Abstract 11990: Ranolazine Reduces Monocrotaline-induced Pulmonary Hypertension when Administered Following Disease Induction
Right ventricular (RV) failure is the major cause of death in patients with pulmonary hypertension (PH), whereas sudden death due to arrhythmia appears to account for 17-28% of the deaths. Ranolazine (RAN), an FDA-approved anti-anginal drug with antiarrhythmic properties, has previously been shown to prevent monocrotaline (MCT)-induced PH in rats, but not when given 2 weeks after MCT. In the present study we determined if RAN is beneficial when given 1 week following MCT, and we used continuous ECG recording to detect potential arrhythmias responsible for sudden cardiac death. Rats were injected with MCT (60 mg/kg, s.c.) and randomized 1 week later to receive: vehicle (rodent chow, n=8), 0.25% RAN (low dose, n=8), or 0.5% RAN (high dose, n=8), as diet admix which yielded plasma levels of 1-2 μM and 4- 7μM, respectively. A sham group (n=5) received a saline injection (s.c.) and was fed standard chow. Pulmonary hemodynamics, RV function and hypertrophy were assessed on day 28. Pulmonary systolic pressure (66±6 vs. 23±1 mmHg) and RV hypertrophy [RV/tibia (mg/mm): 10±0.8 vs. 6±0.1] were increased by MCT compared to sham, and were dose-dependently reduced by RAN (low dose: 58±7 mmHg and 8±0.6; high dose: 37±3 mmHg and 6±0.4). Compared to vehicle, high dose RAN attenuated the decrease in RV ejection fraction (-17 ± 7% vs. -46±8%) and reduced RV expression of collagen and profibrotic mediators. In a separate experiment, rats were maintained on vehicle diet (n=10) or RAN 0.5% (n=6) to evaluate effects on survival following MCT. 70% of vehicle-treated and 100% of RAN-treated survived to endpoint (day 28). Telemetry devices were implanted in a subset of MCT animals (n=5) to continuously record changes on ECG, RV pressure, and systemic pressure. It is worth noting that an occurrence of spontaneous ventricular fibrillation (VF) that resulted in sudden death was recorded in a conscious rat on day 33 following MCT. In summary,RAN reduces MCT-induced PH and RV dysfunction when treatment is initiated 1 week after disease induction. In addition, this is the first in vivo report of sudden death due to spontaneous VF in this experimental PH model. The possibility that the beneficial effects of RAN extend to reducing arrhythmogenesis and sudden cardiac death are currently being investigated.
- © 2012 by American Heart Association, Inc.