Myocardial Fibrosis and Steatosis Burden and Region-Specific Predictors of Progression among ART-treated Women with HIV infection in sub-Saharan Africa (The MUTIMA Study)

项目摘要/摘要 心力衰竭(HF)是撒哈拉以南非洲艾滋病毒感染者(PWH)健康老龄化的主要障碍 (SSA)。感染艾滋病毒(WWH)的女性可能是最脆弱的，感染艾滋病毒的风险增加近两倍-- 女性与男性之间存在可归因性心衰。为什么女性感染艾滋病毒导致心力衰竭的风险更高还不完全 了解，但在WWH中，慢性炎症、代谢因素如肥胖和其他荷尔蒙 据推测，生殖衰老加速等因素将发挥关键作用。一旦建立了HF 在PWH中，1年死亡率为31%，室性心律失常导致的心脏性猝死(SCD)为31%。 很普通。在这方面，迫切需要确定战略，以防止心力衰竭和 WWH中的SCD。心力衰竭和心力衰竭上游最重要的病理过程是心肌 纤维化和心肌脂肪变性。心血管磁共振(CMR)和波谱(MRS)是 被认为是识别心肌组织特征的金标准技术，包括弥漫性 间质纤维化、局灶性疤痕和脂肪变性。在PWH中，心肌纤维化和脂肪变性与 舒张期功能不全；此外，心肌纤维化预示着不良的心血管结局和SCD。至 到目前为止，还没有研究表征抗逆转录病毒治疗的WWH患者心肌纤维化和脂肪变性的程度。 在SSA或经研究的纤维化/脂肪变性进展的预测因子中，该组特有。通过这一创新 建议重点关注SSA中的WWH，我们将：1)表征心肌纤维化负担并确定新的 感染/免疫学进展预测因子；以及2)量化心肌脂肪变性负担并确定 荷尔蒙/代谢进步的预测因子。我们假设，在SSA的WWH中，预测因子 心肌纤维化进展将包括地方性混合感染(例如巨细胞病毒和潜伏感染 结核病)、免疫激活/炎症指数(例如骨桥蛋白和循环免疫细胞亚群)、 和新颖的新陈代谢特征。我们进一步假设，在这组人中，心肌梗死的预测因子 脂肪变性进展包括卵巢储备减少(明显绝经前；特征为 月经史和抗苗勒氏激素水平)、肥胖和/或异位脂肪增加(内脏 和MRI的心外膜脂肪)，对包括整合酶抑制剂在内的选定ART亚型的更长累积暴露， 以及新的代谢体和脂体学特征(一些与特征重叠，一些与特征不同 与纤维化相关)。这项工作将为设计有针对性的心力衰竭预防策略提供参考： 免疫/炎症途径(例如CCR2/CCR5双重拮抗)；与病毒混合感染的对比(例如 巨细胞病毒的治疗)；与内源性雌激素产生的早期/突然减少(例如 经皮雌激素)；与ART相关的体重增加(例如，特定于文化的饮食/运动干预计时 开始或转向罪犯的抗逆转录病毒疗法)。总体而言，这项工作将产生很高的影响，以保存 在SSA的1300万WWH中，健康的心脏代谢老化，占全球WWH的2/3。

Project Summary/Abstract Heart failure (HF) is a major barrier to healthy aging among people with HIV (PWH) in sub-Saharan Africa (SSA). Women with HIV (WWH) may be most vulnerable, with a nearly two-fold increased risk for HIV- attributable HF among women vs. men. Why HIV-attributable HF risk is higher in women is incompletely understood, but among WWH, chronic inflammation, metabolic factors such as obesity, and other hormonal factors such as accelerated reproductive aging are hypothesized to play key roles. Once HF is established among PWH, the 1-year mortality rate is 31% and sudden cardiac death (SCD) from ventricular arrhythmias is common. In this context, strong imperatives exist to identify strategies to prevent the development of HF and SCD among WWH. The most important pathologic processes upstream of HF and SCD are myocardial fibrosis and myocardial steatosis. Cardiovascular magnetic resonance (CMR) and spectroscopy (MRS) are considered gold-standard techniques for identifying myocardial tissue characteristics, including diffuse interstitial fibrosis, focal scar, and steatosis. Among PWH, myocardial fibrosis and steatosis correlate with diastolic dysfunction; in addition, myocardial fibrosis predicts adverse cardiovascular outcomes and SCD. To date, no studies have characterized the extent of myocardial fibrosis and steatosis among ART-treated WWH in SSA or examined predictors of fibrosis/steatosis progression specific to this group. Through this innovative proposal focus on WWH in SSA, we will: 1) characterize myocardial fibrosis burden and identify novel infectious/immunologic predictors of progression; and 2) quantify myocardial steatosis burden and identify hormonal/metabolic predictors of progression. We hypothesize that among WWH in SSA, predictors of myocardial fibrosis progression will include endemic co-infections (e.g. cytomegalovirus and latent tuberculosis), immune activation/inflammation indices (e.g. osteopontin and circulating immune cell subsets), and novel metabolomic signatures. We further hypothesize that among this group, predictors of myocardial steatosis progression will include reduced ovarian reserve (anteceding overt menopause; characterized by menstrual history and levels of anti-Mullerian hormone), obesity and/or increased fat in ectopic depots (visceral and epicardial fat by MRI), longer cumulative exposure to select ART subtypes including integrase inhibitors, and novel metabolomic and lipidomic signatures (some overlapping with and some distinct from the signatures associated with fibrosis). This work will inform the design of HF prevention strategies targeting: select immune/inflammatory pathways (e.g. dual CCR2/CCR5 antagonism); vs. viral co-infections (e.g. letermovir for treatment of cytomegalovirus); vs. early/abrupt decrement in endogenous estrogen production (e.g. transdermal estrogen); vs. ART-associated weight gain (e.g. culturally-specific diet/exercise intervention timed to initiation of or switch to culprit antiretroviral therapeutics). Overall, this work will have high-impact to preserve healthy cardiometabolic aging among 13 million WWH in SSA, representing 2/3 of all WWH globally.