Regulation of hepcidin expression at high altitude.

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores.

Intravenous iron supplementation may protect against acute mountain sickness: a randomized, double-blinded, placebo-controlled trial.

Acute mountain sickness (AMS) is a common and disabling condition that occurs in healthy individuals ascending to high altitude. Based on the ability of iron to influence cellular oxygen sensing pathways, we hypothesized that iron supplementation would protect against AMS. To examine this hypothesis, 24 healthy sea-level residents were randomized to receive either intravenous iron(III)-hydroxide sucrose (200 mg) or saline placebo, before ascending rapidly to Cerro de Pasco, Peru (4340 m). The Lake Louise scoring system was used to assess incidence and severity of AMS at sea level and on the first full day at altitude. No significant difference in absolute AMS score was detected between the two groups either at baseline or at high altitude. However, the mean increase in AMS score was 65% smaller in the iron group than in the saline group (p<0.05), and the change in AMS score correlated negatively with the change in ferritin (R=-0.43; p<0.05). Hematocrit and arterial oxygen saturation were unaffected by iron. In conclusion, this preliminary randomized, double-blinded, placebo-controlled trial suggests that intravenous iron supplementation may protect against the symptoms of AMS in healthy volunteers.

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 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. 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 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. CONCLUSION: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00952302.

Pulmonary pressure and cardiac function in chronic mountain sickness patients.

BACKGROUND: Chronic mountain sickness (CMS) is characterized by a loss of adaptation to hypoxia in high-altitude (HA) dwellers. Chronic hypoxemia, excessive erythrocytosis and frequently pulmonary hypertension (PH), which may lead to cardiac failure, develop in patients. We sought to assess the determinants of cardiac function in CMS patients with hypoxia-induced PH. METHODS: Fifteen healthy men living at sea level (SL) were compared to 15 healthy men living at HA and 55 patients with CMS from Cerro de Pasco, Peru (altitude, 4,300 m). Pulmonary pressures and cardiac function were estimated by echocardiography. RESULTS: None of the subjects had overt cardiac failure symptoms. CMS patients exhibited elevated mean pulmonary pressures as assessed by high-tricuspid pressure gradients (CMS patients, 34 +/- 10 mm Hg; HA subjects, 25 +/- 4 mm Hg [p = 0.002]; and SL subjects, 19 +/- 3 mm Hg [p < 0.001]). They also showed right ventricular (RV) dilation (mean end-diastolic RV area: CMS patients, 17 +/- 2 cm(2); HA subjects, 13 +/- 2 cm(2); SL subjects, 12 +/- 2 cm(2); p < 0.001) but did not display impaired systolic ventricular function. However, the RV Tei index was increased in CMS and HA subjects (CMS patients, 0.56 +/- 0.15; HA subjects, 0.52 +/- 0.12; SL subjects, 0.21 +/- 0.12; p < 0.001). CONCLUSION: Despite obvious pulmonary arterial hypertension and right heart dilation, CMS patients did not show any symptom or echocardiographic parameter of heart failure. TRIAL REGISTRATION: ClinicalTrials.gov. Identifier: NCT00424970.

Acetazolamide for Monge's disease: efficiency and tolerance of 6-month treatment.

RATIONALE: Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit. OBJECTIVES: Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg Acz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function. METHODS: A two-phase study was performed in patients (hematocrit > or = 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double-blind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250 mg Acz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated. MEASUREMENTS AND MAIN RESULTS: First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P < 0.001), and increased arterial O(2) pressure from 42 to 45 mm Hg (P < 0.001). No severe adverse effect or hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A 4-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance. CONCLUSIONS: Acz reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.

Autonomic adaptations in andean trained participants to a 4220-m altitude marathon.

PURPOSE: Both training and chronic hypoxia act on the autonomic nervous system. Because trained Andean high-altitude natives could perform a high-altitude marathon (4220 m above sea level) in 02:27:23 h, we hypothesized that living in chronic hypoxia does not limit the training-induced benefits on the autonomic modulation of the heart. METHODS: Trained (N=13) and sedentary (N=11) Andean high-altitude natives performed an active orthostatic test. Eight of the trained subjects repeated the test 6-8 and 20-24 h after the end of a high-altitude marathon. Resting heart rate (HR) and the autonomic modulation of the heart were assessed by time domain and spectral analysis of HR variability (HRV): sympathetic (RR low frequency (LF)) and parasympathetic (RR high frequency (HF)) modulations, and sympathovagal balance (RR-LF:HF ratio). RESULTS: Trained subjects exhibited a higher total power of HRV and a lower resting HR (+30%, P<0.005) than sedentary subjects secondary to a higher and dominant parasympathetic modulation on sympathetic activity (RR-HF, RR-LF:HF ratio). At 6-8 h after the marathon, total power of HRV decreased (-69%), whereas resting HR increased from basal level (+22%), mainly because of a rise in sympathetic modulation (RR-LF, RR-LF:HF ratio). From 8 to 24 h of recovery, sympathetic modulation fell (RR-LF, RR-LF:HF ratio) and all HRV parameters were restored. Responses to the active standing position did not change between each recording session. CONCLUSION: Living in chronic hypoxia does not limit the training-induced benefits on the autonomic control of the cardiovascular system in Andean high-altitude natives. The sympathetic predominance on the heart observed 6-8 h after the high-altitude marathon disappeared after 1 d of recovery. Therefore, living at high altitude does not impair the autonomic response to training.