Abstract 3864: Arrhythmogenic Cardiomyopathy and Sudden Death in Mice Over-expressing Mutant Desmoglein-2
Objectives - Mutations in desmoglein-2 (DSG2), a major component of cardiac desmosomes, have recently been associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). The aim of this study was to generate a mouse model of DSG2-related ARVC and investigate the pathophysiological mechanisms involved in the disorder.
Methods & Results- We have previously identified the DSG2 N266S mutation, located in the second calcium-binding extracellular cadherin domain of the protein, in a family with ARVC. This mutation was engineered in mouse dsg2 cDNA and subsequently wild-type (WT) and mutant cDNA was cloned downstream of the murine alpha-Myosin Heavy Chain (α-MHC) promoter for cardiac-specific expression. Transgenic mouse lines were generated expressing, respectively, comparable levels of WT dsg2 (Tg-WT) or N266S dsg2 (Tg-NS). Tg-NS mice displayed a high incidence (30%) of sudden death at young age (12–20 weeks). ECG analysis on 10 week-old Tg-NS mice demonstrated prolonged QRS-duration and spontaneous ventricular arrhythmias compared to WT or Tg-WT mice (mean QRS 15±1.0 ms vs 10±0.9 ms; n=12 each; p<0.0001). Echocardiographic investigation (M-mode, B-mode, Doppler) showed decreased left ventricular (LV) fractional shortening (LV%FS 13.5± 7.7 vs 34.8± 4.9; n=5; p=0.002) and increased LV end-systolic and end-diastolic dimensions in Tg-NS mice compared to WT and Tg-WT mice. Epicardial mapping on isolated Langendorff-perfused hearts revealed conduction slowing and increased arrhythmia inducibility in both ventricles of Tg-NS mice (arrhythmia inducibility: 8/10 in Tg-NS vs 1/10 in WT or Tg-WT; p<0.002). Myocyte necrosis was an early histopathologic feature in Tg-NS hearts, starting at about 2–3 weeks of age. This was accompanied by inflammatory infiltration and calcification, followed by fibrosis with biventricular aneurysms at about 4–5 weeks.
Conclusions- Transgenic mice carrying the dsg2 mutation N266S revealed spontaneous ventricular arrhythmias and sudden death associated with impaired contractile function, necrosis, inflammation, calcification and increased collagen deposition.