Intravenous iron therapy in patients with idiopathic pulmonary arterial hypertension and iron deficiency

Abstract

In patients with idiopathic pulmonary arterial hypertension (iPAH), iron deficiency is common and has been associated with reduced exercise capacity and worse survival. Previous studies have shown beneficial effects of intravenous iron administration. In this study, we investigated the use of intravenous iron therapy in iron-deficient iPAH patients in terms of safety and effects on exercise capacity, and we studied whether altered exercise capacity resulted from changes in right ventricular (RV) function and skeletal muscle oxygen handling. Fifteen patients with iPAH and iron deficiency were included. Patients underwent a 6-minute walk test, cardiopulmonary exercise tests, cardiac magnetic resonance imaging, and a quadriceps muscle biopsy and completed a quality-of-life questionnaire before and 12 weeks after receiving a high dose of intravenous iron. The primary end point, 6-minute walk distance, was not significantly changed after 12 weeks (409 ± 110 m before vs. 428 ± 94 m after; P = 0.07). Secondary end points showed that intravenous iron administration was well tolerated and increased body iron stores in all patients. In addition, exercise endurance time (P < 0.001) and aerobic capacity (P < 0.001) increased significantly after iron therapy. This coincided with improved oxygen handling in quadriceps muscle cells, although cardiac function at rest and maximal [Formula: see text] were unchanged. Furthermore, iron treatment was associated with improved quality of life (P < 0.05). In conclusion, intravenous iron therapy in iron-deficient iPAH patients improves exercise endurance capacity. This could not be explained by improved RV function; however, increased quadriceps muscle oxygen handling may play a role. (

Trial registration: ClinicalTrials.gov identifier NCT01288651).

Keywords: exercise capacity; iron; right ventricle; skeletal muscle.

Figure 1

Exercise capacity in iron-deficient idiopathic pulmonary arterial hypertension patients before and after iron administration. Six-minute walk distance (6MWD) was unchanged after iron therapy (A). Time to anaerobic threshold (AT) during maximal cardiopulmonary exercise testing (CPET) was significantly postponed after iron therapy (B). At a submaximal level (75% of maximum achieved workload during CPET), patients were able to bike 51% longer after iron therapy (C).

Figure 2

Oxygen handling in quadriceps muscle fibers after iron therapy in iron-deficient idiopathic pulmonary arterial hypertension patients. Myoglobin concentration was unaltered in high oxidative cells after iron therapy (A); however, a significant increase was observed in low oxidative cells (B) and total myoglobin protein content (C). Mitochondrial oxidative capacity, expressed as maximal oxygen consumption () in high oxidative cells, was unchanged by iron therapy (D). In low oxidative cells, was higher after iron therapy (E).

Figure 3

Quadriceps biopsy samples from idiopathic pulmonary arterial hypertension (iPAH) patients. Shown are typical examples of quadriceps biopsy samples from iPAH patients before (A, C, E) and after (B, D, F) intravenous iron therapy. A, B, Myoglobin staining. C, D, Succinate dehydrogenase activity staining. Type I and II cells are distinguished by color, as type I cells have more myoglobin and succinate dehydrogenase activity (darker cells) than type II cells. E, F, CD31 staining. Every yellow dot represents a capillary.