“Heart Failure Minutes” (Episode 2) - Iron in Heart Failure: Evolving Concepts

HOST: Dr Milica Vukićević - Cardiologist, William Harvey Scholar at Brigham and Women’s Hospital Campus of the MGB Heart and Vascular Institute, Harvard Medical School.
SPEAKER: Prof. Gregory Lewis, Director of HF at Mass General Brigham and a Professor of Medicine at Harvard Medical School.

In this edition, we take a fresh look at iron biology in heart failure. The field is moving beyond traditional markers like ferritin and toward measures that better reflect true iron bioavailability: serum iron and transferrin saturation (TSAT).

Milica Vukićević and Gregory Lewis, Professor of Medicine at Harvard Medical School, discuss the evolution of this science and several hard truths learned over the past decade:

a) Ferritin levels can be misleading.
Ferritin is an intracellular nanocage that stores iron but circulating levels of ferritin are heavily influenced by inflammation—common in HF—that obscures the real burden of functional iron deficiency. New frameworks place TSAT and serum iron at the center of assessment. In a recent analysis, despite ferritin below100 ng/mL being the most common criteria of the disorder for entry into the largest trial to date of intravenous iron repletion in HFrEF (TheHEART-FID Trial), TSAT and iron levels and their changes over time, more than ferritin, were related to functional capacity, hemoglobin levels, and prognosis. (Lewis GD et al. JACC Heart Fail. 2025 Oct 25:102661).

b) Oral iron does not work in HF.
Hepcidin-driven gut blockade prevents meaningful absorption. Trials such as IRONOUT (Lewis GD et al., JAMA 2017) made this unmistakably clear: oral iron is not effective in HFrEF.

c) IV iron repletion trials have yet to deliver primary endpoint success.
Studies including HEART-FID (Mentz RJ et al., NEJM 2023), AFFIRM (Ponikowski P, Lancet 2020) show encouraging signals around HF event reduction, yet pre-specified primary outcomes were not met. The therapeutic story is more nuanced than early optimism suggested.

d) HFpEF remains an open frontier.
Most iron supplementation data in HF pertains to HFrEF. Whether iron repletion improves HFpEF—now understood as a syndrome driven by inflammation across the obesity spectrum—remains unknown. We simply do not have definitive data yet.

e) A new generation of trials is underway.
Upcoming studies such as ICONIC-HF will enroll patients based solely on TSAT below 20%, intentionally ignoring ferritin and focusing purely on iron availability. Their results could redefine how we diagnose and treat iron deficiency across the HF spectrum.

Likewise, IRONMET-HFpEF (NCT04945707)—a single-dose trial of IV ferric derisomaltose in HFpEF evaluating 12-week changes in exercise tolerance—is expected to report in 2026.

In this conversation, we explore these shifts and examine why the field must recalibrate long-held assumptions about the evaluation and treatment of iron deficiency in heart failure.

Evidence, not habit, must guide the next chapter of care with use of IV Iron.
https://www.jacc.org/doi/10.1016/j.jc...

‪@AmericanCollegeOfCardiology‬ ‪@NEJMgroup‬ ‪@JAMANetwork‬

Video Credits:
This video was created and produced by Drs Milica Vukićević, Ameesh Isath and Mandeep Mehra along with Wendy Suero at the Brigham Campus of the MGB Heart and Vascular Institute.