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L-type calcium channels (LTCCs), the major portal for Ca 2+ entry into cardiomyocytes, are essential for excitation-contraction coupling and thus play a central role in regulating overall cardiac function. LTCC function is finely tuned by multiple signaling pathways and accessory proteins. Leucine-rich repeat-containing protein 10 (LRRC10) is a little studied cardiomyocyte-specific protein recently identified as a modulator of LTCCs. LRRC10 exerts a remarkable effect on LTCC function, more than doubling L-type Ca 2+ current (I Ca,L ) amplitude in a heterologous expression system by altering the gating of the channels without changing their surface membrane expression. Genetic ablation of LRRC10 expression in mouse and zebrafish hearts leads to a significant reduction in I Ca,L density and a slowly progressive dilated cardiomyopathy in mice. Rare sequence variants of LRRC10 have been identified in dilated cardiomyopathy and sudden unexplained nocturnal cardiac death syndrome, but these variants have not been clearly linked to disease. Nevertheless, the DCM-associated variant, I195T, converted LRRC10 from a I Ca,L potentiator to a I Ca,L suppressor, thus illustrating the wide dynamic range of LRRC10-mediated I Ca,L regulation. This review focuses on the contemporary knowledge of LTCC modulation by LRRC10 and discusses potential directions for future investigations.

High-fat diet consumption for an extended period causes obesity, systemic metabolic disturbance, and brain insulin resistance, resulting in neuroinflammation. Although the beneficial effect of Cyclosorus terminans extract on obesity-related insulin resistance has been demonstrated, little is known about how it affects neuroinflammation and brain insulin resistance in obese rats. Male Wistar rats were given either a normal diet (ND, n = 6) or a high-fat diet (HFD, n = 24) for a total of 14 weeks. At the beginning of the week, 13 rats in the ND group were given vehicle orally for 2 weeks, while rats on HFD diets were randomized to one of four groups and given either vehicle, 100 mg/kg/day of Cyclosorus terminans extract, 200 mg/kg/day of Cyclosorus terminans extract, or 20 mg/kg/day of pioglitazone orally for 2 weeks. After the experimental period, blood and brain samples were taken to assess metabolic and brain parameters. HFD-fed rats had obesity, systemic and brain insulin resistance, brain inflammation, microglial and astrocyte hyperactivity, and brain necroptosis. Treatment with 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated obesity, insulin resistance, brain insulin dysfunction, and neuroinflammation in insulin resistant rats. Our findings suggest that Cyclosorus terminans extract may hold promise as a therapeutic agent for insulin resistance and neuroinflammation in obese conditions., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Myocardial infarction (MI) and its associated complications including ventricular arrhythmias and heart failure are responsible for a significant incidence of morbidity and mortality worldwide. The ensuing cardiomyocyte loss results in neurohormone-driven cardiac remodeling, which leads to chronic heart failure in MI survivors. Ivabradine is a heart rate modulation agent currently used in treatment of chronic heart failure with reduced ejection fraction. The canonical target of ivabradine is the hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in cardiac pacemaker cells. However, in post-MI hearts, HCN can also be expressed ectopically in non-pacemaker cardiomyocytes. There is an accumulation of intriguing evidence to suggest that ivabradine also possesses cardioprotective effects that are independent of heart rate reduction. This review aims to summarize and discuss the reported cardioprotective mechanisms of ivabradine beyond heart rate modulation in myocardial infarction through various molecular mechanisms including the prevention of reactive oxygen species-induced mitochondrial damage, improvement of autophagy system, modulation of intracellular calcium cycling, modification of ventricular electrophysiology, and regulation of matrix metalloproteinases., (© 2024 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca 2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCU fl/fl ) and conditional MCU knockout (MCU fl/fl-MCM ) mice. LV function was reduced by chronic iron loading in MCU fl/fl mice, but not in MCU fl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCU fl/fl cardiomyocytes, but not in MCU fl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCU fl/fl , but not in MCU fl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCU fl/fl hearts. Isolated cardiomyocytes from MCU fl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca 2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCU fl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCU fl/fl-MCM hearts nor was there a reduction in Ca 2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Cardiomyocyte death is one of the major mechanisms contributing to the development of myocardial infarction (MI) and myocardial ischemia/reperfusion (MI/R) injury. Due to the limited regenerative ability of cardiomyocytes, understanding the mechanisms of cardiomyocyte death is necessary. Pyroptosis, one of the regulated programmed cell death pathways, has recently been shown to play important roles in MI and MI/R injury. Pyroptosis is activated by damage-associated molecular patterns (DAMPs) that are released from damaged myocardial cells and activate the formation of an apoptosis-associated speck-like protein containing a CARD (ASC) interacting with NACHT, LRR, and PYD domains-containing protein 3 (NLRP3), resulting in caspase-1 cleavage which promotes the activation of Gasdermin D (GSDMD). This pathway is known as the canonical pathway. GSDMD has also been shown to be activated in a non-canonical pathway during MI and MI/R injury via caspase-4/5/11. Suppression of GSDMD has been shown to provide cardioprotection against MI and MI/R injury. Although the effects of MI or MI/R injury on pyroptosis have previously been discussed, knowledge concerning the roles of GSDMD in these settings remains limited. In this review, the evidence from in vitro , in vivo , and clinical studies focusing on cardiac GSDMD activation during MI and MI/R injury is comprehensively summarized and discussed. Implications from this review will help pave the way for a new therapeutic target in ischemic heart disease., Competing Interests: The authors declare no conflicts of interest., (© 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)

