Search

Introduction: Cardiotoxicity is one of the leading causes of compound attrition during drug development. Most in vitro screening platforms aim at detecting acute cardio-electrophysiological changes and drug-induced chronic functional alterations are often not studied in the early stage of drug development. Therefore, we developed an assay using human-induced pluripotent stem cellderived cardiomyocytes (hiPSC-CMs) that evaluates both drug-induced acute and delayed electrophysiological and cytotoxic effects of reference compounds with clinically known cardiac outcomes. Methods: hiPSC-CMs were seeded in 48-well multielectrode array (MEA) plates and were treated with four doses of reference compounds (covering and exceeding clinical free plasma peak concentrations -fCmax values) and MEA recordings were conducted for 4 days. Functional-electrophysiological (fieldpotentials) and viability (impedance) parameters were recorded with a MEA machine. Results: To assess this platform, we tested tyrosine-kinase inhibitors with highcardiac risk profile (sunitinib, vandetanib and nilotinib) and low-cardiac risk (erlotinib), as well as known classic cardiac toxic drugs (doxorubicin and BMS-986094), ion-channel trafficking inhibitors (pentamidine, probucol and arsenic trioxide) and compounds without known clinical cardiotoxicity (amoxicillin, cetirizine, captopril and aspirin). By evaluating the effects of these compounds on MEA parameters, the assay was mostly able to recapitulate different druginduced cardiotoxicities, represented by a prolongation of the field potential, changes in beating rate and presence of arrhythmic events in acute (<2 h) or delayed phase =24 h, and/or reduction of impedance during the delayed phase (=24 h). Furthermore, a few reference compounds were tested in hiPSC-CMs using fluorescence- and luminescence-based plate reader assays, confirming the presence or absence of cytotoxic effects, linked to changes of the impedance parameters measured in the MEA assay. Of note, some cardiotoxic effects could not be identified at acute time points (<2 h) but were clearly detected after 24 h, reinforcing the importance of chronic drug evaluation. Discussion: In conclusion, the evaluation of chronic drug-induced cardiotoxicity using a hiPSC-CMs in vitro assay can contribute to the early de-risking of compounds and help optimize the drug development process. [ABSTRACT FROM AUTHOR]

RationaleDrug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery.ObjectiveTo predict the impact of a drug from the drug chemistry on the cardiac rhythm.Methods and resultsIn a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction.ConclusionsWe present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

Introduction: Cardiotoxicity is one of the leading causes of compound attrition during drug development. Most in vitro screening platforms aim at detecting acute cardio-electrophysiological changes and drug-induced chronic functional alterations are often not studied in the early stage of drug development. Therefore, we developed an assay using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) that evaluates both drug-induced acute and delayed electrophysiological and cytotoxic effects of reference compounds with clinically known cardiac outcomes.Methods: hiPSC-CMs were seeded in 48-well multielectrode array (MEA) plates and were treated with four doses of reference compounds (covering and exceeding clinical free plasma peak concentrations -fCmax values) and MEA recordings were conducted for 4 days. Functional-electrophysiological (field-potentials) and viability (impedance) parameters were recorded with a MEA machine.Results: To assess this platform, we tested tyrosine-kinase inhibitors with high-cardiac risk profile (sunitinib, vandetanib and nilotinib) and low-cardiac risk (erlotinib), as well as known classic cardiac toxic drugs (doxorubicin and BMS-986094), ion-channel trafficking inhibitors (pentamidine, probucol and arsenic trioxide) and compounds without known clinical cardiotoxicity (amoxicillin, cetirizine, captopril and aspirin). By evaluating the effects of these compounds on MEA parameters, the assay was mostly able to recapitulate different drug-induced cardiotoxicities, represented by a prolongation of the field potential, changes in beating rate and presence of arrhythmic events in acute (

Accurately predicting cardioactive effects of new molecular entities for therapeutics remains a daunting challenge. Immense research effort has been focused toward creating new screening platforms that utilize human pluripotent stem cell (hPSC)-derived cardiomyocytes and three-dimensional engineered cardiac tissue constructs to better recapitulate human heart function and drug responses. As these new platforms become increasingly sophisticated and high throughput, the drug screens result in larger multidimensional datasets. Improved automated analysis methods must therefore be developed in parallel to fully comprehend the cellular response across a multidimensional parameter space. Here, we describe the use of machine learning to comprehensively analyze 17 functional parameters derived from force readouts of hPSC-derived ventricular cardiac tissue strips (hvCTS) electrically paced at a range of frequencies and exposed to a library of compounds. A generated metric is effective for then determining the cardioactivity of a given drug. Furthermore, we demonstrate a classification model that can automatically predict the mechanistic action of an unknown cardioactive drug.

The major types of Cardiotoxicity in humans are mainly drug-induced, trauma, and stress-induced. Animal models for drug-induced Cardiotoxicity are generated by using various categories of drugs including anticancer, antiretroviral and antidiabetic, etc. Many of these drugs induce Cardiotoxicity via altering ‘redox homeostasis’ by rising the generation of oxygen radicals. Apart from this, many other drugs utilize a different pathway to promote cardiac damage. Here we describe the various categories of drugs that produce Cardiotoxicity by different mechanisms in various animals and cell line methods. Each category of the drug utilizes different pathways to induce Cardiotoxicity, leads to change in the enzyme level and in vivo parameters which can be used as biomarkers. This review gives an idea to the investigator for the section of appropriate animal models to achieve the objectives of the experiment. Identification of lead molecules and selection of a correct drug to induce Cardiotoxicity by using experimental data may allow the investigator to come out with desired outcomes.

Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT.

Purpose: Biologic agent-induced cardiotoxicity is markedly concerning. Rheumatoid arthritis (RA) treated with biologic agents is known to have the potential for cardiotoxicity; however, existing clinical evidence is not adequate to explain real-world patterns of cardiotoxicity. In this study, we quantify the risk of cardiotoxicity in patients with rheumatoid arthritis treated with biological agents.Methods: Cardiotoxicity reports induced by four types of biologic agents, abatacept, adalimumab, tocilizumab, and etanercept were used to mine data from the FDA's adverse event reporting system (FAERS) database from January 1, 2004 through September 30, 2020. Reports of cardiotoxic events were analyzed using a reporting odds ratio (ROR) algorithm, the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), the multi-item gamma Poisson shrinker (MGPS), and logistic regression methods. We use the preferred term of the Medical Dictionary of Regulatory Activities to identify such events.Results: A total of 3,969 reports of cardiotoxic events were identified involving biologic agents used for RA as the suspect drugs in this study, 317 reports of abatacept, 2,137 reports of adalimumab, 273 reports of tocilizumab, and 1,242 reports of etanercept. Adalimumab was the most reported, followed by etanercept. The proportion of death and disability outcomes reported for each targeted treatment represents approximately 20–25% of the total reported severe adverse events. In addition, relatively low cardiotoxicity reporting rates were found with abatacept.Conclusion: Analysis of FAERS data offers a more precise profile on the characteristics and occurrences of cardiotoxic events. The findings are a clinical reminder to physicians that an increased vigilance concerning the cardiotoxic effects of biological agents needs to be implemented. Also, more comparative studies are required in the future to explain the mechanisms that cause these cardiac phenomena.

The major types of Cardiotoxicity in humans are mainly drug-induced, trauma, and stress-induced. Animal models for drug-induced Cardiotoxicity are generated by using various categories of drugs including anticancer, antiretroviral and antidiabetic, etc. Many of these drugs induce Cardiotoxicity via altering ‘redox homeostasis’ by rising the generation of oxygen radicals. Apart from this, many other drugs utilize a different pathway to promote cardiac damage. Here we describe the various categories of drugs that produce Cardiotoxicity by different mechanisms in various animals and cell line methods. Each category of the drug utilizes different pathways to induce Cardiotoxicity, leads to change in the enzyme level and in vivo parameters which can be used as biomarkers. This review gives an idea to the investigator for the section of appropriate animal models to achieve the objectives of the experiment. Identification of lead molecules and selection of a correct drug to induce Cardiotoxicity by using experimental data may allow the investigator to come out with desired outcomes. [ABSTRACT FROM AUTHOR]

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.

