Progression of HIV-Associated Cardiac Fibro-Inflammation in Women

About This Grant

Project Summary / Abstract People with HIV (PWH) experience a high risk of cardiovascular disease (CVD). The risk appears more pronounced for women with HIV (WWH), particularly for heart failure, yet this group remains understudied. Our prior work in the Women’s Interagency HIV Study (WIHS), now the MACS-WIHS Combined Cohort Study (MWCCS), found that WWH exhibit higher MRI-measured myocardial fibro- inflammation than sociodemographically similar women without HIV (WWOH). This risk was more marked in women with unsuppressed viremia or low nadir CD4+ count in the past 5 years. WWH showed frequent viremia in this preceding period, during which adherence with antiretroviral therapy (ART) was suboptimal. Yet viremia was common even among ART-adherent women. Use of integrase inhibitors, which afford greater tolerability but produce weight gain, was recent at the time. Most WWH were post-menopausal, a condition where low estradiol could foster viremia. While post- menopausal estradiol level has been associated with CVD in general populations, its role in HIV- associated heart disease in postmenopausal women is uncertain. Central to the findings is the potential role of dysregulated immune cell subsets – including T-cell differentiation, exhaustion, senescence, cytotoxicity and loss of regenerative capacity – which have been variously implicated in HIV progression and cardiovascular comorbidities, as well as acute myocarditis in non-HIV settings. Here we propose to repeat MRI in returning participants ~8 years after their initial scans to address these questions in a prospective manner. Specifically, we will evaluate the contributions of HIV, subsequent unsuppressed viremia and lymphopenia, and longer duration of integrase inhibitor use to longitudinal progression of cardiac fibro-inflammation; relate circulating post-menopausal estradiol level to progression of cardiac fibro-inflammation and examine its association with unsuppressed viremia; and perform high-density phenotyping of circulating immune cell subsets and features in post-menopausal WWH to determine their associations with progression of cardiac fibro-inflammation progression. The longitudinal study design will permit assessment of the course of myocardial disease and the prospective associations of HIV-specific factors, blood estradiol, and immune cell subsets and functionally relevant features in WWH, strengthening inferences. This proposal will yield valuable new knowledge regarding the HIV, sex hormone and immune determinants of myocardial disease progression in aging women, which will offer insights into pathophysiology and new potential directions for treatment of heart disease in this high-risk group.