Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target

Rhodes, Christopher J.; Wharton, John; Howard, Luke; Gibbs, J. Simon R.; Vonk‐Noordegraaf, Anton; Wilkins, Martin R.

doi:10.1183/09031936.00037711

Cited by 94 publications

(78 citation statements)

References 87 publications

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“…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]). Two European studies investigating the use of intravenous iron in pulmonary arterial hypertension are now underway [5].…”

supporting

confidence: 76%

“…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]). Two European studies investigating the use of intravenous iron in pulmonary arterial hypertension are now underway [5].…”

mentioning

confidence: 93%

“…Two European studies investigating the use of intravenous iron in pulmonary arterial hypertension are now underway [5].…”

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confidence: 99%

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Intravenous iron and pulmonary hypertension in intensive care

et al. 2011

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Dear Editor, We read with interest the case reported by Weber-Carstens et al.[1] of a woman with longstanding idiopathic pulmonary arterial hypertension who presented with severe polytrauma. Her admission was complicated by critical hypoxia and severe acute-onchronic pulmonary hypertension resulting in acute right heart decompensation. During this life-threatening phase, the authors report that the benefits of standard combination therapy in reducing right ventricular afterload were short-lived in the face of worsening hypoxia. Recent work from our group and others has introduced the possibility that intravenous iron may provide additional benefit in this setting.In healthy iron-replete men studied over 1 week at high altitude (equivalent to sea level FiO 2 *0.12) we found that established hypoxiainduced pulmonary hypertension was significantly reversed by a single 200 mg dose of intravenous iron sucrose [2]. This effect was evident within 4 h of infusion-rapid enough to be of possible benefit in offloading the right ventricle in the acute clinical setting. 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.These studies indicate that hypoxic pulmonary hypertension can be attenuated by increasing iron availability and exacerbated by decreasing iron availability. 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]). Two European studies investigating the use of intravenous iron in pulmonary arterial hypertension are now underway [5].We look forward to the results of these and other studies. In the meantime, the available evidence raises the possibility that intravenous iron may be beneficial as a rescue therapy when hypoxia and pulmonary hypertension are acutely life-threatening and conventional treatment is inadequate.

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Intravenous iron and pulmonary hypertension in intensive care

et al. 2011

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“…12 Second, use of the Ganzoni formula may not be reliable in iPAH patients with hypoxemia-driven erythropoiesis and consequent hemoglobin (Hb) levels within the normal range despite iron deficiency. 11,13 Third, previous studies with iron therapy showed that the mean dose of iron needed was around 1,000 mg or even higher. 10 One of the concerns was that patients might increase their Hb levels above reference values, which could be detrimental since this increases blood viscosity.…”

Section: Intravenous Iron Safely Increased Body Iron Stores and Qualimentioning

confidence: 99%

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

et al. 2015

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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 V : O 2 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)

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“…The effect of selexipag exposure on erythrocytes and hemoglobin was investigated since PAH patients frequently encounter anemia 8. Vital signs (blood pressure, heart rate), occurrence of prostacyclin‐related and hemorrhage AEs were investigated since prostacyclin analogs are known to have vasodilatory and platelet aggregation inhibitory effects.…”

Section: Methodsmentioning

confidence: 99%

Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension

Krause

Macháček²,

Lott

et al. 2017

CPT Pharmacom & Syst Pharma

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Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long‐term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT‐333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up‐titration. Using log‐linear regression models linking model‐predicted steady‐state exposure to pharmacodynamics (PD), exposure to selexipag and ACT‐333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin‐related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling.

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Iron deficiency in pulmonary arterial hypertension: a potential therapeutic target

Cited by 94 publications

References 87 publications

Intravenous iron and pulmonary hypertension in intensive care

Intravenous iron and pulmonary hypertension in intensive care

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

Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension

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