title: Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency.
abstract: OBJECTIVE
  The shRNA-mediated loss of expression of the desmosomal protein plakophilin-2 leads to sodium current (I(Na)) dysfunction. Whether pkp2 gene haploinsufficiency leads to I(Na) deficit in vivo remains undefined. Mutations in pkp2 are detected in arrhythmogenic right ventricular cardiomyopathy (ARVC). Ventricular fibrillation and sudden death often occur in the 'concealed phase' of the disease, prior to overt structural damage. The mechanisms responsible for these arrhythmias remain poorly understood. We sought to characterize the morphology, histology, and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts and explore the relation between PKP2 abundance, I(Na) function, and cardiac electrical synchrony.
  
  
  RESULTS
  Hearts of PKP2-Hz mice were characterized by multiple methods. We observed ultrastructural but not histological or gross anatomical differences in PKP2-Hz hearts compared with wild-type (WT) littermates. Yet, in myocytes, decreased amplitude and a shift in gating and kinetics of I(Na) were observed. To further unmask I(Na) deficiency, we exposed myocytes, Langendorff-perfused hearts, and anaesthetized animals to a pharmacological challenge (flecainide). In PKP2-Hz hearts, the extent of flecainide-induced I(Na) block, impaired ventricular conduction, and altered electrocardiographic parameters were larger than controls. Flecainide provoked ventricular arrhythmias and death in PKP2-Hz animals, but not in the WT.
  
  
  CONCLUSIONS
  PKP2 haploinsufficiency leads to I(Na) deficit in murine hearts. Our data support the notion of a cross-talk between desmosome and sodium channel complex. They also suggest that I(Na) dysfunction may contribute to generation and/or maintenance of arrhythmias in PKP2-deficient hearts. Whether pharmacological challenges could help unveil arrhythmia risk in patients with mutations or variants in PKP2 remains undefined.
authors: Division of Cardiology,  New York University School of Medicine, New York, NY,  USA.
authors: Marina
authors: M
authors: Cerrone
authors: Maartje
authors: M
authors: Noorman
authors: Xianming
authors: X
authors: Lin
authors: Halina
authors: H
authors: Chkourko
authors: Feng-Xia
authors: FX
authors: Liang
authors: Roel
authors: R
authors: van der Nagel
authors: Thomas
authors: T
authors: Hund
authors: Walter
authors: W
authors: Birchmeier
authors: Peter
authors: P
authors: Mohler
authors: Toon A
authors: TA
authors: van Veen
authors: Harold V
authors: HV
authors: van Rijen
authors: Mario
authors: M
authors: Delmar
mesh_terms: D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004562:Electrocardiography; D005424:Flecainide / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency; D015640:Ion Channel Gating; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D010477:Perfusion; D010641:Phenotype; D051191:Plakophilins / Q000172:deficiency* / Q000235:genetics; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; C495338:Pkp2 protein, mouse; D051191:Plakophilins; D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D012964:Sodium; D005424:Flecainide