Diastolic Heart Failure in HIV-1 infection

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Abstract: Contemporary estimates suggest that more than 40% of people living with chronic HIV-1 infection (PLWH) have diastolic heart failure (dHF), a harbinger for adverse clinical outcomes including pulmonary abnormalities, frequent hospitalizations, and sudden death. To date, the molecular causes for dHF in PLWH remain poorly understood. This paucity of information and a lack of treatment options have prompted the OAR to list “Strategies to Prevent and Treat HIV-Associated Heart Diseases” as areas of high priority for HIV research. We hypothesize that that “elevation of the cytotoxic glycolysis metabolite, methylglyoxal (MG) is a primary cause for dHF development in PLWH.” This elevation in MG is arising from HIV-1 induce upregulation of glycolysis in infected immunocytes followed by ischemia-induced increase in glycolysis in vascular cells and cardiac myocytes. This multi-PI project brings together the expertise of Drs. Keshore R. Bidasee (M-PI, heart failure) and Santhi Gorantla (M-PI, humanized mice and HIV-1 infection) with assistance from Dr. Prasanta Dash (HIV-1 eradication and cardiovascular complications), to (1) Define pathobiological trajectories of dHF in relation to MG levels in HIV-1 infected Hu-mice with and with ARD treatment; (2) Characterize mechanisms by which MG increases in HIV-I infected immunocytes and in myocytes, macrophages and vascular cells under with and without ARD and hypoxia (3) Show that lowering MG will blunt dHF in HIV-infected Hu-mice with and without ARD. Accomplishments of these aims will not only define a novel link between glycolysis and early-onset dHF in the setting of HIV-1 infection, but the data could pave the way for the development of urgently needed therapeutics to mitigate this disease in PLWH.