Myocardial iron homeostasis and hepcidin expression in a rat model of heart failure at different levels of dietary iron intake

Petrák, Jir̆ı́; Havlenova, Tereza; Krijt, Matyáš; Behounek, Matej; Franeková, Janka; Červenka, Luděk; Pluháček, Tomáš; Vyoral, Daniel; Melenovský, Vojtěch

doi:10.1016/j.bbagen.2019.01.010

Cited by 22 publications

(23 citation statements)

References 45 publications

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“…But, cardiac dysfunction in HF is more closely related to MID compared to indices of anaemia. Furthermore, presence of global ID is not the cause of MID as it was recently shown with animal models . This seems to be in line with the results from human trials in which the relationship between myocardial iron content with specific markers of global ID was modest, while statistical significance of the results was borderline .…”

Section: Resultssupporting

confidence: 88%

“…Cardiac iron import does not seem to be affected during mild or moderate levels of global iron load, especially in acute conditions. This is probably the reason why high dietary iron does not change myocardial iron content . Also, CIO is rarely observed in patients with haemochromatosis (HH), which is a disease characterized with iron overload in different organs .…”

Section: Iron Import In Cardiomyocytesmentioning

confidence: 99%

“…Its loss is accompanied by serious heart dysfunction, and similarly to FPN, it also responds to cardiac iron load . Many studies suggest that cardiac hepcidin is upregulated during cardiac stress and injury, such as ischaemia, hypoxia, inflammation and mechanical stretch . It seems that mechanism of action of cardiac hepcidin is not solely related to its classical interaction with FPN.…”

Section: Iron Export In Cardiomyocytesmentioning

confidence: 99%

“…This is probably why knockdown of cardiac hepcidin is accompanied by dilated cardiomyopathy and low ejection fraction . Further evidence of the importance of cardiac hepcidin upregulation during cardiac injury is its correlation with other markers of cardiac injury such as brain natriuretic protein, atrial natriuretic protein and connective tissue growth factor . In addition, upregulation of cardiac hepcidin in remote myocardium also suggests that this protein is involved in controlling cardiac remodelling during injury, though this remains to be confirmed …”

Section: Iron Export In Cardiomyocytesmentioning

confidence: 99%

“…The relationship of MID with heart dysfunction in HF is correlated with its effect in mitochondria; MID is related to less mitochondrial DNA in the hearts of HF patients, reduced activity of citric acid cycle enzymes, reduced mitochondrial oxygen consumption, but also with reduced activity of ROS protecting enzymes . Parameters of global iron homeostasis and anaemia do not correlate with mitochondrial dysfunction in HF patients, suggesting the importance of local changes in iron metabolism during cardiac mitochondrial dysfunction …”

Section: Role Of Iron In Heart Diseasementioning

confidence: 99%

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Keeping heart homeostasis in check through the balance of iron metabolism

Vela

2019

Acta Physiologica

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Highly active cardiomyocytes need iron for their metabolic activity. In physiological conditions, iron turnover is a delicate process which is dependent on global iron supply and local autonomous regulatory mechanisms. Though less is known about the autonomous regulatory mechanisms, data suggest that these mechanisms can preserve cellular iron turnover even in the presence of systemic iron disturbance.Therefore, activity of local iron protein machinery and its relationship with global iron metabolism is important to understand cardiac iron metabolism in physiological conditions and in cardiac disease. Our knowledge in this respect has helped in designing therapeutic strategies for different cardiac diseases. This review is a synthesis of our current knowledge concerning the regulation of cardiac iron metabolism. In addition, different models of cardiac iron dysmetabolism will be discussed through the examples of heart failure (cardiomyocyte iron deficiency), myocardial infarction (acute changes in cardiac iron turnover), doxorubicin-induced cardiotoxicity (cardiomyocyte iron overload in mitochondria), thalassaemia (cardiomyocyte cytosolic and mitochondrial iron overload) and Friedreich ataxia (asymmetric cytosolic/mitochondrial cardiac iron dysmetabolism). Finally, future perspectives will be discussed in order to resolve actual gaps in knowledge, which should be helpful in finding new treatment possibilities in different cardiac diseases. K E Y W O R D Scardiomyocyte, heart failure, iron chelation, iron metabolism, mitochondria, transferrin receptor 1

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Section: Resultssupporting

confidence: 88%

Section: Iron Import In Cardiomyocytesmentioning

confidence: 99%

Section: Iron Export In Cardiomyocytesmentioning

confidence: 99%

Section: Iron Export In Cardiomyocytesmentioning

confidence: 99%

Section: Role Of Iron In Heart Diseasementioning

confidence: 99%

See 3 more Smart Citations

Keeping heart homeostasis in check through the balance of iron metabolism

Vela

2019

Acta Physiologica

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Cardiac iron concentration in relation to systemic iron status and disease severity in non‐ischaemic heart failure with reduced ejection fraction

Hirsch

Tongers

Bode

et al. 2020

European J of Heart Fail

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Aims Low cardiac iron levels promote heart failure in experimental models. While cardiac iron concentration (CI) is decreased in patients with advanced heart failure with reduced ejection fraction (HFrEF), CI has never been measured in non‐advanced HFrEF. We measured CI in left ventricular (LV) endomyocardial biopsies (EMB) from patients with non‐advanced HFrEF and explored CI association with systemic iron status and disease severity. Methods and results We enrolled 80 consecutive patients with non‐ischaemic HFrEF with New York Heart Association class II or III symptoms and a median (interquartile range) LV ejection fraction of 25 (18–33)%. CI was 304 (262–373) μg/g dry tissue. CI was not related to immunohistological findings or the presence of cardiotropic viral genomes in EMBs and was not related to biomarkers of systemic iron status or anaemia. Patients with CI in the lowest quartile (CIQ1) had lower body mass indices and more often presented with heart failure histories longer than 6 months than patients in the upper three quartiles (CIQ2–4). CIQ1 patients had higher serum N‐terminal pro‐B‐type natriuretic peptide levels than CIQ2–4 patients [3566 (1513–6412) vs. 1542 (526–2811) ng/L; P = 0.005]. CIQ1 patients also had greater LV end‐diastolic (P = 0.001) and end‐systolic diameter indices (P = 0.003) and higher LV end‐diastolic pressures (P = 0.046) than CIQ2–4 patients. Conclusion Low CI is associated with greater disease severity in patients with non‐advanced non‐ischaemic HFrEF. CI is unrelated to systemic iron homeostasis. The prognostic and therapeutic implications of CI measurements in EMBs should be further explored.

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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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Myocardial iron homeostasis and hepcidin expression in a rat model of heart failure at different levels of dietary iron intake

Cited by 22 publications

References 45 publications

Keeping heart homeostasis in check through the balance of iron metabolism

Keeping heart homeostasis in check through the balance of iron metabolism

Cardiac iron concentration in relation to systemic iron status and disease severity in non‐ischaemic heart failure with reduced ejection fraction

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

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