Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Sawicki, Konrad Teodor; Jesus, Adam De; Ardehali, Hossein

doi:10.1161/circresaha.122.321667

Cited by 49 publications

(27 citation statements)

References 188 publications

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“…Consistent with the study's findings, TSAT is low in obese, prediabetic, and DM patients in previous studies, although a contradicting finding also exists 46–49 . Hepcidin, a circulating antimicrobial peptide, is primarily produced by the liver and regulates iron metabolism by inhibiting intestinal iron absorption and ferroportin‐mediated cellular iron export; that is, hepcidin negatively controls serum iron status 12,49 . Activation of inflammatory pathways, mainly the interleukin‐6 pathway, promotes hepcidin synthesis, reducing serum iron levels and iron accumulation in the tissue 50 .…”

Section: Discussionsupporting

confidence: 80%

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes

Ohori,

Yano,

Katano

et al. 2023

ESC Heart Failure

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AimsIron deficiency (ID) is common in patients with heart failure (HF) and is reportedly associated with exercise intolerance and impaired quality of life. Iron supplementation therapy in HF patients with ID improves exercise capacity. Conversely, protective roles of iron depletion in the development of diabetes mellitus (DM) and its complications have been proposed. This study aimed to determine the impact of ID on physical function in HF patients with and without DM.Methods and resultsWe enrolled consecutive patients who were admitted to our institute for HF diagnosis and management. The short physical performance battery (SPPB) was used to evaluate physical function, and low physical function was defined as an SPPB score of <10 points as individuals with SPPB scores of <10 points are most likely to be classified as frail and are at high risk for disability and future adverse events, including death. ID was defined as serum ferritin < 100 or 100–299 ng/mL when transferrin saturation (TSAT) was <20% according to the HF guidelines. Among the 562 HF patients (72 ± 14 years old; 56% male), 329 patients (58%) and 191 patients (34%) had ID and low physical function, respectively. Multivariate logistic regression analysis showed that TSAT as a continuous variable, but not ID, was a predictor of low physical function (odds ratio: 0.980, P = 0.024). Subgroup analysis showed that a significant association between low TSAT and low physical function was lost in HF patients with DM (P for interaction < 0.001). A spline dose–response curve for the relationship between TSAT and risk of low physical function with adjustments for covariates associated with low physical function in non‐DM patients was almost linear with an increase in the risk of low physical function as the TSAT increased, but such a relationship was not found in the analyses of DM patients. A lack of close TSAT–SPPB relationship in HF patients with DM was confirmed also in a propensity‐score‐matched cohort.ConclusionsTSAT as a continuous variable, but not ID, was independently associated with physical function in HF patients, and a significant association was lost in patients with HF and DM, suggesting a limited impact of iron supplementation therapy in HF patients with DM.

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Section: Discussionsupporting

confidence: 80%

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes

Ohori,

Yano,

Katano

et al. 2023

ESC Heart Failure

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“…Patients with thalassemia have been shown to have elevated levels of malondialdehyde and other plasma lipid peroxidation indicators . 25,26,27,28 According to a paper, unstable hemoglobin chains undergo auto-oxidation, which results in the production of H2O2 and superoxide 30,31 . Thus, in the presence of H2O2, this free nonheme iron can catalyze the Haber-Weiss reaction, producing a feral moiety and a hydroxyl radical.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of Serum Iron in the Diagnosis of Iron Deficiency Anemia in Patients from Local Population of Punjab-Lahore

Farheen¹,

Malik²,

Anwar³

et al. 2023

PJMHS

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Background: The main cause of anemia in one-third of the world's population is a lack of iron (ID). Anemia affects between 700 and 800 million individuals globally. Methodology: Only the patients diagnosed with iron deficiency anemia was selected from Ali Fatima Hospital Lahore and Jinnah Hospital Lahore for determination of serum iron concentration in comparison with healthy controls. Results: In our study male patients were 67% and females were 33%. Frequency of children with beta thalassemia major under 5 year of age is 19%, 5-9 year is 24%, 9-15 years is 31% and above 15 years is 26% Practical implications: The current study aims to spread the awareness among community about clinical significance of serum iron in the diagnosis of iron deficiency anemia in patients and ways to control the iron deficiency. This investigation will assist in determining the severity of the condition in our community as well as the status of serum iron levels in individuals with iron deficiency anemia. The evaluation of serum iron levels in anemic individuals will be helpful to medical experts in determining the best course of treatment. Conclusion: We concluded that renal tubular damage and hepatocellular injury may be secondary to oxidative lipid peroxidation mediated by the iron overload. However further investigations are extremely necessary for this interpretation. A better evaluation of iron toxicity and regular monitoring of renal functions, liver functions, accompanied by an improvement in chelation therapy along with the administration of selective antioxidants (vitamins E and C), may protect different organs against oxidative stress and its consequences, specifically endocrine problems. Keywords: Anemia, Iron deficiency, Ferritin, Hemoglobin, Thalassemia, hepatocellular injury.

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“…A role for mitochondrial iron-loading is well established in health and disease (Issitt et al, 2019, Bi et al, 2021, Sawicki et al, 2023). Importantly, mitochondrial responses described here, are similar to responses observed in mesenchymal stromal cells where iron overload resulted in mitochondrial fragmentation in a ROS dependant manner (Zheng et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

The hepcidin-ferroportin axis influences mitochondrial function, proliferation, and migration in pulmonary artery endothelial and smooth muscle cells

Issitt,

Toe,

Pedersen

et al. 2023

Preprint

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RationaleElevated circulating hepcidin levels have been reported in patients with pulmonary artery hypertension (PAH). Hepcidin has been shown to promote proliferation of human pulmonary artery smooth muscle cells (PASMCs) in vitro, suggesting a potential role in PAH pathogenesis. However, the role of human pulmonary artery endothelial cells (PAECs) as either a source of hepcidin, or the effect of hepcidin on PAECfunction has not previously been described.ObjectiveTo define the role of the hepcidin-ferroportin axis on the phenotype of pulmonary artery endothelial cellsMethods and resultsPAECs treated with hepcidin, or IL-6 were investigated for both ferroportin and hepcidin release and regulation with immunofluorescence, mRNA levels and cellular release assays. Effects of hepcidin on PASMC and PAEC mitochondrial function was investigated using immunofluorescence and seahorse assay. Migration and proliferation of PASMC treated with conditioned media from hPAEC treated with hepcidin was investigated using the Xcelligence system and other tools.PAECs express ferroportin; hepcidin treatment of PAECs results in mitochondrial iron accumulation and intracellular hepcidin biosynthesis and release. Conditioned media from hepcidin treated PAECs causes PASMCs to down regulate ferroportin expression whilst promoting migration and proliferation. Inhibition of hepcidin in PAEC conditioned media limits these responses. PASMC cellular and mitochondrial iron retention are associated with migratory and proliferative responses.ConclusionsThe Hepcidin-ferroportin axis is present and operational in PAECs. Modulation of this axis shows distinct differences in responses seen between PAECS and PASMCs. Stimulation of this axis in PAECS with hepcidin may well institute proliferative and migratory responses in PASMCs of relevance to pathogenesis of PAH offering a potential therapeutic target.

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Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

Cited by 49 publications

References 188 publications

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes

Relationship between serum iron level and physical function in heart failure patients is lost by presence of diabetes

Clinical Significance of Serum Iron in the Diagnosis of Iron Deficiency Anemia in Patients from Local Population of Punjab-Lahore

The hepcidin-ferroportin axis influences mitochondrial function, proliferation, and migration in pulmonary artery endothelial and smooth muscle cells

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