Backgruound: High cardiorespiratory fitness (CRF) protects against age-related diseases. However, the mechanisms mediating the protective effect of high intrinsic CRF against metabolic, cardiac, and brain impairments in non-obese versus obese conditions remain incompletely understood. We aimed to identify the mechanisms through which high intrinsic CRF protects against metabolic, cardiac, and brain impairments in non-obese versus obese untrained rats., Methods: Seven-week-old male Wistar rats were divided into two groups (n=8 per group) to receive either a normal diet or a highfat diet (HFD). At weeks 12 and 28, CRF, carbohydrate and fatty acid oxidation, cardiac function, and metabolic parameters were evaluated. At week 28, behavior tests were performed. At the end of week 28, rats were euthanized to collect heart and brain samples for molecular studies., Results: The obese rats exhibited higher values for aging-related parameters than the non-obese rats, indicating that they experienced obesity-induced premature aging. High baseline CRF levels were positively correlated with several favorable metabolic, cardiac, and brain parameters at follow-up. Specifically, the protective effects of high CRF against metabolic, cardiac, and brain impairments were mediated by the modulation of body weight and composition, the lipid profile, substrate oxidation, mitochondrial function, insulin signaling, autophagy, apoptosis, inflammation, oxidative stress, cardiac function, neurogenesis, blood-brain barrier, synaptic function, accumulation of Alzheimer's disease-related proteins, and cognition. Interestingly, this effect was more obvious in HFD-fed rats., Conclusion: The protective effect of high CRF is mediated by the modulation of several mechanisms. These effects exhibit greater efficacy under conditions of obesity-induced premature aging.

