? ? 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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL082895-01
Application #
7018870
Study Section
Clinical Trials Review Committee (CLTR)
Program Officer
Denholm, Elizabeth M
Project Start
2006-03-01
Project End
2011-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
1
Fiscal Year
2006
Total Cost
$432,391
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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
Al-Naamani, Nadine; Palevsky, Harold I; Lederer, David J et al. (2016) Prognostic Significance of Biomarkers in Pulmonary Arterial Hypertension. Ann Am Thorac Soc 13:25-30
Matura, Lea Ann; Ventetuolo, Corey E; Palevsky, Harold I et al. (2015) Interleukin-6 and tumor necrosis factor-? are associated with quality of life-related symptoms in pulmonary arterial hypertension. Ann Am Thorac Soc 12:370-5
Kawut, Steven M; Bagiella, Emilia; Lederer, David J et al. (2011) Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 123:2985-93
Kawut, Steven M; Bagiella, Emilia; Shimbo, Daichi et al. (2011) Rationale and design of a phase II clinical trial of aspirin and simvastatin for the treatment of pulmonary arterial hypertension: ASA-STAT. Contemp Clin Trials 32:280-7
Sims, Michael W; Margolis, David J; Localio, A Russell et al. (2009) Impact of pulmonary artery pressure on exercise function in severe COPD. Chest 136:412-419
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
Lederer, David J; Horn, Evelyn M; Rosenzweig, Erika B et al. (2008) Plasma serotonin levels are normal in pulmonary arterial hypertension. Pulm Pharmacol Ther 21:112-4
Lederer, David J; Benn, Emma K T; Barr, R Graham et al. (2008) Racial differences in waiting list outcomes in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 177:450-4
Snow, Jennifer L; Kawut, Steven M (2007) Surrogate end points in pulmonary arterial hypertension: assessing the response to therapy. Clin Chest Med 28:75-89, viii

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