title: Myocardial expression profiles of candidate molecules in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia compared to those with dilated cardiomyopathy and healthy controls.
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.
  
  
  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 the underlying genetic mutations.
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Deniz
authors.initials: D
authors.lastname: Akdis
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Department of Cardiology, University Hospital Bern, Bern, Switzerland.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.affiliation: Heart and Diabetes Center NRW, Ruhr University Bochum, Bad Oeynhausen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Gaertner-Rommel
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Jeannette I
authors.initials: JI
authors.lastname: Kast
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Enseleit
authors.affiliation: Department of Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Bode
authors.affiliation: Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Department of Molecular Pathology, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Kandolf
authors.affiliation: Laboratoire de Virologie Médicale et Moléculaire, EA 4684 CardioVir, Faculté de Médecine et CHU Robert Debré, Reims, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Renois
authors.affiliation: Laboratoire de Virologie Médicale et Moléculaire, EA 4684 CardioVir, Faculté de Médecine et CHU Robert Debré, Reims, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Andreoletti
authors.affiliation: Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
authors.forename: Cezmi A
authors.initials: CA
authors.lastname: Akdis
authors.affiliation: Department of Cardiology, University Hospital Bern, Bern, Switzerland.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Corinna
authors.initials: C
authors.lastname: Brunckhorst
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland.
authors.forename: Ardan M
authors.initials: AM
authors.lastname: Saguner
authors.affiliation: Department of Cardiology, University Heart Center Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland. Electronic address: firat.duru@usz.ch.
authors.forename: Firat
authors.initials: F
authors.lastname: Duru
mesh_terms: D017209:Apoptosis / Q000235:genetics; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies / Q000379:methods*; D005820:Genetic Testing; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D015415:Biomarkers; D012333:RNA, Messenger
keywords: Adipogenesis; Apoptosis; Arrhythmogenic right ventricular; Cardiomyopathy; Dysplasia; Phospholamban