Background: Caloric restriction and exercise are lifestyle interventions that effectively attenuate cardiometabolic impairment. However, cardioprotective effects of long-term lifestyle interventions and short-term lifestyle interventions followed by weight maintenance in prediabetes have never been compared. High cardiorespiratory fitness (CRF) has been shown to provide protection against prediabetes and cardiovascular diseases, however, the interactions between CRF, prediabetes, caloric restriction, and exercise on cardiometabolic health has never been investigated., Methods: Seven-week-old male Wistar rats were fed with either a normal diet (ND; n = 6) or a high-fat diet (HFD; n = 30) to induce prediabetes for 12 weeks. Baseline CRF and cardiometabolic parameters were determined at this timepoint. The ND-fed rats were fed continuously with a ND for 16 more weeks. The HFD-fed rats were divided into 5 groups (n = 6/group) to receive one of the following: (1) a HFD without any intervention for 16 weeks, (2) 40% caloric restriction for 6 weeks followed by an ad libitum ND for 10 weeks, (3) 40% caloric restriction for 16 weeks, (4) a HFD plus an exercise training program for 6 weeks followed by a ND without exercise for 10 weeks, or (5) a HFD plus an exercise training program for 16 weeks. At the end of the interventions, CRF and cardiometabolic parameters were re-assessed. Then, all rats were euthanized and heart tissues were collected., Results: Either short-term caloric restriction or exercise followed by weight maintenance ameliorated cardiometabolic impairment in prediabetes, as indicated by increased insulin sensitivity, improved blood lipid profile, improved mitochondrial function and oxidative phosphorylation, reduced oxidative stress and inflammation, and improved cardiac function. However, these benefits were not as effective as those of either long-term caloric restriction or exercise. Interestingly, high-level baseline CRF was correlated with favorable cardiac and metabolic profiles at follow-up in prediabetic rats, both with and without lifestyle interventions., Conclusions: Short-term lifestyle modification followed by weight maintenance improves cardiometabolic health in prediabetes. High CRF exerted protection against cardiometabolic impairment in prediabetes, both with and without lifestyle modification. These findings suggest that targeting the enhancement of CRF may contribute to the more effective treatment of prediabetes-induced cardiometabolic impairment., (© 2022. The Author(s).)

Alzheimer's disease is associated with multiple risk factors and is the most common type of dementia. Trimethylamine-N-oxide (TMAO), a gut microbiota metabolite derived from dietary choline and carnitine, has recently been identified as a potential risk factor of Alzheimer's disease. It has been demonstrated that TMAO is associated with Alzheimer's disease through various pathophysiological pathways. As a result of molecular crowding effects, TMAO causes the aggregation of the two proteins, amyloid-beta peptide and tau protein. The aggregation of these proteins is the main pathology associated with Alzheimer's disease. In addition, it has been found that TMAO can activate astrocytes, and inflammatory response. Besides molecular investigation, animal and human studies have also supported the existence of a functional relationship between TMAO and cognitive decline. This article comprehensively summarizes the relationship between TMAO and Alzheimer's disease including emerging evidence from in vitro, in vivo, and clinical studies. We hope that this knowledge will improve the prevention and treatment of Alzheimer's disease in the near future., (© 2021 Wiley Periodicals LLC.)

Osteoporosis is a chronic debilitating disease caused by imbalanced bone remodeling processes that impair the structural integrity of bone. Over the last ten years, the association between fibroblast growth factor 23 (FGF23) and osteoporosis has been studied in both pre-clinical and clinical investigations. FGF23 is a bone-derived endocrine factor that regulates mineral homeostasis via the fibroblast growth factor receptors (FGFRs)/αKlotho complex. These receptors are expressed in kidney and the parathyroid gland. Preclinical studies have supported the link between the local actions of FGF23 on the bone remodeling processes. In addition, clinical evidence regarding the effects of FGF23 on bone mass and fragility fractures suggest potential diagnostic and prognostic applications of FGF23 in clinical contexts, particularly in elderly and patients with chronic kidney disease. However, inconsistent findings exist and there are areas of uncertainty requiring exploration. This review comprehensively summarizes and discusses preclinical and clinical reports on the roles of FGF23 on osteoporosis, with an emphasis on the local action, as opposed to the systemic action, of FGF23 on the bone. Current gaps in knowledge and future research directions are also suggested to encourage further rigorous research in this important field.

