Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study

Pulmonary arterial hypertension ( PAH) is characterized by excessive pulmonary artery smooth muscle cell proliferation and impaired apoptosis leading to obstruction of resistance pulmonary arteries. We hypothesized that antiproliferative ( rapamycin) and proapoptotic ( 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 have indicated that simvastatin regresses and rapamycin prevents, but cannot reverse, PAH. Two PAH regression strategies ( rapamycin monotherapy vs. rapamycin + atorvastatin) and one prevention strategy ( simvastatin) were tested in a rat monocrotaline-PAH model. Adult male Sprague-Dawley rats were randomized to saline ( n = 6) or monocrotaline ( 60 mg/kg ip, n = 36) treatment groups. Monocrotaline rats were randomized to gavage with vehicle, rapamycin ( 2.5 mg.kg(-1).day(-1)), or rapamycin + atorvastatin (10 mg.kg(-1).day(-1)) treatment groups, beginning 12 days postmonocrotaline. Echocardiographic and hemodynamic end points were assessed 2 wk later. Additional monocrotaline-PAH rats ( n = 20) were randomized to vehicle or simvastatin (2 mg.kg(-1).day(-1)) treatment groups and followed echocardiographically for 4 wk. Monocrotaline-PAH increased lung p70 S6 kinase phosphorylation, and this was reversed by rapamycin, confirming the biological activity of rapamycin. Despite the use of 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 wk PAH severity and mortality were not different from placebo. 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).