Proteomic signatures of cardiovascular imaging phenotypes and links with cardiovascular and systemic outcomes: a prospective cohort and Mendelian randomization study

The upstream proteomic determinants of cardiovascular remodeling and their contributions to systemic diseases and mortality risk remain incompletely understood. Here, using longitudinal data from the UK Biobank ( N = 68,566; median follow-up 3.82–3.98 years), we systematically evaluated the associations between 14 cardiovascular magnetic resonance (CMR) metrics and the risks of 41 cardiovascular and systemic diseases, as well as all-cause and cause-specific mortality. We identified 88 significant cross-system associations, supporting the disease relevance of CMR-assessed cardiovascular structural and functional phenotypes. Among a proteomic sub-cohort ( N = 7,892), multivariable-adjusted regression identified 681 unique proteins significantly associated with CMR phenotypes, revealing a biological landscape dominated by immune-inflammatory processes and extracellular matrix remodeling. Utilizing machine learning approaches, we distilled CMR-associated plasma proteins into parsimonious protein-CMR model comprising 26–57 proteins. These models demonstrated moderate to strong predictive performance for CMR metrics (Pearson r : 0.43–0.72) and showed potential utility for predicting and stratifying the risk of incident cardiovascular and other systemic morbidities and mortality. Genetically, Mendelian randomization (MR) prioritized 222 potential causal protein-CMR pairs with effect directions consistent with observational analyses, and highlighted proteins with associations across multiple CMR phenotypes, including ISLR2, EPHA4, and NRCAM. Colocalization analysis further prioritized 6 pairs with moderate-to-strong evidence of shared causal variants. Subsequent two-step MR suggested that left ventricular mass potentially mediates the genetically supported associations of five upstream proteins with atrial fibrillation. Finally, we integrated single-cell transcriptomic annotations and druggability assessment to explore the potential translational relevance of prioritized proteins. Together, these findings characterize circulating proteomic signatures associated with CMR-defined cardiovascular remodeling and provide an integrated framework for understanding their biological and prognostic relevance to cardiovascular and systemic disease risk.