Highlights
Recent evidence suggests that the current European Society of Cardiology (ESC) definitions for iron deficiency (ID) in heart failure (HF) may need refinement. Key takeaways from recent landmark studies include:
- Transferrin saturation (TSAT) <20% and serum iron ≤13 μmol/L are more robustly associated with reduced functional capacity (6-minute walk distance) and worse clinical outcomes than ferritin levels.
- In patients with heart failure with preserved ejection fraction (HFpEF), TSAT <20% shows the strongest association with heart failure hospitalizations and cardiovascular mortality.
- Changes in TSAT and serum iron over time, rather than ferritin, correlate with improvements in hemoglobin levels and exercise tolerance.
- The prognostic value of TSAT <20% remains significant regardless of the patient’s anemia status.
Background: The Burden of Iron Deficiency in Heart Failure
Iron deficiency (ID) is one of the most prevalent comorbidities in patients with heart failure, affecting approximately 50% of the population. Unlike absolute iron deficiency seen in nutritional contexts, ID in HF is often functional, where systemic inflammation leads to the sequestration of iron in the reticuloendothelial system, making it unavailable for metabolic processes. This cellular iron drought impairs myocardial energetics, reduces skeletal muscle function, and exacerbates the symptoms of HF, regardless of the presence of anemia.
Historically, the diagnosis of ID in HF has relied on the ESC guidelines: a ferritin level <100 ng/mL or a ferritin level between 100-299 ng/mL with a TSAT <20%. However, as ferritin is an acute-phase reactant, its levels can be elevated by the chronic inflammatory state of heart failure, potentially masking a true iron-deficient state. This has led to a critical re-evaluation of which iron indices—ferritin, TSAT, or serum iron—best reflect the biological and prognostic reality of the disease.
The Diagnostic Challenge: Current Definitions vs. Clinical Reality
The medical community is currently navigating a transition in how iron status is interpreted. The HEART-FID trial, the Swedish Heart Failure Registry, and the Danish Heart Failure Registry have recently provided massive data sets that challenge the status quo. These studies collectively suggest that the ferritin-heavy definitions traditionally used in clinical trials and guidelines may not be the most effective tools for identifying patients at the highest risk or those most likely to benefit from intravenous iron repletion.
Evidence from HEART-FID: Prioritizing Functional Capacity
The HEART-FID (Ferric Carboxymaltose in Heart Failure with Iron Deficiency) trial evaluated 2,951 patients with heart failure and reduced ejection fraction (HFrEF). While the trial required patients to meet the ESC definition of ID, researchers conducted a post-hoc analysis to determine which individual indices correlated most closely with patient outcomes.
The results were striking: although nearly 90% of participants had ferritin levels <100 ng/mL, only about 40% had a TSAT <20%. Crucially, those with TSAT <20% and serum iron <13 μM exhibited significantly worse baseline NYHA functional class, shorter 6-minute walk distances (6MWD), and lower hemoglobin levels. Furthermore, the study found that changes in TSAT and serum iron over a 6-month period were directly related to improvements in 6MWD and hemoglobin, whereas changes in ferritin did not show the same functional correlation. These findings suggest that TSAT is a more dynamic and clinically relevant marker of available iron for mitochondrial and erythropoietic function.
Insights from the Swedish Heart Failure Registry: Impact Across Ejection Fraction Phenotypes
One of the most comprehensive evaluations of ID definitions comes from the Swedish Heart Failure Registry, which included 20,673 patients. This study assessed four different ID definitions across the spectrum of ejection fractions: HFrEF, HFmrEF (mildly reduced), and HFpEF.
The prevalence of ID was highest in the HFpEF group (up to 54% using guideline criteria). The study found that while all definitions were associated with worse symptoms, ferritin <100 μg/L in isolation was not associated with any adverse clinical outcomes. In contrast, TSAT <20% and the IRONMAN trial criteria (TSAT <20% or ferritin <100 μg/L) were independently associated with higher risks of cardiovascular death and heart failure hospitalizations. Notably, the prognostic strength of TSAT <20% was most pronounced in patients with HFpEF, a group for whom effective treatments are notoriously limited. This suggests that TSAT <20% should be the preferred metric for identifying high-risk patients in both clinical practice and future trial enrollment.
