Ferroptosis has recently been demonstrated to be a novel regulated non-apoptotic cell death characterized by iron-dependence and the accumulation of lipid peroxidation that results in membrane damage. Excessive iron induces ferroptosis by promoting the generation of both soluble and lipid ROS via an iron-dependent Fenton reaction and lipoxygenase (LOX) enzyme activity. Cytosolic glutathione peroxidase 4 (cGPX4) pairing with ferroptosis suppressor protein 1 (FSP1) and mitochondrial glutathione peroxidase 4 (mGPX4) pairing with dihydroorotate dehydrogenase (DHODH) serve as two separate defense systems to detoxify lipid peroxidation in the cytoplasmic as well as the mitochondrial membrane, thereby defending against ferroptosis in cells under normal conditions. However, disruption of these defense systems may cause ferroptosis. Emerging evidence has revealed that ferroptosis plays an essential role in the development of diverse cardiovascular diseases (CVDs), such as hemochromatosis-associated cardiomyopathy, doxorubicin-induced cardiotoxicity, ischemia/reperfusion (I/R) injury, heart failure (HF), atherosclerosis, and COVID-19–related arrhythmias. Iron chelators, antioxidants, ferroptosis inhibitors, and genetic manipulations may alleviate the aforementioned CVDs by blocking ferroptosis pathways. In conclusion, ferroptosis plays a critical role in the pathogenesis of various CVDs and suppression of cardiac ferroptosis is expected to become a potential therapeutic option. Here, we provide a comprehensive review on the molecular mechanisms involved in ferroptosis and its implications in cardiovascular disease.

Alcohol abuse can affect more than the heart and the liver. Many observers often do not appreciate the complex and differing aspects of alcohol’s effects in pathophysiologies that have been reported in multiple organs. Chronic alcohol abuse is known to be associated with pathophysiological changes that often result in life-threatening clinical outcomes, e.g., breast and colon cancer, pancreatic disease, cirrhosis of the liver, diabetes, osteoporosis, arthritis, kidney disease, immune system dysfunction, hypertension, coronary artery disease, cardiomyopathy, and can be as far-reaching as to cause central nervous system disorders. In this review article, we will discuss the various organs impacted by alcohol abuse. The lack of clear guidelines on the amount and frequency of alcohol intake, complicated by personal demographics, make extrapolations to real-life practices at best difficult for public health policy-makers.

Iron (Fe) plays an essential role in many physiological processes. Hereditary hemochromatosis or frequent blood transfusions often cause iron overload (IO), which can lead to cardiomyopathy and arrhythmias; however, the underlying mechanism is not well defined. In the present study, we assess the hypothesis that IO promotes arrhythmias via reactive oxygen species (ROS) production, mitochondrial membrane potential (∆Ψ_m) depolarization, and disruption of cytosolic Ca dynamics. In ventricular myocytes isolated from wild type (WT) mice, both cytosolic and mitochondrial Fe levels were elevated following perfusion with the Fe³⁺/8-hydroxyquinoline (8-HQ) complex. IO promoted mitochondrial superoxide generation (measured using MitoSOX Red) and induced the depolarization of the ΔΨ_m (measured using tetramethylrhodamine methyl ester, TMRM) in a dose-dependent manner. IO significantly increased the rate of Ca wave (CaW) formation measured in isolated ventricular myocytes using Fluo-4. Furthermore, in ex-vivo Langendorff-perfused hearts, IO increased arrhythmia scores as evaluated by ECG recordings under programmed S1-S2 stimulation protocols. We also carried out similar experiments in cyclophilin D knockout (CypD KO) mice in which the mitochondrial permeability transition pore (mPTP) opening is impaired. While comparable cytosolic and mitochondrial Fe load, mitochondrial ROS production, and depolarization of the ∆Ψ_m were observed in ventricular myocytes isolated from both WT and CypD KO mice, the rate of CaW formation in isolated cells and the arrhythmia scores in ex-vivo hearts were significantly lower in CypD KO mice compared to those observed in WT mice under conditions of IO. The mPTP inhibitor cyclosporine A (CsA, 1 µM) also exhibited a protective effect. In conclusion, our results suggest that IO induces mitochondrial ROS generation and ∆Ψ_m depolarization, thus opening the mPTP, thereby promoting CaWs and cardiac arrhythmias. Conversely, the inhibition of mPTP ameliorates the proarrhythmic effects of IO.

