Abstract Background It is uncertain how best to diagnose iron deficiency (ID) in patients with heart failure (HF) as different ID definitions have been proposed with discordant results. Objectives To assess the relationship of different ID definitions with cardiac structure and function, congestion, exercise capacity, and prognosis in outpatients with HF. Methods ID was defined according to guidelines (G-ID: ferritin <100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation [TSAT] <20%) or as TSAT <20%. Alternative definitions (iron <13 ¼mol/L, ferritin <100 and <300 ng/mL) were explored. Relationship with rest and exercise ultrasound findings, cardiopulmonary exercise testing and a composite endpoint of cardiovascular hospitalisations or all-cause mortality were assessed. Results Of 1502 patients (72% with left ventricular ejection fraction [LVEF] ≥50%), 471 (31%) had TSAT <20%, while 728 (48%) had G-ID. Compared to those without ID, patients with TSAT <20% or G-ID showed impaired cardiac structure and function at rest and peak exercise and lower peak oxygen consumption; they were also more likely to display a discontinuous renal venous flow pattern and more lung B-lines. Only TSAT <20% was associated with significant inferior vena cava dilatation. Lower TSAT, iron and haemoglobin were associated with more severe effort intolerance and ultrasound signs of congestion, while ferritin and LVEF were not (Picture 1). During a median follow-up of 16 months, 62 (4%) patients died, and 244 (16%) were hospitalised for cardiovascular reasons. No patients were hospitalised immediately after the enrolment visit because of clinical findings. At Kaplan-Meier analyses, TSAT <20% was associated with a greater risk of adverse events, as were iron ≤13 ¼mol/L, ferritin ≥300 ng/mL and <100 ng/mL (p <0.01 vs ferritin 100-299 ng/mL) and G-ID (Picture 2). After adjusting for age, sex, diabetes, haemoglobin, estimated glomerular filtration rate (eGFR), NT-proBNP, rest LVEF and peak VO2 <16 mL/kg/min, TSAT <20% and iron ≤13 ¼mol/L were associated with worse outcomes (hazard ratio 2.41, 95% confidence interval 1.85-3.14 and 1.90, 1.46-2.47), while G-ID or ferritin <100 or <300 ng/mL were not (Picture 1). Conclusions In outpatients with HF, TSAT <20% is more consistently associated with echocardiographic signs of poorer functional capacity and multi-organ congestion than other ID definitions. TSAT <20% and iron ≤13 ¼mol/L, but not G-ID or ferritin-based ID, seem to predict a worse prognosis.Picture 1Picture 2