Abstract Body: Background: People with HIV (PWH) exhibit a high risk of heart failure (HF). Immune dysregulation has been implicated, but the pathophysiology remains incompletely understood. Left ventricular global longitudinal strain (LVGLS) permits earlier detection of cardiac dysfunction than traditional echocardiography (Echo) measures, allowing evaluation of early mechanisms of disease. We performed proteomic profiling of PWH and sociodemographically similar people without HIV (PWOH) to identify proteins cross-sectionally associated with LVGLS.

Methods: We included men from the Multicenter AIDS Cohort Study (MACS) and women from the Women’s Interagency HIV Study (WIHS) who completed Echo in 2014-2019 and had plasma for analysis using Olink Explore HT (5,416 proteins). We related individual proteins to LVGLS using multivariable linear regression adjusting for sociodemographic, behavioral and clinical factors in each cohort, and combined the results by fixed-effects meta-analysis. FDR<0.05 defined significance.

Results: The study included 1152 MACS (age 58, Black 28%, HIV+ 54.6%) and 1602 WIHS (age 52, Black 75%, HIV+ 70.2%) participants. There was no interaction or heterogeneity by cohort. Meta-analysis identified 6 proteins associated with LVGLS, including two (UMOD, SHBG) with better, and four (MZB1, PRAP1, CES1, PXDNL) with worse, LVGLS (Figure). Both UMOD and SHBG have known inverse associations with CVD events, while PXDNL is upregulated in end-stage HF. The other proteins have not been previously linked to clinical HF. In mice, MZB1 modulates cardiac mitochondrial function and suppresses inflammation in heart and gut; PRAP1 facilitates gut apoB assembly and protects gut epithelium from apoptosis; and CES1, involved in lipid metabolism and drug detoxification, has been linked to atherosclerosis. There was no interaction by race/ethnicity or HIV in either cohort, except for COL3A1, which was associated with worse LVGLS only in women with HIV (WWH).

Conclusions: We identified three novel plasma proteins associated with LV dysfunction in PWH and PWOH, extending three other proteins to the HIV setting. The new proteins have roles in cardiac mitochondrial homeostasis, intestinal epithelial function and lipid metabolism, dysregulation of which is prevalent in HIV. A signal for collagen type 3 in WWH suggests a more prominent role for cardiac fibrosis in this population. Additional work is needed to replicate these associations and evaluate their causal nature.