Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials.
BACKGROUND
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.


METHODS
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 high-altitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru.


METHODS
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.


METHODS
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 mm Hg (95% CI, 4-14 mm Hg), 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.


CONCLUSIONS
Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion.


BACKGROUND
clinicaltrials.gov Identifier: NCT00952302.
Smith
Thomas G
TG
Department of Physiology, Anatomy, and Genetics, University of Oxford, Sherrington Bldg, Parks Road, Oxford OX1 3PT, England.
Talbot
Nick P
NP
Privat
Catherine
C
Rivera-Ch
Maria
M
Nickol
Annabel H
AH
Ratcliffe
Peter J
PJ
Dorrington
Keith L
KL
León-Velarde
Fabiola
F
Robbins
Peter A
PA
D000328:Adult; D000531:Altitude; D000532:Altitude Sickness / Q000150:complications / Q000503:physiopathology*; D001794:Blood Pressure; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015150:Echocardiography, Doppler; D005290:Ferric Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D006801:Humans; D006976:Hypertension, Pulmonary / Q000000981:diagnostic imaging / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D000860:Hypoxia / Q000503:physiopathology; D000090463:Iron Deficiencies; D008297:Male; D008875:Middle Aged; D018962:Phlebotomy; D011651:Pulmonary Artery; D013599:Systole; D055815:Young Adult
D005290:Ferric Compounds; C021024:ferric hydroxide; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid