Endothelial Function in Normal Volunteers

正常志愿者的内皮功能

• 批准号: 7003973
• 负责人: Henry Masur
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7003973
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; antiviral agents; atherosclerosis; blood chemistry; blood lipoprotein metabolism; cardiovascular disorder risk; combination chemotherapy; drug adverse effect; drug screening /evaluation; glucose metabolism; human subject; lipoprotein disorder; ritonavir; vascular endothelium

With the advent of the highly active antiretroviral (ARV) therapy era, patients with human immunodeficiency virus (HIV) have had significantly decreased mortality and morbidity. Concomitant with more patients chronically taking antiretroviral therapy, there has been an increase in atherogenic lipoprotein profiles (high cholesterol, high triglycerides, low HDL's), insulin resistance, fat redistribution and coronary artery disease. HIV viral replication, anti-retroviral treatment regimens, lipids, glucose intolerance, host immune response or a combination of factors may contribute to the increase in cardiovascular risk factors. HIV positive patients, independent of the effect on lipids, appear to have increased cardiovascular risk. Studies are not entirely consistent, but the most convincing study to date, the D.A.D. study from EURO-SIDA, shows a 27% relative increased rate of myocardial infarction per year of exposure over the first seven years of ART[1]. Lopinavir-ritonavir is one of the most commonly used antiretroviral therapy. It also produces lipid abnormalities. Thus, an important part of investigating factors contributing to atherosclerosis would be to determine if this drug can adversely influence endothelial cells in the absence of HIV infection or low CD4 counts. This would suggest that this drug directly or indirectly could predispose to atherosclerosis. Endothelial function is an important contributor to atherosclerosis. Invasive and non-invasive methods to evaluate endothelial cell function have been validated as predictors of coronary artery disease. These techniques have been used at NIH for clinical investigation for many years. This protocol is designed to determine whether there is a pathologic effect on endothelial function from the lopinavir/ritonavir. By measuring endothelial function in HIV non-infected subjects both before and after four weeks of therapy, we will be able to investigate whether the medications have a direct toxic effect on the endothelium. Collection of metabolic data will allow us to evaluate whether endothelial function occurs in conjunction or separate from lipoprotein and glucose metabolic changes. As ARV options increase, it may be possible to choose specific regimens that may minimize acceleration of cardiovascular risk factors associated with endothelial dysfunction, especially in patients with other cardiovascular risk factors. These findings may help elucidate the pathophysiology of premature cardiovascular disease in HIV positive patients and also plan interventions to minimize endothelial dysfunction and subsequent cardiovascular disease.

随着高效抗逆转录病毒（ARV）治疗时代的到来，人类免疫缺陷病毒（HIV）患者的死亡率和发病率显著降低。随着越来越多的患者长期接受抗逆转录病毒治疗，致动脉粥样硬化脂蛋白谱（高胆固醇、高甘油三酯、低HDL）、胰岛素抵抗、脂肪再分布和冠状动脉疾病也有所增加。HIV病毒复制、抗逆转录病毒治疗方案、脂质、葡萄糖耐受不良、宿主免疫反应或多种因素的组合可能导致心血管危险因素的增加。HIV阳性患者，独立于对血脂的影响，似乎有心血管风险增加。研究并不完全一致，但迄今为止最有说服力的研究，来自EURO-SIDA的D.A.D.研究显示，在ART的前七年中，每年暴露的心肌梗死率相对增加27%[1]。 洛匹那韦-利托那韦是最常用的抗逆转录病毒疗法之一。它还产生脂质异常。因此，研究导致动脉粥样硬化的因素的一个重要部分是确定这种药物是否会在没有HIV感染或低CD4计数的情况下对内皮细胞产生不利影响。这表明，这种药物直接或间接地可能导致动脉粥样硬化。内皮功能是动脉粥样硬化的重要因素。评估内皮细胞功能的有创和无创方法已被验证为冠状动脉疾病的预测因子。这些技术已在NIH用于临床研究多年。 本方案旨在确定洛匹那韦/利托那韦是否对内皮功能有病理影响。通过测量治疗前后4周的HIV非感染受试者的内皮功能，我们将能够研究药物是否对内皮有直接的毒性作用。代谢数据的收集将使我们能够评估内皮功能是否与脂蛋白和葡萄糖代谢变化联合或分开发生。随着抗逆转录病毒药物选择的增加，有可能选择特定的治疗方案，以最大限度地减少与内皮功能障碍相关的心血管危险因素的加速，特别是在有其他心血管危险因素的患者中。这些发现可能有助于阐明HIV阳性患者早发心血管疾病的病理生理学，并计划干预措施，以尽量减少内皮功能障碍和随后的心血管疾病。