Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls
Authors: Cezmi A Akdis
Argelia Medeiros-Domingo
Deniz Akdis
Fanny Renois
Reinhard Kandolf
Hendrik Milting
Firat Duru
Laurent Andreoletti
Frank Enseleit
Peter Bode
Karin Klingel
Thomas F Lüscher
Anna Gaertner-Rommel
Ardan M Saguner
Corinna Brunckhorst
Jeannette I Kast
Journal: Heart Rhythm (2016)
Discipline: CLINICAL MEDICINE
Keywords: Adipogenesis; Apoptosis; Arrhythmogenic right ventricular; Cardiomyopathy; Dysplasia
Affiliations: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland., Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Department of Cardiology, University Hospital Bern, Bern, Switzerland., Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany., Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland., Department of Pathology, University Hospital Zurich, Zurich, Switzerland., Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany., Laboratoire de Virologie Médicale et Moléculaire, EA 4684 CardioVir, Faculté de Médecine et CHU Robert Debré, Reims, France., Department of Cardiology, University Hospital Bern, Bern, Switzerland., Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland., Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address: .

Abstract:  Background: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is mainly an 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: The purpose of this study was to investigate myocardial expression profiles of candidate molecules involved in the pathogenesis of ARVC/D. Methods: Myocardial messenger RNA (mRNA) expression of 62 junctional molecules, 5 cardiac ion channel molecules, 8 structural molecules, 4 apoptotic molecules, and 6 adipogenic molecules was studied. The averaged expression of candidate mRNAs was compared between ARVC/D samples (n = 10), nonfamilial dilated cardiomyopathy (DCM) samples (n = 10), and healthy control samples (n = 8). Immunohistochemistry and quantitative protein expression analysis were performed. Genetic analysis using next generation sequencing was performed in all patients with ARVC/D. Results: Following mRNA levels were significantly increased in patients with ARVC/D compared to those with DCM and healthy controls: phospholamban (P ≤ .001 vs DCM; P ≤ .001 vs controls), healthy tumor protein 53 apoptosis effector (P = .001 vs DCM; P ≤ .001 vs controls), and carnitine palmitoyltransferase 1β (P ≤ .001 vs DCM; P = 0.008 vs controls). Plakophillin-2 (PKP-2) mRNA was downregulated in patients with ARVC/D with PKP-2 mutations compared with patients with ARVC/D without PKP-2 mutations (P = .04). Immunohistochemistry revealed significantly increased protein expression of phospholamban, tumor protein 53 apoptosis effector, and carnitine palmitoyltransferase 1β in patients with ARVC/D and decreased PKP-2 expression in patients with ARVC/D carrying a PKP-2 mutation. Conclusion: 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 the underlying genetic mutations. 

Retracted: No

PubPeer comments:
 image duplication ![file] , 
 My team (EA4684 Cardiovir) was associated to this publication as collaborators because we provided frozen endomyocardial samples from patients with DCM and demographical and clinical data related with these patients. We did not perform any confocal mcroscopy assays and we did not compute these findings and we did not participate to the final choice of images for this panel related with ARVC D patients . We did not have the bulk confocal data or initial data for this panel. Please contact the corresponding author (Dr Firat DURU) to obtain a complete and final answer to this query. ,