Cardiovascular disease is a circulatory system disease involving the heart and blood vessels, which is one of the main causes of human health loss and even life-threatening. Ca2+ is an important signal molecule. Free calcium ions in the cytoplasm are involved in various physiological and biochemical reactions of cells. Ferroptosis is a programmed cell death driven by lipid peroxidation dependent on free ferrous ions. The essence of ferroptosis is the accumulation of lipid peroxide caused by the increase of intracellular ferrous ion content, which leads to the damage of the phospholipid membrane and eventually cell death. Studies have shown that calcium homeostasis and ferroptosis are involved in the occurrence and development of cardiovascular diseases, but the relationship between them remains to be clarified. This article reviews the various pathways regulating calcium homeostasis in cells and the occurrence and development mechanism of ferroptosis, and discusses the relationship between the two in cardiovascular diseases, which is expected to provide novel and important strategies for alleviating and treating cardiovascular diseases.

One of the leading causes of death for individuals with iron overload is iron overload cardiomyopathy (IOC). Iron overload causes cardiac mitochondrial dysfunction, which ultimately results in heart failure and death. The potential mechanism of iron overload-induced mitochondrial dysfunction involves the disequilibrium between cardiac mitochondrial fission and fusion. Nevertheless, the information regarding cardiac mitochondrial dynamics under iron overload conditions remains limited. The roles of mitochondrial dynamics were identified in IOC. To induce iron overload, male Wistar rats were injected with iron dextran for four weeks. Then, while continuing iron dextran injection, four groups of iron-overloaded rats were given injections of either vehicle, mitochondrial fusion promoter (M1), mitochondrial division inhibitor 1 (Mdivi-1), or iron chelator deferoxamine (DFO) for two weeks. In the non-iron loaded (control) group, rats received vehicles without iron dextran injection. Cardiac function, mitochondrial function, mitochondrial dynamics, mitophagy/autophagy, and apoptosis were assessed at the end of treatment. The increased expression of mitochondrial fission-, mitophagy/autophagy-, and apoptosis-related proteins were correlated with impaired mitochondrial and cardiac functions in iron-overloaded rats. Interestingly, both mitochondrial dynamics modulators reduced cardiac mitochondrial fission, mitophagy/autophagy, and apoptosis, as well as restored cardiac function to be comparable to those treated with iron chelator DFO. Our findings indicated that the imbalance of mitochondrial dynamics is a potential mechanism responsible for cardiomyocyte death induced by IOC, and this could be a novel target for interventions for IOC via either the promotion of mitochondrial fusion or the inhibition of mitochondrial fission.

Trastuzumab (Trz) is a targeted anticancer therapy that specifically acts on tumors overexpressing the human epidermal growth factor receptor 2 (HER2) protein. Previous research has shown that Trz can induce cardiotoxicity by altering mitochondrial function. While modulating mitochondrial dynamics with Mdivi-1 and M1 has shown cardioprotective effects in various cardiac conditions, their impact on Trz-induced cardiotoxicity in rats remains unclear. In this study, thirty-two male Wistar rats were divided into a control group (CON, n = 8) and a Trz-treated group (4 mg/kg/day, i.p. for 7 days, n = 24). The Trz group was further randomized into subgroups receiving either: 1) vehicle (VEH, 3 % DMSO, i.p., n = 8), 2) the mitochondrial fission inhibitor Mdivi-1 (MDV, 1.2 mg/kg/day, i.p., n = 8), or 3) the mitochondrial fusion promoter M1 (2 mg/kg/day, i.p., n = 8). All interventions began on the first day of Trz administration and continued for 7 days. At the end, cardiac function was then assessed, and heart tissue was collected for biochemical analysis. Trz-treated rats exhibited cardiotoxicity, including cardiac dysfunction and injury, as well as disrupted mitochondrial and autophagic processes, increased inflammation, oxidative stress, apoptosis, ferroptosis, and pyroptosis. Co-administration of either Mdivi-1 or M1 with Trz alleviated these harmful effects, suggesting that modulating mitochondrial dynamics might offer a novel therapeutic strategy to mitigate Trz-induced cardiotoxicity.

Calcium channel blockers (CCBs) for long-term (L) and transient (T) calcium channels (LTCC and TTCC) on cardiomyocytes have been suggested to manage iron-induced cardiomyopathy in transfusion-dependent thalassemia patients. However, the results of clinical trials on the effectiveness of CCBs have been conflicting. Here, we systematically reviewed previous studies to investigate the potential factors that could act as therapeutic modifiers and explain these discrepancies. This systematic review was conducted employing the PRISMA guideline to retrieve clinical trials and animal studies investigating the efficacy of CCBs. Studies in the following databases were collected: Web of Science, PubMed, Scopus, Google Scholar, Clinical Trials, Iranian Registry for Clinical Trials, and Cochrane CENTRAL. Keywords included the trade and generic names of various CCBs, thalassemia, and cardiomyopathy. Our Primary search resulted in 297 studies, of which 21 (n = 7 trials and n = 14 animal studies) were further analyzed. The most important parameters that could potentially influence the clinical effectiveness of CCBs in managing iron-induced cardiomyopathy included baseline cardiac iron content, diversity of iron entry routes (LTCCs, TTCCs, DMT-1, etc.), type of CCBs used, iron-induced irreversible functional/structural cardiac changes, iron-Ca2+ joint metabolic dysregulation, deregulated expression of LTCCs and TTCCs, interaction of CCBs with iron chelators, disease-related complications, interactions of CCBs with various supplements used by patients, vitamin D and other nutrient deficiencies, and duration of treatment with CCBs. These items should be considered in future trials to draw more robust conclusions about the effectiveness of CCBs in preventing cardiac iron deposition and associated cardiomyopathy in TDT patients.

