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Background: The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown., Objective: To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy., Methods: A retrospective cohort study identified 19,874 patients who received 22,202 doses of triple antiemetics during the 2.5-year time frame from March 4, 2020 to September 7, 2022 for surgical nausea prophylaxis or treatment of nausea. These patients above were cross-matched with an electrocardiogram and adverse outcome database; this identified 226 patients with documentation of a QTc > 450 ms, all ventricular tachycardias including TdP within 48 hours of receiving triple antiemetic therapy, or death within 7 days of receiving ondansetron., Results: There were 3 patients who had documented VT (n = 3), but there were no documented incidents of TdP (n = 0). There were 9 codes called on patients within 48 hours of medication administration, and none of them were due to ventricular arrythmias (n = 0). A total of 11 patients died within 7 days of triple antiemetic therapy. Ten of the 11 deaths were determined to not be from the triple antiemetic. One patient died at home within 24 hours of the procedure of an unknown cause (n = 1)., Conclusions and Relevance: No episodes of TdP were identified in patients receiving triple antiemetic therapy perioperatively, though the cause of death in 1 patient could not be determined. This suggest that low-dose triple antiemetic therapy is low risk for the development of TdP., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Numerous non-cardiovascular drugs have a potential to induce life-threatening torsades de pointes (TdP) ventricular cardiac arrhythmias by blocking human ether-à-go-go-related gene (hERG) currents via binding to the channel's inner cavity. Identification of the hERG current-inhibiting properties of candidate drugs is performed focusing on binding sites in the channel pore. It has been suggested that biologicals have a low likelihood of hERG current inhibition, since their poor diffusion across the plasma membrane prevents them from reaching the binding site in the channel pore. However, biologicals could influence hERG channel function by binding to 'unconventional' noncanonical binding sites. This Opinion gives an overview on noncanonical blockers of hERG channels that might be of relevance for the assessment of the possible torsadogenic potential of macromolecular therapeutics., Competing Interests: Declaration of interests The author declares no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The clinical manifestations of licorice-induced pseudoaldosteronism include muscle weakness, periodic paralysis, hypokalemia, and hypertension. Excessive licorice consumption can lead to adverse reactions affecting multiple systems, including the endocrine, cardiovascular, nervous, digestive, and immune systems. Although licorice is a frequently used Chinese herbal medicine, life-threatening adverse reactions have been reported among its users. This article presents a case of severe hypokalemia, torsade de pointes, severe hypertension, and exacerbation of manic symptoms resulting from an overdose of compound licorice tablets. This study aimed to enhance the understanding of the causes of hypokalemia and raise awareness on the potentially fatal adverse reactions associated with licorice drugs.

Introduction: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process., Methods: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec)., Results: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected., Discussion: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous single‑lead ECGs collected from freely moving dogs and monkeys., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Risperidone is a second-generation antipsychotic for treating schizophrenia and bipolar disorder. It can potently inhibit I Kr , but is classified into conditional risk for torsade de pointes (TdP) by CredibleMeds®. Our previous studies using chronic atrioventricular block dogs showed that risperidone alone did not induce TdP, and that dl-sotalol (β-adrenoceptor blockade plus I Kr inhibition) induced TdP three times more frequently than d-sotalol (I Kr inhibition alone). Since risperidone can block α 1 -adrenoceptor and decrease blood pressure, the resulting reflex-mediated increase of sympathetic tone on β-adrenoceptor might protect the heart from its I Kr inhibition-associated TdP. To validate this hypothesis, risperidone was administered to chronic atrioventricular block dogs after β-adrenoceptor blocker atenolol infusion with monitoring J-T peak and T peak -T end , which are proarrhythmic surrogate markers of "substrate" and "trigger" toward TdP, respectively. Atenolol alone induced TdP in 1 out of 5 dogs; moreover, an additional infusion of risperidone induced TdP in 3 out of 4 dogs. Risperidone prolonged QT interval, J-T peak and T peak -T end in animals that induced TdP. These findings indicate that β-adrenoceptor blockade can diminish repolarization reserve to augment risperidone's torsadogenic potential, thus advising caution when using β-adrenoceptor blockers in patients with I Kr inhibition-linked labile repolarization., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Drug-induced QT prolongation increases the risk of Torsade de Pointes (TdP). Drug-induced QT prolongation is a complex and unpredictable system due to many uncertainties. Risk factors such as electrolyte disturbances, heart failure and genetics play an important role in estimating the effect on QT prolongation. Moreover, the degree of QT prolongation is not always directly related to the risk of TdP and the assessment of the QT-interval is variable depending on the type and timing of QT measurement. Therefore, the variation in QT measurement may be larger than the effect of certain drugs on the QT interval. Because of the potentially lethal risk, several measures are undertaken to reduce the risk of QT prolongation and TdP, while their effect and proportionality are unclear. We suggest we should be less stringent in certain settings when risk of TdP is extremely low given the limited availability of our resources.

Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Simon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients., Methods: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG., Results: This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H 2 RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H 2 RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H 2 RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs., Conclusion: In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

A systematic literature review was conducted to determine the incidence and mortality of QT-interval prolongation (QTp), torsades de pointes (TdP), and heart failure (HF) in patients with non-small cell lung cancer (NSCLC) who received epidermal growth factor receptor (EGFR) TKIs. Of 296 identified publications, 95 met eligibility criteria and were abstracted for QTp/TdP and HF outcomes (QTp/TdP: 83 publications, including 5 case study publications; HF: 79 publications, including 6 case study publications [involving 8 patients]). QTp incidence ranged from 0% to 27.8% in observational studies and from 0% to 11% in clinical trials, with no deaths due to QTp. There were no TdP events or deaths due to TdP. The incidence of HF ranged from 0% to 8%, and HF mortality rates ranged from 0% to 4%. Patients receiving treatment with EGFR TKIs should be monitored for signs of QTp, TdP, and HF per prescribing information. Standardized definitions and methods to improve monitoring of QTp, TdP, and HF-related events are needed in patients with NSCLC., Competing Interests: Disclosure B.K. is employed by Takeda. B.C. was employed by Takeda during the time this research was conducted. K.I. consulted on this project through CERobs Consulting, LLC; K.I. reports that Takeda Pharmaceuticals contracted with CERobs Consulting, LLC, a consulting firm with focus on real-world evidence, outcomes research, and epidemiology and clinical outcome assessments, including patient reported outcomes. K.R. consulted on this project through CERobs Consulting, LLC; K.R. reports that Takeda Pharmaceuticals contracted with CERobs Consulting, LLC, a consulting firm with focus on real-world evidence, outcomes research, and epidemiology and clinical outcome assessments, including patient reported outcomes. N.R-O. consulted on this project through CERobs Consulting, LLC; N.R-O. reports that Takeda Pharmaceuticals contracted with CERobs Consulting, LLC, a consulting firm with focus on real-world evidence, outcomes research, and epidemiology and clinical outcome assessments, including patient reported outcomes. W.S. is employed by Takeda. E.F. is employed by Takeda., (Copyright © 2024 Takeda Development Center Americas, Inc. Published by Elsevier Inc. All rights reserved.)