Doxorubicin is an effective chemotherapeutic drug, but causes cardiotoxicity which limits its use. Oxidative stress, mitochondrial dysfunction, and inflammation are closely implicated in doxorubicin-induced cardiotoxicity (DIC). Necroptosis, a new form of programmed cell death, was also upregulated by doxorubicin, leading to cardiomyocyte death and cardiac dysfunction. Donepezil, an acetylcholinesterase inhibitor, exerted cardioprotection against various heart diseases. However, its cardioprotective effects in DIC are still unknown. We hypothesized that donepezil reduces reactive oxygen species (ROS) production, mitochondrial dysfunction, mitochondrial dynamics imbalance, necroptosis, and apoptosis in DIC rats. Male Wistar rats were assigned to receive either normal saline solution (n = 8) or doxorubicin (3 mg/kg, 6 doses, n = 16) via intraperitoneal injection. The doxorubicin-treated rats were further subdivided to receive either sterile drinking water (n = 8) or donepezil (5 mg/kg/day, p.o., n = 8) for 30 days. At the end of the experiment, the left ventricular (LV) function was determined. Serum and heart tissue were collected to evaluate histological and biochemical parameters. Doxorubicin-treated rats exhibited higher levels of inflammatory cytokines and ROS production. Doxorubicin also impaired mitochondrial function, mitochondrial dynamics balance, mitophagy, and autophagy, which culminated in apoptosis. Furthermore, doxorubicin increased necroptosis as evidenced by increased phosphorylation of receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed-lineage kinase domain-like. All of these mechanisms led to LV dysfunction. Interestingly, donepezil alleviated mitochondrial injury, mitophagy, autophagy, and cardiomyocyte death, leading to improved LV function in DIC. In conclusion, donepezil attenuated DIC-induced LV dysfunction by reducing mitochondrial damage, mitophagy, autophagy, apoptosis, and necroptosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.

This study aimed to investigate the mechanistic roles of LCN-2 and LCN-2 receptors (LCN-2R) as iron transporters in cardiomyocytes under iron overload condition. H9c2 cardiomyocytes were treated with either LCN-2 small interfering RNA (siRNA) or LCN-2R siRNA or L-type or T-type calcium channel (LTCC or TTCC) blockers, or iron chelator deferiprone (DFP). After the treatments, the cells were exposed to Fe 3+ or Fe 2+ , after that biological parameters were determined. Silencing of lipocalin-2 or its receptor improved cardiomyocyte viability via decreasing iron uptake, mitochondrial fission, mitophagy and cleaved caspase-3 only in the Fe 3+ overload condition. In contrast, treatments with LTCC blocker and TTCC blocker showed beneficial effects on those parameters only in conditions of Fe 2+ overload. Treatment with DFP has been shown beneficial effects both in Fe 2+ and Fe 3+ overload condition. All of these findings suggested that LTCC and TTCC play crucial roles in the Fe 2+ uptake, whereas LCN-2 and LCN-2R were essential for Fe 3+ uptake into the cardiomyocytes under iron overload conditions., (© 2020 Wiley Periodicals LLC.)

