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

Verdict. 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. It intersects mitochondrial stress/dysfunction themes (systemic metabolic stress).

What the authors report

Heart failure (HF) is a leading cause of morbidity and mortality. 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.

Key results stated in the abstract include the following. 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). 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.

Why it matters for mitochondrial biology

Within mitochondrial research, this work maps primarily to redox biology, metabolism, cardiovascular, therapeutics. It is relevant to mitochondrial dysfunction discourse because the abstract invokes systemic metabolic stress. That does not by itself establish a validated disease mechanism; it indicates thematic proximity. Because a therapeutic or interventional angle is present, the piece is of interest for mitochondrial-targeted drug hypothesis generation—subject to full-text validation of endpoints and safety context. Server: medrxiv. Posted 2026-08-17. Synthesis confidence is bounded by abstract completeness.

Study design (abstract-level)

The abstract does not cleanly separate methods from results. Treat design details as incomplete until the full preprint is inspected.

Principal findings

1. 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.
2. Across HF, HFrEF, and HFpEF, we identified 383 loci (166 novel) and 568 genes (375 novel).
3. 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.
4. Our findings highlight the primordial role of metabolic pathways and adipokines as therapeutic targets for HF management.

Limitations of this brief

• This Mitos brief is an abstract-level synthesis of a preprint; it is not peer review and not a substitute for reading the full paper.
• Preprint status: findings may change with revision or journal review.
• Effect sizes, n numbers, statistics, and full experimental controls are typically incomplete at abstract resolution.
• Comparator/control language is weak or absent in the abstract, limiting causal inference from this brief alone.
• Primary source: medrxiv DOI 10.64898/2026.08.13.26360411 (posted 2026-08-17).

Open scientific questions

• Which specific experimental panels in the full paper establish the strongest causal claim, and how robust are the controls?
• What dose, timing, and off-target profile would be required to take the intervention seriously as a therapeutic hypothesis?
• How do these findings sit relative to prior literature on the same pathway—replication, contradiction, or incremental extension?

Bottom line

For mitochondrial biologists focused on redox biology, metabolism, cardiovascular, this preprint is worth full-text review if the topic matches your program. Abstract-level takeaway: 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. Confirm methods, effect sizes, and controls in the full PDF before citing the result as established.

Bibliographic record

Abstract-based editorial synthesis by Mitos. Not peer review.