Importance: Individuals with dialysis-dependent kidney failure have numerous risk factors for medication-related adverse events, including receipt of care by multiple clinicians and initiation of some QT-prolonging medications with known risk of torsades de pointes (TdP), which is associated with higher risk of sudden cardiac death. Little is known about the prescription and dispensation patterns of QT-prolonging medications among people receiving dialysis, hindering efforts to reduce drug-related harm from these and other medications in this high-risk population., Objective: To examine prescription and dispensation patterns of QT-prolonging medications with known TdP risk and selected interacting medications prescribed to individuals receiving hemodialysis., Design, Setting, and Participants: This cross-sectional study included patients 60 years or older who were enrolled in Medicare Parts A, B, and D receiving in-center hemodialysis from January 1 to December 31, 2019. Analyses were conducted from October 20, 2022, to June 16, 2023., Exposures: New-user prescriptions for the 7 most frequently filled QT-prolonging medications characterized by the timing of the new prescription relative to acute care encounters, the type of prescribing clinician and pharmacy that dispensed the medication, and concomitant use of selected medications known to interact with the 7 most frequently filled QT-prolonging medications with known TdP risk., Main Outcomes and Measures: The main outcomes were the frequencies of the most commonly filled and new-use episodes of QT-prolonging medications; the timing of medication fills relative to acute care events; prescribers and dispensing pharmacy characteristics for new use of medications; and the frequency and types of new-use episodes with concurrent use of potentially interacting medications., Results: Of 20 761 individuals receiving hemodialysis in 2019 (mean [SD] age, 74 [7] years; 51.1% male), 10 992 (52.9%) filled a study drug prescription. Approximately 80% (from 78.6% for odansetron to 93.9% for escitalopram) of study drug new-use prescriptions occurred outside of an acute care event. Between 36.8% and 61.0% of individual prescriptions originated from general medicine clinicians. Between 16.4% and 26.2% of these prescriptions occurred with the use of another QT-prolonging medication. Most potentially interacting drugs were prescribed by different clinicians (46.3%-65.5%)., Conclusions and Relevance: In this cross-sectional study, QT-prolonging medications for individuals with dialysis-dependent kidney failure were commonly prescribed by nonnephrology clinicians and from nonacute settings. Prescriptions for potentially interacting medications often originated from different prescribers. Strategies aimed at minimizing high-risk medication-prescribing practices in the population undergoing dialysis are needed.

Background: Case reports suggest that quetiapine or haloperidol use is associated with severe QT prolongation (SQTP) and torsades de pointes., Objective: The purpose of this study was to examine the incidences, risk factors, and outcomes of SQTP in quetiapine and haloperidol users., Methods: This study accessed electronic medical records from a multicenter health-care hospital system in Taiwan and included patients who received quetiapine or haloperidol therapy and had both baseline and follow-up electrocardiograms. SQTP was defined as a posttreatment corrected QT (QTc) interval exceeding 500 ms or an increase in QTc interval of >60 ms compared with the baseline value. We analyzed the risk factors and outcomes of SQTP using multivariate logistic regression., Results: Mean increases in QTc interval were +8.3 ± 51.8 and +8.9 ± 44.0 ms after the administration of quetiapine (n = 8832) and haloperidol (n = 2341). Among these users, 1149 (13.0%) and 333 (14.2%) developed SQTP, respectively. Common risk factors for SQTP included old age, heart failure, hypokalemia, amiodarone use, and baseline QTc interval. SQTP in quetiapine users was significantly associated with ventricular arrhythmias (odds ratio 2.84; 95% confidence interval 1.95-4.13) and sudden cardiac death (odds ratio 2.29; 95% confidence interval 1.44-3.66)., Conclusion: More than 10% of patients receiving quetiapine or haloperidol therapy developed SQTP, and many of them were exposed to risk factors for SQTP. SQTP in quetiapine users was significantly associated with increased risks of ventricular arrhythmias and sudden cardiac death. Clinicians should be vigilant for ventricular arrhythmias in quetiapine users who have risk factors for SQTP., Competing Interests: Disclosures All authors have no conflicts to disclose., (Copyright © 2023 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Acquired prolonged corrected QT (QTc) interval can lead to life-threatening Torsade de Pointes (TdP) arrhythmia. Multiple risk factors including medications, comorbidities, and electrolyte imbalances contribute significantly to acquired manifestations of the QTc prolongation. Critically ill patients are particularly more vulnerable to TdP due to complex medical conditions, aging, and polypharmacy., Objective: This study aimed to assess the prevalence of TdP-associated medication prescribing, identify risk factors for QTc prolongation and TdP, and determine primary predictors of high TdP medication usage in critically ill patients in Jordan., Methods: We conducted a retrospective cross-sectional analysis of electronic medical records for patients from King Abdullah University Hospital who were admitted to Intensive Care Unit (ICU) between (July 2012-July 2022). We collected data on patients' demographics, clinical characteristics, comorbidities, laboratory results, and prescribed medications. Medications were categorized into three TdP risk levels according to CredibleMeds ® assessment tool. Data were analyzed using descriptive statistics and a binary logistic regression model., Results: Of the 13,300 patients (58.2% male, median age 62 years). Prescribing prevalence for medications with known TdP risk was 19%, possible risk (24.7%), conditional risk (21.6%), and confirmed conditional risk (8.3%). Common comorbidities included hypertension (40.9%), diabetes (33.3%), and cancer (15.4%). Drugs with known TdP risk included citalopram, amiodarone, clarithromycin, and ciprofloxacin. A binary regression model revealed that as age increased, the odds of TdP associated medication prescribing decreased (OR = 0.989, p < 0.001), while patients on more than five medications had higher odds (OR = 4.281, p < 0.001)., Conclusion: The study identified a notable prevalence of prescribing for medications with QTc prolongation/TdP risk in critically ill patients. Healthcare providers in the ICU should exercise caution to minimize the inadvertent prescription of TdP associated medications especially among older patients and those with polypharmacy., Competing Interests: The authors declare no competing interest in this work., (© 2024 Al-Azayzih et al.)

QT prolongation and the potentially fatal arrhythmia Torsades de Pointes are common causes for withdrawing or restricting drugs; however, little is known about similar liabilities of environmental chemicals. Current in vitro-in silico models for testing proarrhythmic liabilities, using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), provide an opportunity to address this data gap. These methods are still low- to medium-throughput and not suitable for testing the tens of thousands of chemicals in commerce. We hypothesized that combining high-throughput population- based in vitro testing in hiPSC-CMs with a fully in silico data analysis workflow can offer sensitive and specific predictions of proarrhythmic potential. We calibrated the model with a published hiPSC-CM dataset of drugs known to be positive or negative for proarrhythmia and tested its performance using internal cross-validation and external validation. Additionally, we used computational down-sampling to examine three study designs for hiPSC-CM data: one replicate of one donor, five replicates of one donor, and one replicate of a population of five donors. We found that the population of five donors had the best performance for predicting proarrhythmic potential. The resulting model was then applied to predict the proarrhythmic potential of environmental chemicals, additionally characterizing risk through margin of exposure (MOE) calculations. Out of over 900 environmental chemicals tested, over 150 were predicted to have proarrhythmic potential, but only seven chemicals had a MOE < 1. We conclude that a high-throughput in vitro-in silico approach using population-based hiPSC-CM testing provides a reasonable strategy to screen environmental chemicals for proarrhythmic potential.

Background: Delamanid (DLM) is a relatively new drug for drug-resistant tuberculosis (DR-TB) that has been used in Indonesia since 2019 despite its limited safety data. DLM is known to inhibit hERG potassium channel with the potential to cause QT prolongation which eventually leads to Torsades de pointes (TdP)., Objective: This study aims to analyse the changes of QTc interval in DR-TB patients on DLM regimen compared to shorter treatment regimens (STR)., Methods: A retrospective cohort was implemented on secondary data obtained from two participating hospitals. The QTc interval and the changes in QTc interval from baseline (ΔQTc) were assessed every 4 weeks for 24 weeks., Results: The maximum increased of QTc interval and ΔQTc interval were smaller in the DLM group with mean difference of 18,6 (95%CI 0.3 to 37.5) and 31.6 milliseconds (95%CI 14.1 to 49.1) respectively. The proportion of QTc interval prolongation in DLM group were smaller than STR group (RR=0.62; 95%CI 0.42 to 0.93)., Conclusion: This study has shown that DLM regimens are less likely to increase QTc interval compared to STR. However, close monitoring of the risk of QT interval prolongation needs to be carried out upon the use of QT interval prolonging antituberculoid drugs.

