A massive multi-ancestry genome-wide association study spanning 345,687 heart failure cases across 4.47 million individuals uncovered 383 genomic loci — 166 previously unknown — and 568 associated genes, 375 of them novel. Crucially, 11 newly identified genes are already targets of approved or investigational cardiovascular drugs, pointing toward indication expansion of aldosterone synthase inhibitors (targeting CYP11B2) and type-II activin receptor antagonists (targeting ACVR2A) specifically for heart failure. Nearly 100 genes cluster around metabolic functions: fatty acid and glucose metabolism, branched-chain amino acid catabolism, mitochondrial energy production, and adipokine signaling.
This preprint, not yet peer-reviewed, represents the most statistically powered heart failure genomics effort to date, and its multi-ancestry design meaningfully improves on Eurocentric predecessors. The separation of HFpEF from HFrEF as distinct genomic phenotypes is particularly valuable — these subtypes respond differently to existing therapies yet have historically been conflated in genetic studies. The metabolic signal is striking: it reinforces emerging evidence that heart failure is partly a disease of myocardial energy starvation, not purely a structural or hemodynamic problem, aligning with the therapeutic success of SGLT2 inhibitors. The drug-target prioritization through proteomics and transcriptomics integration elevates this beyond a simple discovery exercise. Limitations include reliance on retrospective cohort definitions and the inherent gap between genetic association and causality. Results may shift substantially after peer review, but the scale and mechanistic depth here suggest this is a genuinely paradigm-influencing contribution to cardiovascular medicine.