Abstract 2298: Statin therapy, alone or in combination with Rapamycin, does not reverse Monocotaline Pulmonary Arterial Hypertension
Background: Pulmonary arterial hypertension (PAH) is characterized by excessive smooth muscle cell (PASMC) proliferation and impaired apoptosis leading to obstruction of resistance pulmonary arteries. We hypothesized that antiproliferative (rapamycin), pro-apoptotic (statins) agents, already used clinically for other indications, would decrease experimental PAH, facilitating translation to human therapies. Prior studies in the rat monocrotaline-PAH model indicate that simvastatin regresses and rapamycin prevents, but cannot reverse, PAH. Two PAH regression strategies (rapamycin monotherapy versus rapamycin+atorvastatin) and one prevention strategy (simvastatin) were tested in a rat monocrotaline-PAH model.
Methods: Adult male Sprague-Dawley rats were randomized to saline (n=6) or monocrotaline (60mg/kg IP, n=36). Monocrotaline rats were randomized to gavage with vehicle, rapamycin (2.5 mg/kg/day), or rapamycin+atorvastatin (10 mg/kg/day), beginning 12 days post-monocrotaline. Echocardiographic and hemodynamic endpoints were assessed 2 weeks later. Additional monocrotaline-PAH rats (n=20) were randomized to vehicle or simvastatin (2 mg/kg/day) and followed echocardiographically for 4 weeks.
Results: Monocrotaline-PAH increased lung p70 S6 kinase phosphorylation and this was reversed by rapamycin, confirming its biological activity. Despite using high doses, neither rapamcyin nor rapamycin+atorvastatin improved survival nor reduced PAH, vascular remodeling, and right ventricular hypertrophy. Although, prophylactic simvastatin slowed PAH progression, by 4 weeks PAH severity and mortality were not different from placebo.
Conclusion: Apart from the new finding of p70 S6 kinase phosphorylation in monocrotaline-PAH, this is a negative therapeutic trial (none of these promising therapies improved monocrotaline-PAH). These negative results should be considered as human trials with these agents are underway (simvastatin) or proposed (rapamycin).