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)

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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.