Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: Two randomized controlled trials

Context: Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude. Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status, possibly acting through the transcription factor hypoxia-inducible factor, but the pathophysiological and clinical importance of this interaction is unknown. Objective: To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension. Design, Setting, and Participants: Two randomized, double-blind, placebo-controlled protocols conducted in October-November 2008. In the first protocol, 22 healthy sea-level resident men (aged 19-60 years) were studied over 1 week of hypoxia at Cerro de Pasco, Peru (altitude 4340 m). In the second protocol, 11 highaltitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru. Intervention: In the first protocol, participants received intravenous infusions of Fe(III)-hydroxide sucrose (200 mg) or placebo on the third day of hypoxia. In the second protocol, patients underwent staged isovolemic venesection of 2 L of blood. Two weeks later, patients received intravenous infusions of Fe(III)-hydroxide sucrose (400 mg) or placebo, which were subsequently crossed over. Main Outcome Measure: Effect of varying iron availability on pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography. Results In the sea-level resident protocol, approximately 40% of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron, which reduced PASP by 6 mm Hg (95% confidence interval [CI], 4-8 mm Hg), from 37 mm Hg (95% CI, 34-40 mm Hg) to 31 mm Hg (95% CI, 29-33 mm Hg; P=.01). In the chronic mountain sickness protocol, progressive iron deficiency induced by venesection was associated with an approximately 25% increase in PASP of 9 mmHg (95% CI, 4-14 mmHg), from 37 mm Hg (95% CI, 30-44 mm Hg) to 46 mm Hg (95% CI, 40-52 mm Hg; P=.003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected. Conclusion: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. Trial Registration clinicaltrials.gov Identifier: NCT00952302.