Torsades Research Articles

Evaluation of cardiac pro-arrhythmic risks using the artificial neural network with ToR-ORd in silico model output.

Torsades de pointes (TdP) is a type of ventricular arrhythmia that can lead to sudden cardiac death. Drug-induced TdP has been an important concern for researchers and international regulatory boards. The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative was proposed that integrates in vitro testing and computational models of cardiac ion channels and human cardiomyocyte cells to evaluate the proarrhythmic risk of drugs. The TdP risk classification performance using only a single TdP metric may require some improvements because of information limitations and the instability of generalizing results. This study evaluates the performance of TdP metrics from the in silico simulations of the Tomek-O'Hara Rudy (ToR-ORd) ventricular cell model for classifying the TdP risk of drugs. We utilized these metrics as an input to an artificial neural network (ANN)-based classifier. The ANN model was optimized through hyperparameter tuning using the grid search (GS) method to find the optimal model. The study outcomes show an area under the curve (AUC) value of 0.979 for the high-risk category, 0.791 for the intermediate-risk category, and 0.937 for the low-risk category. Therefore, this study successfully demonstrates the capability of the ToR-ORd ventricular cell model in classifying the TdP risk into three risk categories, providing new insights into TdP risk prediction methods.

Mechanisms of torsades de pointes: an update.

Torsades de Pointes (TdP) refers to a polymorphic ventricular tachycardia (VT) with undulating QRS axis that occurs in long QT syndrome (LQTS), although the term has been used to describe polymorphic ventricular tachyarrhythmias in which QT intervals are not prolonged, such as short-coupled variant of TdP currently known as short-coupled ventricular fibrillation (VF) and Brugada syndrome. Extensive works on LQTS-related TdP over more than 50 years since it was first recognized by Dessertennes who coined the French term meaning "twisting of the points", have led to current understanding of the electrophysiological mechanism that TdP is initiated by triggered activity due to early afterdepolarization (EAD) and maintained by reentry within a substrate of inhomogeneous repolarization. While a recently emerging notion that steep voltage gradients rather than EADs are crucial to generate premature ventricular contractions provides additions to the initiation mode, the research to elucidate the maintenance mechanism hasn't made much progress. The reentrant activity that produces the specific form of VT is not well characterized. We have conducted optical mapping in a rabbit model of electrical storm by electrical remodeling (QT prolongation) due to chronic complete atrioventricular block and demonstrated that a tissue-island with prolonged refractoriness due to enhanced late Na+ current (INa-L) contributes to the generation of drifting rotors in a unique manner, which may explain the ECG characteristic of TdP. Moreover, we have proposed that the neural Na+ channel NaV1.8-mediated INa-L may be a new player to form the substrate for TdP. Here we discuss TdP mechanisms by comparing the findings in electrical storm rabbits with recently published studies by others in simulation models and human and animal models of LQTS.

First generation antipsychotic-associated serious adverse events in women: a retrospective analysis of a pharmacovigilance database.

Women have been under-represented in trials of antipsychotic medications. Our primary objective was toevaluate five adverse events (AE) associated with first-generation antipsychotics (FGAs) among women relative to menthrough an analysis of the FDA Adverse Event Reporting System (FAERS). We queried 24.6 million AE reports from 2000 to 2023 involving FGAs. The study cohort consisted of chlorpromazine (n = 3317), fluphenazine (n = 1124), haloperidol (n = 16,709), loxapine (n = 3151), perphenazine (n = 816), thioridazine (n = 665), thiothixene (n = 244), and trifluoperazine (n = 360). Cases of neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), Torsades de Pointes (TdP), agranulocytosis (AG), and cerebrovascular adverse events (CVAE) were identified. Reporting odds ratios (ROR) and associated 95% confidence intervals (CI) were calculated with logistic regression for each AE among women relative to men. A total of 2,857 serious AEs were evaluated in the study cohort (NMS = 1810, TD = 434, TdP = 260, AG = 149, CVAE = 204). The ROR for women compared to men was 0.79 (95% CI, 0.71-0.87) for NMS, 0.83 (0.68-1.01) for TD, 1.21 (0.94-1.53) for TdP, 0.71 (0.51-0.98) for AG, and 0.91 (0.68-1.19) for CVAE. A secondary analysis revealed a higher odds in women compared to men of hospitalization associated with reports of TD (ROR = 1.95, 1.29-2.94) and death associated with reports of AG (ROR = 2.46, 1.15-5.24). A subgroup analysis of haloperidol revealed an ROR = 1.67 (1.26-2.21) for women relative to men for TdP. The subgroup analysis of haloperidol AEs revealed a significantly higher reporting odds ratio for TdP. Additionally, the secondary study findings suggest that women were more vulnerable to worse outcomes associated with certain AEs of FGAs.

