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.

项目摘要/摘要 心力衰竭（HF）是撒哈拉以南非洲艾滋病毒（PWH）健康衰老的主要障碍 （SSA）。患有艾滋病毒（WWH）的妇女可能最脆弱，艾滋病毒风险增加了近两倍 女性与男性的HF归因于HF。为什么女性的艾滋病毒归因于HF的风险较高 理解，但在WWH中，慢性炎症，肥胖症等代谢因素和其他激素因素 假设诸如加速生殖老化等因素起着关键作用。建立HF后 在PWH中，1年的死亡率为31％，心室心律不齐的心脏猝死（SCD）为 常见的。在这种情况下，存在强有力的必须确定防止HF发展的策略 scd中的wwh。 HF和SCD上游的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）和光谱法（MRS）为 被认为是用于识别心肌组织特征的金色标准技术，包括分散 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 舒张功能障碍；此外，心肌纤维化预测心血管不良后果和SCD。到 日期，没有研究表征了经过艺术治疗的WWH中心肌纤维化和脂肪变性的程度 在SSA或该组特有的纤维化/脂肪变性进展的预测指标中。通过这种创新 建议专注于SSA中的WWH，我们将：1）表征心肌纤维化负担并确定新颖 进展的传染性/免疫学预测因素； 2）量化心肌脂肪变性负担并确定 进展的激素/代谢预测指标。我们假设在SSA中的WWH中， 心肌纤维化进展将包括特有的共同感染（例如巨细胞病毒和潜在 结核病），免疫激活/炎症指数（例如骨桥和循环免疫细胞亚群）， 和新型代谢组学特征。我们进一步假设，在该组中，心肌的预测指标 脂肪变性进展将包括减少卵巢储备（明显的更年期；以特征为特征 月经病史和抗毛刺激素的水平），肥胖和/或异位库中脂肪增加（内脏 和心外膜脂肪通过MRI），更长的累积暴露于选择的ART亚型，包括整合酶抑制剂， 以及新型的代谢组和脂肪组信号（有些与特征重叠，有些与特征不同 与纤维化有关）。这项工作将为针对HF预防策略的设计提供信息：选择 免疫/炎症途径（例如双CCR2/CCR5拮抗作用）；与病毒共同感染（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 透皮雌激素）;与艺术相关的体重增加（例如，特定于文化的饮食/运动干预时间 启动或切换到罪犯抗逆转录病毒疗法）。总体而言，这项工作将具有高影响力 SSA中1300万WWH的健康心脏代谢老化，全球所有WWH中有2/3。