Heart failure represents the results of a variety of cardiovascular diseases in which the initial insult to the myocardium may either be identifiable, such as a myocardial infarction, or unknown, such as in dilated cardiomyopathy. In either case, the occurrence of injury to the myocardium leads to an inexorable course of myocardial dysfunction. While most previous investigations have concentrated on the abnormalities in left ventricular function, there is evidence that right ventricular (RV) function is a more important determinant of patients symptoms and prognosis. Few therapies currently exist to improve RV performance, as currently used systemic vasodilator therapy can cause hypotension when nonselective pulmonary vasodilators are added to a patient's therapeutic regimen. Nitric oxide (NO) activates vascular smooth muscle cell soluble guanylate cyclase leading to vasodilation. The vasodilator effect of NO is limited in time by its rapid binding to, and inactivation by hemoglobin. In preliminary studies, inhaled NO has been demonstrated to be a selective pulmonary vasodilator which can improve cardiac performance and exercise capacity in heart failure patients. The goal of this proposal is to combine type 5 (cGMP- specific) phosphodiesterase inhibiton with inhaled NO to: 1. Assess the acute alterations in right ventricular function, overall cardiac performance and exercise capacity in heart failure patients treated with the combination of inhaled NO and the type 5 phosphodiesterase inhibitor sildenafil. 2. Assess the acute and chronic effects of selective pulmonary vasodilation with inhaled nitric oxide and type 5 phosphodiesterase inhibition on pulmonary artery resistance and morphology in patients with pulmonary hypertension due to pulmonary vascular disease or to left heart failure. 3. Assess the effects of acute and chronic pulmonary vasodilator and the subsequent decrease in wall stress on the activity of proteins which regulate myocyte apoptosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Special Emphasis Panel (ZHL1-CSR-F (F1))
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Commarato, Michael
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Massachusetts General Hospital
United States
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