Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease1,2, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure)3,4,5 or pattern (for example, Brugada’s syndrome)6 of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current7. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
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We thank A. F. Connors Jr for support, M. Mustar for illustrations, Y. Cui for experimental assistance, and members of the Jain laboratory for discussions. Funding sources: Heart Rhythm Society Fellowship (D.J.); National Institutes of Health grants HL094660 (D.J.), HL066991 (M.D.M.), HL086614 (S.M.H.), American Heart Association postdoctoral grant (N.S.), HL089598, HL091947 (X.H.W.), HL76446 (S.A.S.), HL102241 (K.H.), HL054807 (D.S.R.), HL075427, HL076754, HL084154, HL086548 and HL097595 (M.K.J.); Swiss National Science Foundation grants 31003A/131086 (U.A.) and M01-RR02635 (B.W.H.); Leducq Foundation grants of the ENAFRA Network 07CVD03 (S.D.); and the Centre National de la Recherche Scientifique (S.D.).
The authors declare no competing financial interests.
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Jeyaraj, D., Haldar, S., Wan, X. et al. Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483, 96–99 (2012). https://doi.org/10.1038/nature10852
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