Heterozygous β-globin gene knockout thalassemia (BKO) mice derived from C57BL/6 wild-type (WT) mice have phenotypic of β-thalassemia (BT) and have been widely used for studying this disease except reproductive disorders. The present study determined whether male BKO mice recapitulate reproductive problems as BT men. Mice were randomly assigned into groups depending on the genotype (WT vs. BKO) and intervention (control vs. iron-loaded). Euthanized mice were collected blood, testes, epididymides, hypothalamus, and anterior pituitary for assessing hematological parameters, plasma iron and testosterone levels, testis iron levels, sperm characteristics, and histological alterations. Iron administration caused significant increases of plasma and testis iron levels (p < 0.001) but had no significant influence on the hematological profile of BKO mice, which indeed had fewer erythrocyte, hemoglobin, and hematocrit but had greater reticulocyte than WT (p < 0.001 to p = 0.017). Furthermore, irrespective of the genotype, iron administration decreased plasma testosterone levels (p = 0.03 to p > 0.05), total sperm count (p < 0.001), and percent normal sperm morphology (p ≤ 0.01). Based on Perls' Prussian blue staining, excess iron was ubiquitously present in the anterior pituitary and testicular interstitium of iron-loaded mice. This mineral, however, caused no significant changes in reproductive organs microstructure as visualized by hematoxylin and eosin staining. In conclusion, besides physiological dysfunction of many organ systems, iron-loaded male BKO mice exhibit reproductive problems and abnormal sperm characteristics similar to BT men. Therefore, this animal model seems invaluable for future biomedical research involved in various aspects of BT-related male reproductive disorders.

Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices.

The pathophysiology of cardiovascular disease (CVD) is complex and presents a serious threat to human health. Cardiomyocyte loss serves a pivotal role in both the onset and progression of CVD. Among various forms of programmed cell death, ferroptosis, along with apoptosis, autophagy and pyroptosis, is closely linked to the advancement of CVD. Ferroptosis, a mechanism of cell death, is driven by the buildup of oxidized lipids and excess iron. This pathway is modulated by lipid, amino acid and iron metabolism. Key characteristics of ferroptosis include disrupted iron homeostasis, increased peroxidation of polyunsaturated fatty acids due to reactive oxygen species, decreased glutathione levels and inactivation of glutathione peroxidase 4. Treatments targeting ferroptosis could potentially prevent or alleviate CVD by inhibiting the ferroptosis pathway. Ferroptosis is integral to the pathogenesis of several types of CVD and inhibiting its occurrence in cardiomyocytes could be a promising therapeutic strategy for the future treatment of CVD. The present review provided an in‑depth analysis of advancements in understanding the mechanisms underlying ferroptosis. The present manuscript summarized the interplay between ferroptosis and CVDs, highlighting its dual roles in these conditions. Additionally, potential therapeutic targets within the ferroptosis pathway were discussed, alongside the current limitations and future directions of these novel treatment strategies. The present review may offer novel insights into preventive and therapeutic approaches for CVDs.

Atrial and ventricular arrhythmias are common in patients with Infiltrative heart diseases. This review discusses ablative techniques for arrhythmias in amyloidosis, sarcoidosis, hemochromatosis, and glycogen storage disorders, primarily focusing on atrial fibrillation (AF). A thorough literature review was conducted on the MEDLINE database to synthesize current knowledge and propose future research directions. AF is the most common arrhythmia identified in patients with amyloidosis due to cellular infiltration and atrial dilation. While catheter ablation is associated with a significantly lower rate of all-cause mortality and admission rate, conflicting data exist regarding the higher risk of pericardial effusion, in-hospital mortality, length of stay, and cost of hospitalization. Cardiac sarcoid predisposes AF due to granulomas, atrial dilation, and scarring. Studies demonstrate encouraging outcomes and low recurrence rates in these patients who undergo ablation for AF, with no difference in complications compared to those without sarcoidosis. AF is the most common arrhythmia in hereditary hemochromatosis (HH), secondary to increased myocardial iron stores and elevated oxidative stress, and is primarily managed by chelation. Scant reports regarding ablation are described for HH and glycogen storage disorders. Catheter ablation is a safe and effective modality for the treatment of AF in infiltrative cardiomyopathy. Future large-scale trials are needed to confirm these findings.

Clostridium perfringens Beta-1 toxin (CPB1) is a lethal toxin, which can lead to necrotic enteritis, but the pathological mechanism has not been elucidated. We investigated whether reactive oxygen species (ROS) participated in CPB1-induced pyroptosis and ferroptosis, and investigated the effects of calpain on CPB1-induced oxidative stress and inflammation. Scavenging ROS by N-Acetyl-L cysteine (NAC) led to the reduction of ROS, inhibited the death of macrophages, cytoplasmic swelling and membrane rupture, the expression of pyroptosis-related proteins and proinflammatory factor, while increased the expression of anti-inflammatory factors in cells treated with rCPB1. Adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 (ATP5A1) was identified specifically interact with rCPB1. Silencing ATP5A1 inhibited accumulation of ATP and ROS, leaded to less cytoplasmic swelling and membrane rupture, attenuated pyroptosis and inflammation in rCPB1-treated cells. We also found that rCPB1 induces ferroptosis in macrophages, and the level of ferroptosis was similar with H2O2. Of note, H2O2 is a major ROS source, indicated that ROS production may play a major role in the regulation of ferroptosis in macrophages treated with rCPB1. This finding was further corroborated in rCPB1- induced human acute monocytic leukemia cells, which were treated with NAC. In addition, the inhibition of ferroptosis using liproxstatin-1 inhibited the shriveled mitochondrial morphology, increased the expression of glutathione peroxidase 4, nicotinamide adenine dinucleotide (phosphate) hydrogen: quinone oxidoreductase 1 and cysteine/glutamic acid reverse transport solute carrier family 7 members 11, decreased the expression of heme oxygenase 1, nuclear receptor coactivator 4 and transferrin receptor proteins, reduced malondialdehyde and lipid peroxidation levels, and increased intracellular L-glutathione levels in cells treated with rCPB1. Furthermore, calpain inhibitor PD151746 was used to investigate how pyroptosis and ferroptosis were involved simultaneously in rCPB1-treated macrophages. We showed that PD151746 inhibited ATP and ROS production, reversed the representative pyroptosis/ferroptosis indicators and subsequently reduced inflammation. The above findings indicate that rCPB1 might lead to macrophage pyroptosis and ferroptosis through the large and sustained increase in intracellular calpain and oxidative stress, further lead to inflammation.

Diabetic cardiomyopathy (DCM) is defined as structural and functional cardiac abnormalities in diabetes, and cardiomyocyte death is the terminal event of DCM. Ferroptosis is iron-dependent oxidative cell death. Evidence has indicated that iron overload and ferroptosis play important roles in the pathogenesis of DCM. Mitochondria, an important organelle in iron homeostasis and ROS production, play a crucial role in cardiomyocyte ferroptosis in diabetes. Studies have shown some anti-diabetic medicines, plant extracts, and ferroptosis inhibitors might improve DCM by alleviating ferroptosis. In this review, we systematically reviewed the evidence of ferroptosis in DCM. Anti-ferroptosis might be a promising therapeutic strategy for the treatment of DCM.

