Abstract 258: Pulmonary Overexpression of SERCA2A Improves Electrical Dysfunction and Suppresses Arrhythmias in Monocrotaline-induced Right Ventricular Failure

Abstract

Background: Pulmonary Arterial Hypertension (PAH) is a major cause of mortality due, in large part to right ventricular (RV) failure. Its electrophysiological (EP) effects however are poorly defined. Recently, a gene therapy approach targeting SERCA2a (S2A) to the lungs improved RV mechanical function in a rodent PAH model. Whether this approach improves myocardial EP properties remains unknown. Methods: Male Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT 60mg/kg) leading to PAH induced RV failure. Three wks later, rats underwent intratracheal delivery of aerosolized AAV1.S2A (1E11 gc, N=6) or no treatment (MCT, N=7). Age matched rats served as controls (CTRL, N=5). The EP substrate and risk of VT were assessed using high resolution optical action potential (AP) mapping in ex vivo perfused hearts. Results: MCT (6/7) but not CTRL (0/5) hearts were prone to pacing-induced VT (P<0.01). S2A gene therapy markedly suppressed the incidence of VT to <15% (P<.05 vs MCT). Investigation of the EP substrate revealed complete reversal of slow myocardial conduction in S2A treated compared to untreated MCT rats (Fig A, B) . AP duration (APD) and heterogeneity were increased in MCT and partially reversed by AAV1.S2A. Underlying the rise in heterogeneity was selective APD prolongation on the RV side causing >90 degree clockwise shift in the orientation of the transepicardial gradient, an effect which was not reversed by AAV1.S2A (Fig C arrows) . Conclusion: S2A gene therapy to the lungs ameliorates PAH induced EP remodeling and arrhythmia propensity. Our findings highlight for the first time the utility of a non-cardiac gene therapy approach for arrhythmia suppression.