Abstract
Imbalances of iron homeostasis are associated with an adverse clinical outcome of pulmonary hypertension (PH). Herein, we aimed to analyze the impact of iron deficiency (ID) in a real-life PH patient cohort according to different currently used ID definitions. In a retrospective study including 153 precapillary PH patients followed over a mean period of five years, iron deficiency was assessed according to five clinical definitions used in previous trials. The impact of ID on clinical, hematological and hemodynamic parameters was investigated. Depending on the different cutoff levels for serum ferritin and transferrin saturation, currently used ID definitions indicated a prevalence of either true or functional ID in 11 to 75 percent of PH patients. A good diagnostic accuracy was achieved by using the sTFRF/log ferritin (sTFRF) index, which identified 33 to 42 percent of PH patients as being iron deficient. The sTFRF index had the best prediction for the association between ID and clinical outcome. Iron deficient patients with precapillary PH had a significantly higher mortality as compared to non-iron deficiency subjects, which was true for both, PH patients with and without anemia. Although levels of the iron hormone hepcidin were rather affected by ID than by inflammation, they were not associated with the clinical course or mortality of PH subjects. To conclude, ID had a significant impact on the clinical course of precapillary PH patients. The appropriate use of robust biomarkers to define ID is a prerequisite to further evaluate the role of ID and the potential benefit of iron supplementation in precapillary PH patients.
Highlights
Iron is a key element for numerous vital processes, including hemoglobin synthesis, mitochondrial respiration, immune-surveillance, cellular proliferation and metabolic activity [1,2,3]
Anemia was previously associated with a worse clinical outcome of pulmonary hypertension (PH) patients [34], anemia may be a relevant driver of increased mortality and impaired performance status of PH patients. As this poses a relevant issue for treatment considerations, we evaluated clinical outcome parameters in iron deficiency (ID) and NID PH subjects, who did not display anemia during the observation period
Anemia in PH patients was found in up to one-third of subjects, with anemia of chronic disease (ACD) either alone or in combination (ACD+ID anemia (IDA)) being most prevalent. This observation indicates already, that alterations of iron homeostasis in PH subjects are of multifactorial nature and that inflammation driven diversion of iron traffic is a dominant reason for anemia
Summary
Iron is a key element for numerous vital processes, including hemoglobin synthesis, mitochondrial respiration, immune-surveillance, cellular proliferation and metabolic activity [1,2,3]. Dietary iron absorption and iron re-distribution from macrophages are controlled. Iron deficiency definition in pulmonary hypertension by the hormone hepcidin [5,6,7], which binds to the cellular iron export protein ferroportin, thereby controlling cellular iron egress. A complex network of signaling cascades control hepcidin expression, and its circulating concentrations are mainly increased by iron loading and inflammation, whereas they are reduced by iron deficiency (ID), hypoxia, erythropoietic activity or hormones [8]. Imbalances in iron homeostasis have been recognized in patients with chronic heart failure and pulmonary arterial hypertension (PAH) [9,10,11]. Inflammatory processes result in functional iron deficiency as a consequence of inflammation and hepcidin driven iron retention in macrophages [1]
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