Background: Patients undergoing dialysis pose therapeutic challenges in terms of polypharmacy, administration of potentially inappropriate drugs, and drugs with the potential risk of toxicity., Objective: This study evaluated the use of drugs, potentially inappropriate medicines (PIM), drugs with risk of Torsades de Pointes (TdP), and the complexity of the prescribed regimen using the medication regimen complexity index scale in patients undergoing hemodialysis., Methods: A retrospective cohort study was carried out amongst patients receiving hemodialysis. Drugs were classified into one of four classes: (i) drugs used in managing renal complications, (ii) cardiovascular drugs, (iii) anti-diabetic drugs, (iv) drugs for symptomatic management, and (v) others. Drugs were considered as PIM according to the Can-SOLVE CKD working group from a network of Canadian nephrology health professionals. The study adhered to the CredibleMeds classification of drugs with known, possible, and conditional risk of TdP and the complexity of prescribed medicines was evaluated based on the pre-validated medication regimen complexity index scale based on form/route, frequency of dosing, and requirement of special instructions., Results: Sixty-three participants were included in the study (49 males and 14 females) with the median (range) age of 45 (21-66) years. Cardiovascular drugs followed by drugs used for managing renal complications were the most common classes administered. Notably, 12 (19.1%) patients received one of the non-steroidal anti-inflammatory drugs, 21 (33.3%) received a proton pump inhibitor, three (4.8%) received pregabalin, two (3.2%) received opioid drugs, and one (1.6%) was administered celecoxib. Atorvastatin, furosemide, omeprazole, and allopurinol were the most common PIM drugs administered to the study participants followed by others. Drugs used for symptomatic management had significantly more PIM compared to other classes (p < 0.0001). Six (9.5%) patients received drugs with known TdP risk, one with possible TdP risk, and 61 with conditional risk. Median (range) medical regimen complexity index score was 26.5 (2-62.5)., Conclusion: A huge burden of drug therapy was observed in the hemodialysis patients in terms of higher proportions of PIM, complex medical regimen, and prescription of drugs with risk of TdP. Implementation of clinical decision support tools enhancing rational prescription and identification of drugs with TdP risk, introducing antimicrobial stewardship, and stepwise deprescription of the drugs with the least benefit-risk ratio are warranted.

Background and Objective: In silico methods are gaining attention for predicting drug-induced Torsade de Pointes (TdP) in different stages of drug development. However, many computational models tended not to account for inter-individual response variability due to demographic covariates, such as sex, or physiologic covariates, such as renal function, which may be crucial when predicting TdP. This study aims to compare the effects of drugs in male and female populations with normal and impaired renal function using in silico methods., Methods: Pharmacokinetic models considering sex and renal function as covariates were implemented from data published in pharmacokinetic studies. Drug effects were simulated using an electrophysiologically calibrated population of cellular models of 300 males and 300 females. The population of models was built by modifying the endocardial action potential model published by O'Hara et al. (2011) according to the experimentally measured gene expression levels of 12 ion channels., Results: Fifteen pharmacokinetic models for CiPA drugs were implemented and validated in this study. Eight pharmacokinetic models included the effect of renal function and four the effect of sex. The mean difference in action potential duration (APD) between male and female populations was 24.9 ms (p<0.05). Our simulations indicated that women with impaired renal function were particularly susceptible to drug-induced arrhythmias, whereas healthy men were less prone to TdP. Differences between patient groups were more pronounced for high TdP-risk drugs. The proposed in silico tool also revealed that individuals with impaired renal function, electrophysiologically simulated with hyperkalemia (extracellular potassium concentration [K + ] o  = 7 mM) exhibited less pronounced APD prolongation than individuals with normal potassium levels. The pharmacokinetic/electrophysiological framework was used to determine the maximum safe dose of dofetilide in different patient groups. As a proof of concept, 3D simulations were also run for dofetilide obtaining QT prolongation in accordance with previously reported clinical values., Conclusions: This study presents a novel methodology that combines pharmacokinetic and electrophysiological models to incorporate the effects of sex and renal function into in silico drug simulations and highlights their impact on TdP-risk assessment. Furthermore, it may also help inform maximum dose regimens that ensure TdP-related safety in a specific sub-population of patients., Competing Interests: Declaration of Competing Interest Samuel Baroudi, Kévin Koloskoff, Mathieu Basset, Sylvain Benito, and Frederic Dayan work for ExactCure®. All the other authors declare no potential commercial or financial relationships., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Current cardiac safety testing focuses on detecting drug-induced QT C prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QT C outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies. To address this knowledge gap, information for peptides and proteins submitted to the US Food and Drug Administration (FDA) was collected. Results of hERG assays, ventricular repolarization assays, and in vivo QT assessment were compared with clinical QT C study outcomes. The results show that 14% clinical QT C studies for approved and investigational products failed to exclude 10-ms QT C prolongation. Clinical QT C prolongation for these molecules lacked concentration-dependence which is expected for hERG block-mediated mechanism or QT C prolongation could not be excluded due to characterization in the clinical study. The hERG and ventricular repolarization assays do not identify clinical QT C prolongation potential for peptides and proteins. Lack of alignment between hERG and ventricular repolarization assay results and clinical QT C outcomes suggests that the mechanisms of QT C prolongation by some peptides and proteins are unrelated to direct cardiac ion channel block. Similar to large targeted proteins and monoclonal antibodies, peptides and proteins regardless of size have a low likelihood of direct cardiac ion channel interactions. This characteristic supports waiving the requirement for thorough QT assessment for products comprised of naturally occurring amino acids unless proarrhythmia potential is suggested by nonclinical or clinical data., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background/aim: Torsade de pointes (TdP)/QT prolongation (QTP) is one of the most life-threatening adverse effects of antifungal triazoles. The aim of the present study was to evaluate the association of antifungal triazoles with TdP/QTP by age group and the profile of the time of TdP/QTP onset by analyzing the spontaneous adverse event database for Japan., Patients and Methods: Data registered in the Japanese Adverse Drug Event Report database (JADER) from April 2004 to March 2022 were analyzed. The association between the administration of antifungal triazoles and TdP/QTP according to age was evaluated using an adjusted reporting odds ratio (aROR). In addition, the time-to-onset of TdP/QTP after antifungal triazole treatment was analyzed using the Weibull distribution according to the route of administration., Results: Antifungal triazole treatment was associated with TdP/QTP (aROR=1.77, 95% confidence interval=1.52-2.07). In the subgroup analyses by age group, antifungal triazole treatments in patients ≤29 years old and ≥50 (except ≥90) years old were associated with TdP/QTP. The medians (quartiles) of time-to-onset for intravenous and oral antifungal triazole treatment were 8 (6-12) and 23 (8-86) days, respectively. In addition, the shape parameter in the Weibull distribution analysis of oral triazole treatment revealed that the hazard exhibited an early failure profile., Conclusion: TdP/QTP is associated with antifungal triazoles even in young patients, and patients should be monitored for the development of TdP/QTP, especially early after the initiation of treatment., (Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Drug-induced QT-prolongation increases the risk of TdP arrhythmia attacks and sudden cardiac death. However, measuring the QT-interval and determining a precise cut-off QT/QTc value that could put a patient at risk of TdP is challenging and influenced by many factors including female sex, drug-free baseline, age, genetic predisposition, and bradycardia., Objectives: This paper presents a novel approach for intuitively and visually monitoring QT-prolongation showing a potential risk of TdP, which can be adjusted according to patient-specific risk factors, using a pseudo-coloring technique and explainable artificial intelligence (AI)., Methods: We extended the development and evaluation of an explainable AI-based technique- visualized using pseudo-color on the ECG signal, thus intuitively 'explaining' how its decision was made -to detect QT-prolongation showing a potential risk of TdP according to a cut-off personalized QTc value (using Bazett's ∆QTc > 60 ms relative to drug-free baseline and Bazett's QTc > 500 ms as examples), and validated its performance using a large number of ECGs (n = 5050), acquired from a clinical trial assessing the effects of four known QT-prolonging drugs versus placebo on healthy subjects. We compared this new personalized approach to our previous study that used a more general approach using the QT-nomogram., Results and Conclusions: The explainable AI-based algorithm can accurately detect QT-prolongation when adjusted to a personalized patient-specific cut-off QTc value showing a potential risk of TdP. Using ∆QTc > 60 ms relative to drug-free baseline and QTc > 500 ms as examples, the algorithm yielded a sensitivity of 0.95 and 0.79, and a specificity of 0.95 and 0.98, respectively. We found that adjusting pseudo-coloring according to Bazett's ∆QTc > 60 ms relative to a drug-free baseline personalized to each patient provides better sensitivity than using Bazett's QTc > 500 ms, which could underestimate a potentially clinically significant QT-prolongation with bradycardia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Depression diagnoses have surged recently, and selective serotonin reuptake inhibitors (SSRIs) are the go-to treatment. However, studies indicate that long-term use of SSRIs can increase cardiovascular risk without systematic evaluation of the drug class. To offer clinical guidance, we performed an evaluation of the association between the six most commonly prescribed SSRIs and cardiovascular adverse events. Using the FDA Adverse Event Reporting System (FAERS) from Q1 2004 to Q2 2022, we conducted a disproportionality analysis and determined the magnitude of significant signals using statistical shrinkage transformations. Our study revealed that arrhythmias, torsades de pointes/QT prolongation, cardiomyopathy, and hypertension were among the most prevalent adverse events linked to SSRIs. Our analysis also showed a significant association between SSRIs and the aforementioned adverse events, with higher incidence in middle-aged and elderly patients and women. We further observed a rising trend in the incidence of arrhythmias, torsades de pointes/QT prolongation, and hypertension, highlighting the need for heightened cardiac monitoring in patients on SSRIs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: There is no consensus for assessment and management of patients with serious mental illness (SMI) who are at risk for cardiac morbidity and mortality due to antipsychotic-associated QTc prolongation. Objective: The objective of this review was to assess methods for risk scoring, QT correction calculation, and clinical management in SMI patients with antipsychotic-associated QTc prolongation. Methods: A search was performed in PubMed for case reports that described QTc prolongation in adult patients with schizophrenia or bipolar disorder prescribed an antipsychotic. Reports published in North America between 2000 and 2020 were eligible. The Mayo, Tisdale, and RISQ-PATH scoring tools were applied to cases to categorize risk level. Results: Seventeen cases were included. Most patients were prescribed a second-generation antipsychotic for schizophrenia, with baseline and maximum QTc values of 429 milliseconds and 545 milliseconds, respectively. The Mayo scoring tool identified 17 (100%) cases as "high risk," Tisdale identified 9 (53%) cases as "moderate risk" and 7 (41%) cases as "low risk," while RISQ-PATH identified 9 (53%) cases as "not low risk" and 8 (47%) cases as "low risk." Three cases reported the QT correction formula utilized (18%). The most common intervention to address antipsychotic-associated QTc prolongation was switching to a different antipsychotic (35%). Approximately one third of patients experienced Torsades de Pointes. Conclusion: There is a lack of standardization for antipsychotic-associated QTc prolongation risk assessment and management in patients with SMI. This review provides real-world data representing actual clinical practice.

