Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy

Maartje Noorman, Sara Hakim, Elise Kessler, Judith A. Groeneweg, Moniek G P J Cox, Angeliki Asimaki, Harold V M Van Rijen, Leonie Van Stuijvenberg, Halina Chkourko, Marcel A G Van Der Heyden, Marc A. Vos, Nicolaas De Jonge, Jasper J. Van Der Smagt, Dennis Dooijes, Aryan Vink, Roel A. De Weger, A. Varró, Jacques M T De Bakker, Jeffrey E. Saffitz, Thomas J. Hund & 4 others Peter J. Mohler, Mario Delmar, Richard N W Hauer, Toon A B Van Veen

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Background: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. Objective: To assess the immunoreactive signal levels of the sodium channel protein Na V1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. Methods: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. Results: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74%, 70%, and 65% of the patients, respectively. Conclusions: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.

Original languageEnglish
Pages (from-to)412-419
Number of pages8
JournalHeart Rhythm
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 2013

Fingerprint

gamma Catenin
Connexin 43
Sodium Channels
Cardiomyopathies
Plakophilins
Cadherins
Desmoplakins
Haploinsufficiency
Mutation
Gap Junctions
Normal Distribution
Advisory Committees
Cardiac Arrhythmias
Fibrosis
Theoretical Models

Keywords

  • AC
  • Arrhythmogenic cardiomyopathy
  • Connexin 43
  • Desmosome
  • Immunohistochemistry
  • Na1.5
  • Plakoglobin
  • Plakophilin-2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Noorman, M., Hakim, S., Kessler, E., Groeneweg, J. A., Cox, M. G. P. J., Asimaki, A., ... Van Veen, T. A. B. (2013). Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. Heart Rhythm, 10(3), 412-419. https://doi.org/10.1016/j.hrthm.2012.11.018

Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. / Noorman, Maartje; Hakim, Sara; Kessler, Elise; Groeneweg, Judith A.; Cox, Moniek G P J; Asimaki, Angeliki; Van Rijen, Harold V M; Van Stuijvenberg, Leonie; Chkourko, Halina; Van Der Heyden, Marcel A G; Vos, Marc A.; De Jonge, Nicolaas; Van Der Smagt, Jasper J.; Dooijes, Dennis; Vink, Aryan; De Weger, Roel A.; Varró, A.; De Bakker, Jacques M T; Saffitz, Jeffrey E.; Hund, Thomas J.; Mohler, Peter J.; Delmar, Mario; Hauer, Richard N W; Van Veen, Toon A B.

In: Heart Rhythm, Vol. 10, No. 3, 03.2013, p. 412-419.

Research output: Contribution to journalArticle

Noorman, M, Hakim, S, Kessler, E, Groeneweg, JA, Cox, MGPJ, Asimaki, A, Van Rijen, HVM, Van Stuijvenberg, L, Chkourko, H, Van Der Heyden, MAG, Vos, MA, De Jonge, N, Van Der Smagt, JJ, Dooijes, D, Vink, A, De Weger, RA, Varró, A, De Bakker, JMT, Saffitz, JE, Hund, TJ, Mohler, PJ, Delmar, M, Hauer, RNW & Van Veen, TAB 2013, 'Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy', Heart Rhythm, vol. 10, no. 3, pp. 412-419. https://doi.org/10.1016/j.hrthm.2012.11.018
Noorman, Maartje ; Hakim, Sara ; Kessler, Elise ; Groeneweg, Judith A. ; Cox, Moniek G P J ; Asimaki, Angeliki ; Van Rijen, Harold V M ; Van Stuijvenberg, Leonie ; Chkourko, Halina ; Van Der Heyden, Marcel A G ; Vos, Marc A. ; De Jonge, Nicolaas ; Van Der Smagt, Jasper J. ; Dooijes, Dennis ; Vink, Aryan ; De Weger, Roel A. ; Varró, A. ; De Bakker, Jacques M T ; Saffitz, Jeffrey E. ; Hund, Thomas J. ; Mohler, Peter J. ; Delmar, Mario ; Hauer, Richard N W ; Van Veen, Toon A B. / Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy. In: Heart Rhythm. 2013 ; Vol. 10, No. 3. pp. 412-419.
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abstract = "Background: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. Objective: To assess the immunoreactive signal levels of the sodium channel protein Na V1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. Methods: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. Results: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74{\%}, 70{\%}, and 65{\%} of the patients, respectively. Conclusions: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.",
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T1 - Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy

AU - Noorman, Maartje

AU - Hakim, Sara

AU - Kessler, Elise

AU - Groeneweg, Judith A.

AU - Cox, Moniek G P J

AU - Asimaki, Angeliki

AU - Van Rijen, Harold V M

AU - Van Stuijvenberg, Leonie

AU - Chkourko, Halina

AU - Van Der Heyden, Marcel A G

AU - Vos, Marc A.

AU - De Jonge, Nicolaas

AU - Van Der Smagt, Jasper J.

AU - Dooijes, Dennis

AU - Vink, Aryan

AU - De Weger, Roel A.

AU - Varró, A.

AU - De Bakker, Jacques M T

AU - Saffitz, Jeffrey E.

AU - Hund, Thomas J.

AU - Mohler, Peter J.

AU - Delmar, Mario

AU - Hauer, Richard N W

AU - Van Veen, Toon A B

PY - 2013/3

Y1 - 2013/3

N2 - Background: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. Objective: To assess the immunoreactive signal levels of the sodium channel protein Na V1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. Methods: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. Results: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74%, 70%, and 65% of the patients, respectively. Conclusions: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.

AB - Background: Arrhythmogenic cardiomyopathy (AC) is closely associated with desmosomal mutations in a majority of patients. Arrhythmogenesis in patients with AC is likely related to remodeling of cardiac gap junctions and increased levels of fibrosis. Recently, using experimental models, we also identified sodium channel dysfunction secondary to desmosomal dysfunction. Objective: To assess the immunoreactive signal levels of the sodium channel protein Na V1.5, as well as connexin43 (Cx43) and plakoglobin (PKG), in myocardial specimens obtained from patients with AC. Methods: Left and right ventricular free wall postmortem material was obtained from 5 patients with AC and 5 controls matched for age and sex. Right ventricular septal biopsies were taken from another 15 patients with AC. All patients fulfilled the 2010 revised Task Force Criteria for the diagnosis of AC. Immunohistochemical analyses were performed using antibodies against Cx43, PKG, NaV1.5, plakophilin-2, and N-cadherin. Results: N-cadherin and desmoplakin immunoreactive signals and distribution were normal in patients with AC compared to controls. Plakophilin-2 signals were unaffected unless a plakophilin-2 mutation predicting haploinsufficiency was present. Distribution was unchanged compared to that in controls. Immunoreactive signal levels of PKG, Cx43, and NaV1.5 were disturbed in 74%, 70%, and 65% of the patients, respectively. Conclusions: A reduced immunoreactive signal of PKG, Cx43, and NaV1.5 at the intercalated disks can be observed in a large majority of the patients. Decreased levels of Nav1.5 might contribute to arrhythmia vulnerability and, in the future, potentially could serve as a new clinically relevant tool for risk assessment strategies.

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KW - Arrhythmogenic cardiomyopathy

KW - Connexin 43

KW - Desmosome

KW - Immunohistochemistry

KW - Na1.5

KW - Plakoglobin

KW - Plakophilin-2

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