Novel Mechanisms Driving Excess Atherosclerotic Cardiovascular Disease Risk in the Context of HIV: The Role of Liver Injury

项目摘要 人类免疫缺陷病毒（HIV）感染者（HIV+）动脉粥样硬化的风险高达50% 心血管疾病（ASCVD，即急性心肌梗死、缺血性卒中）与未感染相比 人这种过度的ASCVD风险不能用传统的心血管疾病（CVD）风险因素（例如， 吸烟、高血压）。肝脏疾病在HIV+人群中很常见，肝脏调节免疫功能， 与动脉粥样硬化相关的代谢过程（例如炎症、血脂异常和微生物代谢） 易位）。肝损伤是否是HIV和ASCVD事件之间的因果关系尚不清楚。的 本申请的目的是了解肝损伤是否会导致ASCVD的过度风险 与未感染者相比，艾滋病毒+。所获得的知识将用于评估如何改进 艾滋病毒阳性人群中现有的ASCVD风险预测工具。为了实现这些目标，我们将利用现有的 NHLBI/NIAAA资助的队列：1）评估肝损伤是否介导了HIV 感染和过度ASCVD风险; 2）研究肝损伤与a） 亚临床CVD，B）HIV状态免疫代谢;和3）评估是否导致肝损伤 提高艾滋病毒感染者ASCVD风险预测。如果肝损伤解释了观察到的一些额外ASCVD风险， 在HIV+人群中，这将具有重要意义：它将揭示一种新的、可预防的、潜在的 可逆的ASCVD风险因素（肝损伤），导致HIV+的临床结局更差， 未受感染的人本研究的两个创新点是：1）使用了退伍军人老龄化的现有数据 队列研究（VACS），一项大型（N~ 150，000），全国性的HIV+和未感染退伍军人样本，具有丰富的 纵向临床数据的收集;和2）因果推理策略结合流行病学研究， 临床ASCVD事件、亚临床动脉粥样硬化风险的机制研究和ASCVD风险预测。博士 So-Armah拥有流行病学博士学位，设计和进行生物统计分析的经验， 在艾滋病毒、共病和心血管疾病领域有着良好的出版和合作记录。成功 完成这个职业发展奖，他将追求进一步的教学，经验（临床轮换）， 专业训练通过本申请中提出的活动，他将过渡到独立的 研究者，在HIV背景下具有CVD（例如肝损伤）新潜在机制的专业知识。他 将能够结合联合收割机1）人口和临床科学，2）在分子水平上对病理学的理解， 3)因果推理流行病学和生物统计学方法，以及4）大数据分析，以回答以下问题 艾滋病毒和CVD的公共卫生重要性。这种跨学科的K 01应用程序是由多个支持， 一个学科指导小组，具有成功合作的历史和跨越艾滋病毒的专业知识， 肝病学、CVD、因果推断、纵向数据分析和人口、临床和基础科学。

Project Summary Human immunodeficiency virus (HIV) infected (HIV+) people have up to 50% excess risk of atherosclerotic cardiovascular disease (ASCVD, i.e. acute myocardial infarction, ischemic stroke) compared to uninfected people. This excess ASCVD risk is not explained by traditional cardiovascular disease (CVD) risk factors (e.g. smoking, hypertension). Liver disease is common among HIV+ people, and the liver regulates immuno- metabolic processes associated with atherosclerosis (e.g. inflammation, dyslipidemia and microbial translocation). Whether liver injury is in the causal pathway between HIV and incident ASCVD is unknown. The objective of this application is to understand whether liver injury contributes to the excess risk of ASCVD among HIV+ compared to uninfected people. The knowledge gained will be used to assess ways to improve existing ASCVD risk prediction tools in HIV+ populations. For these objectives, we will leverage existing NHLBI/NIAAA-funded cohorts to: 1) assess whether liver injury mediates the relationship between HIV infection and excess ASCVD risk; 2) investigate associations between liver injury and biomarkers of a) subclinical CVD, b) immuno-metabolism by HIV status; and 3) assess whether accounting for liver injury improves ASCVD risk prediction in HIV. If liver injury explains some of the excess ASCVD risk observed among HIV+ people, this would have important implications: It would reveal a novel, preventable, potentially reversible ASCVD risk factor (liver injury) that results in worse clinical outcomes for HIV+ compared to uninfected people. Two innovations in this study are: 1) the use of existing data from the Veteran's Aging Cohort Study (VACS), a large (N~150,000), national sample of HIV+ and uninfected Veterans with a rich collection of longitudinal clinical data; and 2) a causal inference strategy combining epidemiological studies of clinical ASCVD events, mechanistic studies of subclinical atherosclerosis risk and ASCVD risk prediction. Dr. So-Armah has a PhD in Epidemiology, experience designing and conducting biostatistical analyses, and a strong publication and collaboration record in the field of HIV, comorbid diseases and CVD. To successfully complete this career development award, he will pursue further didactic, experiential (clinical rotations), and professional training. With the activities proposed in this application, he will transition to an independent investigator, with expertise in novel potential mechanisms of CVD (e.g. liver injury), in the setting of HIV. He will be able to combine 1) population and clinical science, 2) understanding of pathology at the molecular level, 3) causal inference epidemiology and biostatistics methods, and 4) big data analytics to answer questions of public health importance in HIV and CVD. This inter-disciplinary K01 application is supported by a multi- disciplinary mentorship team that has a history of successful collaboration and expertise spanning HIV, hepatology, CVD, causal inference, longitudinal data analysis, and population, clinical and basic sciences.