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)

撒哈拉以南非洲接受 ART 治疗的 HIV 感染女性的心肌纤维化和脂肪变性负担以及进展的区域特异性预测因子（MUTIMA 研究）

• 批准号: 10756056
• 负责人: Chris Todd Longenecker
• 金额: $ 74.94万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10756056
• 关键词: Acceleration; Africa South of the Sahara; Aging; Anti-Retroviral Agents; Biological Markers; CCR5 gene; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Chronic; Cicatrix; Clinical; Country; Cytomegalovirus; Development; Diffuse; Estrogens; Exposure to; Fatty acid glycerol esters; Fibrosis; Flow Cytometry; Functional disorder; Funding; Future; Geography; Goals; HIV; HIV Infections; Heart failure; Hormonal; Imaging Techniques; Immune; Immunologic Factors; Immunologics; Income; Inflammation; Inflammatory; Integrase Inhibitors; Investigation; Magnetic Resonance; Magnetic Resonance Imaging; Menopause; Metabolic; Myocardial; Myocardial tissue; National Heart, Lung, and Blood Institute; Obesity; Outcome; Pathogenesis; Pathologic Processes; Pathway interactions; Persons; Phenotype; Play; Population; Populations at Risk; Positioning Attribute; Prevention strategy; Production; Recording of previous events; Research; Research Design; Risk; Risk Factors; Site; South Africa; Spectrum Analysis; Techniques; Therapeutic; Triglycerides; Tuberculosis; Uganda; Ventricular Arrhythmia; Viral; Visceral; Weight Gain; Woman; Work; antagonist; cardiac magnetic resonance imaging; cardiac muscle disease; cardiometabolism; cardiovascular imaging; co-infection; cohort; coronary fibrosis; design; diet and exercise; exercise intervention; experience; extracellular; fine particles; follow-up; healthy aging; imaging study; immune activation; indexing; innovation; interstitial; lipidomics; male; men; metabolic phenotype; metabolomics; mortality; mullerian-inhibiting hormone; novel; osteopontin; ovarian reserve; preservation; prevent; preventive intervention; recruit; reproductive senescence; sex; sudden cardiac death; transdermal estrogen

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.

项目总结/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）。感染艾滋病毒的妇女（WWH）可能是最脆弱的，感染艾滋病毒的风险增加了近两倍。 女性与男性之间的归因性HF。为什么HIV引起的HF风险在女性中更高， 理解，但在WWH，慢性炎症，代谢因素，如肥胖，和其他激素 据推测，生殖老化加速等因素起着关键作用。一旦建立HF 在PWH中，1年死亡率为31%， 共同在这种情况下，迫切需要确定预防HF发展的策略， 在WWH中的SCD。HF和SCD上游最重要的病理过程是心肌梗死， 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，包括弥散性 间质纤维化、局灶性瘢痕和脂肪变性。在PWH中，心肌纤维化和脂肪变性与 舒张功能障碍;此外，心肌纤维化预测不良心血管结局和SCD。到 迄今为止，尚无研究描述ART治疗的WWH患者心肌纤维化和脂肪变性的程度 或检查该组特异性纤维化/脂肪变性进展的预测因子。通过这一创新 我们将：1）描述心肌纤维化负荷并识别新的 进展的感染/免疫学预测因子;和2）量化心肌脂肪变性负荷并识别 激素/代谢进展的预测因子。我们假设，在SSA的WWH中， 心肌纤维化进展将包括地方性合并感染（例如巨细胞病毒和潜伏性心肌纤维化）。 结核），免疫活化/炎症指数（例如骨桥蛋白和循环免疫细胞亚群）， 和新的代谢组学特征。我们进一步假设，在该组中，心肌梗死的预测因素 脂肪变性进展将包括卵巢储备减少（在明显绝经前;特征为 月经史和抗苗勒管激素水平）、肥胖和/或异位贮库中脂肪增加（内脏 和心外膜脂肪），较长的累积暴露于选择的ART亚型，包括整合酶抑制剂， 以及新的代谢组学和脂质组学标记（一些与标记重叠，一些与标记不同 与纤维化相关）。这项工作将为HF预防策略的设计提供信息， 免疫/炎症途径（例如，双重CCR 2/CCR 5拮抗作用）;与病毒共感染（例如，莱特莫韦用于 巨细胞病毒治疗）;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，文化特异性饮食/运动干预定时 开始或改用罪魁祸首抗逆转录病毒疗法）。总的来说，这项工作将有很大的影响，以保持 健康的心脏代谢老化，占全球WWH的2/3。