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. 项目总结/摘要 在美国，110 万艾滋病毒 (PHIV) 感染者中近一半年龄在 50 岁及以上。这种老化的艾滋病毒 人群特别容易罹患某些心血管 (CV) 合并症，包括心肌梗塞 （MI）。感染艾滋病毒 (WHIV) 的女性面临最高的艾滋病毒所致 MI 风险：与非艾滋病毒女性相比，风险增加 3 倍 受感染的妇女。鉴于心肌梗死相关发病率和死亡率对公共卫生的影响，迫切需要采取措施 更好地了解 WHIV 中 MI 风险的潜在机制。诱发途径的特征 将 WHIV 转化为 MI 将有助于制定合理的 MI 预防策略并有针对性地提供此类治疗 向有需要的妇女提供的策略。通过这项提案，我们的跨学科团队将结合最先进的技术 无创 CV 成像，通过详细的分子免疫细胞和内皮细胞表型来定义 WHIV 诱发 MI 的机制。研究前瞻性招募的 WHIV 与非 HIV 感染者队列 对于女性，我们将探索一个得到充分证实的中心假设：在女性中，艾滋病毒感染提示 全身单核细胞活化和内皮细胞病理学，易导致动脉炎症增加。 动脉炎症和内皮细胞病理反过来不仅促进心外膜动脉的非钙化 斑块还可能导致冠状动脉微血管功能障碍。我们计划证明动脉炎症和冠状动脉 微血管功能障碍代表了迄今为止被忽视但可能是艾滋病毒归因的关键机制 女性心梗风险——缺失的拼图（目标 1-2）。我们还旨在在分子水平上描绘- WHIV 与非 HIV 感染者之间的循环单核细胞和血管内皮细胞表型有何不同 女性。最后，我们将研究病理性单核细胞/内皮细胞表型如何产生 动脉炎症、非钙化心外膜动脉斑块和/或冠状动脉微血管功能障碍 WHIV（目标 3）。我们的中心假设的证实将带来艾滋病毒概念的范式转变 女性的心肌梗死风险——不仅关注心外膜的宏观动脉粥样硬化斑块 动脉还与动脉炎症和冠状动脉微血管功能障碍有关。此外，我们的工作 WHIV 中引起 CV 病理学的机制途径将为未来研究的设计提供信息 场地。具体来说，我们预计我们的工作将提出减轻单核细胞磨削的策略 血管系统（例如 CCR2 阻断）或改善血管内皮细胞功能的策略（例如二甲双胍） 应测试预防或逆转 WHIV 中导致 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 心脏保护干预措施的研究能够 最合适的心血管替代风险终点——本研究中发现的差异最显着的终点 感染艾滋病毒的女性与未感染艾滋病毒的女性之间的比较。由于 MI 是一种发病率很高、与年龄相关的合并症，WHIV 是其中之一 特别容易受到伤害，我们的工作将对改善心血管疾病的预防产生重大影响 感染艾滋病毒的高危女性。