Background: Despite the FDA guidelines for studies to be performed to rule out potential cardiac toxicity, many drugs have nevertheless entered the market only to be later withdrawn from the market owing to cardiac toxicity. Cardiac toxicity may result from drugs causing impaired function or death of cardiomyocytes, valvular damage, myocardial ischemia and/or ventricular arrhythmias. Negative cardiovascular events have been implicated in 28% of drug withdrawals in the USA. The significance for patients, regulators and the pharmaceutical industry is immense. Objective: We address whether a more rigorous and integrative approach is needed for cardiovascular safety screening of all new drug candidates. Furthermore, we will present a cardionomics approach that looks at several in vitro and in vivo models that can be applied to all drugs independent of category, therapeutic area or class. Methods: We present examples of drugs demonstrating cardiac toxicity and provide an in-depth review of how calcium homeostasis may be a unifying theme in clinically observed cardiotoxic events. We introduce a cardionomics approach that detects clinical cardiac toxicity early in the drug discovery process, thus, preventing costly late attrition. Conclusion: The consequences of a failure to detect potential cardiovascular safety issues before clinical launch can have an enormous cost for the pharmaceutical industry, when major drugs are withdrawn due to lawsuits as well as loss of time and resources. An integrated cardionomics approach may reduce the risk of drug withdrawals as a result of unexpected clinical cardiac safety issues.

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) play a crucial role in maintaining intracellular/cytosolic calcium ion (Ca²⁺_i) homeostasis. The release of Ca²⁺ from IP₃Rs serves as a second messenger and a modulatory factor influencing various intracellular and interorganelle communications during both physiological and pathological processes. Accumulating evidence from in vitro, in vivo, and clinical studies supports the notion that the overactivation of IP₃Rs is linked to the pathogenesis of various cardiac conditions. The overactivation of IP₃Rs results in the dysregulation of Ca²⁺ concentration ([Ca²⁺]) within cytosolic, mitochondrial, and nucleoplasmic cellular compartments. In cardiovascular pathologies, two isoforms of IP₃Rs, i.e., IP₃R1 and IP₃R2, have been identified. Notably, IP₃R1 plays a pivotal role in cardiac ischemia and diabetes-induced arrhythmias, while IP₃R2 is implicated in sepsis-induced cardiomyopathy and cardiac hypertrophy. Furthermore, IP₃Rs have been reported to be involved in various programmed cell death (PCD) pathways, such as apoptosis, pyroptosis, and ferroptosis underscoring their multifaceted roles in cardiac pathophysiology. Based on these findings, it is evident that exploring potential therapeutic avenues becomes crucial. Both genetic ablation and pharmacological intervention using IP₃R antagonists have emerged as promising strategies against IP₃R-related pathologies suggesting their potential therapeutic potency. This review summarizes the roles of IP₃Rs in cardiac physiology and pathology and establishes a foundational understanding with a particular focus on their involvement in the various PCD pathways within the context of cardiovascular diseases.

Global contractile heart failure was induced in turkey poults by furazolidone feeding (700 ppm). Abnormal calcium regulation appears to be a key factor in the pathophysiology of heart failure, but the cellular mechanisms contributing to changes in calcium fluxes have not been clearly defined. Isolated ventricular myocytes from non-failing and failing hearts were therefore used to determine whether the whole heart and ventricular muscle contractile dysfunctions were realized at the single cell level. Whole cell current- and voltage-clamp techniques were used to evaluate action potential configurations and L-type calcium currents, respectively. Intracellular calcium transients were evaluated in isolated myocytes with fura-2 and in isolated left ventricular muscles using aequorin. Action potential durations were prolonged in failing myocytes, which correspond to slowed cytosolic calcium clearing. Calcium current-voltage relationships were normal in failing myocytes; preliminary evidence suggests that depressed transient outward potassium currents contribute to prolonged action potential durations. The number of calcium channels (as measured by radioligand binding) were also similar in non-failing and failing hearts. Isolated ventricular muscles from failing hearts had enhanced inotropic responses, in a dose-dependent fashion, to a calcium channel agonist (Bay K 8644). These data suggest that changes in intracellular calcium mobilization kinetics and longer calcium-myofilament interaction may be able to compensate for contractile failure. We conclude that the relationship between calcium current density and sarcoplasmic reticulum calcium release is a dynamic process that may be altered in the setting of heart failure at higher contraction rates.