Abstract 37: Proteomic Signatures of Obesity-Related Heart Failure in the Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: Obesity is a strong risk factor for cardiovascular disease. The excess heart failure (HF) risk associated with obesity is uniquely unexplained by traditional risk mediators. We sought to identify proteomic signatures that reflect mechanistic pathways associated with obesity-related HF. Methods: We quantified 4955 plasma proteins in stored plasma samples of ARIC Visit 2 (1990-1992) participants without HF using an aptamer-based platform (SOMAScan v4.0). We used Cox regression to identify the proteins associated with incident HF, stratified by obesity (BMI≥30 kg/m 2 ). We used Bonferroni-corrected p-values to assess statistical significance in 2/3 discovery and 1/3 validation subsets. We assessed the biological pathways overexpressed by these proteins using a canonical pathway analysis. Results: We included 9940 participants (28% with obesity, mean age 57 years, 55% female, 22% Black adults). Over a median 21-year follow-up, 2,345 HF events (886 in obesity) occurred. In the discovery subset with obesity, we identified 110 proteins associated with incident HF after demographic adjustment, 19 proteins (7 specific to obesity, Figure B) had robust HF associations after additional adjustment for lifestyle and cardiometabolic risk factors (p<10 -5 ) (Figure A). Of 19 proteins, 12 were also linked to prevalent obesity status. Angiopoietin-2 was associated with higher risk of HF and higher odds of obesity. Conversely, ephrin type-A receptor 4 and seizure 6-like protein were linked to lower HF risk and lower odds of obesity. Lipid and bile acid metabolism (inhibited), cytokine signaling and wound healing pathways (activated) were overexpressed by HF-associated proteins in those with obesity. Conclusion: We identified established and novel proteins associated with HF risk in obesity. Many proteins linked to incident HF in obesity are also strongly associated with prevalent obesity. Formal mediation analysis can help elucidate the potential role of these proteins in the development of obesity-related HF.