Mitochondrial Haplogroups and Left Ventricular Diastolic Dysfunction in People Living With and Without HIV

BACKGROUND: Cardiac dysfunction is more common in people with HIV (PWH) than those without HIV (PWoH), with mitochondrial dysfunction implicated in pathogenesis. We investigated whether variations in mitochondrial DNA (mtDNA) and certain dideoxynucleoside analogs (D-drugs) relate to left ventricular diastolic dysfunction (LVDD) in PWH. METHODS: We included individuals with echocardiograms from the Multicenter AIDS Cohort Study and Women's Interagency HIV Study. LVDD was defined using characterizing heart function on antiretroviral therapy criteria. mtDNA haplogroups were inferred using HaploGrep. Separate exploratory multivariable logistic regressions examined associations between LVDD and African (L0L1, L2, L3, or "other") or European haplogroups (UK, H, JT, or "other"), D-drugs, and their interactions. No adjustments were made for multiple comparisons. RESULTS: Among 842 men (455 PWH and 387 PWoH) and 898 women (620 PWH and 278 PWoH), LVDD prevalence was 29% in women and 24% in men. Among non-Hispanic White men with HIV, European haplogroup H was associated with lower odds of LVDD (odds ratio [OR], 0.50; 95% CI, 0.26-0.93), while haplogroup clade JT was associated with increased odds (OR, 2.09; 95% CI, 1.00-4.36). In men with HIV, D-drug exposure was associated with increased odds of LVDD (OR, 1.94; 95% CI, 1.21-3.13). No significant associations were observed between haplogroups and LVDD in women. HIV serostatus modified the association of haplogroup L2 (pinteraction = 0.036) and L3 (pinteraction = 0.045) with LVDD in women. CONCLUSIONS: Mitochondrial genetic variation and D-drug use were associated with altered LVDD risk in men with HIV, highlighting potential biological mechanisms that may be targeted for surveillance or therapeutic strategies.