Arterial Inflammation and Coronary Microvascular Dysfunction among Women with HIV: Missing Pieces to the MI Risk Puzzle

女性艾滋病毒感染者的动脉炎症和冠状动脉微血管功能障碍：心肌梗死风险之谜中的缺失部分

• 批准号: 10231141
• 负责人: Markella V. Zanni
• 金额: $ 83.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231141
• 关键词: Address; Aging; Arterial Fatty Streak; Arteries; Arteriogram; Automobile Driving; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cell physiology; Cells; Coronary; Coronary artery; Data; Development; Disease; Endothelial Cells; Endothelium; Event; Face; Functional disorder; Future; Gold; HIV; HIV Infections; Imaging Techniques; Immune; Inflammation; Inflammatory; Intervention; Leukocyte Adhesion Molecules; Low Prevalence; Matched Group; Metformin; Microvascular Dysfunction; Molecular; Morbidity - disease rate; Morphology; Myocardial Infarction; Nitric Oxide; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Phenotype; Population; Positron-Emission Tomography; Prevalence; Prevention strategy; Process; Production; Public Health; Publishing; Relative Risks; Research; Risk; Rupture; Sex Differences; Signal Transduction; Techniques; Testing; Thinking; United States National Institutes of Health; Vascular Endothelial Cell; Woman; Women' s Group; Work; age related; aged; cardioprotection; cardiovascular disorder prevention; cardiovascular imaging; chemokine; cohort; comorbidity; comparison group; coronary computed tomography angiography; design; endothelial dysfunction; high risk; improved; macrophage; macrovascular disease; men; monocyte; mortality; neglect; novel; prevent; prospective; receptor; recruit; single photon emission computed tomography; targeted delivery; translational study

7. Project Summary/Abstract In the US, nearly half of the 1.1 million people with HIV (PHIV) are aged 50 and older. This aging HIV population is uniquely vulnerable to select cardiovascular (CV) comorbidities, including myocardial infarction (MI). Women with HIV (WHIV) face the highest HIV-attributable risk of MI: a 3-fold increased risk vs. non-HIV- infected women. Given the public health impact of MI-related morbidity and mortality, strong imperatives exist to better understand mechanisms underlying MI risk among WHIV. Characterization of pathways predisposing WHIV to MI will enable the development of rational MI prevention strategies and the targeted delivery of such strategies to women in need. Through this proposal, our interdisciplinary team will combine state-of-the-art non-invasive CV imaging with detailed molecular immune cell and endothelial cell phenotyping to define mechanisms predisposing WHIV to MI. Studying a prospectively recruited cohort of WHIV vs. non-HIV-infected women, we will explore a well-substantiated central hypothesis: Among women, HIV infection prompts systemic monocyte activation and endothelial cell pathology, predisposing to increased arterial inflammation. Arterial inflammation and endothelial cell pathology, in turn, promote not only non-calcified epicardial artery plaque but also coronary microvascular dysfunction. We plan to show that arterial inflammation and coronary microvascular dysfunction represent thus far neglected but potentially critical mechanisms of HIV-attributable MI risk among women – missing puzzle pieces (Aims 1-2). We also aim to delineate - on a molecular level - how circulating monocyte and vascular endothelial cell phenotypes differ among WHIV vs. non-HIV-infected women. Finally, we will investigate how pathologic monocyte/endothelial cell phenotypes may engender arterial inflammation, non-calcified epicardial artery plaque, and/or coronary microvascular dysfunction among WHIV (Aim 3). Confirmation of our central hypothesis will introduce a paradigm-shift in conceptualizing HIV- attributable MI risk among women – focused not only on macroscopic atherosclerotic plaque in the epicardial arteries but also on arterial inflammation and coronary microvascular dysfunction. Moreover, our work on mechanistic pathways engendering CV pathology among WHIV will inform the design of future research in the field. Specifically, we anticipate our work will suggest that strategies to mitigate monocyte honing to the vasculature (e.g. CCR2 blockade) or strategies to improve vascular endothelial cell function (e.g. metformin) should be tested for ability to forestall or reverse the key pathologic processes driving MI risk among WHIV. Further, our work will enable future studies on cardioprotective interventions among WHIV to be powered to the most appropriate CV surrogate risk endpoints – those which are found in this study to differ most strikingly among women with vs. without HIV. As MI is a highly-morbid, age-related comorbidity to which WHIV are particularly vulnerable, our work will have significant implications to improve cardiovascular disease prevention among at-risk women aging with HIV.

7。项目摘要/摘要 在美国，在110万艾滋病毒（PHIV）的110万人中，几乎一半的年龄50岁及50岁。这种老化的艾滋病毒 人口非常容易受到精选心血管（CV）合并症的攻击，包括心肌梗塞 （Mi）。艾滋病毒（WHIV）的妇女面临MI的最高艾滋病毒率风险：风险增加了3倍与非HIV- 感染的妇女。鉴于与MI相关的发病率和死亡率的公共卫生影响，存在强大的命令 更好地了解WHIV中MI风险的机制。途径的表征 MI将能够制定理性的MI预防策略，并有针对性地交付此类策略 对有需要的妇女的策略。通过该建议，我们的跨学科团队将结合最先进的 具有详细的分子免疫细胞和内皮细胞表型的非侵入性CV成像以定义 机制使WHIV倾向于MI。研究一个前瞻性招募的WHIV与非HIV感染的队列 妇女，我们将探索一个良好成立的中心假设：在妇女中，艾滋病毒感染提示 全身性单核细胞激活和内皮细胞病理学，倾向于增加动脉炎症。 动脉炎症和内皮细胞病理学反过来不仅促进非car症的心外心动脉 斑块，但也是冠状动脉微血管功能障碍。我们计划表明动脉注射和冠状动脉 迄今为止，微血管功能障碍代表了HIV - 归类的忽视但潜在的至关重要的机制 女性中的MI风险 - 缺少拼图碎片（目标1-2）。我们还旨在在分子水平上描绘 - WHIV与非HIV感染的循环单核细胞和血管内皮细胞表型如何不同 女性。最后，我们将研究病理单核细胞/内皮细胞表型如何产生 动脉炎症，非鉴定心外动脉斑块和/或冠状动脉微血管功能障碍 WHIV（目标3）。确认我们的中心假设将引入一个范式，以概念化HIV- 妇女中可归因的MI风险 - 不仅专注于心外膜的宏观动脉粥样硬化斑块 动脉，但还进行动脉注射和冠状动脉微血管功能障碍。而且，我们的工作 WHIV中引起CV病理的机械途径将为未来研究的设计提供信息 菲尔德。特别是，我们预计我们的工作将暗示减轻单核细胞磨练的策略 脉管系统（例如CCR2封锁）或改善血管内皮细胞功能的策略（例如二甲双胍） 应测试是否能够阻止或扭转WHIV中驱动MI风险的关键病理过程的能力。 此外，我们的工作将使未来关于WHIV中心脏保护干预措施的研究能够推动 最合适的简历替代风险终点 - 在本研究中发现的那些最有明显的差异 在没有艾滋病毒的妇女中。因为Mi是一种高度多重的，与年龄有关的合并症 特别容易受到伤害，我们的工作将对改善预防心血管疾病有重大影响 在患有艾滋病毒的高危妇女中。