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Circadian rhythms govern cardiac repolarization and arrhythmogenesis.

ABSTRACT: Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, 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) or pattern (for example, Brugada's syndrome) 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 current. 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.

SUBMITTER: Jeyaraj D

PROVIDER: S-EPMC3297978 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature

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Circadian rhythms govern cardiac repolarization and arrhythmogenesis.

Jeyaraj Darwin D Haldar Saptarsi M SM Wan Xiaoping X McCauley Mark D MD Ripperger Jürgen A JA Hu Kun K Lu Yuan Y Eapen Betty L BL Sharma Nikunj N Ficker Eckhard E Cutler Michael J MJ Gulick James J Sanbe Atsushi A Robbins Jeffrey J Demolombe Sophie S Kondratov Roman V RV Shea Steven A SA Albrecht Urs U Wehrens Xander H T XH Rosenbaum David S DS Jain Mukesh K MK

Nature 20120222 7387

Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, 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) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular ar ...[more]

PMID: 22367544

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Project description:BackgroundTime-domain and non-linear methods can be used to quantify beat-to-beat repolarization variability but whether measures of repolarization variability can predict ventricular arrhythmogenesis in mice have never been explored.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during constant right ventricular 8 Hz pacing in Langendorff-perfused mouse hearts, in the presence or absence of the gap junction and sodium channel inhibitor heptanol (0.1, 0.5, 1 or 2 mM).ResultsUnder control conditions, mean action potential duration (APD) was 39.4 ± 8.1 ms. Standard deviation (SD) of APDs was 0.3 ± 0.2 ms, coefficient of variation was 0.9 ± 0.8% and the root mean square (RMS) of successive differences in APDs was 0.15 ± 0.14 ms. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with a SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ± 2.1. Approximate and sample entropy were 0.61 ± 0.12 and 0.76 ± 0.26, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.49 ± 0.27 and 0.81 ± 0.36, respectively. Heptanol at 2 mM induced ventricular tachycardia in five out of six hearts. None of the above parameters were altered by heptanol during which reproducible electrical activity was observed (KW-ANOVA, P > 0.05). Contrastingly, SD2/SD1 decreased to 2.03 ± 0.41, approximate and sample entropy increased to 0.82 ± 0.12 and 1.45 ± 0.34, and short-term fluctuation slope decreased to 0.82 ± 0.19 during the 20-s period preceding spontaneous ventricular tachy-arrhythmias (n = 6, KW-ANOVA, P < 0.05).ConclusionMeasures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention.

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Circadian rhythms govern cardiac repolarization and arrhythmogenesis.

Publications

Circadian rhythms govern cardiac repolarization and arrhythmogenesis.

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