Cardiovascular diseases and cancers are the leading causes of deaths globally, and an increasing proportion of cancer patients is suffering from cardiac adverse effects of chemotherapeutic drugs. Trastuzumab, a monoclonal antibody that inhibits the activity of the human epidermal growth factor receptor 2 (HER2), is a potent targeted therapy for HER2-positive malignancies. Despite the impressive antineoplastic efficacy, the cardiotoxicity of trastuzumab frequently limits its use. Trastuzumab-induced cardiac contractile dysfunction has been extensively studied, yet the electrophysiological side effect of trastuzumab remains poorly characterized. Growing evidence from basic and clinical studies supports the link between trastuzumab treatment and arrhythmias. This review comprehensively summarizes relevant information from those reports, discusses their limitations, and suggests future research directions. We aim to encourage further investigations that will provide valuable insights to devise cardioprotective strategies against trastuzumab-induced cardiotoxicity., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Cardiovascular diseases (CVDs) are considered the predominant cause of morbidity and mortality globally. Of these, myocardial infarction (MI) is the most common cause of CVD mortality. MI is a life-threatening condition which occurs when coronary perfusion is interrupted leading to cardiomyocyte death. Subsequent to MI, consequences include adverse cardiac remodeling and cardiac dysfunction mainly contribute to the development of heart failure (HF). It has been shown that loss of functional cardiomyocytes in MI-induced HF are associated with several cell death pathways, in particular necroptosis. Although the entire mechanism underlying necroptosis in MI progression is still not widely recognized, some recent studies have reported beneficial effects of necroptosis inhibitors on cell viability and cardiac function in chronic MI models. Therefore, extensive investigation into the necroptosis signaling pathway is indicated for further study. This article comprehensively reviews the context of the underlying mechanisms of necroptosis in chronic MI-induced HF in in vitro, in vivo and clinical studies. These findings could inform ways of developing novel therapeutic strategies to improve the clinical outcomes in MI patients from this point forward.

Ventricular fibrillation (VF) and sudden cardiac arrest (SCA) remain some of the most important public health concerns worldwide. For the past 50 years, the recommendation in the Advanced Cardiac Life Support (ACLS) guidelines has been that defibrillation is the only option for shockable cardiac arrest. There is growing evidence to demonstrate that mitochondria play a vital role in the outcome of postresuscitation cardiac function. Although targeting mitochondria to improve resuscitation outcome following cardiac arrest has been proposed for many years, understanding concerning the changes in mitochondria during cardiac arrest, especially in the case of VF, is still limited. In addition, despite new research initiatives and improved medical technology, the overall survival rates of patients with SCA still remain the same. Understanding cardiac mitochondrial alterations during fatal arrhythmias may help to enable the formulation of strategies to improve the outcomes of resuscitation. The attenuation of cardiac mitochondrial dysfunction during VF through pharmacological intervention as well as ischaemic postconditioning could also be a promising target for intervention and inform a new paradigm of treatments. In this review, the existing evidence available from in vitro, ex vivo and in vivo studies regarding the roles of mitochondrial dysfunction during VF is comprehensively summarized and discussed. In addition, the effects of interventions targeting cardiac mitochondria during fatal ventricular arrhythmias are presented. Since there are no clinical reports from studies targeting mitochondria to improve resuscitation outcome available, this review will provide important information to encourage further investigations in a clinical setting., (© 2021 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: Arrhythmias and heart failure are common cardiac complications leading to substantial morbidity and mortality in patients with hemochromatosis, yet mechanistic insights remain incomplete. We investigated the effects of iron (Fe) on electrophysiological properties and intracellular Ca 2+ (Ca 2+ i ) handling in mouse left ventricular cardiomyocytes., Methods: Cardiomyocytes were isolated from the left ventricle of mouse hearts and were superfused with Fe 3+ /8-hydroxyquinoline complex (5-100 μM). Membrane potential and ionic currents including TRPC (transient receptor potential canonical) were recorded using the patch-clamp technique. Ca 2+ i was evaluated by using Fluo-4. Cell contraction was measured with a video-based edge detection system. The role of TRPCs in the genesis of arrhythmias was also investigated by using a mathematical model of a mouse ventricular myocyte with the incorporation of the TRPC component., Results: We observed prolongation of the action potential duration and induction of early and delayed afterdepolarizations in myocytes superfused with 15 µmol/L Fe 3+ /8-hydroxyquinoline complex. Iron treatment decreased the peak amplitude of the L-type Ca 2+ current and total K + current, altered Ca 2+ i dynamics, and decreased cell contractility. During the final phase of Fe treatment, sustained Ca 2+ i waves and repolarization failure occurred and ventricular cells became unexcitable. Gadolinium abolished Ca 2+ i waves and restored the resting membrane potential to the normal range. The involvement of TRPC activation was confirmed by TRPC channel current recordings in the absence or presence of functional TRPC channel antibodies. Computer modeling captured the same action potential and Ca 2+ i dynamics and provided additional mechanistic insights., Conclusions: We conclude that iron overload induces cardiac dysfunction that is associated with TRPC channel activation and alterations in membrane potential and Ca 2+ i dynamics.

