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+)感染者患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、缺血性中风)与未感染的比较 人民。这种额外的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)。肝病在HIV+人群中很常见，肝脏调节免疫- 与动脉粥样硬化相关的代谢过程(如炎症、血脂异常和微生物 易位)。肝损伤是否在HIV和ASCVD事件之间的因果通路中尚不清楚。这个 这项应用的目的是了解肝损伤是否导致ASCVD的额外风险 在HIV+人群中与未感染人群进行比较。所获得的知识将用于评估改进的方法 艾滋病毒+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)评估肝损伤是否调节艾滋病毒与 感染和过量的ASCVD风险；2)调查肝损伤与a)生物标志物之间的关系) 亚临床脑血管病，b)由HIV状态引起的免疫代谢；以及3)评估是否导致肝损伤 改进了艾滋病毒中ASCVD风险的预测。如果肝损伤可以解释观察到的某些过度的ASCVD风险 对于艾滋病毒携带者来说，这将具有重要的影响：它将揭示一种新的、可预防的、潜在的 可逆性ASCVD危险因素(肝脏损伤)，导致HIV+的临床结局比 未受感染的人。这项研究的两个创新是：1)使用现有的退伍军人年龄数据 队列研究(Vacs)，一个大的(N~150,000)全国样本，HIV+和未感染的退伍军人具有丰富的 收集纵向临床数据；以及2)结合流行病学研究的因果推断策略。 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。Dr。 So-Armah拥有流行病学博士学位，有设计和进行生物统计分析的经验，以及 在艾滋病毒、并存疾病和心血管疾病领域有良好的出版和合作记录。为了成功 完成这一职业发展奖，他将追求进一步的教学，经验(临床轮换)，和 专业培训。随着这份申请中提出的活动，他将过渡到一个独立的 在艾滋病毒的背景下，具有心血管疾病新的潜在机制(如肝脏损伤)的专业知识的调查员。他 将能够结合1)人口和临床科学，2)在分子水平上理解病理学， 3)因果推断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 艾滋病毒和心血管疾病对公共卫生的重要性。这项跨学科的K01应用程序由多个 纪律指导团队，拥有成功合作的历史和跨越艾滋病毒的专业知识， 肝脏学、心血管疾病、因果推断、纵向数据分析、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.