The use of recreational drugs, including new psychoactive substances (NPS), is paralleled by emergency department visits of drug users with severe cardiotoxicity. Drug-induced cardiotoxicity can be the (secondary) result of increased norepinephrine blood concentrations, but data on potential drug-induced direct effects on cardiomyocyte function are scarce. The presence of hundreds of NPS therefore calls for efficient screening models to assess direct cardiotoxicity. We investigated effects of four reference compounds (3–30 nM dofetilide, nifedipine and isoproterenol, and 1–10 μM mexiletine) and six recreational drugs (0.01–100 μM cocaine, 0.01–1000 μM amphetamine, MDMA, 4-fluoroamphetamine, α-PVP and MDPV) on cardiomyocyte function (beat rate, spike amplitude and field potential duration (FPD ≈ QT interval in ECGs)), using Pluricyte® human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes cultured on ready-to-use CardioPlate™ multi-well microelectrode arrays (mwMEAs). Moreover, the effects of exposure to recreational drugs on cell viability were assessed. Effects of reference compounds were in accordance with the literature, indicating the presence of hERG potassium (dofetilide), sodium (mexiletine) and calcium (nifedipine) channels and α-adrenergic receptors (isoproterenol). All recreational drugs decreased the spike amplitude at 10–100 μM. All amphetamine-type stimulants and α-PVP decreased the beat rate at 300 μM, while cocaine and MDPV did so at 10 μM and 30 μM, respectively. All drugs increased the FPD, however at varying concentrations. MDMA, MDPV and amphetamine affected cardiomyocyte function at concentrations relevant for human exposure, while other drugs affected cardiomyocyte function only at higher concentrations (≥ 10 μM). Cell viability was only mildly affected at concentrations well above the lowest concentrations affecting cardiomyocyte function. We demonstrate that MEA recordings of hiPSC-derived cardiomyocytes enable screening for acute, direct effects on cardiomyocyte function. Our data further indicate that tachycardia in patients exposed to recreational drugs is likely due to indirect drug effects, while prolonged repolarization periods (prolonged QT c interval) could (partly) result from direct drug effects on cardiomyocyte function. • CardioPlate™ MEAs with hiPSC-CMs enable functional cardiotoxicity screening. • New psychoactive substances and illicit drugs directly affect cardiomyocyte function. • All recreational drugs affected the spike amplitude, the beat rate and the (corrected) FPD. • Direct drug effects may cause QT c prolongation, although tachycardia is unlikely. • During an overdose, all drugs have direct effects on cardiomyocyte function. [ABSTRACT FROM AUTHOR]

Introduction: The abuse of psychoactive substances, including illicit drugs, prescription medications, and certain legal substances, remains a global public health concern. Beyond the well-known neurological and psychological consequences, the relationship between psychoactive substance abuse and cardiovascular events, particularly sudden cardiac death (SCD), is gaining recognition as a critical issue. The use and abuse of various psychoactive substances, including stimulants (e.g., cocaine, amphetamines), opioids (e.g., heroin, fentanyl), cannabis, and even prescription medications (e.g., opioids, benzodiazepines), have been associated with an increased risk of SCD. The mechanisms linking psychoactive substances to SCD are multifaceted and may involve drug-induced arrhythmias, coronary artery spasm, myocardial infarction, and structural cardiac changes. Additionally, the combination of substances or concurrent use of psychoactive drugs and alcohol can further exacerbate the risk. Case report: We present the case of 27-year-old patient who had a significant medical history. In the first hospitalization in 2016, the patient experienced an out-of-hospital cardiorespiratory arrest due to ventricular fibrillation (VF), requiring two defibrillation shocks (DC 2x150 J). During that hospitalization, coronary angiography revealed normal findings, but the patient declined the implantation of an implantable cardioverter-defibrillator (ICD). Unfortunately, there was no record of regular cardiology follow-up. This year, the patient was referred to our center following repeated out-of-hospital cardiorespiratory arrests due to VF, each successfully resuscitated (DC 1x 150 J). Upon admission, the patient was unconscious, unresponsive, comatose, and required mechanical ventilation in synchronized intermittent mandatory ventilation mode, although he remained hemodynamically stable. On the second day of hospitalization, the patient demonstrated improved respiratory function and was successfully weaned from the ventilator. Subsequently, he was extubated. Heteroanamnestically, it was noticed that the patient had a history of anabolic and alkaloid substance use. However, toxicology screening upon admission yielded negative results. A psychiatric consultation was scheduled, and the patient consented to undergo surgery on the 9th day of hospitalization under general anesthesia. During this procedure, a subcutaneous cardioverter defibrillator (S-ICD) was implanted. The intervention proceeded without complications, and a defibrillation test confirmed the proper functioning of the S-ICD. During the hospital stay, a complication emerged in the form of a second-degree decubitus ulcer on the right heel. Following evaluation by a plastic surgeon, the patient was discharged with recommendations for Aquacel dressings and anti-decubitus measures, with the expectation of continued home care. [ABSTRACT FROM AUTHOR]

