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

7.项目摘要/摘要 在美国，110万艾滋病毒(PHIV)携带者中，近一半的人年龄在50岁及以上。这个老龄化的艾滋病毒 人群特别容易患特定的心血管(CV)合并症，包括心肌梗塞 (Mi)。携带艾滋病毒(WHIV)的妇女面临着最高的艾滋病毒致心肌梗死风险：与非艾滋病毒携带者相比，风险增加了3倍。 被感染的女性。鉴于与心肌梗死相关的发病率和死亡率对公共健康的影响，存在着强烈的紧迫性 为了更好地了解WHIV中MI风险的潜在机制。易感通路的特征 WHIV to MI将有助于制定合理的MI预防战略，并有针对性地提供这些 为有需要的妇女制定战略。通过这项提议，我们的跨学科团队将把最先进的 无创性循环血管成像结合详细的分子免疫细胞和内皮细胞表型以确定 WHIV易患心肌梗死的机制。研究WHIV感染者与非HIV感染者的前瞻性招募队列 ，我们将探索一个得到充分证实的中心假设：在女性中，艾滋病毒感染促使 全身单核细胞活化和内皮细胞病理，易导致动脉炎症增加。 反过来，动脉炎症和内皮细胞病理不仅促进非钙化的心外膜动脉 斑块也有冠脉微血管功能障碍。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但可能是HIV致病的关键机制 女性的心肌梗塞风险--遗失拼图碎片(目标1-2)。我们的目标也是在分子水平上描绘- WHIV感染者与非HIV感染者循环单核细胞和血管内皮细胞表型的差异 女人。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)。我们中心假说的确认将带来艾滋病毒概念化的范式转变-- 女性心肌梗死的归因性风险--不仅关注心外膜宏观动脉粥样硬化斑块 而且对动脉炎症和冠状动脉微血管功能障碍也有影响。此外，我们的工作是 在WHIV中产生心血管病理的机制通路将为未来研究的设计提供信息 菲尔德。具体地说，我们预计我们的工作将建议减少单核细胞磨削到 血管系统(如CCR2阻断)或改善血管内皮细胞功能的策略(如二甲双胍) 应测试预防或逆转导致WHIV中MI风险的关键病理过程的能力。 此外，我们的工作将使未来对WHIV中心脏保护干预的研究成为可能 最合适的简历替代风险终点--在这项研究中发现差异最大的终点 在感染艾滋病毒的女性和没有感染艾滋病毒的女性中。由于心肌梗塞是一种高度病态的、与年龄相关的共病，WHIV是 我们的工作将对改善心血管疾病的预防具有重要意义 在感染艾滋病毒的高危女性中。

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.