Cardiac proteomic and phosphoproteomic profiling defines clinically relevant molecular subgroups in human heart failure.

Molecular heterogeneity in heart failure (HF) is increasingly recognized as a major barrier to effective therapy development. Here we performed proteomic profiling of left ventricular tissues from 149 patients with advanced HF spanning nine clinical etiologies. Despite clinical diversity, etiology-stratified analyses revealed convergence toward a shared end-stage proteomic landscape. By contrast, unbiased proteome-based clustering stratified patients into two molecular subgroups characterized by divergent remodeling phenotypes, including differences in fibrosis and immune cell infiltration. Phosphoproteomic profiling was consistent with this stratification, and the analyses further uncovered selective activation of druggable signaling networks in a molecularly defined subgroup of patients. Moreover, our remodeling-associated subgrouping proteins also stratified patients and predicted survival trajectories in an independent plasma-based HF cohort from the UK Biobank, extending our findings to earlier disease stages. Together, our study provides a rich resource for molecular classification of patients with HF, supporting the development of precision-guided therapeutic strategies.