Lee S; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA;
Houstis NE; Cunningham TF; Brooks LC; Chen K; Slocum CL; Ostrom K; Birchenough C; Moore E;  Tattersfield H; Sigurslid H; Guo Y; Landsteiner I;
Rouvina JN; Lewis GD; Malhotra R;

JACC. Heart failure [JACC Heart Fail] 2025 Jun 10; Vol. 13 (8), pp. 102478.
Date of Electronic Publication: 2025 Jun 10.

Background: Iron is a critical factor in cardiac function, oxygen carrying capacity in the blood, and mitochondrial function in skeletal muscle, all of which are key elements of oxygen uptake and utilization during exercise. However, the impact of iron status on hemodynamic responses to exercise and component variables of peak oxygen consumption in patients with heart failure with preserved ejection fraction (HFpEF) is unknown.
Objectives: The authors sought to determine the relationship between markers of iron status and comprehensive exercise response patterns and clinical outcomes in patients with HFpEF.
Methods: Cardiopulmonary exercise testing using cycle ergometry with invasive hemodynamic assessment was performed in 372 patients with HFpEF. Serum iron, transferrin saturation (Tsat), hepcidin, and ferritin were measured at the time of cardiopulmonary exercise testing, and additionally the Tsat/hepcidin ratio was used as a measure of iron homeostasis and hepcidin dysregulation, with low values reflecting inappropriate elevation in hepcidin level relative to iron bioavailability.
Results: In this cohort, 66% had iron deficiency defined as ferritin <100 μg/L or ferritin 100-300 μg/L with Tsat <20%. Higher peak oxygen consumption was associated with higher Tsat% (ρ = 0.33; P < 0.0001), Tsat/hepcidin ratio (ρ = 0.23; P < 0.0001), and serum iron (ρ = 0.30; P < 0.0001) but was not associated with ferritin level. After adjustment for age, hypertension, diuretic use, hemoglobin level, and cardiac index at rest, the association between higher peak oxygen consumption with higher Tsat, Tsat/hepcidin, and iron remained significant (P ≤ 0.006 for all). Tsat, Tsat/hepcidin, and iron were also associated with lower pulmonary artery pressure/cardiac output slope and pulmonary capillary wedge pressure/cardiac output slope, whereas ferritin did not correlate with these exercise hemodynamic measures. Finally, Tsat independently predicted heart failure-free survival, with every higher tertile of Tsat corresponding to an HR of 0.60 (P = 0.002), whereas ferritin was not associated with outcomes.
Conclusions: In patients with HFpEF, Tsat%, but not ferritin levels, relates to more favorable overall metabolic and hemodynamic responses to exercise and better outcomes.
Competing Interests: Funding Support and Author Disclosures Support for this work was provided by the National Heart, Lung, and Blood Institute, including R01HL159514 (to Drs Lewis and Malhotra), R01HL131029 (to Dr Lewis), and R01HL151841 (to Dr Lewis). Drs Lewis and Malhotra have served as consultants for Pharmacosmos. Dr Lewis has served on the scientific advisory board for American Regent.