Iron deficiency in pulmonary vascular disease: pathophysiological and clinical implications

Abstract

Aims: Iron deficiency is common in pulmonary hypertension, but its clinical significance and optimal definition remain unclear.

Methods and results: Phenotypic data for 1028 patients enrolled in the Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics study were analyzed. Iron deficiency was defined using the conventional heart failure definition and also based upon optimal cut-points associated with impaired peak oxygen consumption (peakVO2), 6-min walk test distance, and 36-Item Short Form Survey (SF-36) scores. The relationships between iron deficiency and cardiac and pulmonary vascular function and structure and outcomes were assessed. The heart failure definition of iron deficiency endorsed by pulmonary hypertension guidelines did not identify patients with reduced peakVO2, 6-min walk test, and SF-36 (P > 0.208 for all), but defining iron deficiency as transferrin saturation (TSAT) <21% did. Compared to those with TSAT ≥21%, patients with TSAT <21% demonstrated lower peakVO2 [absolute difference: -1.89 (-2.73 to -1.04) mL/kg/min], 6-min walk test distance [absolute difference: -34 (-51 to -17) m], and SF-36 physical component score [absolute difference: -2.5 (-1.3 to -3.8)] after adjusting for age, sex, and hemoglobin (all P < 0.001). Patients with a TSAT <21% had more right ventricular remodeling on cardiac magnetic resonance but similar pulmonary vascular resistance on catheterization. Transferrin saturation <21% was also associated with increased mortality risk (hazard ratio 1.63, 95% confidence interval 1.13-2.34; P = 0.009) after adjusting for sex, age, hemoglobin, and N-terminal pro-B-type natriuretic peptide.

Conclusion: The definition of iron deficiency in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines does not identify patients with lower exercise capacity or functional status, while a definition of TSAT <21% identifies patients with lower exercise capacity, worse functional status, right heart remodeling, and adverse clinical outcomes.

Trial registration: ClinicalTrials.gov 02980887.

Keywords: Functional capacity; Iron deficiency; Pulmonary hypertension; Right ventricular remodeling.

Structured Graphical Abstract

Mild PH was defined as mean pulmonary arterial pressure 21–24 mmHg, exercise-induced PH, or mPAP >24 mmHg with pulmonary vascular resistance (PVR) <3 Wood units. WSPH, World Symposium on Pulmonary Hypertension; PH, pulmonary hypertension; mPAP, mean pulmonary artery pressure; TSAT, transferrin saturation; QoL, quality of life; CMR, cardiac magnetic resonance; RHC, right heart catheterization; RV, right ventricle; RAP, right atrial pressure; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RC, resistance/compliance.

Figure 1

Flowchart of study population and prevalence of iron deficiency according to novel transferrin saturation definition. Flowchart of patients in the study and the prevalence of iron deficiency by novel transferrin saturation definition. PVD, pulmonary vascular disease; TSAT, transferrin saturation; PH, pulmonary hypertension.

Figure 2

Limitation of current guideline definition of iron deficiency in pulmonary vascular disease. Impact of the components of the heart failure definition of iron deficiency on peak oxygen consumption (panel A), 6-min walk testing (panel B), and 36-Item Short Form Survey physical component summary score (panel C). Patients with iron deficiency based on isolated hypoferritinemia (ferritin <100 ng/mL but transferrin saturation >20%) had similar peak oxygen consumption as patients without iron deficiency and better 6-min walk testing and 36-Item Short Form Survey, while patients with a low transferrin saturation component in the definition had significantly worse peak oxygen consumption, 6-min walk testing, and 36-Item Short Form Survey. P-values are from unadjusted t-test analysis. peakVO₂, peak oxygen consumption; TSAT, transferrin saturation; 6MWT, 6-min walk testing; SF-36, 36-Item Short Form Survey.

Figure 3

Impact of iron deficiency on exercise capacity. Bar charts illustrating differences between iron-deficient and non-iron–deficient patients across the pulmonary vascular disease spectrum. Error bars indicate 95% confidence interval. P-values are from an analysis of covariance model adjusted for age, sex, and hemoglobin. Blue indicates transferrin saturation ≥21%, and red indicates transferrin saturation <21%. PVD, pulmonary vascular disease; PH, pulmonary hypertension; peakVO₂, peak oxygen consumption; 6MWT, 6-min walk testing; SF-36, 36-Item Short Form Survey.

Figure 4

Forrest plot of impact of iron deficiency according to the World Symposium on Pulmonary Hypertension group. Subgroup analysis from a generalized linear regression model with an interaction term of iron deficiency and the World Symposium on Pulmonary Hypertension groups. Blue indicates transferrin saturation ≥21%, and red indicates transferrin saturation <21%. WSPH, World Symposium on Pulmonary Hypertension; peakVO₂, peak oxygen consumption; 6MWT, 6-min walk testing; SF-36, 36-Item Short Form Survey.