Metabolic and redox pathway dysregulation in HIV-associated coronary endothelial dysfunction.

People with HIV (PWH) remain at increased risk for cardiovascular disease despite sustained viral suppression on antiretroviral therapy, but the biological mechanisms underlying this risk are incompletely understood. We hypothesized that coronary endothelial dysfunction in virally suppressed PWH is associated with specific circulating proteomic signatures reflecting metabolic and redox pathway dysregulation. We conducted a prospective observational study integrating in vivo stress cardiovascular magnetic resonance imaging with high-throughput serum proteomics to investigate mechanisms of coronary endothelial dysfunction in treated HIV. Forty-five virally suppressed PWH and 29 age- and sex-matched healthy controls underwent coronary magnetic resonance imaging during isometric handgrip exercise to quantify coronary endothelial function, defined as the percent change in coronary cross-sectional area from rest to stress, with an increase <2% indicating endothelial dysfunction. Parallel serum proteomic profiling was performed using the SomaScan 7 K platform, and differential protein expression was analyzed using linear modeling. Coronary endothelial dysfunction was significantly more prevalent among PWH than in controls (67% vs. 10%, P < 0.001). Pathway enrichment analysis of differentially expressed proteins between participants with and without endothelial dysfunction identified significant dysregulation of glutathione-dependent detoxification, oxidative metabolism, and fatty acid β-oxidation pathways (adjusted P < 0.05). However, despite the higher prevalence of coronary endothelial dysfunction among PWH compared with controls without HIV, we did not identify a distinct baseline clinical or proteomic profile that fully explained this difference. These findings demonstrate that coronary endothelial dysfunction in virally suppressed PWH is associated with metabolic and redox imbalance, identifying glutathione and fatty acid oxidation pathways as potential therapeutic targets to mitigate residual cardiovascular risk in this population.NEW & NOTEWORTHY Coronary endothelial dysfunction is highly prevalent in people with HIV despite durable viral suppression and minimal differences in the global circulating proteome compared with uninfected controls. By coupling in vivo coronary magnetic resonance imaging-based endothelial function testing with unbiased serum proteomics, this study identifies dysregulation of glutathione-dependent redox balance and fatty acid β-oxidation as key correlates of impaired endothelial function, implicating metabolic and oxidative mechanisms in persistent vascular dysfunction in treated HIV.