Transferrin Saturation, Serum Iron, and Ferritin in Heart Failure: Prognostic Significance and Proteomic Associations.

Summary

In 2,050 heart failure patients, low transferrin saturation and serum iron, but not ferritin, were associated with higher all-cause mortality, with stronger effects in HFpEF. Proteomics linked low TSAT to inflammatory and lipid metabolism pathways, suggesting biological plausibility and a need to re-evaluate iron deficiency criteria.

Key Findings

• Ferritin levels were not associated with outcomes, whereas low TSAT and serum iron predicted higher all-cause mortality.
• Associations of low TSAT with adverse outcomes were stronger in HFpEF than in HFrEF/HFmrEF.
• Proteomic profiling (4,928 proteins) linked low TSAT to inflammatory and lipid metabolism pathways.

Clinical Implications

Prioritize TSAT in iron status assessment for HF patients, especially HFpEF, and consider TSAT-guided selection for iron therapy. Reassess reliance on ferritin alone in clinical algorithms.

Limitations

• Observational design precludes causal inference and treatment effects
• Single cohort; external validation and standardized TSAT thresholds were not established

Future Directions

Validate TSAT-centric definitions in external cohorts and test TSAT-guided iron therapy in randomized trials, including HFpEF. Investigate proteome-anchored mechanisms linking iron handling, inflammation, and outcomes.