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EP News, Basic and Translational April 5, 2012

Posted by Peng-Sheng Chen, MD, FHRS in Science & Research.
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Circadian Variation of Ion Channel Expression

The susceptibility to ventricular arrhythmia or sudden death is determined by the duration (e.g. short or long QT syndromes and heart failure) or pattern (e.g. Brugada syndrome) of ventricular repolarization. It is also known that there is circadian variation of the susceptibility to ventricular arrhythmias. However, the molecular mechanism by which the body’s diurnal biological clock controls the circadian variations of repolarization remains unknown. 

Jeyaraj et al (Nature 2012; 483:96, PMID 22367544) used the mice model to study the relationship between Krüppel-like family of transcription factors (Klfs) and myocardial repolarization. The term Krüppel (German for “cripple”) describes the crippled appearance of fruit fly larva caused by the mutation of the Krüppel gap gene. The Klfs is named for their homology to the fruit fly Krüppel protein. The Klfs have been extensively studied for their roles in cell proliferation, differentiation and survival.

Among them, Klf15 is linked to the pathobiology in heart failure. Jeyaraj et al show in mice heart that the cardiac ion-channel expression and QT-interval duration exhibit endogenous circadian rhythmicity under the control of Klf15, which is a biological clock-dependent oscillator. Klf15 transcriptionally controls rhythmic expression of Kv channel interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium (K) current. Because transient outward K current of the mice is primarily responsible for cardiomyocyte repolarization, deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. Klf15 is the first link between the biological clock and arrhythmogenesis.

The authors conclude that circadian transcription of ion channels is a mechanism for cardiac arrhythmogenesis.

Epistatic Effects of Potassium Channel Variation on Cardiac Repolarization and Atrial Fibrillation Risk

Exome sequencing data showed that functionally deleterious variants in numerous sodium and calcium ion channels as well as other cardiomyocyte components are present in every person, and it is the net effect of all these variants together with acquired “environmental” factors that contribute to the electrophysiological properties of the atrial wall. Therefore, looking at the electrophysiological effects of a single gene variant may not be enough to determine the relationship between genetic mutations and atrial fibrillation (AF). For example, the K channels play a major role in atrial repolarization, but single mutations in cardiac K channel genes are infrequently present in AF families. It is possible that instead of the mutation in a single gene, the variance of multiple different genes may collectively affect the K channel conductance and lead to sufficient electrophysiological changes to cause AF.

Mann et al (JACC 2012;59:1017; PMID 22402074) aimed to evaluate the role of cardiac K channel gene variants in families with atrial fibrillation (AF). Genes encoding the major cardiac K channels were resequenced in 80 AF probands. Nonsynonymous coding sequence variants identified in AF probands were evaluated in 240 control subjects. Novel variants were characterized using patch-clamp techniques and in silico modeling.

The authors found 19 nonsynonymous variants in 9 genes, including 11 rare variants. Rare variants were more frequent in AF probands (18.8% vs. 4.2%, p < 0.001), and the mean number of variants was greater (0.21 vs. 0.04, p < 0.001). The majority of K channel variants individually had modest functional effects. Modeling simulations to evaluate combinations of K channel variants of varying population frequency indicated that simultaneous small perturbations of multiple current densities had nonlinear interactions and could result in substantial (>30 ms) shortening or lengthening of action potential duration as well as increased dispersion of repolarization.

The authors conclude that families with AF show an excess of rare functional K channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.

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