Abstract 1239: Preload-Reducing Therapy Prevents Development of Arrhythmogenic Right Ventricular Cardiomyopathy Without Affecting Conduction Slowing in Trained Plakoglobin-Deficient Mice
Introduction: Heterozygous plakoglobin deficiency (Pg+/−) in mice causes right ventricular enlargement, right ventricular dysfunction, and ventricular tachycardias (VTs) of right ventricular origin, compatible with human arrhythmogenic right ventricular cardiomyopathy (ARVC). Lack of right ventricular histological changes and accelerated development of the phenotype by endurance training suggest a functional desmosome associated defect in this model. We tested whether preload-reducing therapy prevents ARVC in Pg+/− mice.
Methods and results: Fourteen littermate pairs of 3-months-old Pg+/− mice and 5 pairs of matched wildtype (WT) mice underwent 7 weeks of endurance training by swimming (increasing from 10 to 90 min/day). Half of the mice received preload-reducing therapy (furosemide, nitrates, and molsidomine). All functional measurements were performed by investigators blinded to genotype and therapy. Right ventricular size was increased in untreated Pg+/− mice after training, but not in treated Pg+/− mice (echocardiographic RV area untreated 58±6 vs. treated Pg+/− 37±3 mm2; p < 0.001; WT 35±3 mm2; mean±SD; 15–50 Mhz transducers). Preload-reduction lowered the inducibility of VT (> 1 s duration) by a single right ventricular extra stimulus in isolated, Langendorff-perfused hearts (1/6 treated vs. 10/14 untreated Pg+/− mice; p < 0.05). High density epicardial mapping showed activation patterns consistent with re-entrant VT in Pg+/− mice. Right and left ventricular effective refractory periods (ERP) were not different between groups. Right ventricular longitudinal and transversal conduction velocities (Vl and Vt) were reduced in Pg+/− mice following premature stimulation (ERP + 10ms; WT Vl 62±10, Vt 37±7 vs. Pg+/− Vl 51±8, Vt 30±7 cm/sec; mean±SD; p=0.015/0.058), but were not affected by preload-reducing therapy.
Conclusions: Heterozygous plakoglobin deficiency leads to right ventricular enlargement in response to increased preload and directly affects myocardial conduction velocity. Preload-reducing therapy prevents right ventricular enlargement and lowers the inducibility of re-entrant VT in trained Pg+/− mice without affecting conduction slowing.