Cardiac cytochrome P450 2J2 (CYP2J2) metabolizes endogenous polyunsaturated fatty acid, arachidonic acid (AA), to bioactive regioisomeric epoxyeicosatrienoic acid (EET) metabolites. This endogenous metabolic pathway has been postulated to play a homeostatic role in cardiac electrophysiology. However, it is unknown if drugs that cause intermediate to high risk torsades de pointes (TdP) exhibit inhibitory effects against CYP2J2 metabolism of AA to EETs. In this study, we demonstrated that 11 out of 16 drugs screened with intermediate to high risk of TdP as defined by the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative are concurrently reversible inhibitors of CYP2J2 metabolism of AA, with unbound inhibitory constant (K i,AA,u ) values ranging widely from 0.132 to 19.9 µM. To understand the physiological relevancy of K i,AA,u , the in vivo unbound drug concentration within human heart tissue (C u,heart ) was calculated via experimental determination of in vitro unbound partition coefficient (K puu ) for 10 CYP2J2 inhibitors using AC16 human ventricular cardiomyocytes as well as literature-derived values of fraction unbound in plasma (f u,p ) and plasma drug concentrations in clinical scenarios leading to TdP. Notably, all CYP2J2 inhibitors screened belonging to the high TdP risk category, namely vandetanib and bepridil, exhibited highest K puu values of 18.2 ± 1.39 and 7.48 ± 1.16 respectively although no clear relationship between C u,heart and risk of TdP could eventually be determined. R values based on basic models of reversible inhibition as per FDA guidelines were calculated using unbound plasma drug concentrations (C u,plasma ) and adapted using C u,heart which suggested that 4 out of 10 CYP2J2 inhibitors with intermediate to high risk of TdP demonstrate greatest potential for clinically relevant in vivo cardiac drug-AA interactions. Our results shed novel insights on the relevance of CYP2J2 inhibition in drugs with risk of TdP. Further studies ascertaining the role of CYP2J2 metabolism of AA in cardiac electrophysiology, characterizing inherent cardiac ion channel activities of drugs with risk of TdP as well as in vivo evidence of drug-AA interactions will be required prior to determining if CYP2J2 inhibition could be an alternative mechanism contributing to drug-induced TdP., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization., Competing Interests: Declaration of competing interest The authors indicated no potential conflict of interest., (Copyright © 2023 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background It was Dissertenne who first described a cardiac phenomenon known as the Torsades de Pointes (TdP). QT prolongation caused by drugs is one of the most important causes for acquired QT prolongation syndrome. Objective To observe the prescribing practices of QT interval prolonging drugs among a highrisk population of critically ill older adults in a tertiary care hospital in South India The objectives were to identify the most commonly prescribed QT prolonging drugs, to analyse types of QT prolonging drugs based on risk of causing QT prolongation, to study the frequency of occurrence of common risk factors for QT prolongation and to identify presence of any significant relationships among the study variables. Method We have conducted a one-year cross-sectional descriptive study of the prescribing practices of QT interval prolonging drugs among 319 critically ill older adults in a tertiary care hospital in South India. Data was analysed to categorize the most common drugs which prolong QT interval; the type and frequency of use of QT interval prolonging drugs and to find the most common risk factors for QT prolongation in this study population. Result In this study, ondansetron, clarithromycin, azithromycin,and amiodarone were the most prescribed among the drugs with known risk of QTc (Corrected QT interval) prolongation. Among the drugs with conditional risk of QTc prolongation, pantoprazole, frusemide, piperacillin-tazobactam and esomeprazole were the most prescribed. The most common risk factors for QTc prolongation that were identified in this study were bradycardia, acute kidney injury, chronic kidney disease and low serum potassium. Conclusion This study helps to inform our physicians regarding the commonly prescribed QT interval prolonging drugs so that they may reduce co prescription of multiple QT prolonging drugs in high-risk patients. It identifies kidney injury, low potassium, and bradycardia as common risk factors for QT interval prolongation in these patients.

