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Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls


Akdis, Deniz; Medeiros-Domingo, Argelia; Gaertner-Rommel, Anna; Kast, Jeannette I; Enseleit, Frank; Bode, Peter; Klingel, Karin; Kandolf, Reinhard; Renois, Fanny; Andreoletti, Laurent; Akdis, Cezmi A; Milting, Hendrik; Lüscher, Thomas F; Brunckhorst, Corinna; Saguner, Ardan M; Duru, Firat (2016). Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls. Heart Rhythm, 13(3):731-741.

Abstract

BACKGROUND Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) is a mainly autosomal-dominant disease characterized by fibrofatty infiltration of the right ventricle leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE To investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS Myocardial mRNA expression of 62 junctional molecules, five cardiac ion channel molecules, eight structural molecules, four apoptotic molecules and six adipogenic molecules was studied. The averaged expression of candidate mRNAs between ARVC/D samples (n=10), non-familial dilated cardiomyopathy (DCM) samples (n=10) and healthy control samples (n=8) were compared. Immunohistochemistry and quantitative protein expression analysis was performed. Genetic analysis using next-generation sequencing was performed in all ARVC/D patients. RESULTS Following mRNA levels were significantly increased in ARVC/D compared to DCM and controls: phospholamban (p=<0.001 vs DCM; p=<0.001 vs controls), tumor protein 53 apoptosis effector (PERP) (p=0.001 vs DCM; p=<0.001 vs controls), and carnitine palmitoyltransferase 1 beta (CPT1B) (p=<0.001 vs DCM; p=0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in ARVC/D patients with PKP-2 mutations compared to ARVC/D patients without PKP-2 mutations (p=0.04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, PERP and CPT1B in ARVC/D patients, and decreased PKP-2 expression in ARVC/D patients carrying a PKP-2 mutation. CONCLUSIONS Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of underlying genetic mutations.

Abstract

BACKGROUND Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC/D) is a mainly autosomal-dominant disease characterized by fibrofatty infiltration of the right ventricle leading to ventricular arrhythmias. Mutations in desmosomal proteins can be identified in about half of the patients. The pathogenic mechanisms leading to disease expression remain unclear. OBJECTIVE To investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. METHODS Myocardial mRNA expression of 62 junctional molecules, five cardiac ion channel molecules, eight structural molecules, four apoptotic molecules and six adipogenic molecules was studied. The averaged expression of candidate mRNAs between ARVC/D samples (n=10), non-familial dilated cardiomyopathy (DCM) samples (n=10) and healthy control samples (n=8) were compared. Immunohistochemistry and quantitative protein expression analysis was performed. Genetic analysis using next-generation sequencing was performed in all ARVC/D patients. RESULTS Following mRNA levels were significantly increased in ARVC/D compared to DCM and controls: phospholamban (p=<0.001 vs DCM; p=<0.001 vs controls), tumor protein 53 apoptosis effector (PERP) (p=0.001 vs DCM; p=<0.001 vs controls), and carnitine palmitoyltransferase 1 beta (CPT1B) (p=<0.001 vs DCM; p=0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in ARVC/D patients with PKP-2 mutations compared to ARVC/D patients without PKP-2 mutations (p=0.04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, PERP and CPT1B in ARVC/D patients, and decreased PKP-2 expression in ARVC/D patients carrying a PKP-2 mutation. CONCLUSIONS Changes in the expression profiles of sarcolemmal calcium channel regulation, apoptosis and adipogenesis suggest that these molecular pathways may play a critical role in the pathogenesis of ARVC/D, independent of underlying genetic mutations.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
04 Faculty of Medicine > Swiss Institute of Allergy and Asthma Research
04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2016
Deposited On:26 Nov 2015 11:28
Last Modified:03 Mar 2017 04:08
Publisher:Elsevier
ISSN:1547-5271
Publisher DOI:https://doi.org/10.1016/j.hrthm.2015.11.010
PubMed ID:26569459

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