Integrative proteomic analyses across common cardiac diseases yield new mechanistic insights and enhanced prediction

Abstract Cardiac diseases represent common highly morbid conditions for which underlying molecular mechanisms remain incompletely understood. Here, we leveraged 1,459 protein measurements in 44,313 UK Biobank participants to characterize the circulating proteome associated with incident coronary artery disease, heart failure, atrial fibrillation, and aortic stenosis. Multivariable-adjusted Cox regression identified 820 protein-disease associations—including 441 proteins—at Bonferroni-adjusted P <8.6×10 −6 . Cis -Mendelian randomization suggested causal roles that aligned with epidemiological findings for 6% of proteins identified in primary analyses, prioritizing novel therapeutic targets for different cardiac diseases (e.g., interleukin-4 receptor for heart failure and spondin-1 for atrial fibrillation). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (vs. clinical risk factors alone) improved prediction for coronary artery disease, heart failure, and atrial fibrillation. These results lay a foundation for future investigations to uncover novel disease mechanisms and assess the clinical utility of protein-based prevention strategies for cardiac diseases.