Background: Drug-induced or acquired long QT syndrome occurs as a result of the unintended disruption of cardiac repolarization due to drugs that block cardiac ion channels. These side effects have been responsible for the withdrawal of a range of drugs from market and are a common reason for termination of the development of new drugs in the preclinical stage. Existing approaches to risk prediction are expensive and overly sensitive meaning that recently there have been renewed efforts, largely driven by the comprehensive proarrhythmic assay initiative, to develop more accurate methods for allocation of proarrhythmic risk., Methods: In this study, we aimed to quantify changes in the morphology of the repolarization phase of the cardiac action potential as an indicator of proarrhythmia, supposing that these shape changes might precede the emergence of ectopic depolarizations that trigger arrhythmia. To do this, we describe a new method of quantifying action potential morphology by measuring the radius of curvature of the repolarization phase both in simulated action potentials, as well as in action potentials measured from induced pluripotent stem cell-derived cardiomyocytes. Features derived from the curvature signal were used as inputs for logistic regressions to predict proarrhythmic risk., Results: Optimal risk classifiers based on morphology were able to correctly classify risk to drugs in the comprehensive proarrhythmic assay initiative panels with very high accuracy (0.9375) and outperformed conventional metrics based on action potential duration at 90% repolarization, triangulation, and charge movement (qNet)., Conclusions: Analysis of action potential morphology in response to proarrhythmic drugs improves prediction of torsadogenic risk. Furthermore, morphology metrics can be measured directly from the action potential, potentially eliminating the burden of undertaking complex screens of potency and drug-binding kinetics against multiple cardiac ion channels. As such, this method has the potential to improve and streamline regulatory assessment of proarrhythmia in preclinical drug development., Competing Interests: Disclosures None.

Licorice has been traditionally prescribed for palpitation, whereas its overdose has caused lethal arrhythmias including torsade de pointes. Licorice contains glycyrrhizic acid of ≥ 2% (w/w), which is hydrolyzed to glycyrrhetinic acid (GRA) in the intestine. Since their cardiac electropharmacological properties are not fully understood, we assessed them to ask mechanism of licorice-induced torsade de pointes. GRA at 0.1, 1 and 10 μg/mL was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes sheets (n = 6). GRA shortened spontaneous activation interval and repolarization period, and decreased maximum contraction velocity, indicating Ca 2+ channel blockade. It prolonged effective refractory period and post-repolarization refractoriness with a steep frequency-dependency, whereas it delayed conduction with a modest use-dependency, resembling lidocaine in the mode of Na + channel-blocking action. Meanwhile, Kanzoto containing a decoction of licorice alone in a dose of 2 or 6 g/body/day was orally administered to the conscious chronic atrioventricular block dogs for 3 days (n = 4). Kanzoto prolonged QT interval with increasing its temporal dispersion, suggesting K + channel suppression, and slightly decreased the plasma K + concentration without inducing torsade de pointes. Moreover, it significantly suppressed atrial and idioventricular rates, leading to sinus arrest along with the onset of ventricular fibrillation in one animal, possibly due to Na + channel blockade. These results indicate that electropharmacological profile of licorice can be explained by Na + , Ca 2+ and K + channels blockade, which may be associated with low torsadogenic risk, but might contribute to the onset of other types of lethal ventricular arrhythmias., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine)., Methods: Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD 90 ) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate I Kr inhibition at varying IL-6 and quetiapine concentrations., Results: IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p = .0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD 90 :179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p = .0357). When hypokalemia was introduced, the APD 90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p = .2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p = .2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate I Kr inhibition., Conclusions: Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Nabil El-Sherif reports financial support was provided by Narrows Institute for Biomedical Research and Education, Inc. Mohamed Boutjdir reports financial support was provided by Biomedical Laboratory Research & Development Service of Veterans Affairs Office of Research and Development. Mohamed Boutjdir reports financial support was provided by National Heart Lung and Blood Institute. Mohamed Boutjdir reports financial support was provided by US Department of Defense., (Published by Elsevier Inc.)

In pharmaceutical treatment, many non-cardiac drugs carry the risk of prolonging the QT interval, which can lead to fatal cardiac complications such as torsades de points (TdP). Although the unexpected blockade of ion channels has been widely considered to be one of the main reasons for affecting the repolarization phase of the cardiac action potential and leading to QT interval prolongation, the lack of knowledge regarding chemical structures in drugs that may induce the prolongation of the QT interval remains a barrier to further understanding the underlying mechanism and developing an effective prediction strategy. In this study, we thoroughly investigated the differences in chemical structures between QT-prolonging drugs and drugs with no drug-induced QT prolongation (DIQT) concerns, based on the Drug-Induced QT Prolongation Atlas (DIQTA) dataset. Three categories of structural alerts (SAs), namely amines, ethers, and aromatic compounds, appeared in large quantities in QT-prolonging drugs, but rarely in drugs with no DIQT concerns, indicating a close association between SAs and the risk of DIQT. Moreover, using the molecular descriptors associated with these three categories of SAs as features, the structure-activity relationship (SAR) model for predicting the high risk of inducing QT interval prolongation of marketed drugs achieved recall rates of 72.5% and 80.0% for the DIQTA dataset and the FDA Adverse Event Reporting System (FAERS) dataset, respectively. Our findings may promote a better understanding of the mechanism of DIQT and facilitate research on cardiac adverse drug reactions in drug development.

Aims: Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QT-DDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drug-related factors., Methods: We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference)., Results: The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], p adj  = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI -17.7% to -4.7%], p adj  ≤ 0.001)., Conclusion: The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting., (© 2022 British Pharmacological Society.)

Although rare, long QT syndrome (LQTS) and peripartum cardiomyopathy (PPCM) are the major causes of maternal cardiovascular death. We herein present a case study of a 23-year-old woman with LQTS, pregnancy-induced hypertension, and PPCM. During the postpartum period, her left ventricular systolic function had severely decreased, requiring the administration of loop diuretics. Diuretics cause several changes in the circulating blood volume, electrolyte balance, and hormonal status during pregnancy, delivery, and the peripartum period. Extreme QTc prolongation and fatal ventricular arrhythmia require frequent defibrillation. For the patient in this study, we corrected her electrolyte abnormality, and eventually, we controlled the arrhythmia by administering a β-blocker and Na-channel blocker. Although the arrhythmia subsided, she continued on medication after discharge to prevent the recurrence of fatal arrhythmia. In conclusion, close attention should be paid to patients with LQTS, especially when some changes that may lead to QTc prolongation could occur during the peripartum period.

Aims: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS)., Methods and Results: Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (P < 0.0001 vs. control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and peak VGs were more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs. 44 ± 27 ms, P < 0.0001) and spatially (1.0 ± 0.7 vs. 3.6 ± 0.9 mm, P < 0.0001). PVCs were initiated at estimated voltages of ∼ -40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL, respectively) abolished both PVCs and TdP in the continued presence of aLQTS., Conclusion: These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

We present a case of Torsades de Pointes (TdP) in a patient with COVID-19 infection and multiple TdP risk factors including QT-interval prolongation, hemodialysis, bradycardia, and treatment with remdesivir, citalopram, and quetiapine. The case was complicated by post-resuscitation anxiety superimposed on a history of medical trauma since childhood. Top experts in the field of consultation-liaison psychiatry, trauma informed care, and cardiac electrophysiology provide perspectives on this case with a review of the literature. Key teaching topics include identification of TdP risk factors in patients with a complex illness; the necessity for prompt electrophysiology consultation in clinical scenarios with high risk for TdP; and the approach to patients with medical trauma using a trauma-informed lens. We highlight the contributions of COVID-19, the pharmacokinetics of QT-interval-prolonging psychotropic medications, the risks of hemodialysis, and the role of remdesivir-induced bradycardia in this first reported case of TdP in a patient treated with remdesivir., (Copyright © 2022 Academy of Consultation-Liaison Psychiatry. Published by Elsevier Inc. All rights reserved.)

