Finding. In more than four million people, heart-failure genetics keeps pointing at how the heart eats and how its mitochondrial proteome is staffed. 383 loci, 166 of them new; 568 genes, 375 new. Almost a hundred of those genes live in appetite and energy expenditure, fatty-acid, glucose, and branched-chain amino-acid metabolism, and the mitochondrial proteome that keeps ATP coming. Eleven new genes are already drug targets, including a genetic nudge to try aldosterone-synthase inhibitors and activin-receptor antagonists in HF. Six cardiomyopathy genes are new as HF genes and move cardiac structure.
Why this paper matters
HF target lists have been sarcomere, fibrosis, and hemodynamics. A map this large that still lights up myocardial energy is a reminder that the failing heart is a metabolic organ. The mitochondrial-proteome clause is the reason it is here.
Indication-expansion language is genetics, not a phase 3.
What they actually measured
Huge multi-ancestry GWAS, subtype splits, proteomic and transcriptomic integration, druggability overlay.
How to read the score
Low seventies as a mitochondrial brief (atlas, not assay), high as an HF genetics brief. Score 73. Confidence is medium for any single new gene, high for the metabolic enrichment as a theme.
What to do with it
Pull the mitochondrial-proteome and fuel-metabolism gene lists, split by HFpEF/HFrEF. If you develop CYP11B2 or ACVR2A drugs, read the expansion argument. Do not treat a GWAS hit as a mitochondrial mechanism. The directional implication is that myocardial energy production and adipokine biology are genetically central to HF, not peripheral color.