Large-scale multi-omics identifies drug targets for heart failure with reduced and preserved ejection fraction.

Summary

Using Mendelian randomization across >420,000 participants, the authors identified 70 HFrEF and 10 HFpEF causal targets, largely non-overlapping, highlighting the need for subtype-specific therapies. Druggable candidates include IL6R, ADM, and EDNRA for HFrEF and LPA for both subtypes; findings were replicated in >175,000 multi-ancestry participants.

Key Findings

• Identified 70 causal targets for HFrEF and 10 for HFpEF; 58 were novel and targets were non-overlapping across subtypes.
• Validated roles of ubiquitin–proteasome system, SUMO pathway, inflammation, and mitochondrial metabolism in HFrEF.
• Druggable candidates include IL6R, ADM, EDNRA (HFrEF) and LPA (both HFrEF and HFpEF); 14 loci reclassified as HFrEF.

Clinical Implications

While not immediately practice-changing, the prioritized targets (e.g., IL6R, ADM, EDNRA, LPA) inform trial design and companion biomarker strategies for subtype-specific HF therapies.

Limitations

• Causal inference depends on MR assumptions and potential horizontal pleiotropy
• Translational impact requires interventional trials to confirm therapeutic efficacy

Future Directions

Prospective trials targeting prioritized pathways (e.g., IL6R, ADM/EDNRA signaling, LPA lowering) with subtype-specific enrollment and biomarker-guided stratification.