Global genomics in over 4 million individuals prioritizes therapeutic targets for heart failure and its subtypes

<jats:p>Heart failure (HF) is a leading cause of morbidity and mortality. We conducted multi-ancestry genome-wide association studies of 345,687 HF cases (4,468,166 individuals), and 47,192 and 46,934 cases of HF with preserved (HFpEF) and reduced ejection fraction (HFrEF), respectively, integrating plasma proteomics and multi-tissue transcriptomics to identify druggable targets. Across HF, HFrEF, and HFpEF, we identified 383 loci (166 novel) and 568 genes (375 novel). Eleven novel genes are targets of approved or investigational cardiovascular therapies, supporting indication expansion of aldosterone synthase inhibitors (CYP11B2) and type-II activin receptor antagonists (ACVR2A) to HF. Six cardiomyopathy genes were novel for HF and associated with cardiac structure and function. We identified nearly 100 genes involved in food intake and energy expenditure; metabolism of fatty acids, glucose, and branched-chain amino acids; and mitochondrial proteome, sustaining myocardial energy production. Our findings highlight the primordial role of metabolic pathways and adipokines as therapeutic targets for HF management.</jats:p>