The increase in pulmonary arterial pressure caused by hypoxia depends on iron status

Abstract

Hypoxia is a major cause of pulmonary hypertension. Gene expression activated by the transcription factor hypoxia-inducible factor (HIF) is central to this process. The oxygen-sensing iron-dependent dioxygenase enzymes that regulate HIF are highly sensitive to varying iron availability. It is unknown whether iron similarly influences the pulmonary vasculature. This human physiology study aimed to determine whether varying iron availability affects pulmonary arterial pressure and the pulmonary vascular response to hypoxia, as predicted biochemically by the role of HIF. In a controlled crossover study, 16 healthy iron-replete volunteers undertook two separate protocols. The 'Iron Protocol' studied the effects of an intravenous infusion of iron on the pulmonary vascular response to 8 h of sustained hypoxia. The 'Desferrioxamine Protocol' examined the effects of an 8 h intravenous infusion of the iron chelator desferrioxamine on the pulmonary circulation. Primary outcome measures were pulmonary artery systolic pressure (PASP) and the PASP response to acute hypoxia ( PASP), assessed by Doppler echocardiography. In the Iron Protocol, infusion of iron abolished or greatly reduced both the elevation in baseline PASP (P < 0.001) and the enhanced sensitivity of the pulmonary vasculature to acute hypoxia (P = 0.002) that are induced by exposure to sustained hypoxia. In the Desferrioxamine Protocol, desferrioxamine significantly elevated both PASP (P < 0.001) and PASP (P = 0.01). We conclude that iron availability modifies pulmonary arterial pressure and pulmonary vascular responses to hypoxia. Further research should investigate the potential for therapeutic manipulation of iron status in the management of hypoxic pulmonary hypertensive disease.

Intravenous iron and pulmonary hypertension in intensive care

“…This interaction between iron, hypoxia and the pulmonary circulation is consistent with known effects of iron on the hypoxiainducible factor (HIF) family of transcription factors and involvement of HIF in regulating cardiopulmonary physiology [2][3][4]. Studies from several centres have subsequently confirmed a link between iron status and idiopathic pulmonary arterial hypertension, demonstrating that iron deficiency is unexpectedly common in this disease and independently worsens morbidity and mortality (recently reviewed by Rhodes et al [5]).…”

“…We also studied patients with chronic mountain sickness over 1 month at high altitude and found that depletion of iron by venesection was associated with worsening pulmonary hypertension despite a large reduction in haematocrit (although this effect was not immediately reversed by subsequent iron infusions) [2]. This work was preceded by an 8-h laboratory study of healthy ironreplete volunteers in which the increase in pulmonary arterial pressure caused by hypoxia was blunted by prior intravenous infusion of iron sucrose (200 mg), while the pulmonary vascular response to hypoxia was enhanced by reduction of iron availability with desferrioxamine [3]. The dose of iron used in these studies is small relative to total body iron stores (approximately 4 g), and current intravenous formulations such as iron sucrose are very safe.…”

Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to homozygous VHLR200W mutation (Chuvash polycythemia)

“…It was recently reported that iron chelation promoted and iron infusion limited the increase in systolic pulmonary artery pressure resulting from exposure to acute hypoxia in 16 normal volunteers. 14 It has also been shown that iron depletion exacerbated the increase in systolic pulmonary artery pressure associated with high altitude hypoxia in 11 subjects and iron infusion ameliorated this increase in 22 subjects. 5 These observations pointed to the possibility that iron status may influence the expression of pulmonary hypertension in Chuvash polycythemia as well.…”

Intravenous Iron Therapy in Patients with Idiopathic Pulmonary Arterial Hypertension and Iron Deficiency

“…Under hypoxic conditions and at high altitude, ID resulted in an increase in pulmonary arterial pressure in otherwise healthy subjects. 24,25 This has been mainly attributed to stabilization and transcription of hypoxia-inducible factors linked to contraction, proliferation, and migration of pulmonary artery smooth muscle cells. [25][26][27] Another proposed concept is that (ID-induced) anemia may limit the conversion of nitrite to nitric oxide, thereby inhibiting the antiproliferative and vasodilatation effects of nitric oxide on the pulmonary vasculature.…”