The Role of Endothelias Dysfunction in HIV-Associated Pulmonary Hypertension

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DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a devastating condition with a high short-term mortality rate and significant morbidity in young to middle-aged individuals. The prevalence of PAH in HIV-infected individuals is several thousand times that of the general population. Although the association between PAH and HIV is well-described, the underlying pathophysiology is not well established. Previous studies have suggested that HIV proteins may indirectly activate endothelium, and increased levels of endothelin-1 and other inflammatory markers have been described. It is also known that HIV-infected individuals have increased rates of endothelial dysfunction as measured by flow-mediated dilation (FMD) of the brachial artery, and that treatment with antiretroviral therapy leads to dramatic improvement in endothelial function. Therefore the overall hypothesis of our proposal is that endothelial dysfunction is associated with the development of PAH in HIV-infected individuals. This hypothesis will be tested by the following Specific Aims: Aim 1 will determine the relationship between PAH and endothelial function in HIV-infected patients. Endothelial dysfunction will be measured peripherally by FMD of the brachial artery, and systemically via endothelin-1, thromboxane A2 metabolite, and prostacyclin levels, and will be compared in HIV-infected individuals without PAH, with preclinical PAH, and clinical PAH. Aim 2 will determine the role of endothelial-dependent versus endothelial-independent peripheral vasoreactivity by comparing brachial artery FMD with nitroglycerin administration response in HIV-infected patients with PAH, respectively. Aim 3 will assess the clinical response to an acute vasodilator challenge with inhaled iloprost in HIV-infected patients with PAH during right heart catheterization. The study design will involve a cross-sectional study of HIV-infected patients already enrolled in Dr. Hsue's cohort of patients with HIV-associated PAH. Public Health Relevance: Patients with HIV have a higher risk of developing pulmonary hypertension, where pressures inside the blood vessels of the lungs are abnormally high and lead to symptoms such as shortness of breath. We aim to study the possible relationship between this condition and abnormal blood vessel function.