Regulatory authorities put major emphasis on QT (interval)-prolonging properties of new molecular entities. Product information/Summaries of Product Characteristics (SmPCs) of multiple drugs contain warnings or contraindications regarding QT prolongation, e.g., on coadministration of QT-prolonging drugs (QT drugs). To characterize the development of the QT drug burden, we performed a trend analysis of prescriptions and co-prescriptions of QT drugs in a large geriatric inpatient cohort. The German SmPCs (status of 2014 and of 2021) and the year-wise listings in the CredibleMeds ® database from 2011 to 2021 were used as sources. There were 402,631 geriatric cases included. The group of QT drugs according to SmPCs in 2014, which must not be combined with other QT drugs, was less frequently involved in contraindicated co-prescriptions in 2021 compared with 2015 (3.0% (2.5-3.7%) of cases with at least one of those drugs in 2021 vs. 4.0% (3.5-4.5%) in 2015), with citalopram, escitalopram, and amiodarone involved in nearly 90% of the co-prescriptions. The number of CredibleMeds-QT-drugs per patient increased from 0.4 (SD=1.1) in 2011 to 1.8 (SD=3.9) in 2021. The percentage of contraindicated co-prescriptions of drugs with known risk for torsade de pointes according to CredibleMeds ® listings at the beginning of the respective years increased from 1.7% in 2011 to 6.1% in 2021. Considering the regularly updated CredibleMeds ® QT drugs list, the contraindicated co-prescriptions of QT drugs markedly increased in the last decade. If prescribers considered only the few most frequently (co-) prescribed QT drugs, then most of the medication errors regarding QT drugs could be prevented., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an in vitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of in vitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of in vitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia in people. The risk profile of the test drugs was similar across hiPSC-CMs derived from different healthy donors. In contrast, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high-risk drugs in the hiPSC-CMs. Thus, deep learning can identify in vitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia., Competing Interests: Declaration of interests R.S. is a paid consultant of Vala Sciences, which manufactures a high content instrument used in these studies. M.M. serves on the scientific advisory board of Vala Sciences. J.C.W. is co-founder and scientific advisory board member of Greenstone Biosciences., (Copyright © 2022 Elsevier Inc. All rights reserved.)

To clarify the pharmacological properties of the Na + /Ca 2+ exchanger (NCX) inhibitor SEA0400 as an antiarrhythmic agent, we assessed its effects on rapid component of delayed rectifier K + current (I Kr ) blocker-induced torsade de pointes (TdP) in isoflurane-anesthetized rabbits. Atrioventricular block was induced in rabbits using a catheter ablation technique, and the monophasic action potential (MAP) of the right ventricle was measured under electrical pacing at 60 beats/min. In non-treated control animals, intravenous administration of low-dose (0.3 mg/kg) or high-dose nifekalant (3 mg/kg) prolonged the MAP duration (MAP 90 ) by 113 ± 11 ms (n = 5) and 237 ± 39 ms (n = 5), respectively, where TdP was induced in 1/5 animals treated with a low dose and in 3/5 animals treated with a high dose of nifekalant. In SEA0400-treated animals, low- and high-dose nifekalant prolonged the MAP 90 by 65 ± 13 ms (n = 5) and 230 ± 20 ms (n = 5), respectively. No TdP was induced by the low dose but 1/5 animals treated with a high dose of nifekalant developed TdP. In verapamil-treated animals, low-dose and high-dose nifekalant prolonged MAP 90 by 50 ± 12 ms (n = 5) and 147 ± 30 ms (n = 5), respectively, without inducing TdP. These results suggest that SEA0400 has the potential to inhibit low-dose nifekalant-induced TdP by suppressing the MAP-prolonging action of nifekalant, whereas the drug inhibited high-dose nifekalant-induced TdP without affecting the MAP-prolonging action of nifekalant. This may reveal that, in contrast to verapamil, the antiarrhythmic effects of SEA0400 on I Kr blocker-induced TdP may be multifaceted, depending on the severity of the proarrhythmogenic conditions present.

Clozapine is an atypical neuroleptic used to manage treatment-resistant schizophrenia which is known to inhibit cardiac hERG/K V 11.1 potassium channels, a pharmacological property associated with increased risk of potentially fatal Torsades de Pointes (TdP) and sudden cardiac death (SCD). Yet, the long-standing clinical practice of clozapine does not show a consistent association with increased incidence of TdP, although SCD is considerably higher among schizophrenic patients than in the general population. Here, we have established the inhibitory profile of clozapine at the seven cardiac ion currents proposed by the ongoing comprehensive in vitro pro-arrhythmia (CiPA) initiative to better predict new drug cardio-safety risk. We found that clozapine inhibited all CiPA currents tested with the following rank order of potency: K V 11.1 > Na V 1.5 (late current) ≈ Ca V 1.2 ≈ Na V 1.5 (peak current) ≈ K V 7.1 > K V 4.3 > K ir 2.1 (outward current) . Half-maximal inhibitory concentrations (IC 50 ) at the repolarizing K V 11.1 and K V 7.1 channels, and at the depolarizing Ca V 1.2 and Na V 1.5 channels fell within a narrow half-log 3-10 µM concentration range, suggesting that mutual compensation could explain the satisfactory arrhythmogenic cardio-safety profile of clozapine. Although the IC 50 values determined herein using an automated patch-clamp (APC) technique are at the higher end of clozapine plasmatic concentrations at target therapeutic doses, this effective antipsychotic appears prone to distribute preferentially into the cardiac tissue, which supports the clinical relevance of our in vitro pharmacological findings., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

What Is Known and Objective: Fenspiride, a drug that had been used for decades for the treatment of respiratory diseases, was recently withdrawn from the market due to the potential risk of QT prolongation and proarrhythmia. This is the first such withdrawal for many years and hence poses a question whether such risk could have been predicted and to what degree non-drug-specific parameters play a role in the reported QT prolongation and cases of TdP. The study aim was to test various 'what-if' scenarios to assess the influence of age, gender, heart rate, and plasma potassium concentration on QT interval prolongation due to various doses of fenspiride with the use of mechanistic mathematical modelling., Methods: Concentration-time profiles were simulated with the use of a PBPK model developed based on published physico-chemical data, data from in vitro ADME experiments, and in vivo PK study results. Pharmacodynamic effect, that is, drug-triggered pseudoECG signal modification was simulated using a biophysically detailed model of human cardiac myocytes. Analysis of the qNet metric was also performed to classify proarrhythmic risk related to fenspiride., Results: In the simulation study, arrhythmia was not observed even in the 'what-if' scenarios with extreme exposure, age, heart rate, and plasma potassium concentration. The qNet metric value positioned fenspiride in the intermediate risk class., What Is New and Conclusion: It can be hypothesized that the clinically observed arrhythmia cases were not directly caused by fenspiride alone but a combination of multiple factors, including comedications., (© 2022 John Wiley & Sons Ltd.)

Sex differences exist in the structure and function of human heart. The patterns of ventricular repolarization in normal electrocardiograms (ECG) differ in men and women: men ECG pattern displays higher T-wave amplitude and increased ST angle. Generally, women have longer QT duration because of reduced repolarization reserve, and thus, women are more susceptible for the occurrence of torsades de pointes associated with drugs prolonging ventricular repolarization. Sex differences are also observed in the prevalence, penetrance and symptom severity, and also in the prognosis of cardiovascular disease. Generally, women live longer, have less clinical symptoms of cardiac diseases, and later onset of symptoms than men. Sex hormones also play an important role in regulating ventricular repolarization, suggesting that hormones directly influence various cellular functions and adrenergic regulation. From the clinical perspective, sex-based differences in heart physiology are widely recognized, but in daily practice, cardiac diseases are often underdiagnosed and untreated in the women. The underlying mechanisms of sex differences are, however, poorly understood. Here, we summarize sex-dependent differences in normal cardiac physiology, role of sex hormones, and differences in drug responses. Furthermore, we also discuss the importance of human induced pluripotent stem cell-derived cardiomyocytes in further understanding the mechanism of differences in women and men., (© 2022. The Author(s).)

