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 H. Bishopric; Elisabeth M. Lodder; Jacques M T De Bakker; Robert Fischer; Ruben Coronel; Arthur A M Wilde; Michael Gotthardt; Carol Ann Remme

doi:10.1016/j.jacc.2013.10.062

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 H. Bishopric, Elisabeth M. Lodder, Jacques M T De Bakker, Robert Fischer, Ruben Coronel, Arthur A M Wilde, Michael GotthardtCarol Ann Remme^*

^*Corresponding author for this work

Pharmacology

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

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 Na_V1.5 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 language	English (US)
Pages (from-to)	549-559
Number of pages	11
Journal	Journal of the American College of Cardiology
Volume	63
Issue number	6
DOIs	https://doi.org/10.1016/j.jacc.2013.10.062
State	Published - Feb 18 2014

Funding

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.

Keywords

arrhythmia
ion channels
ischemia
single nucleotide polymorphism genetics
ventricular fibrillation

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2013.10.062

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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., ... Remme, C. A. (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, 63(6), 549-559. https://doi.org/10.1016/j.jacc.2013.10.062

@article{ee4b660de3b14a6085cb57c7652838c8,

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

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.",

keywords = "arrhythmia, ion channels, ischemia, single nucleotide polymorphism genetics, ventricular fibrillation",

author = "Marsman, {Roos F J} and Bezzina, {Connie R.} and Fabian Freiberg and Verkerk, {Arie O.} and Adriaens, {Michiel E.} and Svitlana Podliesna and Chen Chen and Bettina Purf{\"u}rst and Bastian Spallek and Koopmann, {Tamara T.} and Istvan Baczko and {Dos Remedios}, {Cristobal G.} and George, {Alfred L.} and Bishopric, {Nanette H.} and Lodder, {Elisabeth M.} and {De Bakker}, {Jacques M T} and Robert Fischer and Ruben Coronel and Wilde, {Arthur A M} and Michael Gotthardt and Remme, {Carol Ann}",

note = "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. ",

year = "2014",

month = feb,

day = "18",

doi = "10.1016/j.jacc.2013.10.062",

language = "English (US)",

volume = "63",

pages = "549--559",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "6",

}

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, NH, 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

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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DO - 10.1016/j.jacc.2013.10.062

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SN - 0735-1097

VL - 63

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EP - 559

JO - Journal of the American College of Cardiology

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IS - 6

ER -

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

Abstract

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ASJC Scopus subject areas

UN SDGs

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