Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency


  • M. Cerrone
  • M. Noorman
  • X. Lin
  • H. Chkourko
  • F.X. Liang
  • R. van der Nagel
  • T. Hund
  • W. Birchmeier
  • P. Mohler
  • T.A. van Veen
  • H.V. van Rijen
  • M. Delmar


  • Cardiovascular Research


  • Cardiovasc Res 95 (4): 460-468


  • AIMS: 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 Cardiomyopathy. 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.Methods and ResultsHearts of PKP2-Hz mice were characterized by multiple methods. We observed ultrastructural, but not histological or gross anatomical differences in PKP2-Hz hearts, compared to wild-type 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 anesthetized 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 wild-type. 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.