forms of heart disease. In both forms, a common mechanism that enhances susceptibility to ventricular arrhythmias is abnormal myocardial repolarization. Despite rigorous investigation of ion channels that control myocardial repolarization, the molecular basis for the diurnal variation in occurrence of ventricular arrhythmias has remained unknown.

The current study, published in the journal Nature on February 22, 2012, identified circadian transcription of ion channels as part of a mechanism for cardiac arrhythmogenesis. The researchers demonstrated that cardiac ion-channel expression and QT-interval duration (a time index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 was also shown to transcriptionally control rhythmic expression of potassium channel-interacting protein 2 (KChIP2), a critical subunit in generating the transient outward potassium current. Experiments with mice harboring a genetic change that caused them to make more Klf15 than normal, and with mice that lacked Klf15, increased the risk of deadly arrhythmias.

This "is the first example of a molecular mechanism for the circadian change in susceptibility to cardiac arrhythmias," said coauthor Xander Wehrens, professor of molecular physiology and biophysics and cardiology at Baylor College of Medicine (BCM; Houston, TX, USA). "If there was too much Klf15 or none, the mice were at risk for developing the arrhythmias," he said.

Although human heart repolarization is more complex than that of mice, these results provide a mechanistic foundation for future efforts to understand the process in humans and to prevent or treat human cardiac arrhythmias by modulating the circadian clock through behavioral or pharmacological means.

The study was performed by an international consortium of researchers, predominantly carried out at Case Western Reserve University School of Medicine (Cleveland, OH, USA), BCM, and the University of Fribourg (Fribourg, Switzerland).

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Case Western Reserve University School of Medicine
Baylor College of Medicine
University of Fribourg