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

Roos F J Marsman, Connie R. Bezzina, Fabian Freiberg, Arie O. Verkerk, Michiel E. Adriaens, Svitlana Podliesna, Chen Chen, Bettina Purfürst, Bastian Spallek, Tamara T. Koopmann, Istvan Baczko, Cristobal G. Dos Remedios, Alfred L. George, Nanette Bishopric, Elisabeth M. Lodder, Jacques M T De Bakker, Robert Fischer, Ruben Coronel, Arthur A M Wilde, Michael Gotthardt & 1 others Carol Ann Remme

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish
Pages (from-to)549-559
Number of pages11
JournalJournal of the American College of Cardiology
Volume63
Issue number6
DOIs
StatePublished - Feb 18 2014

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Coxsackie and Adenovirus Receptor-Like Membrane Protein
Myocardial Ischemia
Cardiac Arrhythmias
Ventricular Fibrillation
Genome-Wide Association Study
Myocardial Infarction
Connexin 43
Sodium Channels
Cell Adhesion Molecules

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia. / Marsman, Roos F J; Bezzina, Connie R.; Freiberg, Fabian; Verkerk, Arie O.; Adriaens, Michiel E.; Podliesna, Svitlana; Chen, Chen; Purfürst, Bettina; Spallek, Bastian; Koopmann, Tamara T.; Baczko, Istvan; Dos Remedios, Cristobal G.; George, Alfred L.; Bishopric, Nanette; Lodder, Elisabeth M.; De Bakker, Jacques M T; Fischer, Robert; Coronel, Ruben; Wilde, Arthur A M; Gotthardt, Michael; Remme, Carol Ann.

In: Journal of the American College of Cardiology, Vol. 63, No. 6, 18.02.2014, p. 549-559.

Research output: Contribution to journalArticle

Marsman, RFJ, Bezzina, CR, Freiberg, F, Verkerk, AO, Adriaens, ME, Podliesna, S, Chen, C, Purfürst, B, Spallek, B, Koopmann, TT, Baczko, I, Dos Remedios, CG, George, AL, Bishopric, N, Lodder, EM, De Bakker, JMT, Fischer, R, Coronel, R, Wilde, AAM, Gotthardt, M & Remme, CA 2014, 'Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia', Journal of the American College of Cardiology, vol. 63, no. 6, pp. 549-559. https://doi.org/10.1016/j.jacc.2013.10.062
Marsman, Roos F J ; Bezzina, Connie R. ; Freiberg, Fabian ; Verkerk, Arie O. ; Adriaens, Michiel E. ; Podliesna, Svitlana ; Chen, Chen ; Purfürst, Bettina ; Spallek, Bastian ; Koopmann, Tamara T. ; Baczko, Istvan ; Dos Remedios, Cristobal G. ; George, Alfred L. ; Bishopric, Nanette ; Lodder, Elisabeth M. ; De Bakker, Jacques M T ; Fischer, Robert ; Coronel, Ruben ; Wilde, Arthur A M ; Gotthardt, Michael ; Remme, Carol Ann. / Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia. In: Journal of the American College of Cardiology. 2014 ; Vol. 63, No. 6. pp. 549-559.
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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 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.",
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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

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

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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