The Role of Endothelias Dysfunction in HIV-Associated Pulmonary Hypertension

描述(申请人提供)：肺动脉高压(PAH)是一种破坏性的疾病，在年轻人到中年人中具有很高的短期死亡率和显著的发病率。艾滋病毒感染者中多环芳烃的流行率是普通人群的几千倍。尽管多环芳烃和艾滋病毒之间的联系已经被很好地描述，但潜在的病理生理学还没有很好地建立起来。以前的研究表明，HIV蛋白可能间接激活血管内皮细胞，并已描述内皮素-1和其他炎症标志物水平的增加。众所周知，艾滋病毒感染者的内皮功能障碍的比率增加，通过血流介导的肱动脉扩张(FMD)来衡量，并且抗逆转录病毒治疗导致内皮功能的显著改善。因此，我们建议的总体假设是，内皮功能障碍与HIV感染者的PAH的发生有关。这一假设将通过以下具体目标来检验：目标1将确定艾滋病毒感染患者的PAH和内皮功能之间的关系。内皮功能障碍将通过臂动脉的FMD进行外周测量，并通过内皮素-1、血栓素A2代谢物和前列环素水平进行系统测量，并将在没有PAH的HIV感染者、有临床前PAH的HIV感染者和临床PAH患者中进行比较。目的2将通过比较HIV感染的PAH患者的臂动脉FMD和硝酸甘油给药反应来确定内皮依赖性和非内皮依赖性外周血管反应性的作用。目的3将评估吸入性伊洛前列素对右心导管术中患有PAH的HIV感染患者的急性血管扩张剂挑战的临床反应。这项研究设计将涉及一项横断面研究，研究对象是已经在徐博士的HIV相关PAH患者队列中登记的HIV感染患者。公共卫生相关性：艾滋病毒患者患上肺动脉高压的风险更高，肺部血管内的压力异常高，并导致呼吸急促等症状。我们的目的是研究这种情况与血管功能异常之间的可能关系。

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.