title: Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study.
abstract: OBJECTIVE
  Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin.
  
  
  RESULTS
  Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S(1)-S(2) protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation-repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P = 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution.
  
  
  CONCLUSIONS
  Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction-repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.
authors.affiliation: Department of Medicine,  UCL, London,  UK.
authors.forename: John
authors.initials: J
authors.lastname: Gomes
authors.forename: Malcolm
authors.initials: M
authors.lastname: Finlay
authors.forename: Akbar K
authors.initials: AK
authors.lastname: Ahmed
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Ciaccio
authors.forename: Angeliki
authors.initials: A
authors.lastname: Asimaki
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Quarta
authors.forename: Muriel
authors.initials: M
authors.lastname: Nobles
authors.forename: Petros
authors.initials: P
authors.lastname: Syrris
authors.forename: Sanjay
authors.initials: S
authors.lastname: Chaubey
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Andrew
authors.initials: A
authors.lastname: Tinker
authors.forename: Pier D
authors.initials: PD
authors.lastname: Lambiase
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D016022:Case-Control Studies; D051180:Desmoplakins / Q000172:deficiency / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D017353:Gene Deletion; D006329:Heart Conduction System / Q000502:physiology; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000502:physiology; D055815:Young Adult
chemical_list: D051180:Desmoplakins; D015222:Sodium Channels