Abstract 2294: Preload-Reducing Therapy Prevents Right Ventricular Enlargement, Dysfunction, Conduction Slowing and Arrhythmogenesis in Heterozygous Plakoglobin-Deficient Mice
Introduction: No therapy is currently available to prevent the progression of arrhythmogenic right ventricular cardiomyopathy (ARVC). Decreased tolerance of mechanical stress by desmosomal dysfunction is thought to be pivotal in ARVC. We hypothesized that reduction of mechanical intercellular stress by preload-reducing therapy prevents progression of the ARVC-phenotype and tested this in heterozygous plakoglobin-deficient (plako+/−) mice.
Methods and results: Littermate pairs of 3-months-old plako+/− and wild-type mice underwent 7 weeks of endurance training (increasing to 90 min/day). Mice were randomized to receive preload-reducing therapy (furosemide, nitrates, and molsidomine). Right ventricular (RV) volume was increased after training in untreated, but not in treated plako+/− mice (untreated plako+/− 136±5; treated plako+/− 78±5 μl; p<0.01; wild-type 81±5 μl; mean±SEM). Inducibility of ventricular tachycardias (VT) in isolated, Langendorff-perfused hearts was higher in untreated plako+/− (15/25) compared to treated plako+/− hearts (5/19); p<0.05). The latter was similar to wild-type hearts (6/21). Epicardial mapping of the right ventricle (RV) showed activation patterns consistent with re-entrant VT in untreated plako+/− mice. RV longitudinal conduction velocity was reduced in untreated but not in treated plako+/− mice (untreated plako+/− 44±6 cm/s; treated plako+/− 53±8 cm/s; p<0.01; wild-type 53±5 cm/s; mean±SD). Localization of desmosomal proteins and connexin43 was not different between study groups. Expression of phosphorylated connexin43 in untreated, but not treated plako+/− mice was markedly reduced compared to wild-type mice (p<0.05).
Conclusions: Preload-reduction completely prevents training-induced development of the ARVC-phenotype in plako+/− mice and may provide a simple therapy for ARVC patients.