Cardiovascular autonomic function in HIV virologic failure

描述(由申请者提供)：这份建议书描述了一个为期4年的培训计划，旨在培养多米尼克·周博士成为与人类免疫缺陷病毒1型(HIV-1)相关的心血管自主研究领域的独立研究员。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攻艾滋病药物的内科和儿科医生。由美国国立卫生研究院NIAID资助的抗逆转录病毒治疗管理策略(SMART)试验在一项有5472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，结果显示，与继续使用ART的患者相比，中断抗逆转录病毒治疗(ART)的患者心血管疾病的发病率和死亡率更高。解释与STI相关的心血管风险相对迅速(在几个月内)增加的一个假设是，停用ART导致的病毒血症导致已经易受自主神经功能障碍影响的人群中心血管自主神经功能障碍的增加。在普通人群中，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会导致心血管自主神经功能障碍的增加。一项涉及3组患者的前瞻性研究被提出，以检验这一假设的关键组成部分。具体目的是：1)通过间接测试[心脏迷走神经、肾上腺素能和定量运动轴突反射(QSART)测试]来评估自主神经功能并将其与ART改变的三组受试者的血浆HIV RNA的存在与否相关联；2)通过直接测试[肌交感神经活动(MSNA)]来评估和比较在存在或不存在血浆HIV RNA的情况下的自主(交感)功能；3)确定血浆儿茶酚胺(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]的关系是否随着交感活动和血浆HIV、RNA的存在或不存在而升高4)确定交感神经活性和血流介导的臂动脉扩张(内皮功能和早期动脉粥样硬化进展的标志)之间的关系是否与血浆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，这将为全面的临床研究提供基础。这项工作的意义将是了解自主神经系统与HIV疾病中心血管疾病的发展之间的相互关系。 (摘要结束)

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)