title: Remodeling of the cardiac sodium channel, connexin43, and plakoglobin at the intercalated disk in patients with arrhythmogenic cardiomyopathy.
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 NaV1.5, 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.
authors.affiliation: Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Noorman
authors.forename: Sara
authors.initials: S
authors.lastname: Hakim
authors.forename: Elise
authors.initials: E
authors.lastname: Kessler
authors.forename: Judith A
authors.initials: JA
authors.lastname: Groeneweg
authors.forename: Moniek G P J
authors.initials: MG
authors.lastname: Cox
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Harold V M
authors.initials: HV
authors.lastname: van Rijen
authors.forename: Leonie
authors.initials: L
authors.lastname: van Stuijvenberg
authors.forename: Halina
authors.initials: H
authors.lastname: Chkourko
authors.forename: Marcel A G
authors.initials: MA
authors.lastname: van der Heyden
authors.forename: Marc A
authors.initials: MA
authors.lastname: Vos
authors.forename: Nicolaas
authors.initials: N
authors.lastname: de Jonge
authors.forename: Jasper J
authors.initials: JJ
authors.lastname: van der Smagt
authors.forename: Dennis
authors.initials: D
authors.lastname: Dooijes
authors.forename: Aryan
authors.initials: A
authors.lastname: Vink
authors.forename: Roel A
authors.initials: RA
authors.lastname: de Weger
authors.forename: Andras
authors.initials: A
authors.lastname: Varro
authors.forename: Jacques M T
authors.initials: JM
authors.lastname: de Bakker
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.forename: Mario
authors.initials: M
authors.lastname: Delmar
authors.forename: Richard N W
authors.initials: RN
authors.lastname: Hauer
authors.forename: Toon A B
authors.initials: TA
authors.lastname: van Veen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D003896:Desmosomes / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051191:Plakophilins / Q000235:genetics / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult; D051185:gamma Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D015820:Cadherins; D018031:Connexin 43; C495337:PKP2 protein, human; D051191:Plakophilins; D015222:Sodium Channels; D051185:gamma Catenin; D004247:DNA