Cardiac fibroblast growth factor 2 (FGF2) exerts multiple paracrine activities related to cardiac response to injury. Endogenous FGF2 is composed of a mixture of 70% high- and 30% low-molecular-weight isoforms (Hi-FGF2 and Lo-FGF2, respectivley); although exogenously added Lo-FGF2 is cardioprotective, the roles of endogenous Hi-FGF2 or Lo-FGF2 have not been well defined. Therefore, we investigated the effect of elimination of Hi-FGF2 expression on susceptibility to acute cardiac damage in vivo caused by an injection of the genotoxic drug doxorubicin (Dox). Mice genetically depleted of endogenous Hi-FGF2 and expressing only Lo-FGF2 [FGF2(Lo) mice] were protected from the Dox-induced decline in ejection fraction displayed by their wild-type FGF2 [FGF2(WT)] mouse counterparts, regardless of sex, as assessed by echocardiography for up to 10 days post-Dox treatment. Because cardiac FGF2 is produced mainly by nonmyocytes, we next addressed potential contribution of fibroblast-produced FGF2 on myocyte vulnerability to Dox. In cocultures of neonatal rat cardiomyocytes (r-cardiomyocytes) with mouse fibroblasts from FGF2(WT) or FGF2(Lo) mice, only the FGF2(Lo)-fibroblast cocultures protected r-cardiomyocytes from Dox-induced mitochondrial and cellular damage. When r-cardiomyocytes were cocultured with or exposed to conditioned medium from human fibroblasts, neutralizing antibodies for human Hi-FGF-2, but not total FGF2, mitigated Dox-induced injury of cardiomyocytes. We conclude that endogenous Hi-FGF2 reduces cardioprotection by endogenous Lo-FGF2. Antibody-based neutralization of endogenous Hi-FGF2 may offer a prophylactic treatment against agents causing acute cardiac damage. [ABSTRACT FROM AUTHOR]

Cardiac safety assessments are significant in drug discovery, as drug-induced cardiotoxicity (DIC) is the primary cause of drug attrition. Despite heart-on-a-chip (HoC) technology becoming an increasingly popular tool for evaluating DIC, its development remains a challenge owing to the anisotropic cardiac structure of the native myocardium. Herein, an anisotropic multiscale cardiac scaffold is presented via a hybrid biofabrication method by combining 3D printing with electrospinning technology, where the 3D-printed micrometer-scale scaffold frames enable mimicking the interwoven myocardium anatomical structure and the branched-aligned electrospun nanofibers network is able to directionally guide cellular arrangements. The in vitro 3D bioengineered cardiac tissues are then fabricated by encapsulating three-layer multiscale scaffolds within a photocurable methacrylated gelatin hydrogel shell. It is demonstrated that such an anisotropic multiscale structure could contribute to enhancing cardiomyocyte maturation and synchronous beating behavior. More attractively, with the integration of 3D bioengineered cardiac tissues and a self-designed microfluidic perfusion system, a 3D anisotropic HoC platform is established for evaluating DIC and cardioprotective efficacy. Collectively, these results indicate that the HoC model developed by integrating the 3D bioengineered cardiac tissues could effectively recapitulate the clinical manifestations, thereby highlighting their efficacy as a valuable preclinical platform for testing drug efficacy and cardiotoxicity., (© 2023 Wiley-VCH GmbH.)

