Associations of iron deficiency with cardiac function, congestion, exercise capacity and prognosis in heart failure

Nicolò De Biase; Lavinia Del Punta; Wouter L'Hoyes; Pierpaolo Pellicori; John G F Cleland; Gabriele Masini; Luna Gargani; Sara Moura-Ferreira; Sarah Hoedemakers; Valerio Di Fiore; Lieven Herbots; Jan Stassen; Alessandro Mengozzi; Silvia Armenia; Stefano Taddei; Stefano Masi; Jan Verwerft; Nicola Riccardo Pugliese

doi:10.1002/ejhf.3534

Associations of iron deficiency with cardiac function, congestion, exercise capacity and prognosis in heart failure

Eur J Heart Fail. 2024 Nov 28. doi: 10.1002/ejhf.3534. Online ahead of print.

Authors

Nicolò De Biase^#¹, Lavinia Del Punta^#¹, Wouter L'Hoyes^#², Pierpaolo Pellicori³, John G F Cleland³, Gabriele Masini⁴, Luna Gargani⁴, Sara Moura-Ferreira^{2

5}, Sarah Hoedemakers^{2

5}, Valerio Di Fiore¹, Lieven Herbots², Jan Stassen², Alessandro Mengozzi¹, Silvia Armenia¹, Stefano Taddei¹, Stefano Masi¹, Jan Verwerft^#², Nicola Riccardo Pugliese^#¹

Affiliations

¹ Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
² Department of Cardiology, Jessa Hospital, Hasselt, Belgium.
³ School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
⁴ Cardiac, Thoracic and Vascular Department, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
⁵ UHasselt, Faculty of Rehabilitation Sciences, Rehabilitation Research Center, Diepenbeek, Belgium.

^# Contributed equally.

PMID: 39607281
DOI: 10.1002/ejhf.3534

Abstract

Aims: Uncertainty exists about defining true iron deficiency (ID) in heart failure (HF) patients. We assessed the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in HF outpatients.

Methods and results: Iron deficiency was defined according to guidelines (G-ID: ferritin <100 ng/ml or ferritin 100-299 ng/ml with transferrin saturation [TSAT] <20%). Alternative ID definitions based on TSAT (<20%), iron (≤13 μmol/L), and ferritin (<100 or < 300 ng/ml) were explored. Relationships with rest/exercise measures of cardiac function and congestion using ultrasound, effort intolerance and adverse outcome (HF hospitalizations or all-cause mortality) were assessed. Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G-ID. Patients with TSAT <20% or G-ID had greater left atrial volume but similar LVEF. Lower TSAT, iron and haemoglobin, but not ferritin, were associated with more signs of congestion by ultrasound. After correcting for multiple clinical variables, including haemoglobin, TSAT was directly associated with peak oxygen uptake (standardized coefficient 0.069, p = 0.041), while ferritin was not. There was no interaction with HF phenotype (HF with preserved vs. reduced LVEF). During a median follow-up of 18 months, TSAT <20% and iron ≤13 μmol/L were associated with worse outcomes in models adjusted for clinical variables, including LVEF and N-terminal pro-B-type natriuretic peptide (hazard ratio 2.48, 95% confidence interval 1.88-3.17 and 1.93, 1.48-2.52, respectively), while G-ID or ferritin <100 or <300 ng/ml were not.

Conclusion: In HF outpatients, TSAT <20% is more consistently associated with congestion by ultrasound and poorer functional capacity than other ID definitions, irrespective of LVEF. TSAT <20% and iron ≤13 μmol/L, but not G-ID or ferritin-based ID, predict a worse prognosis in HF outpatients with preserved and reduced LVEF.

Keywords: Congestion; Exercise capacity; Heart failure; Heart failure with preserved ejection fraction; Iron deficiency; Prognosis.