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

Cardiac diseases represent common highly morbid conditions for which molecular mechanisms remain incompletely understood. Here we report the analysis of 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 aligning with epidemiological findings for 4% of proteins identified in primary analyses, prioritizing therapeutic targets across cardiac diseases (for example, spondin-1 for atrial fibrillation and the Kunitz-type protease inhibitor 1 for coronary artery disease). Interaction analyses identified seven protein-disease associations that differed Bonferroni-significantly by sex. Models incorporating proteomic data (versus 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 disease mechanisms and assess the utility of protein-based prevention strategies for cardiac diseases.