Clinical and immunologic factors underlying heart failure with preserved ejection fraction among persons with HIV in South Africa

Premise: HIV associated CVD is a significant cause of clinical morbidity and a barrier to successful aging among persons living with HIV (PWH). To date, HIV-CVD research has emphasized ischemic coronary heart disease. However, nearly 80% of the global CVD burden exists in developing nations and 70% of the HIV

epidemic exists in sub-Saharan Africa (SSA) where heart failure (HF) is the predominant CVD manifestation. Data from high income countries (HIC) has established that chronic HIV disease contributes to increased risk for ventricular dysfunction and clinical HF. We have shown that asymptomatic PWH in South Africa (SA) have

greater diffuse myocardial fibrosis by CMR, when compared to uninfected controls, representing structural changes that may increase risk for HF with preserved ejection fraction (HFpEF). These findings support our hypothesis that risk for HF will be increased among PWH taking ART in SA, and will manifest predominantly as

HFpEF. Unifying mechanistic features of HFpEF have been proposed but the pathogenesis is heavily influenced by the presence of co-morbid end-organ diseases. This has motivated attempts to characterize clinical `phenogroups' of HFpEF based on the profile of comorbid conditions. When compared to HICs, the

relative frequencies of co-morbid conditions (e.g., obesity, hypertension) and other risk factors (e.g., mTB, substance use) differs in low-to-middle income countries like SA. The unique risk factor profiles of PWH in SA will then result in distinct HFpEF phenogroups and changes to underlying cardiac structure.

Approach: We propose to enroll PWH and uninfected controls, utilize echocardiography to adjudicate HF subgroups, and then identify a cohort of PWH with HFpEF to study clinical and biologic factors in greater detail. The target population includes patients living in Khayelitsha township, outside of Cape Town, SA, who are age

≥40-years and on ART with viral suppression (if living with HIV). Standardized clinical echocardiogram (ECHO) will be used to adjudicate HF status and cardiac magnetic resonance (CMR) will be used to characterize the injury pattern of cardiac fibrosis among those with HF. Our proposal includes following specific aims:

Aim 1: Estimate the prevalence of HF due to ventricular dysfunction in SA, as well as the effect of treated-HIV. Aim 2: Determine the clinical phenogroup(s) that define HFpEF among PWH on ART, age ≥40, in SA. Aim 3: Explore immunologic factors that may contribute to myocardial fibrosis and HFpEF risk in PWH.

Research and Health Implications: This proposal targets a large unmet need in the HIV-CVD field. HIV associated HF is a clinically significant challenge, and data from HIC do not adequately represent LMIC like SA. In addition, HFpEF can result from heterogeneous pathologies, and HIV disease may influence HFpEF risk

through multiple pathways depending on underlying risk. Our proposal will determine the burden of HFpEF among PWH, develop POC approaches for identifying those at risk, and identify clinical and biologic features that may be targeted in HIV-CVD clinical trials within a global region where most of the HIV epidemic resides.