Molecular insights in HIV-associated cardiac dysfunction

Le résumé fourni par la source

Antiretroviral therapy (ART) in human immunodeficiency virus (HIV) markedly improved life expectancy in persons living with HIV (PLWH), but cardiac disease has emerged as the leading cause of death in this population. The prevalence of impaired diastolic function and heart failure with preserved ejection fraction (HFpEF) is higher among PLWH on ART. However, the specific role that HIV itself, and/or ART may have on the cardiomyocyte phenotype is unknown. We investigated modified molecular pathways in cardiomyocytes after exposure to serum from the same patients who were initially ART-naïve and then subsequently ART-treated. Rat cardiomyocytes were treated for 24 hours with serum obtained longitudinally from PLWH (N = 10) before and after being on ART for 6 months. Transcriptomic changes were determined by RNA sequencing. Measures of apoptosis, calcium handling, and extracellular matrix remodeling were analyzed using TUNEL assay and western blot. Here we show that exposure to serum from ART-naïve PLWH increases cardiomyocyte cell death. In contrast, exposure to serum obtained from the same PLWH after six months on ART results in altered expression of calcium-handling proteins and upregulation of profibrotic and extracellular matrix–related markers, indicating altered contraction and relaxation, and adverse cardiac remodeling. These findings demonstrate dysregulated molecular pathways in cardiomyocytes following exposure to untreated HIV serum versus ART-treated HIV serum from patients followed longitudinally. Altogether, these data suggest that HIV infection and ART contribute to changes seen in the cardiomyocyte phenotype and play complementary roles in the pathogenesis of diastolic dysfunction and HFpEF in PLWH. Valero-Muñoz, Saw et al. apply a translational model in which adult cardiac myocytes are exposed to serum from people with HIV before and after initiation of ART. The authors identify distinct molecular signatures, indicating that HIV infection and antiretroviral therapy engage separate biological pathways that may precede diastolic dysfunction and the development of HFpEF. Effective HIV treatments have greatly increased the lifespan of people living with HIV, but heart disease has become a leading cause of death in this group. To better understand how HIV and its treatment affect heart muscle cells (cardiomyocytes), we studied rat heart cells that were exposed to blood samples taken from the same people before they started HIV therapy and again after six months of treatment. Blood taken before HIV therapy caused more heart cells to die, while blood taken after six months of treatment changed signals in these cells that affect how the heart contracts and adapts to stress over time. These findings suggest that both HIV infection and its treatment can directly influence heart cells and may help explain the higher risk of heart disease in people living with HIV.

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