Iron deficiency in heart failure is associated with worse outcomes across the LVEF spectrum: the role of serum iron in HFpEF

Background/purpose Iron deficiency (ID) is common in heart failure (HF) and associated with worse clinical outcomes in patients with a left ventricular ejection fraction (LVEF) <50% (HFrEF & HFmrEF). However, its role in those with LVEF ≥50% (HFpEF) remains unclear. We aimed to assess the clinical relevance of ID across the LVEF spectrum. Methods Patients with known LVEF and iron parameters from the index (n = 2111) and validation cohort (n = 1532) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled (n=3643). ID was defined using two definitions, either as transferrin saturation (TSAT) <20% or a serum iron ≤13 μmol/L. Results ID, according to both TSAT or serum iron respectively, was observed in 2130 (58%) or 2580 (71%) patients and followed a U-shaped distribution across the LVEF spectrum, with the highest prevalence in those with LVEF <20% and HFpEF. Among patients with TSAT >20%, those with serum iron ≤13 µmol/L exhibited worse clinical characteristics when compared to those with iron>13 µmol/L. ID defined by either definitions was associated with lower quality of life and reduced physical activity as reflected by KCCQ overall summary score and physical limitation score across all groups (p < 0.01). Independent predictors of ID included female sex, higher heart rate, proton pump inhibitor use, low hemoglobin and albumin levels, elevated white blood cells, fluid retention, and impaired kidney function, none of which were modified by LVEF (all interaction p >0.1). In multivariable survival analyses, ID was associated with increased all-cause mortality (HR: 1.38 [95% CI: 1.17–1.63], p < 0.001) and HF hospitalization (HR: 1.29 [95% CI: 1.10–1.51], p = 0.002) in LVEF<50% irrespective of the definition. However, in HFpEF, ID defined by TSAT was not associated with increased all-cause mortality (HR: 1.02 [95% CI: 0.73–1.42], p = 0.899) or combined endpoints (HR: 0.97 [95% CI: 0.75-1.26], p = 0.877). By contrast, when ID was defined using serum iron, the association with all-cause mortality and combined endpoints appeared stronger, though it did not reach statistical significance. Interaction analyses between the two definitions revealed that HFpEF patients with TSAT >20%, but serum iron <13 µmol/L had significantly worse combined outcomes (HR: 1.71 [95% CI: 1.13-2.61], p = 0.011) compared to those with serum iron ≥13 µmol/L and TSAT>20% (interaction p = 0.018). Conclusion ID is common across the HF spectrum and is associated with reduced quality of life and exercise capacity regardless of LVEF. While ID, defined by TSAT <20%, is linked to worse prognosis in LVEF<50%, it was not predictive of outcomes in HFpEF. However, serum iron appears to better identify patients at risk for adverse outcomes, suggesting it may be a more clinically relevant marker of impaired iron availability that is not fully captured by TSAT alone particularly in HFpEF.