HIV infection has been associated with an increased prevalence of pulmonary hypertension. In addition, recent data suggests that a state of endothelial dysfunction develops in HIV disease secondary to anti-retroviral therapy and associated dyslipidemia or secondary to direct viral infection of the endothelium. This leads to premature atherosclerosis and possibly contributes to avascular necrosis of the hip. Similar effects on the pulmonary vasculature may be involved in the development of pulmonary vasculopathy.? ? In this study we plan to invasively characterize the status of pulmonary and systemic endothelial function and determine the mechanisms of pulmonary vascular endothelial dysfunction in HIV disease. To this end we will catheterize healthy volunteers and volunteers with HIV infection with and without pulmonary hypertension and directly measure acetylcholine-dependent blood flow in the pulmonary and brachial artery to assess pulmonary and systemic endothelium-dependent blood flow. Simultaneous measurement of exhaled NO and pulmonary capillary artery NO2- will allow for complete characterization of the contribution of NO production to endothelium-dependent vasomotor control. We will also use recently developed MRI techniques to measure pulmonary artery blood flow during infusion of acetylcholine (ACH), sodium nitroprusside (SNP) and NG monomethyl-L-arginine (L-NMMA) to establish responsiveness to an endothelium dependent vasodilator, endothelium-independent vasodilator and an NO inhibitor, respectively. Volunteers with pulmonary hypertension will have the option to undergo open label phase I/II treatment with sildenafil for 16 weeks and return for a repeat assessment of pulmonary hemodynamics as well as pulmonary and systemic endothelial function.? ? Endothelial cells will be isolated using novel flow-cytometry methodologies developed over the last two years at the NIH intramural division utilizing combinations of positive and negative selection based on specific surface markers for activated T cells and endothelial cells and markers of cell viability. Endothelial cells will subsequently be interrogated using amplified real time PCR methodologies and affymetrix based gene expression profiling developed in our laboratories. The levels of expression in endothelial cells of HIV virus, HHV8, eNOS, caveolin, HO-1, endothelin receptors A and B, and endothelin 1, in addition to other proteins regulating vascular homeostasis and cellular host defense (i.e. epidermal growth factor, transforming growth factor beta, platelet derived growth factor and interleukin-6), will be assessed.? ? These studies will provide insights into the mechanisms of pulmonary artery endothelial dysfunction and suggest rationally designed therapies targeting viral load, HHV8, and/or the NO/endothelin pathways. These studies have the promise of opening the door to the study of pulmonary artery endothelial dysfunction at the physiological, cellular and molecular level.? ? 1040 HIV positivie individuals will be screened to obtain 40 individuals with HIV infection with pulmnary arterial hypertension, 40 indvidiuals with HIV infection without pulmonary arterial hypersension. We will also include 20 healthy volunteers. This study began enrollment in July 2006 and we current have 13 controls enrolled.