Intravenous iron therapies contain iron-carbohydrate complexes, designed to ensure iron becomes bioavailable via the intermediary of spleen and liver reticuloendothelial macrophages. How other tissues obtain and handle this iron remains unknown. This study addresses this question in the context of the heart.

A prospective observational study was conducted in 12 patients receiving ferric carboxymaltose (FCM) for iron deficiency. Myocardial, spleen, and liver magnetic resonance relaxation times and plasma iron markers were collected longitudinally. To examine the handling of iron taken up by the myocardium, intracellular labile iron pool (LIP) was imaged in FCM-treated mice and cells.

In patients, myocardial relaxation time T1 dropped maximally 3 h post-FCM, remaining low 42 days later, while splenic T1 dropped maximally at 14 days, recovering by 42 days. In plasma, non-transferrin-bound iron (NTBI) peaked at 3 h, while ferritin peaked at 14 days. Changes in liver T1 diverged among patients. In mice, myocardial LIP rose 1 h and remained elevated 42 days after FCM. In cardiomyocytes, FCM exposure raised LIP rapidly. This was prevented by inhibitors of NTBI transporters T-type and L-type calcium channels and divalent metal transporter 1.

Intravenous iron therapy with FCM delivers iron to the myocardium rapidly through NTBI transporters, independently of reticuloendothelial macrophages. This iron remains labile for weeks, reflecting the myocardium's limited iron storage capacity. These findings challenge current notions of how the heart obtains iron from these therapies and highlight the potential for long-term dosing to cause cumulative iron build-up in the heart.

Unfavorable phenotypes characterized by low immunogenicity and acidity within the tumor microenvironment (TME) contribute to immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional nanoregulator by encapsulating DOX and erianin into calcium carbonate (CaCO3)-based nanoparticles using a modified double emulsion method. The DOX and erianin-loaded CaCO3-based nanoparticles, termed DECaNPs, could effectively induce the calcium overload by triggering calcium influx and absorbing CaCO3 nanoparticles. Additionally, DECaNPs also neutralize the acidic TME by interacting with extracellular protons and limiting lactic acid production, a result of metabolic remodeling in cancer cells. As a result, DECaNPs elicit cellular oxidative stress damage, which mediates the activation of ferroptosis/apoptosis hybrid pathways, and profound immunogenic cell death. Treatment with DECaNPs could inhibit the growth of tumors by promoting oxidative stress, acid neutralization, metabolic remodeling, and protective antitumor immunity in vivo. In addition, DECaNPs could synergistically amplify the antitumor effects of αPD-L1 in a bilateral tumor model by eliciting systemic immune responses. In all, our work presents the preparation of CaCO3-based nanoregulators designed to reverse the unfavorable TME and enhance αPD-L1 immunotherapy through multiple mechanisms.

Sepsis is a global health challenge that results in systemic inflammation, oxidative stress, and multi-organ dysfunction, with the heart being particularly susceptible. This study aimed to elucidate the effect of FTO, a key regulator in m6A methylation in septic cardiomyopathy, and its potential therapeutic implications. Cellular and animal models of septic myocardial injury were established. Moreover, it was revealed that ferroptosis, which is a form of programmed necrosis occurring with iron dependence, was activated within cardiomyocytes during septic conditions. The overexpression of FTO-suppressed ferroptosis alleviated heart inflammation and dysfunction and improved survival rates in vivo. However, the protective effects of FTO were attenuated by the overexpression of BACH1, which is a molecule negatively correlated with FTO. Mechanistically, FTO modulated the m6A modification of BACH1, suggesting a complex interplay in the regulation of cardiomyocyte damage and sepsis. Our findings reveal the potential of targeting the FTO/BACH1 axis and ferroptosis inhibitors as therapeutic strategies for sepsis-induced cardiac injuries.

There is controversy regarding the relationship between serum iron levels and atherosclerotic cardiovascular disease (ASCVD).

To investigate the relationship between serum iron levels and ASCVD among older adults using data from the 2009-2018 National Health and Nutrition Examination Survey (NHANES).

We performed a cross-sectional analysis involving 8,682 participants aged 60 years and older, with complete data on serum iron levels and confirmed ASCVD status, sourced from the 2009-2018 National Health and Nutrition Examination Survey (NHANES). Multivariable logistic regression models were used to examine the association between serum iron levels and ASCVD. To assess the consistency of this association across different demographic groups, subgroup analyses, and interaction tests were performed.

The group with the highest serum iron levels (fourth quartile, 100-369 μg/dL) exhibited several distinct characteristics: they were the youngest on average (69.57 ± 6.91 years), had the highest proportion of males (61.42%), and the highest hemoglobin levels (14.43 ± 1.33 g/dL). This group also showed the lowest iron supplement usage (19.71 ± 12.85 mg/30 days), white blood cell counts (6.73 ± 2.41 1,000 cells/μL), and serum creatinine levels (0.98 ± 0.45 mg/dL). Moreover, they had higher levels of education and income, a higher likelihood of being married, and a lower body mass index (BMI). Additionally, they had significantly lower rates of diabetes, hypertension, stroke, and heart attacks (all p < 0.05). After adjusting for potential confounders, a linear relationship between serum iron levels and ASCVD was initially observed (OR = 0.97; 95% CI, 0.95-0.99, p < 0.05). However, further analysis using a two-part logistic regression model with an inflection point at 131 μg/dL revealed more nuanced results. For serum iron levels below 131 μg/dL, each 10 μg/dL increase was associated with a 4% decrease in the odds of ASCVD (OR = 0.96; 95% CI, 0.93-0.98, p < 0.001). Conversely, for serum iron levels above 131 μg/dL, each 10 μg/dL increase corresponded to a 1% increase in the odds of ASCVD, though this finding was not statistically significant (OR = 1.01; 95% CI, 0.98-1.08, p > 0.05).

In the US elderly population, serum iron levels are negatively associated with ASCVD, particularly when serum iron levels are below 131 μg/dL.