The tyrosine kinase inhibitor Sunitinib is used to treat cancer and is linked to severe adverse cardiovascular events. Mitogen activated kinase kinase 7 (MKK7) is involved in the development of cardiac injury and is a component of the c-Jun N-terminal kinase (JNK) signal transduction pathway. Apoptosis signal-regulating kinase 1 (ASK1) is the upstream activator of MKK7 and is specifically inhibited by 2,7-dihydro-2,7-dioxo-3 H -naphtho[1,2,3- de ]quinoline-1-carboxylic acid ethyl ester (NQDI-1). This study investigates the role of ASK1, MKK7 and JNK during Sunitinib-induced cardiotoxicity. Infarct size were measured in isolated male Sprague-Dawley rat Langendorff perfused hearts treated for 125 min with Sunitinib in the presence and absence of NQDI-1. Left ventricular cardiac tissue samples were analysed by qRT-PCR for MKK7 mRNA expression and cardiotoxicity associated microRNAs (miR-1, miR-27a, miR-133a and miR-133b) or Western blot analysis to measure ASK1/MKK7/JNK phosphorylation. Administration of Sunitinib (1 μM) during Langendorff perfusion resulted in increased infarct size, increased miR-133a expression, and decreased phosphorylation of the ASK1/MKK7/JNK pathway compared to control. Co-administration of NQDI-1 (2.5 μM) attenuated the increased Sunitinib-induced infarct size, reversed miR-133a expression and restored phosphorylated levels of ASK1/MKK7/JNK. These findings suggest that the ASK1/MKK7/JNK intracellular signalling pathway is important in Sunitinib-induced cardiotoxicity. The anti-cancer properties of Sunitinib were also assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell viability assay. Sunitinib significantly decreased the cell viability of human acute myeloid leukemia 60 cell line (HL60). The combination of Sunitinib (1 nM–10 μM) with NQDI-1 (2.5 μM) enhanced the cancer-fighting properties of Sunitinib. Investigations into the ASK1/MKK7/JNK transduction pathway could lead to development of cardioprotective adjunct therapy, which could prevent Sunitinib-induced cardiac injury. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is one of the most serious side effects of new drugs. Early detection of the drug induced cardiotoxicity based on the biomarkers provides an important preventative strategy for detecting potential cardiotoxicity of candidate drugs. In this study, we aim to identify the predictive genomics biomarkers for drug-induced cardiac toxicity based on the RTCA coupled with PCR Array technology in primary cells. Three prototypical cardiotoxic compounds (doxorubicin, isoproterenol, ouabain) with different mechanisms were firstly real-time monitored to diagnose the cytotoxicity by using the RTCA, while the functional alterations of cardiomyocytes were also monitored by analyzing the beating frequency of cardiomyocytes. Then cardiac specific toxicity gene expression changes were studied by using the technology of PCR Array, which can detect the changes of 84 cardiac functions related genes. Rps6kb1 was identified to be the common cardiac biomarkers by using multivariate statistical and integration analyses. The biomarker was further verified by selecting other drugs with or without cardiotoxicity, and the results showed that the gene exhibited specific changes in cardiac toxicity. Moreover, IPA was applied to combine relevant pathways of Rps6kb1, and identify the main types of cardiac toxicity. These results would further enrich the evaluating strategy of drug-induced cardiotoxicity in vitro, and Rps6kb1 could be used as the specific biomarker of cardiotoxcity during safety assessment of the novel drug candidates. [ABSTRACT FROM AUTHOR]

