Gut metabolites and their role in diastolic dysfunction in HIV+ individuals

Award amount: 50,000.00

Considerable progress in the recognition, diagnosis, and treatment of HIV has led to a significant increase in the life expectancy of this population. With this change, however, HIV+ individuals are at higher risk of developing certain co-morbidities including cardiovascular disease (CVD). HIV infection has emerged as an independent risk factor for left ventricular diastolic dysfunction (DD), predisposing these individuals to chronic illnesses including atrial fibrillation, pulmonary hypertension, and heart failure with preserved ejection fraction (HFpEF). The pathophysiology by which HIV infection leads to DD remains unclear. Recently, alterations in the gut microbiome have been implicated in a number of disease entities. Transmethylamine-N-oxide (TMAO) is a gut metabolite of dietary choline which has been identified as a biomarker and prognostic measure in individuals with systolic heart failure in the general population; treatment options targeting this pathway are being actively investigated. TMAO levels correlate with the presence of DD in the systolic HF population, and mouse models of TMAO overexpression result in increased myocardial fibrosis. Because HIV infection results in increased gut permeability, we hypothesize that gut metabolism and translocation of TMA and its metabolite, TMAO, may play a key role in the development of DD in the HIV+ population. We propose an observational, cross-sectional study to investigate the association of levels of gut metabolites with myocardial fibrosis and DD in HIV+ individuals. We will utilize the Characterizing Heart Function on Anti-Retroviral Therapy (CHART-HIV) cohort, a multicenter study being performed within the Heart Failure Network, in which ART-treated, virally-suppressed HIV+ individuals with and without DD are undergoing extensive characterization including blood testing, metabolomics / proteomics, and cardiac imaging (echocardiogram and cardiac MR). Uninfected individuals with DD will also be included. We expect that this work will identify novel mechanisms of DD in HIV-infected individuals, and ultimately inform preventative and therapeutic strategies in this at-risk population.