Coxsackie and adenovirus receptor (CAR) is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia

Tools

Item Type:	Article
Title:	Coxsackie and adenovirus receptor (CAR) is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia
Creators Name:	Marsman, R.F.J., Bezzina, C.R., Freiberg, F., Verkerk, A.O., Adriaens, M.E., Podliesna, S., Chen, C., Purfürst, B., Spallek, B., Koopmann, T.T., Baczko, I., Dos Remedios, C.G., George, A.L., Bishopric, N.H., Lodder, E.M., de Bakker, J.M.T., Fischer, R., Coronel, R., Wilde, A.A.M., Gotthardt, M. and Remme, C.A.
Abstract:	Objectives: To investigate the modulatory effect of the Coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Background: A heritable component in risk for ventricular fibrillation (VF) during myocardial infarction (MI) has been well established. A recent genome-wide association study (GWAS) for VF during acute MI has led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the coxsackie and adenovirus receptor (CAR), a cell adhesion molecule predominantly located at intercalated discs of the cardiomyocyte. Methods: The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed CAR haploinsufficient mice (CAR+/-). Results: In human left ventricular samples, the risk allele at the chr21q21 GWAS locus was associated with lower CXADR mRNA levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced VF. Hearts from CAR+/- mice displayed ventricular conduction slowing in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia following LAD ligation. Connexin43 expression and distribution was unaffected, but CAR+/- hearts displayed increased arrhythmia susceptibility upon pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR+/- myocytes showed reduced sodium current magnitude specifically at the intercalated disc. Moreover, CAR co-precipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. Conclusion: We identify CAR as a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease.
Keywords:	Arrhythmia, Ventricular Fibrillation, Ischemia, Single Nucleotide Polymorphism Genetics, Ion Channels, Animals, Mice
Source:	Journal of the American College of Cardiology
ISSN:	0735-1097
Publisher:	Elsevier
Volume:	63
Number:	6
Page Range:	549-559
Date:	18 February 2014
Official Publication:	https://doi.org/10.1016/j.jacc.2013.10.062
PubMed:	View item in PubMed

Repository Staff Only: item control page