Circadian rhythms govern cardiac repolarization and arrhythmogenesis

Abstract

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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Figure 1: Klf15 expression, ECG QTc interval and expression of repolarizing ion channels exhibit endogenous circadian rhythm.
Figure 2: Klf15 regulates KChIP2 expression in the heart.
Figure 3: Deficiency or excess of Klf15 modulates rhythmic variation in repolarization.
Figure 4: Klf15 deficiency or excess increases susceptibility to ventricular arrhythmias.

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Acknowledgements

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.).

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D.J. and M.K.J. designed the research; D.J., S.M.H., X.W., M.D.M., J.A.R., Y.L., B.L.E. and M.J.C. carried out the experiments; J.G., A.S., J.R. and R.V.K. contributed critical reagents; D.J., N.S., S.D., R.V.K., S.A.S., U.A., X.H.T.W., D.S.R. and M.K.J. supervised the research; D.J., S.M.H., X.W., M.D.M., J.A.R., K.H., B.L.E., E.F., S.A.S., U.A., X.H.T.W., D.S.R. and M.K.J. analysed and interpreted the data; and D.J. and M.K.J. wrote the manuscript.

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Correspondence to Darwin Jeyaraj or Mukesh K. Jain.

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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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