ICH S7B recommends screening for hERG channel block using patch clamp recordings to assess a drug's proarrhythmic risk. Block of the hERG channel has been associated with clinical QT C prolongation as well as the rare, but potentially fatal ventricular tachyarrhythmia Torsade de Pointes (TdP). During recording, drug concentrations perfused to the cells can deviate from nominal concentrations due to molecule-specific properties (such as non-specific binding), thereby introducing error when assessing drug potency. To account for this potential source of error, both the original ICH S7B and the newly released ICH E14/S7B Q&As guidelines call for verifying drug solutions' concentrations. Dofetilide, cisapride, terfenadine, sotalol and E-4031 are hERG blockers commonly used as positive controls to illustrate hERG assay sensitivity. The first four compounds are also clinical drugs associated with high TdP risk; therefore, their safety margins may be useful comparators to better understand an investigational product's TdP risk. Having analytical methods to quantify these five compounds in the hERG external solution that will be used for patch clamp recordings is important from a regulatory science research perspective. However, a literature search revealed no analytical methods or stability information for these molecules in the high salt, serum-free matrix that constitutes the hERG external solution. This study was conducted to develop and validate LC-MS/MS methods to quantify these 5 molecules in hERG external solution. The bioanalytical methods for these positive controls were validated as per the FDA's bioanalytical method validation guidance along with various stabilities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Introduction: The use of high throughput patch clamp profiling to determine mixed ion channel-mediated arrhythmia risk was assessed using profiling data generated using proprietary internal and clinical reference compounds. We define the reproducibility of the platform and highlight inherent platform issues. The data generated was used to develop predictive models for cardiac arrhythmia risk, specifically Torsades de Pointes (TdP)., Methods: A retrospective analysis was performed using profiling data generated over a 3-year period, including patch clamp data from hERG, Ca v 1.2, and Na v 1.5 (peak/late), together with hERG binding., Results: Assay reproducibility was robust over the 3-year period examined. High throughput hERG patch IC 50 values correlated well with GLP-hERG data (Pearson = 0.87). A disconnect between hERG binding and patch was observed for ∼10% compounds and trended with passive cellular permeability. hERG and Ca v 1.2 potency did not correlate for proprietary compounds, with more potent hERG compounds showing selectivity versus Ca v 1.2. For clinical compounds where hERG and Ca v 1.2 activity was more balanced, an analysis of TdP risk versus hERG/Ca v 1.2 ratio demonstrated low TdP probability when the hERG/Ca v 1.2 potency ratios were < 1. Modeling of clinical compound data revealed a lack of impact of the Na v 1.5 (late) current in predicting TdP. Moreover, models using hERG binding data (ROC AUC = 0.876) showed an improved ability to predict TdP risk versus hERG patch clamp (ROC AUC = 0.787)., Discussion: The data highlight the value of high throughput patch clamp data in the prediction of TdP risk, as well as some potential limitations with this approach., Competing Interests: Declaration of Competing Interest Authors are employees of Pfizer Inc. and/or are stockholders in Pfizer Inc., (Copyright © 2022. Published by Elsevier Inc.)

Validation of risk-stratification method for the chronic atrioventricular block cynomolgus monkey model and its mechanistic interpretation was performed using 6 pharmacologically distinct drugs. The following drugs were orally administered in conscious state, astemizole: 1, 5, and 10 mg/kg (n = 6); haloperidol: 1, 10, and 30 mg/kg (n = 5); amiodarone: 30 mg/kg (n = 4); famotidine: 10 mg/kg (n = 4); levofloxacin: 100 mg/kg (n = 4); and tolterodine: 0.2, 1, and 4.5 mg/kg (n = 4). Astemizole of 5 and 10 mg/kg significantly prolonged ΔΔQTcF, whereas no significant change was observed by the others. Torsade de pointes (TdP) was induced by astemizole of 5 and 10 mg/kg in 3/6 and 6/6, and by haloperidol of 10 and 30 mg/kg in 1/5 and 1/5, respectively, which was not observed in the others. Torsadogenic risk of the drugs was quantified using the criteria for the monkey model specified in our previous study. Namely, high-risk drugs induced TdP at ≤ 3 times of their maximum clinical daily dose. Intermediate-risk drugs did not induce TdP at this dose range, but induced it at higher doses. Low/no-risk drugs never induced TdP at any dose tested. The magnitude of risk was intermediate for astemizole and haloperidol, and low/no risk for the others. The prespecified, risk-stratification method for the monkey model may solve the issue existing between nonclinical models and patients with labile repolarization, which can reinforce the regulatory decision-making and labeling at time of marketing application of nondouble-negative drug candidate (hERG assay positive and/or in vivo QT study positive)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Impaired I Ks induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and I Kr inhibitor dofetilide. We tested the proarrhythmic effect of I Ks inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein., Methods: Dofetilide-inducible animals were included to test the proarrhythmic effect of 1) I Ks inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) I Ks inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10)., Results: JNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P < 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dt max from 1725 ± 273 to 4147 ± 611 mmHg/s, P < 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P < 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2., Conclusion: Mimicking LQT1 using I Ks inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. Induction of the more severe arrhythmic events (TdP) demands a combination of I Ks inhibition with enhanced inotropy or ending the anesthetic regime., Competing Interests: Declaration of interest The authors declare no conflict of interest and all authors approved publication. Coauthor H.J. van der Linde is an employee of Janssen Pharmaceutica and has no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: A case of loperamide-induced recurrent torsades de pointes is reported to raise awareness of an increasingly common phenomenon that could be encountered by medical providers during the current opioid epidemic., Summary: A 40 year-old-man with a prior history of opioid abuse who presented to the emergency department after taking up to 100 tablets of loperamide 2 mg daily for 5 years to blunt opioid withdrawal symptoms and was subsequently admitted to the intensive care unit for altered mental status and hyperthermia. The patient had prolonged QTc and 2 episodes of torsades de pointes (TdP) that resulted in cardiac arrest with return of spontaneous circulation. He was managed with isoproterenol, overdrive pacing, and methylnatrexone with no other events of TdP or cardiac arrest., Conclusion: A 40-year-old male who developed torsades de pointes from loperamide overdose effectively treated with overdrive pacing, isoproterenol, and methylnatrexone.

