Immunoadsorption for heart failure is associated with normalization of iron metabolism

Weinmann, Karolina; Werner, Jakob; Rottbauer, Wolfgang; Keßler, Mirjam

doi:10.1080/1354750x.2021.1904001

Cited by 2 publications

(6 citation statements)

References 25 publications

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“…The finding that SGLT2 inhibitors can rapidly correct anaemia without iron supplementation 10 indicates that iron deficiency in these patients (who had mild‐to‐moderate heart failure) was likely to be functional, rather than absolute, that is, it was related to inflammation‐mediated increases in hepcidin and ferritin, which were reversed by treatment with SGLT2 inhibitors. Such a conclusion is consistent with previous studies 7,46–54 . Reports that patients with heart failure suffer from an absolute iron deficiency have been based on a small sample size, 55,56,63 the lack of confirmed bone marrow iron depletion, 53,55 or the evaluation of people with advanced disease 47 …”

Section: Implications For Understanding the Pathogenesis And Conseque...supporting

confidence: 89%

“…Circulating levels of hepcidin are increased in patients with heart failure 9,46,47 in proportion to the activation of proinflammatory pathways, 48–51 and the increase retards the entry of iron from the gastrointestinal tract and from macrophages, leading to a state of functional iron deficiency (akin to the anaemia of chronic disease 49,52,53 ), which is resistant to oral iron supplementation, but can be responsive to treatment with intravenous iron 54 . Patients with heart failure can suffer from either absolute iron depletion or the functional iron deficiency of chronic inflammation, or both 8,18,44,46–56 . The relative importance of the two mechanisms in clinical practice has been difficult to discern from the available studies, most of which were small and evaluated highly selected patients.…”

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

“… 54 Patients with heart failure can suffer from either absolute iron depletion or the functional iron deficiency of chronic inflammation, or both. 8 , 18 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 The relative importance of the two mechanisms in clinical practice has been difficult to discern from the available studies, most of which were small and evaluated highly selected patients. Furthermore, it is possible that the mechanisms leading to iron deficiency may shift as heart failure advances.…”

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

“…Such a conclusion is consistent with previous studies. 7 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 Reports that patients with heart failure suffer from an absolute iron deficiency have been based on a small sample size, 55 , 56 , 63 the lack of confirmed bone marrow iron depletion, 53 , 55 or the evaluation of people with advanced disease. 47 …”

Section: Implications For Understanding the Pathogenesis And Conseque...mentioning

confidence: 99%

“…In heart failure, the assessment of iron deficiency is complicated by the fact that such patients often have a systemic inflammatory state, 44 which enhances the production of hepcidin in the liver ( Figure ) 45 . Circulating levels of hepcidin are increased in patients with heart failure 9,46,47 in proportion to the activation of proinflammatory pathways, 48–51 and the increase retards the entry of iron from the gastrointestinal tract and from macrophages, leading to a state of functional iron deficiency (akin to the anaemia of chronic disease 49,52,53 ), which is resistant to oral iron supplementation, but can be responsive to treatment with intravenous iron 54 . Patients with heart failure can suffer from either absolute iron depletion or the functional iron deficiency of chronic inflammation, or both 8,18,44,46–56 .…”

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

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How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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Many patients with heart failure have an iron‐deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium–glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron‐deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe2+. By alleviating inflammation and oxidative stress, SGLT2 inhibitors down‐regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild‐to‐moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation‐mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo‐controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.

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Section: Implications For Understanding the Pathogenesis And Conseque...supporting

confidence: 89%

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

Section: Implications For Understanding the Pathogenesis And Conseque...mentioning

confidence: 99%

Section: Changes In Iron Homeostasis Proteins In Patients With Heart ...mentioning

confidence: 99%

See 3 more Smart Citations

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Packer

2022

European J of Heart Fail

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Redefining Iron Deficiency in Patients With Chronic Heart Failure

Packer,

Anker,

Butler

et al. 2024

Circulation

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A serum ferritin level <15 to 20 μg/L historically identified patients who had absent bone marrow iron stores, but serum ferritin levels are distorted by the systemic inflammatory states seen in patients with chronic kidney disease or heart failure. As a result, nearly 25 years ago, the diagnostic ferritin threshold was increased 5-to 20-fold in patients with chronic kidney disease (ie, iron deficiency was identified if the serum ferritin level was <100 μg/L, regardless of transferrin saturation [TSAT], or 100 to 299 μg/L if TSAT was <20%). This guidance was motivated not by the findings of studies of total body or tissue iron depletion, but by a desire to encourage the use of iron supplements to potentiate the response to erythropoiesis-stimulating agents in patients with renal anemia. However, in patients with heart failure, this definition does not reliably identify patients with an absolute or functional iron-deficiency state, and it includes individuals with TSATs (≥20%) and serum ferritin levels in the normal range (20-100 mg/L) who are not iron deficient, have an excellent prognosis, and do not respond favorably to iron therapy. Furthermore, serum ferritin levels may be distorted by the use of both neprilysin and sodium-glucose cotransporter 2 inhibitors, both of which may act to mobilize endogenous iron stores. The most evidencebased and trial-tested definition of iron deficiency is the presence of hypoferremia, as reflected by as a TSAT <20%. These hypoferremic patients are generally iron deficient on bone marrow examination, and after intravenous iron therapy, they exhibit an improvement in exercise tolerance and functional capacity (when meaningfully impaired) and show the most marked reduction (ie, 20%-30%) in the risk of cardiovascular death or total heart failure hospitalizations. Therefore, we propose that the current ferritin-driven definition of iron deficiency in heart failure should be abandoned and that a definition based on hypoferremia (TSAT <20%) should be adopted.

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Immunoadsorption for heart failure is associated with normalization of iron metabolism

Cited by 2 publications

References 25 publications

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

How can sodium–glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron‐deficient? Implications for understanding iron homeostasis in heart failure

Redefining Iron Deficiency in Patients With Chronic Heart Failure

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