MicroRNA(miRNA) is a class of 19-25-nucleotide non-coding RNAs that plays an important role in cellular proliferation, differentiation, development as well as cell death. The miRNA that can be detected in the plasma is known as circulating miRNA, and it can exist stable in the circulation of the blood. Recently, circulating miRNA has been increasingly suggested as novel potential biomarkers of a series of myocardial lesions. This review article summarized the progress of clinical and experimental studies of circulating miRNA as early diagnosis index for cardiopathologic conditions, including acute myocardial infarction, heart failure along with drug-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Cardiotoxicity is one of the major safety concerns in the use of drug and is the most common reason for drug removal from the market. At present, several drugs that have been recognized as the clinically effective drug have been reported to be associated with a high risk of cardiotoxicity during clinical use. The most representative ones are doxorubicin, arsenic trioxide, isoproterenol, cyclophosphamide, etc. The adverse effects seriously affect the human health and limit the clinical application of the drugs mentioned above. Over the past years, many strategies have been carried out to prevent the occurrence of drug-induced cardiotoxicity, including early detection of cardiotoxicity by biomarkers, limitation of doses, changing of drug-delivery way, combining with cardioprotective agent. Among them, combining with cardioprotective agent has gained increased interest and has been considered as a promising approach for continued treatment. Therefore, looking for effective cardioprotective agent to avoid the occurrence of drug-induced cardiotoxicity has become a great challenge for many researchers. Interestingly, some phenolic acids compounds from natural plants have been demonstrated to establish a significant protective effect in drug-induced cardiotoxicity. In this work, we reviewed the cardioprotective potentials and the involved mechanisms of phenolic acids in drug-induced cardiotoxicity. To provide a reference for the further application of phenolic acids in the prevention of drug-induced cardiotoxicity. [Display omitted] • Drug-induced cardiotoxicity refers to the side effects of drugs that damage cardiac tissues and disrupt electrophysiology of heart. • Drug-induced cardiotoxicity mainly caused by increased oxidative stress, mitochondrial damage, apoptosis, calcium homeostasis disorder, inflammation, blockage of hERG channel, abnormal expression of microRNAs, autophagy dysfunction. • Phenolic acids have huge potential on the prevention of drug-induced cardiotoxicity. [ABSTRACT FROM AUTHOR]

Drug toxicity is a key issue for drug R&D, a fundamental challenge of which is to screen for the targets genome-wide. The anticancer tyrosine kinase inhibitor sunitinib is known to induce cardiotoxicity. Here, to understand the molecular insights of cardiotoxicity by sunitinib at the genome level, we used a genome-wide drug target screening technology (GPScreen) that measures drug-induced haploinsufficiency (DIH) in the fission yeast Schizosaccharomyces pombe genome-wide deletion library and found a mitochondrial DNA polymerase (POG1). In the results, sunitinib induced more severe cytotoxicity and mitochondrial damage in POG1-deleted heterozygous mutants compared to wild type (WT) of S. pombe. Furthermore, knockdown of the human ortholog POLG of S. pombe POG1 in human cells significantly increased the cytotoxicity of sunitinib. Notably, sunitinib dramatically decreased the levels of POLG mRNAs and proteins, of which downregulation was already known to induce mitochondrial damage of cardiomyocytes, causing cardiotoxicity. These results indicate that POLG might play a crucial role in mitochondrial damage as a gene of which expressional pathway is targeted by sunitinib for cardiotoxicity, and that genome-wide drug target screening with GPScreen can be applied to drug toxicity target discovery to understand the molecular insights regarding drug toxicity. [ABSTRACT FROM AUTHOR]

Drug-induced cardiotoxicity (DICT) is an important concern of drug safety in both drug development and clinical application. The clinical manifestations of DICT include cardiomyopathy, arrhythmia, myocardial ischemia, heart failure, and a series of cardiac structural and functional changes. The occurrence of DICT has negative impacts on the life quality of the patients, brings additional social and economic burden. It is important to identify the potential factors and explore the mechanisms of DICT. Traditional cardiovascular risk factors can only partially explain the risk of DICT. Pharmacogenomic studies show accumulated evidence of genetics in DICT and suggest the potential to guide precision therapy to reduce risk of cardiotoxicity. The comprehensive application of technologies such as third-generation sequencing, human induced pluripotent stem (iPS) cells and genome editing has promoted the in-depth understanding of the functional role of susceptible genes in DICT. This paper reviewed drugs that cause DICT, the clinical manifestations and laboratory tests, as well as the related content of genetic variations associated with the risk of DICT, and further discussed the implication of new technologies in pharmacogenomics of DICT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Peng and Chen.)

Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric α-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure. [ABSTRACT FROM PUBLISHER]

Abstract: Drug-induced prolongation of ventricular repolarization with arrhythmia is a major concern in clinic safety pharmacology, and has been a common reason for the withdrawal of several promising drugs from the market. Therefore, novel techniques should be developed to evaluate cardiotoxicity of new drugs in preclinical research. A cardiomyocyte based biosensor was developed using the light addressable potentiometric sensor (LAPS). Mouse embryonic stem cells cultured on the surface of LAPS were induced to differentiate into synchronized spontaneity beating cardiomyocytes. Changes of extracellular potentials and cell shapes with their mechanical beatings could induce modulation of photocurrents in the LAPS system, and finally change the output of the sensor. With the characteristics of light addressability, LAPS can record cell clusters at any desired position. The sensor can be used to record the prolongation of ventricular action potentials with the cardiotoxicity induced by drugs such as amiodarone, levofloxacin, sparfloxacin, and noradrenaline. The quick and on time characteristics of the sensor were promising to establish a high-throughput platform for pharmacological toxicity investigation. [Copyright &y& Elsevier]

Abstract: Cardiac troponin T (cTnT) and troponin I (cTnI) are becoming acknowledged as useful biochemical markers of drug-induced cardiotoxicity. In this study we examined the release kinetics of cTnT and cTnI using an in vitro model of isolated rat neonatal ventricular cardiomyocytes (NVCM, 72h treatment with 0.1–3μM of daunorubicin) and compared it with data from a rabbit model of chronic anthracycline-induced cardiomyopathy in vivo (3mg/kg of daunorubicin weekly, 10 weeks). In cell-culture media, the cTnI and cTnT concentrations were concentration- and time-dependently increasing in response to daunorubicin exposure and were negatively exponentially related to cardiomyocyte viability. With 3μM daunorubicin, the relative increase of AUC of cTnT and cTnI was 2.4- and 5.3-fold higher than the increase of LDH activity, respectively. In rabbits, the daunorubicin-induced cardiomyopathy was associated with progressive increase of both cTnT and cTnI. Although the correlation between cTnT and cTnI cumulative release (AUCs) was found (R =0.81; P <0.01) and both cardiac troponins corresponded well with the echocardiographically-assessed systolic dysfunction (R =0.83 and 0.81 for cTnT and cTnI, respectively; P <0.001), the first significant increase in cTnI levels was observed earlier (at a cumulative daunorubicin dose of 200mg/m2) than with cTnT (350mg/m2). In conclusion, our study has confirmed cTnT and cTnI as very sensitive and specific markers of anthracycline-induced cardiotoxicity. The troponins can become not only the bridge between the clinical and experimental studies of drug-induced cardiotoxicity but also the linkage between the preclinical experiments in vitro and in vivo. [Copyright &y& Elsevier]

Purpose: Biologic agent-induced cardiotoxicity is markedly concerning. Rheumatoid arthritis (RA) treated with biologic agents is known to have the potential for cardiotoxicity; however, existing clinical evidence is not adequate to explain real-world patterns of cardiotoxicity. In this study, we quantify the risk of cardiotoxicity in patients with rheumatoid arthritis treated with biological agents. Methods: Cardiotoxicity reports induced by four types of biologic agents, abatacept, adalimumab, tocilizumab, and etanercept were used to mine data from the FDA's adverse event reporting system (FAERS) database from January 1, 2004 through September 30, 2020. Reports of cardiotoxic events were analyzed using a reporting odds ratio (ROR) algorithm, the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), the multi-item gamma Poisson shrinker (MGPS), and logistic regression methods. We use the preferred term of the Medical Dictionary of Regulatory Activities to identify such events. Results: A total of 3,969 reports of cardiotoxic events were identified involving biologic agents used for RA as the suspect drugs in this study, 317 reports of abatacept, 2,137 reports of adalimumab, 273 reports of tocilizumab, and 1,242 reports of etanercept. Adalimumab was the most reported, followed by etanercept. The proportion of death and disability outcomes reported for each targeted treatment represents approximately 20-25% of the total reported severe adverse events. In addition, relatively low cardiotoxicity reporting rates were found with abatacept. Conclusion: Analysis of FAERS data offers a more precise profile on the characteristics and occurrences of cardiotoxic events. The findings are a clinical reminder to physicians that an increased vigilance concerning the cardiotoxic effects of biological agents needs to be implemented. Also, more comparative studies are required in the future to explain the mechanisms that cause these cardiac phenomena., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tang, Xu, Li and Zhao.)

Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications' cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development. [ABSTRACT FROM AUTHOR]

Drug-induced abnormal heart rhythm known as Torsades de Pointes (TdP) is a potential lethal ventricular tachycardia found in many patients. Even newly released anti-arrhythmic drugs, like ivabradine with HCN channel as a primary target, block the hERG potassium current in overlapping concentration interval. Promiscuous drug block to hERG channel may potentially lead to perturbation of the action potential duration (APD) and TdP, especially when with combined with polypharmacy and/or electrolyte disturbances. The example of novel anti-arrhythmic ivabradine illustrates clinically important and ongoing deficit in drug design and warrants for better screening methods. There is an urgent need to develop new approaches for rapid and accurate assessment of how drugs with complex interactions and multiple subcellular targets can predispose or protect from drug-induced TdP. One of the unexpected outcomes of compulsory hERG screening implemented in USA and European Union resulted in large datasets of IC 50 values for various molecules entering the market. The abundant data allows now to construct predictive machine-learning (ML) models. Novel ML algorithms and techniques promise better accuracy in determining IC 50 values of hERG blockade that is comparable or surpassing that of the earlier QSAR or molecular modeling technique. To test the performance of modern ML techniques, we have developed a computational platform integrating various workflows for quantitative structure activity relationship (QSAR) models using data from the ChEMBL database. To establish predictive powers of ML-based algorithms we computed IC 50 values for large dataset of molecules and compared it to automated patch clamp system for a large dataset of hERG blocking and non-blocking drugs, an industry gold standard in studies of cardiotoxicity. The optimal protocol with high sensitivity and predictive power is based on the novel eXtreme gradient boosting (XGBoost) algorithm. The ML-platform with XGBoost displays excellent performance with a coefficient of determination of up to R 2 ~0.8 for pIC 50 values in evaluation datasets, surpassing other metrics and approaches available in literature. Ultimately, the ML-based platform developed in our work is a scalable framework with automation potential to interact with other developing technologies in cardiotoxicity field, including high-throughput electrophysiology measurements delivering large datasets of profiled drugs, rapid synthesis and drug development via progress in synthetic biology.

Adverse drug reactions (ADRs) are an important cause of morbidity and mortality. Genetic factors predispose to many ADRs, affecting susceptibility to both type A and type B reactions. The overall contribution of genetics will vary according to drug and ADR, and should be considered when attempting to predict and prevent ADRs. Genetic risk factors are considered in detail for a number of type A ADRs, especially those relating to warfarin and thiopurines, and type B ADRs affecting skin, the liver, and the heart. As the availability of whole genome sequencing increases, it is likely that prospective genotype for particular ADRs prior to drug prescription will become more common in the future. Current examples of genetic testing to prevent ADRs which have already been implemented and future prospects for developments in the field are discussed in detail., (© 2018 Elsevier Inc. All rights reserved.)

Drug toxicity is a key issue for drug R&D, a fundamental challenge of which is to screen for the targets genome-wide. The anticancer tyrosine kinase inhibitor sunitinib is known to induce cardiotoxicity. Here, to understand the molecular insights of cardiotoxicity by sunitinib at the genome level, we used a genome-wide drug target screening technology (GPScreen) that measures drug-induced haploinsufficiency (DIH) in the fission yeast Schizosaccharomyces pombe genome-wide deletion library and found a mitochondrial DNA polymerase (POG1). In the results, sunitinib induced more severe cytotoxicity and mitochondrial damage in POG1-deleted heterozygous mutants compared to wild type (WT) of S. pombe. Furthermore, knockdown of the human ortholog POLG of S. pombe POG1 in human cells significantly increased the cytotoxicity of sunitinib. Notably, sunitinib dramatically decreased the levels of POLG mRNAs and proteins, of which downregulation was already known to induce mitochondrial damage of cardiomyocytes, causing cardiotoxicity. These results indicate that POLG might play a crucial role in mitochondrial damage as a gene of which expressional pathway is targeted by sunitinib for cardiotoxicity, and that genome-wide drug target screening with GPScreen can be applied to drug toxicity target discovery to understand the molecular insights regarding drug toxicity., (© The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)