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. 2025 Feb;18(2):e011728.
doi: 10.1161/CIRCHEARTFAILURE.124.011728. Epub 2025 Jan 20.

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

Sushrima Gan #  1   2 , Joe David Azzo #  1   2 , Lei Zhao  3 , Bianca Pourmussa  1   2 , Marie Joe Dib  1   2 , Oday Salman  1   2 , Ozgun Erten  1   2 , Christina Ebert  3 , A Mark Richards  4   5 , Ali Javaheri  6   7 , Douglas L Mann  6 , Ernst Rietzschel  8 , Payman Zamani  1   2 , Vanessa van Empel  9 , Thomas P Cappola  1   2 , Julio A Chirinos  1   2
Affiliations

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

Sushrima Gan et al. Circ Heart Fail. 2025 Feb.

Abstract

Background: Iron deficiency (ID) is currently defined as a serum ferritin level <100 or 100 to 299 ng/mL with transferrin saturation (TSAT) <20%. Serum ferritin and TSAT are currently used to define absolute and functional ID. However, individual markers of iron metabolism may be more informative than current arbitrary definitions of ID.

Methods: We assessed prognostic associations of ferritin, serum iron, and TSAT among 2050 participants with heart failure (HF) with reduced/mid-range (n=1821) or preserved (n=229) left ventricular ejection fraction enrolled in the PHFS (Penn HF Study), a prospective cohort study. We measured 4928 plasma proteins using an aptamer-based assay (SOMAScanv4) and assessed prognostic and proteomic associations of markers of iron metabolism.

Results: Ferritin concentrations were not associated with outcomes, whereas low TSAT and serum iron were associated with the risk of all-cause death (TSAT: standardized hazard ratio, 0.84 [95% CI, 0.76-0.93]; P=0.001; serum iron: standardized hazard ratio, 0.87 [95% CI, 0.79-0.96]; P=0.007). Similarly, TSAT was associated with the risk of death or HF-related admission (standardized hazard ratio, 0.89 [95% CI, 0.83-0.95]; P=0.0006). Significant interactions between TSAT and HF with preserved ejection fraction status were found such that TSAT was more strongly associated with the risk of death and death or HF-related admission in HF with preserved ejection fraction. We identified 359 proteins associated with TSAT, including TFRC (transferrin receptor protein; β, -0.455; P<0.0001) and CRP (C-reactive protein; β, -0.355; P<0.0001). Pathway analyses demonstrated associations with lipid metabolism, complement activation, and inflammation. In contrast to the robust associations between TSAT and outcomes, ID and absolute ID defined by current criteria were not associated with death or death or HF-related admission. TSAT was associated with outcomes regardless of the presence of functional versus absolute ID.

Conclusions: Low TSAT, but not ferritin concentrations, is significantly associated with adverse outcomes in HF. Low TSAT is more strongly associated with outcomes in HF with preserved ejection fraction. Pathways related to inflammation and lipid metabolism are associated with low TSAT in HF.

Keywords: ferritins; heart failure; inflammation; iron deficiencies; lipid metabolism.

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Conflict of interest statement

Dr Chirinos has recently consulted for Bayer, Fukuda Denshi, Bristol Myers Squibb (BMS), Johnson & Johnson, Edwards Lifesciences, Merck, Biohaven, the University of Delaware, Emory University, and the Galway-Mayo Institute of Technology. He received the University of Pennsylvania research grants from the National Institutes of Health, Fukuda Denshi, BMS, Microsoft, and Abbott Laboratories. He is named the inventor in a patent related to the use of inorganic nitrate in heart failure with preserved ejection fraction (HFpEF), patent applications related to the use of plasma, and urine protein biomarkers in HFpEF. He received payments for editorial roles from the American Heart Association, the American College of Cardiology, and Wiley. He received research device loans from AtCor Medical, Fukuda Denshi, Uscom, ndd Medical Technologies, Microsoft, and MicroVision Medical. Dr Zamani is supported by the grants R01 HL155599, R01 HL157264, R01 HL149722, U01-HL160277, and UH3DK128298. He also received research support from Amgen. He has consulted for Pfizer and Vyaire. Dr Rietzschel received unrestricted educational grants from Amgen, Merck Sharp & Dohme, AstraZeneca, Sanofi, and Unilever and speakers or consultancy fees from Daiichi Sankyo, Novo Nordisk, Boehringer Ingelheim, Servier, Amgen, Sanofi, Novartis, and Teva, all paid directly to the Ghent University. Dr Richards is supported by grants from the Singapore National Medical Research Council and the Health Research Council of New Zealand. He holds the New Zealand Heart Foundation Chair in Cardiovascular Studies. In-kind support and research grants are received from Roche Diagnostics, Abbott Laboratories, and Novo Nordisk. He is named on ≈30 cardiovascular biomarker patents. The general disclosure statement of all BMS coauthors includes BMS employees and BMY stockholders. The other authors report no conflicts.

Comment in

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