The coronavirus disease 2019 (COVID-19) is the third major coronavirus outbreak of this century. Its aetiological agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), requires angiotensin converting enzyme 2 (ACE2) for cellular entry. The commonly used angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) could affect SARS-CoV-2 infectivity and may alter COVID-19 disease progression by altering ACE2 expression. Current evidence of ACEI/ARB-ACE2 interaction as well as the effects of ACEIs/ARBs on viral-associated acute lung injury is summarized and discussed in this review. This review assesses the evidence gathered so far and highlights the research that needs to be done to help inform clinical decision making., (© 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society.)

Excessive iron accumulation in the heart can lead to iron overload cardiomyopathy (IOC), the leading cause of death in hemochromatosis patients. Current understanding regarding the mechanism by which iron overload causes a deterioration in cardiac performance, mitochondrial dysfunction, and impaired mitochondrial dynamics remains limited. Ferroptosis, a newly identified form of regulated cell death, has recently been revealed influencing the pathophysiological process of IOC. Nevertheless, the direct effect of cardiac iron overload on ferroptotic cell death is incompletely characterized. This review article comprehensively summarizes and discusses the effects of iron overload on cardiac mitochondrial function, cardiac mitochondrial dynamics, ferroptosis of cardiomyocytes, and left ventricular function in in vitro and in vivo reports. This review also provides relevant consistent and controversial information which can facilitate further mechanistic investigation into iron-induced cardiac dysfunction in the clinical setting in the near future., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The cancer burden on health and socioeconomics remains exceedingly high, with more than ten million new cases reported worldwide in 2018. The financial cost of managing cancer patients has great economic impact on both an individual and societal levels. Currently, many chemotherapeutic agents are available to treat various malignancies. One of these agents is doxorubicin, which was isolated from Streptomyces peucetius in the 1960s. Doxorubicin is frequently administered in combination with other agents as a mainstay chemotherapeutic regimen in many settings, since there is well-documented evidence that it is effective in eliminating malignant cells. Doxorubicin exerts its anti-tumor properties through DNA intercalation and topoisomerase inhibition. It also contains a quinone moiety which is susceptible to redox reactions with certain intracellular molecules, thereby leading to the production of reactive oxygen species. The oxidative stress following doxorubicin exposure is responsible for its well-documented cardiotoxicity, impairing cardiac contractility, ultimately resulting in congestive heart failure. Despite the cumulative evidence noting its adverse effects on the heart, limited information is available regarding the mechanistic association between doxorubicin and cardiac arrhythmias. There is compelling evidence to suggest that doxorubicin also causes proarrhythmic effects. Several case reports and studies in cancer patients have attributed many arrhythmic events to doxorubicin, some of which are life-threatening such as complete heart block and ventricular fibrillation. In this review, reports regarding the potential arrhythmic complications associated with doxorubicin from previous studies investigating the effects of doxorubicin on cardiac electrophysiological properties are comprehensively summarized and discussed. Consistencies and controversial findings from in vitro, in vivo, ex vivo, and clinical studies are presented and mechanistic insights regarding the effects of doxorubicin are also discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The morbidity and mortality in thalassemia patients are predominantly caused by iron overload cardiomyopathy (IOC). Iron-induced cardiac intracellular Ca 2+ ([Ca 2+ ] i ) dysregulation is among the core pathophysiological processes in IOC-related heart failure. Although cardioprotective roles of deferiprone (DFP) and N-acetylcysteine (NAC) have been reported, their effect on cardiac [Ca 2+ ] i transients and Ca 2+ -regulatory protein expression in thalassemic mice is unknown. In the present study, iron overload condition was induced in wild-type (WT) and heterozygous β-thalassemic (HT) mice by a high-iron diet. The iron-overloaded mice subsequently received a vehicle, DFP, NAC, or DFP plus NAC co-therapy. In both WT and HT iron-overloaded mice, DFP and NAC had similar efficacy in decreasing plasma non-transferrin-bound iron, decreasing cardiac iron concentration (CIC) and relieving systolic dysfunction. DFP plus NAC co-therapy, however, was better than the monotherapy in reducing CIC and restoring cardiac [Ca 2+ ] i transient amplitude and rising rate. All regimens produced no change in cardiac Ca 2+ -regulatory protein expression. We provided the first evidence regarding the synergistic effect of combined iron chelator-antioxidant therapy on cardiac [Ca 2+ ] i homeostasis in iron-overloaded thalassemic mice, with consistent improvement of cardiac contractility., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Iron, the most abundant transition metal element in the human body, plays an essential role in many physiological processes. However, without a physiologically active excretory pathway, iron is subject to strict homeostatic processes acting upon its absorption, storage, mobilization, and utilization. These intricate controls are perturbed in primary and secondary hemochromatoses, leading to a deposition of excess iron in multiple vital organs including the heart. Iron overload cardiomyopathy is the leading cause of mortality in patients with iron overload conditions. Apart from mechanical deterioration of the siderotic myocardium, arrhythmias reportedly contribute to a substantial portion of cardiac death associated with iron overload. Despite this significant impact, the cellular mechanisms of electrical disturbances in an iron-overloaded heart are still incompletely characterized. This review article focuses on cellular electrophysiological studies that directly investigate the effects of iron overload on the function of cardiac ion channels, including trans-sarcolemmal and sarcoplasmic reticulum Ca 2+ fluxes, as well as cardiac action potential morphology. Our ultimate aim is to provide a comprehensive summary of the currently available information that will encourage and facilitate further mechanistic elucidation of iron-induced pathoelectrophysiological changes in the heart.