We analyzed role of cardiac α 1 -adrenoreceptors for the torsadogenic action of I Kr blocker nifekalant in isoflurane-anesthetized atrioventricular block rabbits. Bradycardia was induced by atrioventricular node ablation, and the ventricle was electrically driven at a constant rate of 60 beats/min throughout the experiments to prevent rate-dependent modification by the I Kr blocker in ventricular repolarization phase. Nifekalant (3 mg/kg per 10 min, n = 5) prolonged the duration of monophasic action potential (MAP 90 ) by +178 ± 43 ms, increased the short-term variability of repolarization (STV) to 4.2 ± 1.2 ms, and induced torsade de pointes (TdP) in 1 animal. In the presence of methoxamine (n = 5), nifekalant prolonged the MAP 90 by +328 ± 32 ms, increased the STV to 8.0 ± 1.0 ms, and induced TdP in 2 animals. In the presence of prazosin and methoxamine (n = 5), nifekalant prolonged the MAP 90 by +267 ± 22 ms, increased the STV to 9.2 ± 3.6 ms, and induced no TdP. These results suggest that cardiac α 1 -adrenoreceptor activation by methoxamine essentially sensitizes the rabbit heart to nifekalant-induced QT interval prolongation, leading to the onset of TdP., Competing Interests: Declaration of competing interest The authors state no conflict of interest., (Copyright © 2022 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Many drugs carry some risk of QT interval prolongation, which can lead to life-threatening dysrhythmias including Torsades de Pointes (TdP). CredibleMeds.org identifies medications categorized as "Known Risk of TdP" but does not stratify risk in acute supratherapeutic ingestions. We sought to determine the proportion of cases exhibiting QTc prolongation and life-threatening dysrhythmias including ventricular tachycardia (VT)/ventricular fibrillation (VF), TdP, and asystole in patients exposed to these substances. Retrospective chart review of cases reported to our Regional Poison Center from 2014 to 2019 of exposures to one or more of the "Known Risk" substances was performed. Demographics, therapies, clinical effects, and medical outcome for each case were analyzed. There were 1125 exposures, of which 760 had a documented QTc interval. QTc ≥ 500 ms was reported in 138 (18.2%) of the 760 cases. The most common "Known Risk" substances were citalopram, escitalopram and cocaine. Although not in the "Known Risk" category, mirtazapine, amitriptyline, diphenhydramine, and trazodone had a statistically significant association with QTc > 500 ms. Life-threatening dysrhythmias occurred in 13 cases, with VT/VF in 6 of the 760 (0.8%) cases, and one case of TdP. Flecainide (OR 11.1, 95% CI 2.2-55.8) and methadone (OR 7.1, 95% CI 2.1-23.4) were associated with increased risk of all life-threatening dysrhythmias. Exposures to medications on the Credible Meds list of "Known Risk of TdP" QTc prolongation is common, but life-threatening dysrhythmias are rare. Mirtazapine, amitriptyline, diphenhydramine, and trazodone were associated with prolonged QTc. Flecainide and methadone had the highest associated risk of life-threatening dysrhythmias., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with cancer are prone to prolongation of the corrected QT interval (QTc) due to the use of anticancer drugs with QTc-prolonging potential in combination with electrolyte imbalances caused by, for example, gastrointestinal side-effects. However, most anticancer drugs were approved with little information on their QTc-prolonging potential and the added risk of torsade de pointes. The absence of this information on the drug label poses a considerable challenge to clinicians regarding the measures that need to be taken to safely start anticancer treatment. In this Review, we provide a comprehensive overview of the evidence for the QTc-prolonging properties of 205 anticancer drugs and 14 antiemetic drugs available from drug labels, assessment reports, and published studies. We classify the drugs as low-risk, moderate-risk, or high-risk for QTc prolongation. We also discuss the clinical relevance of these findings and include practical recommendations to guide clinicians to select the drugs with the least QTc-prolonging properties and to adequately monitor susceptible patients., Competing Interests: Declaration of interests NS has received research grants for the Antoni van Leeuwenhoek Ziekenhuis from AB Science, AbbVie, Actuate Therapeutics, ADC Therapeutics, Amgen, Array, Ascendis Pharma, Astex Pharmaceuticals, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol-Myers Squibb, Cantargia, Celgene, CellCentric, Crescendo Biologics, Cytovation, Deciphera, Eli Lilly, Exelixis, Genentech, Genmab, Gilead Sciences, GlaxoSmithKline, Incyte, InteRNA Technologies, Janssen/Johnson & Johnson, Kinnate Biopharma, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Numab, Pfizer, Laboratoires Pierre Fabre, Regeneron, Roche, Sanofi, Seattle Genetics, Servier, Taiho Pharmaceutical, and Takeda, outside of the submitted work. NS also attended advisory boards for Boehringer Ingelheim and Ellipses Pharma. NPvE has received research grants for Radboudumc from Astellas Pharma, Janssen-Cilag, Ipsen, KWF, and ZonMW, and has received payments for Radboudumc from Sanofi, Bayer, and Pfizer. IMED has received a research grant for Radboudumc from EORTC-QLG and has received honoraria for the institute from Zorginstituut Nederland. NAGL has received honoraria from Roche Nederland. KRMF, ELG, EJS, and RJB declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background and Purpose: HERG blocking drugs known for their propensity to trigger Torsades de Pointes (TdP) were reported to induce a sympatho-vagal coactivation and to enhance High Frequency heart rate (HFHR) and QT oscillations (HFQT) in telemetric data. The present work aimed to characterize the underlying mechanism(s) leading to these autonomic changes., Experimental Approach: Effects of 15 torsadogenic hERG blocking drugs (astemizole, chlorpromazine, cisapride, droperidol, ibutilide, dofetilide, haloperidol, moxifloxacin, pimozide, quinidine, risperidone, sotalol, sertindole, terfenadine, and thioridazine) were assessed by telemetry in beagle dogs. Haemodynamic effects on diastolic and systolic arterial pressure were analysed from the first doses causing QTc prolongation and/or HFQT oscillations enhancement. Autonomic control changes were analysed using the high frequency autonomic modulation (HFAM) model., Key Results: Except for moxifloxacin and quinidine, all torsadogenic hERG blockers induced parasympathetic activation or sympatho-vagal coactivation combined with enhancement of HFQT oscillations. These autonomic effects result from reflex compensatory mechanisms in response to mild haemodynamic side effects. These haemodynamic mechanisms were characterized by transient HR acceleration during HF oscillations. A phenomenon of concealed QT prolongation was unmasked for several torsadogenic hERG blockers under β-adrenoceptor blockade with atenolol. Resulting enhancement of HFQT oscillations was shown to contribute directly to triggering dofetilide-induced ventricular arrhythmias., Conclusion and Implications: This work supports for the first time a contribution of haemodynamic side properties to ventricular arrhythmias triggered by torsadogenic hERG blocking drugs. These haemodynamic side effects may constitute a second component of their arrhythmic profile, acting as a trigger alongside their intrinsic arrhythmogenic electrophysiological properties., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Drug-induced human ether-à-go-go-related gene (hERG) channel block and QT interval prolongation increase torsade de pointes (TdP) risk. However, some drugs block hERG channels and prolong QT interval with low TdP risk, likely because they block additional inward currents. We investigated the utility of J-T peak interval, a novel biomarker of inward current block and TdP risk, in conscious telemetered guinea pigs. Electrocardiogram parameters were analysed in Hartley guinea pigs orally administered one of eight test compounds (dofetilide, flecainide, nifedipine, quinidine, quinine, ranolazine, sotalol, verapamil) or vehicle alone as controls. Heart rate-corrected QT (QTcX) and J-T peak (J-T peak cX) were calculated to evaluate the relations of QT-RR and J-T peak -RR. Dofetilide and sotalol significantly increased ΔQTcX and ΔJ-T peak cX intervals to similar degrees. Quinidine, quinine and flecainide also increased ΔQTcX and ΔJ-T peak cX intervals, but the degrees of ΔJ-T peak cX interval prolongation were shorter than those of ΔQTcX interval prolongation. Ranolazine showed slight increasing trends in ΔQTcX and ΔJ-T peak cX intervals, but the differences were not significant. Verapamil and nifedipine did not increase the ΔQTcX or ΔJ-T peak cX intervals. Based on the relations of ΔΔJ-T peak cX and ΔΔQTcX intervals, dofetilide, sotalol and quinidine were classified as high risk for TdP, quinine, flecainide and ranolazine were classified as intermediate risk and verapamil and nifedipine were classified as low risk. These results supported the usefulness of J-T peak interval assessment in conscious guinea pigs for predicting drug-induced balanced block of inward currents and TdP risk in early-stage preclinical studies., (Copyright © 2022 Elsevier B.V. All rights reserved.)