Doxorubicin (DOX) is an anti-tumor agent for chemotherapy, but its use is often hindered by the severe and life-threatening side effect of cardiovascular toxicity. In recent years, studies have focused on dysregulated iron metabolism and ferroptosis, a unique type of cell death induced by iron overload, as key players driving the development of DOX-induced cardiotoxicity (DIC). Recent advances have demonstrated that DOX disturbs normal cellular iron metabolism, resulting in excessive iron accumulation and ferroptosis in cardiomyocytes. This review will explore how dysregulated iron homeostasis and ferroptosis drive the progression of DIC. We will also discuss the current approaches to target iron metabolism and ferroptosis to mitigate DIC. Besides, we will discuss the limitations and challenges for clinical translation for these therapeutic regimens.

Objectives: This multicenter, retrospective, population-based, matched-cohort study compared clinical characteristics and magnetic resonance imaging (MRI) findings, including hepatic, pancreatic, and cardiac iron levels and cardiac function, between 135 adult regularly transfused thalassemia intermedia (TI) patients (44.73 ± 12.16 years, 77 females) and 135 age- and sex-matched thalassemia major (TM) patients (43.35 ± 9.83 years, 77 females), enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. Methods: The MRI protocol included the quantification of hepatic, pancreatic, and cardiac iron levels (R2* technique), the assessment of biventricular function parameters (cine images), and the detection of replacement myocardial fibrosis (late gadolinium enhancement technique). Results: Age, sex, frequency of splenectomy and chelation, and serum ferritin levels were not significantly different (p > 0.05) between the two groups, but TI patients started regular transfusions significantly later (p < 0.0001) and showed significantly lower pre-transfusion hemoglobin levels (p = 0.005). No difference was found in hepatic iron levels (p = 0.853). TI patients exhibited significantly lower pancreatic R2* values (p < 0.0001), also correcting for the duration of regular transfusions, and significantly lower cardiac R2* values (p < 0.0001). In the receiver operating characteristic analysis, pancreatic iron was the strongest discriminator between the two diseases. Left and right ventricular end-diastolic volume indexes were significantly higher in TI than in TM patients (p = 0.003 and p = 0.046, respectively), but the correction for the duration of regular transfusions removed the disease-specific differences (p > 0.05). Left ventricular (LV) mass index was significantly higher in TI (p = 0.049), while no difference (p > 0.05) was found in biventricular ejection fractions and replacement myocardial fibrosis. Conclusions: TI patients showed lower pancreatic and cardiac iron burden and more pronounced LV hypertrophy. These differences could not be explained by the different duration of the transfusional regimen.

Ferroptosis represents a distinct form of cell death that is not associated with necrosis, autophagy, apoptosis, or pyroptosis. It is characterised by intracellular iron-dependent lipid peroxidation. The current literature indicates that a number of botanical drugs and isolated metabolites can modulate ferroptosis, thereby exerting inhibitory effects on lung cancer cells or animal models. The aim of this review is to elucidate the mechanisms through which botanical drugs and isolated metabolites regulate ferroptosis in the context of lung cancer, thereby providing potential insights into lung cancer treatment. It is crucial to highlight that these preclinical findings should not be interpreted as evidence that these treatments can be immediately translated into clinical applications. In the future, we will continue to study the pharmacology, pharmacokinetics and toxicology of these drugs, as well as evaluating their efficacy and safety in clinical trials, with the aim of providing new approaches to the development of new agents for the treatment of lung cancer.

Non-anaemic iron deficiency (NAID) is a strategic target in cardiovascular medicine because of its association with a range of adverse effects in various conditions. Endeavours to tackle NAID in heart failure have yielded mixed results, exposing knowledge gaps in how best to define 'iron deficiency' and the handling of iron therapies by the body. To address these gaps, we harness the latest understanding of the mechanisms of iron homeostasis outside the erythron and integrate clinical and preclinical lines of evidence. The emerging picture is that current definitions of iron deficiency do not assimilate the multiple influences at play in patients with heart failure and, consequently, fail to identify those with a truly unmet need for iron. Additionally, current iron supplementation therapies benefit only certain patients with heart failure, reflecting differences in the nature of the unmet need for iron and the modifying effects of anaemia and inflammation on the handling of iron therapies by the body. Building on these insights, we identify untapped opportunities in the management of NAID, including the refinement of current approaches and the development of novel strategies. Lessons learned from NAID in cardiovascular disease could ultimately translate into benefits for patients with other chronic conditions such as chronic kidney disease, chronic obstructive pulmonary disease and cancer.

Mendelian randomization (MR) studies suggest a causal effect of iron status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables on CVD risk factors. We aimed to investigate the effect of iron status on CVD risk controlling for CVD risk factors.

Iron biomarker instrumental variables (total iron-binding capacity [n=208 422], transferrin saturation [n=198 516], serum iron [n=236 612], ferritin [n=257 953]) were selected from a European genome-wide association study meta-analysis. We performed 2-sample univariate MR of each iron trait on CVD outcomes (all-cause ischemic stroke, cardioembolic ischemic stroke, large-artery ischemic stroke, small-vessel ischemic stroke, and coronary heart disease) from MEGASTROKE (n=440 328) and CARDIoGRAMplusC4D (Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease Genetics) (n=183 305). We then implemented multivariate MR conditioning on 7 CVD risk factors from independent European samples to evaluate their potential confounding or mediating effects on the observed iron-CVD associations. With univariate MR analyses, we found higher genetically predicted iron status to be associated with a greater risk of cardioembolic ischemic stroke (transferrin saturation: odds ratio, 1.17 [95% CI, 1.03-1.33]; serum iron: odds ratio, 1.21 [95% CI, 1.02-1.44]; total iron-binding capacity: odds ratio, 0.81 [95% CI, 0.69-0.94]). The detrimental effects of iron status on cardioembolic ischemic stroke risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure to mediate between 7.1 and 8.8% of the total effect of iron status on cardioembolic ischemic stroke incidence. Univariate MR initially suggested a protective effect of iron status on large-artery stroke and coronary heart disease, but controlling for CVD factors using multivariate MR substantially diminished these associations (all P>0.05).

Higher iron status was associated with a greater risk of cardioembolic ischemic stroke independent of CVD risk factors, and this effect was partly mediated by diastolic blood pressure. These findings support a role of iron status as a modifiable risk factor for cardioembolic ischemic stroke.

Ferroptosis, distinct from apoptosis, necrosis, autophagy, and other types of cell death, is a novel iron-dependent regulated cell death characterized by the accumulation of lipid peroxides and redox imbalance with distinct morphological, biochemical, and genetic features. Dysregulation of iron homeostasis, the disruption of antioxidative stress pathways and lipid peroxidation are crucial in ferroptosis. Ferroptosis is involved in the pathogenesis of several cardiovascular diseases, including atherosclerosis, cardiomyopathy, myocardial infarction, ischemia-reperfusion injury, abdominal aortic aneurysm, aortic dissection, and heart failure. Therefore, a comprehensive understanding of the mechanisms that regulate ferroptosis in cardiovascular diseases will enhance the prevention and treatment of these diseases. This review discusses the latest findings on the molecular mechanisms of ferroptosis and its regulation in cardiovascular diseases, the application of ferroptosis modulators in cardiovascular diseases, and the role of traditional Chinese medicines in ferroptosis regulation to provide a comprehensive understanding of the pathogenesis of cardiovascular diseases and identify new prevention and treatment options.

The progression of heart failure (HF) is complex and involves multiple regulatory pathways. Iron ions play a crucial supportive role as a cofactor for important proteins such as hemoglobin, myoglobin, oxidative respiratory chain, and DNA synthetase, in the myocardial energy metabolism process. In recent years, numerous studies have shown that HF is associated with iron dysmetabolism, and deficiencies in iron and overload of iron can both lead to the development of various myocarditis diseases, which ultimately progress to HF. Iron toxicity and iron metabolism may be key targets for the diagnosis, treatment, and prevention of HF. Some iron chelators (such as desferrioxamine), antioxidants (such as ascorbate), Fer-1, and molecules that regulate iron levels (such as lactoferrin) have been shown to be effective in treating HF and protecting the myocardium in multiple studies. Additionally, certain natural compounds can play a significant role by mediating the imbalance of iron-related signaling pathways and expression levels. Therefore, this review not only summarizes the basic processes of iron metabolism in the body and the mechanisms by which they play a role in HF, with the aim of providing new clues and considerations for the treatment of HF, but also summarizes recent studies on natural chemical components that involve ferroptosis and its role in HF pathology, as well as the mechanisms by which naturally occurring products regulate ferroptosis in HF, with the aim of providing reference information for the development of new ferroptosis inhibitors and lead compounds for the treatment of HF in the future.

Cardiovascular diseases (CVDs) are the main diseases that endanger human health, and their risk factors contribute to high morbidity and a high rate of hospitalization. Cell death is the most important pathophysiology in CVDs. As one of the cell death mechanisms, ferroptosis is a new form of regulated cell death (RCD) that broadly participates in CVDs (such as myocardial infarction, heart transplantation, atherosclerosis, heart failure, ischaemia/reperfusion (I/R) injury, atrial fibrillation, cardiomyopathy (radiation-induced cardiomyopathy, diabetes cardiomyopathy, sepsis-induced cardiac injury, doxorubicin-induced cardiac injury, iron overload cardiomyopathy, and hypertrophic cardiomyopathy), and pulmonary arterial hypertension), involving in iron regulation, metabolic mechanism and lipid peroxidation. This article reviews recent research on the mechanism and regulation of ferroptosis and its relationship with the occurrence and treatment of CVDs, aiming to provide new ideas and treatment targets for the clinical diagnosis and treatment of CVDs by clarifying the latest progress in CVDs research.

Mendelian randomization (MR) studies suggest a causal effect of iron (Fe) status on cardiovascular disease (CVD) risk, but it is unknown if these associations are confounded by pleiotropic effects of the instrumental variables (IV) on CVD risk factors. We aimed to investigate the effect of Fe status on CVD risk controlling for CVD risk factors.

Fe biomarker IVs (total Fe binding capacity (TIBC, n=208,422), transferrin saturation (TSAT, n=198,516), serum Fe (SI, n=236,612), ferritin (n=257,953)) were selected from a European GWAS meta-analysis. We performed two-sample univariate (UV) MR of each Fe trait on CVD outcomes (all-cause ischemic stroke (IS), cardioembolic IS (CES), large artery IS (LAS), small vessel IS (SVS), and coronary heart disease (CHD)) from MEGASTROKE (n=440,328) and CARDIoGRAMplusC4D (n=183,305). We then implemented multivariate (MV) MR conditioning on six CVD risk factors from independent European samples to evaluate their potential confounding and/or mediating effects on the observed Fe-CVD associations.

With UVMR analyses, we found higher genetically predicted Fe status to be associated with a greater risk of CES (TSAT: OR 1.17 [95%CI 1.03, 1.33], SI: OR 1.21 [ 95%CI 1.02, 1.44]; TIBC: OR 0.81 [95%CI 0.69, 0.94]). The detrimental effects of Fe status on CES risk remained unaffected when adjusting for CVD risk factors (all P<0.05). Additionally, we found diastolic blood pressure (DBP) to mediate between 7.1-8.8% of the total effect of Fe status on CES incidence. While UVMR initially suggested a protective effect of Fe status on LAS and CHD, MVMR analyses factoring CVD risk factors revealed a complete annulment of this perceived protective effect (all P>0.05).

Higher Fe status was associated with a greater risk of CES independent of CVD risk factors, and this effect was partly mediated by DBP. These findings support a role of Fe status as a modifiable risk factor for CES.

Introduction: Recent studies suggest that calcium channel blockers (CCBs) could reduce the risk of active tuberculosis and improve clinical outcomes. We aimed to synthesize the evidence regarding the effect of CCBs on the risk of developing active tuberculosis and mortality. Methods: We systematically searched for observational studies and clinical trials published in six databases until 31 August 2023, following a PECO/PICO strategy. Results: We included eight observational studies, 4,020,830 patients, among whom 241,761 had diabetes mellitus and 30,397 had active tuberculosis. According to our results, CCBs reduce the risk of developing active tuberculosis by 29% (RR 0.71; 95% CI 0.67-0.75) in patients with and without diabetes mellitus. However, CCBs do not show any benefit in terms of tuberculosis-related mortality (RR 1.00; 95% CI 0.98-1.02). For both outcomes, no statistical heterogeneity was found (I2 = 0, p > 0.10). This protective effect of CCBs on the risk of active tuberculosis remained independent of the type of patient (with diabetes mellitus vs. general population) or the class of CCB administered (DHP-CCB vs. non-DHP-CCB) (test for subgroup differences I2 = 0, p > 0.10). However, this beneficial effect was more significant among the general population (RR 0.70; 95% CI 0.66-0.74) compared to patients with diabetes mellitus (RR 0.72; 95% CI 0.61-0.86) and among those patients treated with DHP-CCBs (RR 0.69; 95% CI 0.63-0.74) compared to patients treated with non-DHP-CCBs (RR 0.72; 95% CI 0.67-0.78). Conclusion: CCBs may reduce the risk of active TB in patients with diabetes and the general population. On the contrary, CCBs do not seem to have a protective effect on tuberculosis-related mortality. However, more evidence is still needed. We recommend developing clinical trials to verify these findings, including more diverse populations. Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352129].

In the 21st century, cardiovascular disease (CVD) has become one of the leading causes of death worldwide. The prevention and treatment of CVD remain pressing scientific issues. Several recent studies have suggested that ferroptosis may play a key role in CVD. Most studies conducted thus far on ferroptosis and CVD have supported the link. Ferroptosis mediated by different signaling and metabolic pathways can lead to ischemic heart disease, myocarditis, heart failure, ischemia-reperfusion injury, and cardiomyopathy. Still, the specific mechanism of ferroptosis in CVD, the particular organ areas affected, and the stage of disease involved need to be further studied. Therefore, understanding the mechanisms regulating ferroptosis in CVD may improve disease management. Throughout this review, we summarized the mechanism of ferroptosis and its effect on the pathogenesis of CVD. We also predicted and discussed future research directions, aiming to provide new ideas and strategies for preventing and treating CVD.

We evaluated the association of vitamin D and parathormone (PTH) levels with cardiac iron and function in beta-thalassemia major (β-TM) patients. Two-hundred and seventy-eight TM patients (39.04 ± 8.58 years, 56.8% females) underwent magnetic resonance imaging for the assessment of iron overload (T2* technique), biventricular function parameters (cine images), and replacement myocardial fibrosis (late gadolinium enhancement technique). Vitamin D levels were deficient (<20 ng/dL) in 107 (38.5%) patients, insufficient (20-30 ng/dL) in 96 (34.5%) patients, and sufficient (≥30 ng/dL) in 75 (27.0%) patients. Deficient vitamin D patients had a significantly higher frequency of myocardial iron overload (MIO; global heart T2* < 20 ms) than patients with sufficient and insufficient vitamin D levels and a significantly higher left ventricular end-diastolic volume index and mass index than patients with sufficient vitamin D levels. PTH was not associated with cardiac iron, function, or fibrosis. In the multivariate regression analysis, vitamin D, serum ferritin, and pancreatic iron levels were the strongest predictors of global heart T2* values. In receiver operating characteristic curve analysis, a vitamin D level ≤ 17.3 ng/dL predicted MIO with a sensitivity of 81.5% and a specificity of 75.3% (p < 0.0001). In TM, the periodic and regular assessment of vitamin D levels can be beneficial for the prevention of cardiac iron accumulation and subsequent overt dysfunction.

Ferroptosis is a newly identified myocardial cell death mechanism driven by iron-dependent lipid peroxidation. The presence of elevated intramyocardial lipid levels and excessive iron in patients with diabetes suggest a predominant role of ferroptosis in diabetic cardiomyopathy. As myocardial cell death is a precursor of heart failure, and intensive glycemic control cannot abate the increased risk of heart failure in patients with diabetes, targeting myocardial cell death via ferroptosis is a promising therapeutic avenue to prevent and/or treat diabetic cardiomyopathy. This review provides updated and comprehensive molecular mechanisms underpinning ferroptosis, clarifies several misconceptions about ferroptosis, emphasizes the importance of ferroptosis in diabetes-induced myocardial cell death, and offers valuable approaches to evaluate and target ferroptosis in the diabetic heart. Furthermore, basic concepts and ideas presented in this review, including glutathione peroxidase-4-independent and mitochondrial mechanisms of ferroptosis, are also important for investigating ferroptosis in other diabetic organs, as well as nondiabetic and metabolically compromised hearts.

Beta-thalassaemia is an inherited blood disorder that reduces the production of haemoglobin. The most severe form requires recurrent blood transfusions, which can lead to iron overload. Cardiovascular dysfunction caused by iron overload is the leading cause of morbidity and mortality in people with transfusion-dependent beta-thalassaemia. Iron chelation therapy has reduced the severity of systemic iron overload, but removal of iron from the myocardium requires a very proactive preventive strategy. There is evidence that calcium channel blockers may reduce myocardial iron deposition. This is an update of a Cochrane Review first published in 2018.

To assess the effects of calcium channel blockers plus standard iron chelation therapy, compared with standard iron chelation therapy (alone or with a placebo), on cardiomyopathy due to iron overload in people with transfusion-dependent beta thalassaemia.

We searched the Cochrane Haemoglobinopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books, to 13 January 2022. We also searched ongoing trials databases and the reference lists of relevant articles and reviews.

We included randomised controlled trials (RCTs) of calcium channel blockers combined with standard chelation therapy versus standard chelation therapy alone or combined with placebo in people with transfusion-dependent beta thalassaemia.

We used standard Cochrane methods. We used GRADE to assess certainty of evidence.

We included six RCTs (five parallel-group trials and one cross-over trial) with 253 participants; there were 126 participants in the amlodipine arms and 127 in the control arms. The certainty of the evidence was low for most outcomes at 12 months; the evidence for liver iron concentration was of moderate certainty, and the evidence for adverse events was of very low certainty. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may have little or no effect on cardiac T2* values at 12 months (mean difference (MD) 1.30 ms, 95% confidence interval (CI) -0.53 to 3.14; 4 trials, 191 participants; low-certainty evidence) and left ventricular ejection fraction (LVEF) at 12 months (MD 0.81%, 95% CI -0.92% to 2.54%; 3 trials, 136 participants; low-certainty evidence). Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may reduce myocardial iron concentration (MIC) after 12 months (MD -0.27 mg/g, 95% CI -0.46 to -0.08; 3 trials, 138 participants; low-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on heart T2*, MIC, or LVEF after six months, but the evidence is very uncertain. Amlodipine plus standard iron chelation compared with standard iron chelation (alone or with placebo) may increase liver T2* values after 12 months (MD 1.48 ms, 95% CI 0.27 to 2.69; 3 trials, 127 participants; low-certainty evidence), but may have little or no effect on serum ferritin at 12 months (MD 0.07 μg/mL, 95% CI -0.20 to 0.35; 4 trials, 187 participants; low-certainty evidence), and probably has little or no effect on liver iron concentration (LIC) after 12 months (MD -0.86 mg/g, 95% CI -4.39 to 2.66; 2 trials, 123 participants; moderate-certainty evidence). The results of our analysis suggest that amlodipine has little or no effect on serum ferritin, liver T2* values, or LIC after six months, but the evidence is very uncertain. The included trials did not report any serious adverse events at six or 12 months of intervention. The studies did report mild adverse effects such as oedema, dizziness, mild cutaneous allergy, joint swelling, and mild gastrointestinal symptoms. Amlodipine may be associated with a higher risk of oedema (risk ratio (RR) 5.54, 95% CI 1.24 to 24.76; 4 trials, 167 participants; very low-certainty evidence). We found no difference between the groups in the occurrence of other adverse events, but the evidence was very uncertain. No trials reported mortality, cardiac function assessments other than echocardiographic estimation of LVEF, electrocardiographic abnormalities, quality of life, compliance with treatment, or cost of interventions.

The available evidence suggests that calcium channel blockers may reduce MIC and may increase liver T2* values in people with transfusion-dependent beta thalassaemia. Longer-term multicentre RCTs are needed to assess the efficacy and safety of calcium channel blockers for myocardial iron overload, especially in younger children. Future trials should also investigate the role of baseline MIC in the response to calcium channel blockers, and include a cost-effectiveness analysis.

Iron overload cardiomyopathy (IOC) is the leading cause of death in cases of iron overload in patients. Previous studies demonstrated that iron overload led to cardiomyocyte dysfunction and death through multiple pathways including apoptosis, necroptosis and ferroptosis. However, the dominant cell death pathway in the iron-overloaded heart needs clarification. We tested the hypothesis that ferroptosis, an iron-dependent cell death, plays a dominant role in IOC, and ferroptosis inhibitor exerts greater efficacy than inhibitors of apoptosis and necroptosis on improving cardiac function in iron-overloaded rats. Iron dextran was injected intraperitoneally into male Wistar rats for four weeks to induce iron overload. Then, the rats were divided into 5 groups: treated with vehicle, apoptosis inhibitor (z-VAD-FMK), necroptosis inhibitor (Necrostatin-1), ferroptosis inhibitor (Ferrostatin-1) or iron chelator (deferoxamine) for 2 weeks. Cardiac function, mitochondrial function, apoptosis, necroptosis and ferroptosis were determined. The increased expression of apoptosis-, necroptosis- and ferroptosis-related proteins, were associated with impaired cardiac and mitochondrial function in iron-overloaded rats. All cell death inhibitors attenuated cardiac apoptosis, necroptosis and ferroptosis in iron-overloaded rats. Ferrostatin-1 was more effective than the other drugs in diminishing mitochondrial dysfunction and Bax/Bcl-2 ratio. Moreover, both Ferrostatin-1 and deferoxamine reversed iron overload-induced cardiac dysfunction as indicated by restored left ventricular ejection fraction and E/A ratio, whereas z-VAD-FMK and Necrostatin-1 only partially improved this parameter. These results indicated that ferroptosis could be the predominant form of cardiomyocyte death in IOC, and that inhibiting ferroptosis might be a potential novel treatment for IOC.

Trastuzumab (Trz) is a targeted anticancer drug for human epidermal growth factor receptor 2 (HER2)-positive tumors, as Trz-induced cardiotoxicity (TIC) is commonly observed in Trz-treated patients. Since cardiac autonomic modulation with electrical vagus nerve stimulation (VNS) and acetylcholinesterase (AChE) inhibitors exerts cardioprotection against various heart diseases, the comparative effects of electrical VNS and an AChE inhibitor (donepezil) on cardiac and mitochondrial functions and programmed cell death pathways in TIC are not known. VNS devices were implanted in thirty-two male Wistar rats and were divided into 4 groups: (i) Control-Sham (CSham), (ii) Trz-Sham (TSham), (iii) Trz-VNS (TVNS), and (iv) Trz-donepezil (TDPZ). Rats in the Trz-treated groups were intraperitoneally injected with Trz (4 mg/kg/day) for 7 days, while CSham rats were injected with NSS. VNS devices were activated in the TVNS rats during the 7-day Trz treatment, but not in the sham rats. Rats in the TDPZ group received donepezil orally (5 mg/kg/day) for 7 days. At the end, left ventricular (LV) function and heart rate variability were evaluated, and heart tissue was collected for biochemical and histological analysis. Trz rats showed LV dysfunction and cardiac sympathovagal imbalance. In addition, mitochondrial function and dynamics were impaired in TIC rats. Trz also increased cardiomyocyte death by inducing apoptosis, pyroptosis, and ferroptosis. Electrical VNS and donepezil had similar efficacy in alleviating cardiac mitochondrial dysfunction, dynamic imbalances, and cardiomyocyte death, leading to improved LV function. These findings suggested that parasympathetic activation via either VNS or an AChE inhibitor could be a promising therapeutic intervention against TIC.

Ferroptosis is a novel type of regulated cell death (RCD) discovered in recent years, where abnormal intracellular iron accumulation leads to the onset of lipid peroxidation, which further leads to the disruption of intracellular redox homeostasis and triggers cell death. Iron accumulation with lipid peroxidation is considered a hallmark of ferroptosis that distinguishes it from other RCDs. Myocardial ischemia-reperfusion injury (MIRI) is a process of increased myocardial cell injury that occurs during coronary reperfusion after myocardial ischemia and is associated with high post-infarction mortality. Multiple experiments have shown that ferroptosis plays an important role in MIRI pathophysiology. This review systematically summarized the latest research progress on the mechanisms of ferroptosis. Then we report the possible link between the occurrence of MIRI and ferroptosis in cardiomyocytes. Finally, we discuss and analyze the related drugs that target ferroptosis to attenuate MIRI and its action targets, and point out the shortcomings of the current state of relevant research and possible future research directions. It is hoped to provide a new avenue for improving the prognosis of the acute coronary syndrome.

