Format

Send to

Choose Destination
See comment in PubMed Commons below
J Am Coll Cardiol. 2014 Feb 18;63(6):549-59. doi: 10.1016/j.jacc.2013.10.062. Epub 2013 Nov 27.

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

Author information

  • 1Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
  • 2Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
  • 3Heart Failure Research Center, Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, the Netherlands.
  • 4Electron Microscopy Core Facility, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
  • 5Universitätsklinikum Benjamin Franklin, Charité, University Medicine Berlin, Berlin, Germany.
  • 6Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
  • 7Muscle Research Unit, Institute for Biomedical Research, University of Sydney, Sydney, Australia.
  • 8Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
  • 9University of Miami Cardiovascular Genomics Laboratory, University of Miami Miller School of Medicine, Miami, Florida.
  • 10Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
  • 11Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; DZHK (German Centre for Cardiovascular Research), partner site, Berlin, Germany.
  • 12Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.a.remme@amc.uva.nl.

Abstract

OBJECTIVES:

The aim of this study was 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 the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks 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 using CAR haploinsufficient (CAR⁺/⁻) mice.

RESULTS:

In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR⁺/⁻ mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR⁺/⁻ hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR⁺/⁻ myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5.

CONCLUSIONS:

CAR is 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.

Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

KEYWORDS:

arrhythmia; ion channels; ischemia; single nucleotide polymorphism genetics; ventricular fibrillation

[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk