Multimodal Machine Learning Reveals the Genomic and Proteomic Architecture of Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) affects over 30 million people and lacks disease-modifying therapies. Although genomic-led drug discovery increases success by more than 2.6-fold, HFpEF genomic discovery remains constrained by imprecise phenotyping in biobanks, with only two loci identified to date. Biobanks lack HFpEF diagnostic codes and echocardiograms, yet HFpEF diagnosis exists along a continuum and is inherently probabilistic, presenting an opportunity for multimodal prediction. Here we introduce TRI-modal Assessment and Discovery of HFpEF (TRIAD-HFpEF), a machine learning framework integrating electrocardiograms, cardiac magnetic resonance imaging, and biomarkers to assign HFpEF probabilities. Deployed in UK Biobank, these probabilities validate with respect to mortality, hospitalizations, and structural and functional HFpEF features. Genome-wide and proteomic analyses reveal over 90 novel loci, a 45-fold expansion, and distinguish causal proteins from non-causal biomarkers of disease progression, prioritizing 11 therapeutic targets and 7 non-causal biomarkers. We identify FLT3 as one of the 11 therapeutic targets, consistent with the reported 7-fold increased heart failure risk from FLT3 inhibitors in leukemia. We validate this finding by demonstrating significant worsening of diastolic function following FLT3 inhibitor treatment in an independent clinical cohort. Conversely, MPO emerged as one of the 7 non-causal biomarkers, aligning with three recent negative MPO inhibitor trials. TRIAD-HFpEF demonstrates that machine learning-derived phenotypes can unlock genetic discovery in complex syndromes, identifying actionable targets while deprioritizing associations reflecting disease consequences rather than causes.