Cardiovascular autonomic function in HIV virologic failure

描述（由申请人提供）：本提案描述了一项为期4年的培训计划，旨在将Dominic Chow博士培养为与人类免疫缺陷病毒1型（HIV-1）相关的心血管自主神经研究领域的独立研究者。他的长期目标是研究HIV疾病中心血管疾病（CVD）的发病机制。周博士是夏威夷大学专门研究艾滋病毒医学的内科医生和儿科医生。来自NIAID，NIH资助的抗逆转录病毒治疗管理策略（SMART）试验的结果，该试验在一项有5，472名参与者的多中心试验中评估了抗逆转录病毒结构化治疗中断（STI）策略的安全性和有效性，在中断抗逆转录病毒治疗（ART）的患者中，与那些继续使用ART的人相比，（月内）与STI相关的CVD风险增加的一个重要原因是，停止ART诱导的病毒血症导致心血管自主神经功能障碍增加，自主神经功能紊乱一般人群中的心血管自主神经功能障碍与心律失常、心肌病和急性心肌梗死的增加有关。因此，候选人的假设是病毒血症的存在导致心血管自主神经功能障碍增加。一项涉及3组患者的前瞻性研究，因为他们经历了他们的ART的变化，提出了测试这一假设的关键组成部分。具体目的是：1）通过间接测试[心迷走神经、肾上腺素能和定量催汗轴突反射（QSART）测试]评估自主神经功能并将其与经历ART变化的3组受试者中血浆HIV RNA的存在或不存在相关联，2）评估和比较自主神经在存在或不存在血浆HIV RNA的情况下，通过直接测试[肌肉交感神经活动（MSNA）]来确定（交感）功能，3）以确定血浆儿茶酚胺是否与（多巴胺，去甲肾上腺素和肾上腺素）和炎症标志物[C-反应蛋白和肿瘤坏死因子]随着交感神经活动和血浆HIV RNA的存在或不存在而升高，以及4）确定交感神经活性与流量介导的肱动脉扩张之间的关系（内皮功能和早期动脉粥样硬化发展的标志物）与血浆HIV RNA的存在或不存在呈负相关。这里提出的职业发展计划包括指导和以患者为导向的研究经验，将提供全面的临床研究的基础。这项工作的意义将是了解自主神经系统和HIV疾病中CVD发展之间的相互关系。 (End摘要）

DESCRIPTION (provided by applicant): This proposal describes a 4-year training program designed to develop Dr. Dominic Chow as an independent investigator in the field of cardiovascular autonomic research related to human immunodeficiency virus type 1 (HIV-1). His long term goal is to study the pathogenesis of cardiovascular disease (CVD) in HIV disease. Dr. Chow is an internist and pediatrician specializing in HIV medicine at the University of Hawaii. Findings from the Strategies for Management of Anti-Retroviral Therapy (SMART) trial funded by the NIAID, NIH which assessed the safety and efficacy of antiretroviral structured treatment interruption (STI) strategies in a multi-center trial of 5,472 participants, showed increased morbidity and mortality from CVD in those who interrupted antiretroviral therapy (ART) compared to those who continued to utilize ART. One hypothesis to explain this relatively prompt (within months) increase in CVD risk associated with STI is that viremia induced by discontinuation of ART leads to an increase in cardiovascular autonomic dysfunction in a population already vulnerable to autonomic dysfunction. Cardiovascular autonomic dysfunction in the general population has been associated with increased arrhythmia, cardiomyopathy and acute myocardial infarction. Thus, the candidate's hypothesis is that the presence of viremia leads to increased cardiovascular autonomic dysfunction. A prospective study involving 3 groups of patients as they undergo alterations in their ART is proposed to test the critical components of this hypothesis. The specific aims are 1) to assess and correlate autonomic function by indirect testing [cardiovagal, adrenergic, and quantitative sudomotor axon reflex (QSART) tests] to the presence or absence of plasma HIV RNA in the 3 groups of subjects undergoing changes in ART, 2) to assess and compare autonomic (sympathetic) function by direct testing [muscle sympathetic nerve activity (MSNA)] in the presence or absence of plasma HIV RNA, 3) to determine if the relationship of plasma catecholamines (dopamine, noradrenaline and adrenaline) and inflammatory markers [C-reactive protein and tumor necrosis factor] are elevated with sympathetic activity and presence or absence of plasma HIV RNA, and 4) to determine if the relationship between sympathetic activity and flow-mediated brachial artery dilation (a marker of endothelial function and early atherosclerosis development) are inversely correlated with respect to the presence or absence of plasma HIV RNA. The career development plan proposed here incorporates mentoring and a patient-oriented research experience that will provide the foundation for comprehensive clinical research. The significance of this work will be to understand the interrelationships between the autonomic nervous system and the development of CVD in HIV disease. (End of Abstract)