title: Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.
abstract: OBJECTIVE
  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.
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Roos F J
authors.initials: RF
authors.lastname: Marsman
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Freiberg
authors.affiliation: Heart Failure Research Center, Department of Anatomy, Embryology and Physiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Michiel E
authors.initials: ME
authors.lastname: Adriaens
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Svitlana
authors.initials: S
authors.lastname: Podliesna
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Electron Microscopy Core Facility, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Purfürst
authors.affiliation: Universitätsklinikum Benjamin Franklin, Charité, University Medicine Berlin, Berlin, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Spallek
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Tamara T
authors.initials: TT
authors.lastname: Koopmann
authors.affiliation: Department of Pharmacology and Pharmacotherapy, University of Szeged, Szeged, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Baczko
authors.affiliation: Muscle Research Unit, Institute for Biomedical Research, University of Sydney, Sydney, Australia.
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: Dos Remedios
authors.affiliation: Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
authors.affiliation: University of Miami Cardiovascular Genomics Laboratory, University of Miami Miller School of Medicine, Miami, Florida.
authors.forename: Nanette H
authors.initials: NH
authors.lastname: Bishopric
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Lodder
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, the Netherlands.
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.affiliation: Universitätsklinikum Benjamin Franklin, Charité, University Medicine Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Ruben
authors.initials: R
authors.lastname: Coronel
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany; DZHK (German Centre for Cardiovascular Research), partner site, Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.affiliation: Heart Failure Research Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, Amsterdam, the Netherlands. Electronic address: c.a.remme@amc.uva.nl.
authors.forename: Carol Ann
authors.initials: CA
authors.lastname: Remme
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D002229:Carbenoxolone; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000502:physiology*; D005260:Female; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000503:physiopathology*; D006801:Humans; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D016276:Ventricular Function
chemical_list: D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D002229:Carbenoxolone
keywords: arrhythmia; ion channels; ischemia; single nucleotide polymorphism genetics; ventricular fibrillation