Endothelial dysfunction and platelet aggregation cause pulmonary artery vasoconstriction, mitogenesis, thrombosis, and vascular obliteration in pulmonary arterial hypertension (PAH) The recognition of abnormal eicosanoid metabolism and increased endothelin-1 (ET-1) production were major advances in understanding the pathophysiology of PAH. Parenteral prostacyclin analogs and ET-1 receptor antagonists are now the standard of care for PAH. While these therapies intervene on downstream effects of endothelial dysfunction, none adequately addresses the proximal endothelial insult or the platelet response. HMG-CoA reductase inhibitors (statins) and aspirin are very safe, highly-effective cardiovascular therapies used by millions of people. Simvastatin decreases cholesterol, stabilizes the endothelial cell layer, increases the bioavailability of nitric oxide, reduces oxidative stress, and decreases inflammation. Aspirin arrests platelet thromboxane A2 production, inhibiting platelet aggregation. We have studied simvastatin and aspirin in animal models and humans with PAH with encouraging results. Increasing nitric oxide and reducing platelet aggregation will likely decrease pulmonary vascular resistance and increase cardiac output, therefore improving outcomes in PAH. We have designed a Phase II trial to initiate the study of these two potentially useful therapies with maximum efficiency and minimum expense. We propose a randomized, placebo-controlled 2 X 2 factorial trial of simvastatin and aspirin enrolling 128 patients to answer these Specific Aims: 1) To determine whether simvastatin affects exercise function at six months in patients with PAH. 2) To determine whether aspirin affects exercise function at six months in patients with PAH. We hypothesize that simvastatin and aspirin will increase the distance walked in six minutes in patients with PAH. 3) To determine whether simvastatin affects endothelial dysfunction and injury at six months in patients with PAH. We hypothesize that simvastatin will increase brachial artery flow-mediated dilatation and lower von Willebrand factor compared to placebo. 4) To determine whether aspirin affects platelet function in patients with PAH. We hypothesize that aspirin will decrease soluble P-selectin, serum thromboxane B2, and /Mhromboglobulin in patients with PAH compared to placebo over six months. PAH strikes young individuals, drastically shortening their lifespan.
We aim to investigate safe but innovative therapies which could remodel the pulmonary vasculature and improve outcomes in this currently incurable disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical Trials Review Committee (CLTR)
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Moore, Timothy M
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Kawut, Steven M; Archer-Chicko, Christine L; DeMichele, Angela et al. (2017) Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial. Am J Respir Crit Care Med 195:360-368
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Jelic, Sanja; Padeletti, Margherita; Kawut, Steven M et al. (2008) Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation 117:2270-8
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