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

7.项目总结/摘要 在美国，110万艾滋病毒（PHIV）感染者中有近一半年龄在50岁及以上。这种老化的艾滋病病毒 人群特别容易发生选定的心血管（CV）合并症，包括心肌梗死 （密歇根州）。感染HIV的女性（WHIV）面临着最高的HIV归因的MI风险：与非HIV感染者相比，风险增加了3倍。 被感染的女人鉴于MI相关发病率和死亡率对公共卫生的影响， 以更好地了解WHIV中MI风险的潜在机制。易感途径的表征 WHIV to MI将有助于制定合理的MI预防策略， 为有需要的妇女制定战略。通过这项提案，我们的跨学科团队将联合收割机 非侵入性CV成像和详细的分子免疫细胞和内皮细胞表型，以确定 使WHIV易患MI的机制。研究WHIV与非HIV感染者的前瞻性招募队列 我们将探讨一个得到充分证实的中心假设：在妇女中，艾滋病毒感染促使 全身单核细胞活化和内皮细胞病理学，易诱发动脉炎症增加。 动脉炎症和内皮细胞病理，反过来，不仅促进非钙化的心外膜动脉 斑块和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 微血管功能障碍是迄今为止被忽视的，但可能是艾滋病毒可归因的重要机制。 妇女的心肌梗死风险-缺失的拼图（目标1-2）。我们的目标也是在分子水平上描绘- WHIV与非HIV感染者循环单核细胞和血管内皮细胞表型的差异 妇女最后，我们将研究病理性单核细胞/内皮细胞表型是如何产生的， 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， （目标3）。我们的中心假设的证实将引入艾滋病毒概念化的范式转变， 女性中可归因的MI风险-不仅关注心外膜中肉眼可见的动脉粥样硬化斑块， 动脉炎症和冠状动脉微血管功能障碍。此外，我们在 在WHIV中产生CV病理学的机制途径将为未来研究的设计提供信息。 领域具体地说，我们预计我们的工作将表明，减轻单核细胞磨练的策略， 血管系统（例如CCR 2阻断）或改善血管内皮细胞功能的策略（例如二甲双胍） 应检测预防或逆转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中心脏保护干预的研究能够获得动力， 最合适的CV替代风险终点-本研究中发现差异最显著的终点 感染艾滋病毒的妇女与未感染艾滋病毒的妇女之间的差异。由于MI是一种高度病态的、与年龄相关的合并症， 特别是脆弱的人群，我们的工作将对改善心血管疾病的预防产生重大影响。 艾滋病病毒携带者中的比例。

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.