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

HIV 背景下导致动脉粥样硬化性心血管疾病风险过高的新机制：肝损伤的作用

• 批准号: 9183689
• 负责人: Kaku So-Armah
• 金额: $ 11.88万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9183689
• 关键词: Accounting; Acute myocardial infarction; Aging; Alcohol abuse; Alcohols; Atherosclerosis; Automobile Driving; Award; B-Lymphocyte Subsets; Basic Science; Big Data; Biological Markers; Biometry; Blood coagulation; Calcium; Calibration; Cardiac; Cardiovascular Diseases; Caring; Cause of Death; Cirrhosis; Clinical; Clinical Data; Clinical Sciences; Coagulation Process; Code; Cohort Studies; Collaborations; Collection; Conflict (Psychology); Coronary artery; Data; Data Analyses; Data Analytics; Data Element; Data Set; Discrimination; Disease; Doctor of Philosophy; Dyslipidemias; Electronic Health Record; Epidemiologic Studies; Epidemiology; Event; Fibrosis; Funding; HIV; Heart Diseases; Hepatitis C; Hepatitis C co-infection; Hepatitis C virus; Hepatology; Hypertension; Immune Tolerance; Inflammation; Insulin Resistance; Ischemic Stroke; K-Series Research Career Programs; Knowledge; Link; Lipids; Lipoproteins; Liver; Liver Fibrosis; Liver diseases; Longitudinal Surveys; Measures; Mediating; Medicare; Mentors; Mentorship; Metabolic; Metabolism; Methods; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Institute on Alcohol Abuse and Alcoholism; Natural Immunity; Observational Study; Outcome; Pathology; Pathway interactions; Play; Population; Population Sciences; Public Health; Publications; Recording of previous events; Research Personnel; Risk; Risk Factors; Role; Rotation; Sampling; Severities; Smoking; Source; Structure; Testing; Training; Veterans; Virus Diseases; Work; adaptive immunity; cardiovascular disorder risk; cohort; design; experience; glucose metabolism; heart disease risk; improved; indexing; innovation; lipid metabolism; liver injury; microbial; monocyte; novel; tool; virtual

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.

项目概要 人类免疫缺陷病毒 (HIV) 感染者 (HIV+) 患动脉粥样硬化的风险高出 50% 与未感染者相比，心血管疾病（ASCVD，即急性心肌梗塞、缺血性中风） 人们。这种过高的 ASCVD 风险无法用传统的心血管疾病 (CVD) 风险因素（例如，心血管疾病）来解释。 吸烟、高血压）。肝病在艾滋病病毒感染者中很常见，肝脏调节免疫系统 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 易位）。肝损伤是否是 HIV 与 ASCVD 之间的因果关系尚不清楚。这 本申请的目的是了解肝损伤是否会导致 ASCVD 风险过高 与未感染者相比，艾滋病毒阳性者的情况。获得的知识将用于评估改进方法 HIV+ 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 资助的队列旨在：1) 评估肝损伤是否介导 HIV 之间的关系 感染和 ASCVD 风险过高； 2) 研究肝损伤与 a) 生物标志物之间的关联 亚临床 CVD，b) HIV 状态的免疫代谢； 3) 评估是否解释了肝损伤 改善 HIV 的 ASCVD 风险预测。如果肝损伤可以解释观察到的一些过高的 ASCVD 风险 对于艾滋病病毒感染者来说，这将产生重要影响：它将揭示一种新颖的、可预防的、潜在的 可逆性 ASCVD 危险因素（肝损伤），导致 HIV+ 患者的临床结果比 未感染的人。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)，一个大型（N~150,000）全国艾滋病毒+和未感染退伍军人样本，具有丰富的 收集纵向临床数据； 2）结合流行病学研究的因果推理策略 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。博士。 So-Armah 拥有流行病学博士学位，拥有设计和进行生物统计分析的经验，以及 在艾滋病毒、合并症和心血管疾病领域拥有丰富的发表和合作记录。才能成功 完成此职业发展奖后，他将追求进一步的教学、体验（临床轮换）和 专业培训。通过本申请中提议的活动，他将过渡为独立的 研究人员，在 HIV 背景下的 CVD 潜在机制（例如肝损伤）方面拥有专业知识。他 将能够结合 1) 人口和临床科学，2) 在分子水平上对病理学的理解， 3）因果推断流行病学和生物统计学方法，以及4）大数据分析来回答以下问题 公共卫生在艾滋病毒和心血管疾病方面的重要性。这个跨学科的 K01 申请得到了多方的支持 学科指导团队在艾滋病毒领域拥有成功合作的历史和专业知识， 肝病学、心血管疾病、因果推理、纵向数据分析以及人口、临床和基础科学。