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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL004021-05
Application #
6638095
Study Section
Special Emphasis Panel (ZHL1-CSR-F (F1))
Program Officer
Commarato, Michael
Project Start
1999-04-12
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2006-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$113,411
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Malhotra, Rajeev; Hess, Dean; Lewis, Gregory D et al. (2011) Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension. Pulm Circ 1:250-258
Semigran, Marc (2009) Myocardial effects of PDE5 inhibition: more function with less mass. J Am Coll Cardiol 53:216-7
Lewis, Gregory D; Shah, Ravi V; Pappagianopolas, Paul P et al. (2008) Determinants of ventilatory efficiency in heart failure: the role of right ventricular performance and pulmonary vascular tone. Circ Heart Fail 1:227-33
Lewis, Gregory D; Lachmann, Justine; Camuso, Janice et al. (2007) Sildenafil improves exercise hemodynamics and oxygen uptake in patients with systolic heart failure. Circulation 115:59-66
Lewis, Gregory D; Shah, Ravi; Shahzad, Khurram et al. (2007) Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension. Circulation 116:1555-62
Ferencik, Maros; Gregory, Shawn A; Butler, Javed et al. (2007) Analysis of cardiac dimensions, mass and function in heart transplant recipients using 64-slice multi-detector computed tomography. J Heart Lung Transplant 26:478-84
Gregory, Shawn A; Ferencik, Maros; Achenbach, Stephan et al. (2006) Comparison of sixty-four-slice multidetector computed tomographic coronary angiography to coronary angiography with intravascular ultrasound for the detection of transplant vasculopathy. Am J Cardiol 98:877-84
Lewis, Gregory D; Witzke, Christian; Colon-Hernandez, Pedro et al. (2006) Sildenafil improves coronary artery patency in a canine model of platelet-mediated cyclic coronary occlusion after thrombolysis. J Am Coll Cardiol 47:1471-7
Lepore, John J; Maroo, Anjli; Bigatello, Luca M et al. (2005) Hemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension: combined administration with inhaled nitric oxide. Chest 127:1647-53
Inglessis, Ignacio; Shin, Jordan T; Lepore, John J et al. (2004) Hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock. J Am Coll Cardiol 44:793-8

Showing the most recent 10 out of 14 publications