TY - JOUR
T1 - Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia
AU - Marsman, Roos F.J.
AU - Bezzina, Connie R.
AU - Freiberg, Fabian
AU - Verkerk, Arie O.
AU - Adriaens, Michiel E.
AU - Podliesna, Svitlana
AU - Chen, Chen
AU - Purfürst, Bettina
AU - Spallek, Bastian
AU - Koopmann, Tamara T.
AU - Baczko, Istvan
AU - Dos Remedios, Cristobal G.
AU - George, Alfred L.
AU - Bishopric, Nanette H.
AU - Lodder, Elisabeth M.
AU - De Bakker, Jacques M.T.
AU - Fischer, Robert
AU - Coronel, Ruben
AU - Wilde, Arthur A.M.
AU - Gotthardt, Michael
AU - Remme, Carol Ann
N1 - Funding Information:
This study was supported by the Netherlands Heart Foundation ( 2005T025 , 2007B010 , 2010B175 ), the Deutsche Forschungsgemeinschaft (to Dr. Gotthardt), the National Institutes of Health (grant HL068880 to Dr. George), the Netherlands Heart Institute ( ICIN 061.02 ), and the Division for Earth and Life Sciences (project 836.09.003 to Dr. Remme), with financial aid from the Netherlands Organization for Scientific Research. This research was performed within the framework of the Center for Translational Molecular Medicine, project COHFAR (grant 01C-203). Dr. Wilde is a member of the scientific advisory board for Sorin. All other authors have reported that they have no relationships relevant to the content of this paper to disclose.
PY - 2014/2/18
Y1 - 2014/2/18
N2 - 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 Na V1.5. 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.
AB - 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 Na V1.5. 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.
KW - arrhythmia
KW - ion channels
KW - ischemia
KW - single nucleotide polymorphism genetics
KW - ventricular fibrillation
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U2 - 10.1016/j.jacc.2013.10.062
DO - 10.1016/j.jacc.2013.10.062
M3 - Article
C2 - 24291282
AN - SCOPUS:84893838296
VL - 63
SP - 549
EP - 559
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 6
ER -