New-Onset Heart Failure: Lessons from the Danish Registry
The Danish Heart Failure Registry provided insights into 9,477 patients with new-onset chronic HF. This registry underscored the limitations of the ESC definition. Approximately 26% of patients with low serum iron and 15.5% of those with low TSAT did not meet the ESC guidelines’ ID criteria, meaning a significant portion of iron-deficient patients might be overlooked in standard care.
The Danish data revealed that ID defined by TSAT <20% or serum iron ≤13 μmol/L was associated with increased all-cause and cardiovascular mortality regardless of whether the patient was anemic. For non-anemic patients, the hazard ratio (HR) for all-cause mortality with TSAT <20% was 1.57 (95% CI: 1.30-1.89). Conversely, the ESC guideline definition was only associated with mortality in non-anemic patients, losing its prognostic significance in those with anemia. This reinforces the idea that TSAT and serum iron are more reliable indicators of the systemic impact of iron deficiency.
Expert Commentary: Mechanistic Rationale and Clinical Translation
Why does TSAT outperform ferritin in predicting outcomes? Mechanistically, TSAT reflects the ratio of serum iron to total iron-binding capacity, representing the amount of iron immediately available for transport to tissues. In the heart, iron is a vital cofactor for enzymes in the mitochondrial electron transport chain. When TSAT is low, the supply of iron to cardiomyocytes is compromised, leading to impaired ATP production and reduced contractile efficiency.
Ferritin, while reflecting total body iron stores in healthy individuals, becomes unreliable in the setting of chronic heart failure. As an acute-phase protein, it is up-regulated by pro-inflammatory cytokines such as IL-6 and TNF-alpha. Therefore, a heart failure patient might have a “normal” ferritin level despite having severely depleted functional iron. The recent data suggests that clinicians should place greater weight on TSAT <20% and serum iron ≤13 μmol/L when evaluating a patient’s need for iron therapy.
Study Limitations and Considerations
While the evidence strongly supports TSAT, it is important to note that most randomized controlled trials (such as FAIR-HF, CONFIRM-HF, and AFFIRM-AHF) used the ESC definition for enrollment. Therefore, current evidence for the benefit of intravenous iron (specifically ferric carboxymaltose) is technically tied to those guideline criteria. However, the secondary analyses from HEART-FID and the registry data suggest that the subset of patients with low TSAT likely derives the greatest benefit.
Conclusion: Moving Toward a TSAT-Centric Approach
The landscape of iron deficiency management in heart failure is evolving. The collective evidence from HEART-FID and major European registries indicates that our current reliance on ferritin may be misplaced. TSAT <20% and serum iron ≤13 μmol/L consistently emerge as superior markers for functional impairment, hospitalization risk, and mortality across all heart failure phenotypes.
For clinicians, these findings suggest a practical shift: when reviewing iron studies, the TSAT value should perhaps be the first metric scrutinized. Identifying and treating patients with low TSAT—even if their ferritin appears deceptively high—may be the key to improving quality of life and clinical trajectories in the heart failure population.
References
- Lewis GD, et al. Functional and Prognostic Implications of Different Iron Deficiency Definitions in Heart Failure: Insights From HEART-FID. JACC Heart Fail. 2025;13(12):102661.
- Lindberg F, et al. Iron Deficiency Definitions in Heart Failure Across Ejection Fraction Phenotypes: Prevalence, Symptoms, and Cause-Specific Outcomes. JACC Heart Fail. 2025;13(11):102662.
- Mohamed AA, et al. Prognostic impact of iron deficiency in new-onset chronic heart failure: Danish Heart Failure Registry insights. ESC Heart Fail. 2025;12(2):1346-1357.
- Ponikowski P, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42(36):3599-3726.