We assessed the value of pancreatic T2* magnetic resonance imaging (MRI) for predicting cardiac events from a large prospective database of transfusion-dependent thalassemia (TDT) patients. We considered 813 TDT patients (36.47 ± 10.71 years, 54.6% females) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network. MRI was used to measure hepatic, pancreatic, and cardiac iron overload (IO), to assess biventricular function and atrial dimensions, and to detect replacement myocardial fibrosis. The mean follow-up was 50.51 ± 19.75 months. Cardiac complications were recorded in 21 (2.6%) patients: one with heart failure (HF) and 20 with arrhythmias. The single patient who developed HF had, at the baseline MRI, a reduced pancreas T2*. Out of the 20 recorded arrhythmias, 17 were supraventricular. Pancreatic T2* values were a significant predictor of future arrhythmia-related events (hazard ratio = 0.89; p = 0.015). Pancreas T2* remained significantly associated with future arrhythmias after adjusting for any other univariate predictor (age and male sex, diabetes, history of previous arrhythmias, or left atrial area index). According to the receiver-operating characteristic curve analysis for arrhythmias, a pancreas T2* < 6.73 ms was the optimal cut-off value. In TDT, pancreatic iron levels had significant prognostic power for arrhythmias. Regular monitoring and the development of targeted interventions to manage pancreatic IO may help improve patient outcomes.

Heart disease is a worldwide health menace. Both intractable primary and secondary cardiomyopathies contribute to malignant cardiac dysfunction and mortality. One of the key cellular processes associated with cardiomyopathy is cardiomyocyte death. Cardiomyocytes are terminally differentiated cells with very limited regenerative capacity. Various insults can lead to irreversible damage of cardiomyocytes, contributing to progression of cardiac dysfunction. Accumulating evidence indicates that majority of cardiomyocyte death is executed by regulating molecular pathways, including apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis. Importantly, these forms of regulated cell death (RCD) are cardinal features in the pathogenesis of various cardiomyopathies, including dilated cardiomyopathy, diabetic cardiomyopathy, sepsis-induced cardiomyopathy, and drug-induced cardiomyopathy. The relevance between abnormity of RCD with adverse outcome of cardiomyopathy has been unequivocally evident. Therefore, there is an urgent need to uncover the molecular and cellular mechanisms for RCD in order to better understand the pathogenesis of cardiomyopathies. In this review, we summarize the latest progress from studies on RCD pathways in cardiomyocytes in context of the pathogenesis of cardiomyopathies, with particular emphasis on apoptosis, necroptosis, ferroptosis, autophagy, and pyroptosis. We also elaborate the crosstalk among various forms of RCD in pathologically stressed myocardium and the prospects of therapeutic applications targeted to various cell death pathways.

Because women with transfusion-dependent thalassemia are seeking pregnancy, ensuring the best outcomes for both mother and baby require concerted and collaborative efforts between the hematologist, obstetrician, cardiologist, hepatologist, and genetic counselor among others. Proactive counseling, early fertility evaluation, optimal management of iron overload and organ function, and application of advances in reproductive technology and prenatal screening are important in ensuring a healthy outcome. Many unanswered questions remain requiring further study, including fertility preservation, non-invasive prenatal diagnosis, chelation therapy during pregnancy, and indications and duration of anticoagulation.

Iron overload in patients with thalassemia represents a serious complication by affecting numerous organ systems. This meta-analysis aims to establish an evidence regarding the effect of amlodipine on cardiac iron overload in thalassemia patients.

We searched PubMed, Scopus, Web of Science, Cochrane Central, and EMBASE for all relevant randomized controlled trials (RCTs). The primary outcomes were cardiac T2* and myocardial iron concentration (MIC). Secondary outcomes were liver iron concentration (LIC), risk of Gastrointestinal (G.I.) upset and risk of lower limb edema. We used Hedges' g to pool continuous outcomes, while odds ratio was used for dichotomous outcomes.

Seven RCTs were eligible for this systematic review and meta-analysis, comprising of 233 patients included in the analysis. Amlodipine had a statistically significant lower MIC (Hedges' g = -0.82, 95% confidence interval [CI] [-1.40, -0.24], p < .001) and higher cardiac T2* (Hedges' g = 0.36, 95% CI [0.10, 0.62], p = .03). Amlodipine was comparable to standard chelation therapy in terms of the risk of lower limb edema and GI upset.

Our meta-analysis found that amlodipine significantly increases cardiac T2* and decreases MIC, hence decreasing the incidence of cardiomyopathy-related iron overload in thalassemia patients.

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, generates a serious threat to the health of the elderly. The AD brain is microscopically characterized by amyloid plaques and neurofibrillary tangles. There are still no effective therapeutic drugs to restrain the progression of AD though much attention has been paid to exploit AD treatments. Ferroptosis, a type of programmed cell death, has been reported to promote the pathological occurrence and development of AD, and inhibition of neuronal ferroptosis can effectively improve the cognitive impairment of AD. Studies have shown that calcium (Ca²⁺) dyshomeostasis is closely related to the pathology of AD, and can drive the occurrence of ferroptosis through several pathways, such as interacting with iron, and regulating the crosstalk between endoplasmic reticulum (ER) and mitochondria. This paper mainly reviews the roles of ferroptosis and Ca²⁺ in the pathology of AD, and highlights that restraining ferroptosis through maintaining the homeostasis of Ca²⁺ may be an innovative target for the treatment of AD.

Atrial fibrillation (AF), one of the most common arrhythmias in clinical practice, is classified into paroxysmal, persistent, and permanent AF according to its duration. The development of AF is associated with increased cardiovascular morbidity and mortality. However, the exact etiology of this disease remains poorly understood. Recent studies found disorders of iron metabolism might be involved in the progression of AF. Abnormal iron metabolism in cardiomyocytes provides arrhythmogenic substrates through a variety of mechanisms, including calcium mishandling, ion channel remodeling, and oxidative stress overaction. Interestingly, in AF patients with iron overload, interventions on iron metabolism, such as iron chelators and ferroptosis inhibitors, has been shown to prevent AF via reducing ferroptosis. Herein, we review the possible mechanisms, consequences, and therapeutic implications of altered atrial iron handling for AF pathophysiology.

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage. While mammalian cells have several redundant iron import mechanisms, they are equipped with a single iron-exporting protein, which makes the cardiovascular system particularly sensitive to iron overload. As a result, iron levels are tightly regulated at many levels to maintain homeostasis. Iron dysregulation ranges from iron deficiency to iron overload and is seen in many types of cardiovascular disease, including heart failure, myocardial infarction, anthracycline-induced cardiotoxicity, and Friedreich's ataxia. Recently, the use of intravenous iron therapy has been advocated in patients with heart failure and certain criteria for iron deficiency. Here, we provide an overview of systemic and cellular iron homeostasis in the context of cardiovascular physiology, iron deficiency, and iron overload in cardiovascular disease, current therapeutic strategies, and future perspectives.