Thalassemia is among the most common genetic diseases worldwide. Ineffective erythropoiesis, chronic hemolysis, and regular blood transfusion in thalassemia patients lead to increased iron burden. Iron overload cardiomyopathy is the most severe co-morbidity and most common cause of mortality in thalassemia patients. Although its associated mechanisms are still not completely understood, cellular iron mishandling, chronic inflammation, and oxidative stress appear to be the key processes involved. In order to acquire a more comprehensive insight of the impact of cardiac iron overload, these alterations need to be intensively investigated. This comprehensive mini-review focuses on two emergent molecules which have been shown to potentially play significant roles in iron overload cardiomyopathy. These two molecules are an iron-transporting protein, lipocalin 2, and an anti-inflammatory adipokine, adiponectin. Reports from in vitro and in vivo studies are comprehensively summarized. Clinical studies examining the roles of these molecules in thalassemia patients are also presented and discussed., (© 2017 Wiley Periodicals, Inc.)

Introduction: Thalassemia is among the most common genetic diseases. Patients with severe forms of the disease are transfusion-dependent, leading to iron overload. A condition which can eventually develop in the iron-loaded heart is iron overload cardiomyopathy, a debilitating disease that accounts for the majority of deaths in thalassemia patients. Areas covered: This review article provides a comprehensive summary of the diagnosis and treatment of cardiac iron overload in transfusion-dependent thalassemia patients, with discussion covering current weak points and potential improvements of the relevant diagnostic and therapeutic strategies. Expert commentary: Current limitations of various diagnostic techniques for iron overload cardiomyopathy include suboptimal accuracy, untimely detection, or inadequate accessibility, and novel modalities are required to overcome these shortcomings. Treatment should address key pathophysiologic mechanisms of iron overload cardiomyopathy, which include cardiac iron mishandling and iron-induced oxidative injury. Apart from the promotion of iron removal by chelators, prevention of cardiac iron deposition and attenuation of oxidative damage should also be rigorously investigated on a cell-to-bedside basis.

Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) effects on cardiac ischemia/reperfusion (I/R) injury are unclear. Unlike SGLT2-i, dipeptidyl peptidase 4 inhibitors (DPP4-i) have shown effective cardioprotection in cardiac I/R injury. We aimed to investigate whether SGLT2-i reduces myocardial dysfunction and myocardial injury to a greater extent than DPP4-i in obese insulin-resistant rats with/without cardiac I/R injury. The high-fat (HF) diet-induced obese insulin-resistant rats were divided into 4 groups and received the following treatments for 28 days: vehicle (HFV); vildagliptin at a dosage of 3 mg/kg/day (HFVil); dapagliflozin at a dosage of 1 mg/kg/day (HFDa) and combination drugs (HFDaVil). At the end, I/R injury was induced by a 30-min left anterior descending coronary occlusion and 120-min reperfusion. Dapagliflozin showed a greater efficacy than vildagliptin in improving the metabolic impairments, low frequency/high frequency (LF/HF) ratio, systolic blood pressure and left ventricular (LV) function in comparison to HFV rats. In cardiac I/R injury, dapagliflozin had a greater efficacy than vildagiptin in decreasing mitochondrial DRP1, cleaved caspase 3, LV dysfunction and infarct size in comparison to HFV rats. However, the combined therapy showed the greatest efficacy in attenuating LV dysfunction, mitochondrial DRP1 and infarct size in comparison to HFV rats. In conclusion, dapagliflozin has a more pronounced effect than vildagliptin in obese insulin-resistant rats for the improvement of LV function. In rats with cardiac I/R injury, although dapagliflozin had a greater efficacy on cardioprotection than vildagliptin, the combined therapy exerted the highest cardioprotective effects potentially by reducing mitochondrial fission., (© 2018 Society for Endocrinology.)

Long-term high-fat diet (HFD) consumption causes cardiac dysfunction. Although calorie restriction (CR) has been shown to be useful in obesity, we hypothesized that combined CR with dipeptidyl peptidase-4 (DPP-4) inhibitor provides greater efficacy than monotherapy in attenuating cardiac dysfunction and metabolic impairment in HFD-induced obese-insulin resistant rats. Thirty male Wistar rats were divided into 2 groups to be fed on either a normal diet (ND, n = 6) or a HFD (n = 24) for 12 weeks. Then, HFD rats were divided into 4 subgroups (n = 6/subgroup) to receive just the vehicle, CR diet (60% of mean energy intake and changed to ND), vildagliptin (3 mg/kg/day) or combined CR and vildagliptin for 4 weeks. Metabolic parameters, heart rate variability (HRV), cardiac mitochondrial function, left ventricular (LV) and fibroblast growth factor (FGF) 21 signaling pathway were determined. Rats on a HFD developed insulin and FGF21 resistance, oxidative stress, cardiac mitochondrial dysfunction and impaired LV function. Rats on CR alone showed both decreased body weight and visceral fat accumulation, whereas vildagliptin did not alter these parameters. Rats in CR, vildagliptin and CR plus vildagliptin subgroups had improved insulin sensitivity and oxidative stress. However, vildagliptin improved heart rate variability (HRV), cardiac mitochondrial function and LV function better than the CR. Chronic HFD consumption leads to obese-insulin resistance and FGF21 resistance. Although CR is effective in improving metabolic regulation, vildagliptin provides greater efficacy in preventing cardiac dysfunction by improving anti-apoptosis and FGF21 signaling pathways and attenuating cardiac mitochondrial dysfunction in obese-insulin-resistant rats., (© 2017 Society for Endocrinology.)

Background: Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients., Methods: Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined., Results: The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb., Conclusions: This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.