Abstract 19020: Angiotensin Converting Enzyme-2 Activation Attenuates Right Ventricular Hypertrophy and Dysfunction After Pulmonary Artery Banding in Rats

Abstract

Background: Right ventricular (RV) hypertrophy and dysfunction are important prognostic factors in pulmonary hypertension. Pharmacological therapies aimed at improving RV function reduce symptoms, enhance cardiac hemodynamics, and potentially increase survival in pulmonary hypertensive subjects. We hypothesized that activation of angiotensin-converting enzyme 2 (ACE2) using Diminazene (DIZE) will improve RV function in a chronic pressure overload model of pulmonary artery banding (PAB). METHODS: Chronic pressure-overload RV hypertrophy and dysfunction was induced by PAB in adult male rats (9 weeks of age). A subset of rats was treated with DIZE (15mg/kg/day, subcutaneous injection) following PAB. After 5 weeks of banding, right ventricular hemodynamics and cardiac functions were evaluated. RESULTS: Five-weeks of PAB resulted in significant increase in right ventricular systolic pressure, which was not affected by DIZE treatment (Control: 31± 1mmHg; PAB: 49± 3mmHg; PAB+DIZE: 44± 2mmHg). However, DIZE injection significantly improved RV function. Specifically, DIZE decreased right ventricular end diastolic pressure (RVEDP; Control: 3.55± 0.71mmHg; PAB: 10± 0.92mmHg PAB+DIZE: 7.51± 0.83mmHg), reduced +dP/dt (Control: 2466± 62mmHg/s; PAB: 3055± 172mmHg/s; PAB+DIZE: 2670± 193mmHg/s) and -dP/dt (Control: -1735± 54mmHg/s; PAB:-2628± 166mmHg/s; PAB+DIZE: -2281± 144mmHg/s). In addition, DIZE decreased RV hypertrophy as measured by RV/LV+S ratio (Control: 0.24± 0.01; PAB: 0.42± 0.02; PAB+DIZE: 0.37± 0.010). CONCLUSIONS: Treatment with DIZE, an ACE2 activator led to significant improvements in RV function and decreased hypertrophy in a chronic pressure-overload rat model. Thus, DIZE may represent a novel treatment for RV dysfunction and failure.