Objectives This study sought to understand the prevalence and clinical relevance of iron deficiency in patients with idiopathic pulmonary arterial hypertension (IPAH). Background Iron availability ...influences the pulmonary vascular response to hypoxia in humans and may be significant in the pathogenesis of IPAH. Methods Iron deficiency, defined by raised levels of soluble transferrin receptor (sTfR), was investigated in 98 patients with IPAH. Hepcidin and erythropoietin (EPO) levels were also measured. The effect of bone morphogenetic protein (BMP) receptor knockdown on BMP-6–stimulated hepcidin production was assessed in human hepatoma HepG2 cells. Relationships between sTfR and exercise capacity, functional class, and all-cause mortality were analyzed. Results Circulating sTfR levels were raised in 63% of IPAH patients, indicating significant iron deficiency. Consistent with this, iron, ferritin, and transferrin saturation levels were reduced and red cell distribution width increased, without overt anemia. Hepcidin correlated inversely with sTfR and positively with increasing ferritin. Hepcidin was inappropriately raised in IPAH independent of the inflammatory marker interleukin-6. EPO levels were also raised and correlated inversely with hepcidin. BMP receptor-type 2 ( BMPR2 ) knockdown in HepG2 cells increased BMP-6–stimulated hepcidin expression. sTfR increased with World Health Organization functional class (p < 0.05), correlated negatively with exercise capacity (p = 0.027), and values >28.1 nmol/l independently predicted survival (p = 0.011). Conclusions Iron deficiency is common in IPAH patients and associated with disease severity and poor clinical outcome. Inappropriately raised hepcidin levels, which impair iron absorption from the gut, may be a factor.
BACKGROUND Patients with pulmonary arteriovenous malformations (PAVMs) are unusual because hypoxemia results from right-to-left shunting and not airway or alveolar disease. Their surprisingly ...well-preserved exercise capacity is not generally appreciated. METHODS To examine why exercise tolerance is preserved, cardiopulmonary exercise tests were performed while breathing room air in 21 patients with radiologically proven PAVMs, including five restudied 3 to 12 months after embolization when their PAVMs had regressed. Where physiologic matching was demonstrable, comparisons were made with 12 healthy control subjects. RESULTS The majority of patients achieved their predicted work rate despite a resting arterial oxygen saturation (Sao2 ) of 80% to 96%. Peak work rate and oxygen consumption ( V ˙ o2 ) were no lower in patients with more hypoxemia. Despite higher Sao2 following embolization (median, 96% and 90%; P = .009), patients achieved similar work rates and similar peak V ˙ o2 . Strikingly, treated patients reset to virtually identical peak oxygen pulses (ie, V ˙ o2 per heart beat) and in many cases to the same point on the peak oxygen pulse/work rate plot. The 21 patients had increased minute ventilation ( V ˙ e) for given increases in CO2 production ( V ˙ e/ V ˙ co2 slope), but perceived dyspnea was no greater than in the 12 control subjects or in the same patients before compared to after embolization comparison. Overall, work rate and peak V ˙ o2 were associated not with oxygenation parameters but with V ˙ e/ V ˙ co2 slope, BMI, and anaerobic threshold. CONCLUSIONS Patients with hypoxemia and PAVMs can maintain normal oxygen delivery/ V ˙ o2 during peak exercise. Following improvement of Sao2 by embolization, patients appeared to reset compensatory mechanisms and, as a result, achieved similar peak V ˙ o2 per heart beat and peak work rates.
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