A real-world pharmacovigilance study of QT interval prolongation and Torsades de Pointes associated with CDK4/6 inhibitors in breast cancer patients: findings from the FDA adverse event reporting system

ABSTRACT Background The aim of this study was to evaluate the association between CDK4/6 inhibitors and QT interval prolongation (QTp) and Torsades de Pointes (TdP) in breast cancer patients. Method The cases with breast cancer from 2015 to 2022 were extracted from the FDA adverse event database (FARES) and further divided into a CDK4/6 inhibitor group and a positive control group. The associations between CDK4/6 inhibitors and QTp and TdP adverse events were evaluated using the reporting odds ratio (ROR) and the information component (IC). Results A total of 172,266 breast cancer patients were included. A total of 234 QTp/TdP events occurred in the CDK4/6 inhibitor group. Disproportionality analysis revealed that ribociclib was related to QTp/TdP. The ROR was 10.10 (95% 8.56–11.92), and the IC was 2.84 (95% 2.28–3.32). Palbociclib and abemaciclib had no correlation with QTP/TDP events. Conclusion Based on this real-world pharmacovigilance analysis, this study demonstrated a significant association between ribociclib and QTp/TdP events, which should attract clinical attention. The QT interval was monitored before and after medication. Attention should be given to adjusting the drugson time.

Antipsychotics and the QTc Interval During Delirium in the Intensive Care Unit

Antipsychotic medications, often prescribed for delirium in intensive care units (ICUs), may contribute to QTc interval prolongation. To determine whether antipsychotics increase the QTc interval in patients with delirium in the ICU. An a priori analysis of a randomized clinical trial in medical/surgical ICUs within 16 centers across the US was conducted. Participants included adults with delirium in the ICU with baseline QTc interval less than 550 ms. The study was conducted from December 2011 to August 2017. Data analysis was performed from April 25 to August 18, 2021. Patients were randomized 1:1:1 to intravenous haloperidol, ziprasidone, or saline placebo administered twice daily until resolution of delirium, ICU discharge, or 14 days. Twelve-lead electrocardiograms were used to measure baseline QTc before study drug initiation and telemetry was used to measure QTc before each subsequent dose of study drug. Unadjusted day-to-day changes in QTc were calculated and multivariable proportional odds regression was used to estimate the effects of antipsychotics vs placebo on next-day maximum QTc interval, adjusting for prespecified baseline covariates and potential interactions with sex. Safety end points, including the occurrence of torsade de pointes, were evaluated. All analyses were conducted based on the intention to treat principle. A total of 566 patients were randomized to haloperidol (n = 192), ziprasidone (n = 190), or placebo (n = 184). Median age was 60.1 (IQR, 51.4-68.7) years; 323 were men (57%). Baseline median QTc intervals across the groups were similar: haloperidol, 458.0 (IQR, 432.0-479.0) ms; ziprasidone, 451.0 (IQR, 424.0-472.0) ms; and placebo, 452.0 (IQR, 432.0-472.0) ms. From day 1 to day 2, median QTc changed minimally: haloperidol, -1.0 (IQR, -28.0 to 15.0) ms; ziprasidone, 0 (IQR, -23.0 to 20.0) ms; and placebo, -3.5 (IQR, -24.8 to 17.0) ms. Compared with placebo, neither haloperidol (odds ratio [OR], 0.95; 95% CI, 0.66-1.37; P = .78) nor ziprasidone (OR, 1.09; 95% CI, 0.75-1.57; P = .78) was associated with next-day QTc intervals. Effects were not significantly modified by sex (P = .41 for interaction). There were 2 occurrences of nonfatal torsade de pointes, both in the haloperidol group. Neither was associated with study drug administration. The findings of this trial suggest that daily QTc interval monitoring during antipsychotic use may have limited value in patients in the ICU with normal baseline QTc and few risk factors for QTc prolongation. ClinicalTrials.gov Identifier: NCT01211522.

Characterization of hERG K+ channel inhibition by the new class III antiarrhythmic drug cavutilide.

Cavutilide (niferidil, refralon) is a new class III antiarrhythmic drug which effectively terminates persistent atrial fibrillation (AF; 84.6% of patients, mean AF duration 3 months) and demonstrates low risk of torsade de pointes (1.7%). ERG channels of rapid delayed rectifier current(IKr) are the primary target of cavutilide, but the particular reasons of higher effectiveness and lower proarrhythmic risk in comparison with other class III IKr blockers are unclear. The inhibition of hERG channels expressed in CHO-K1 cells by cavutilide was studied using whole-cell patch-clamp. The present study demonstrates high sensitivity of IhERG expressed in CHO-K1 cells to cavutilide (IC50 = 12.8 nM). Similarly to methanesulfonanilide class III agents, but unlike amiodarone and related drugs, cavutilide does not bind to hERG channels in their resting state. However, in contrast to dofetilide, cavutilide binds not only to opened, but also to inactivated channels. Moreover, at positive constantly set membrane potential (+ 60 mV) inhibition of IhERG by 100 nM cavutilide develops faster than at 0 mV and, especially, - 30 mV (τ of inhibition was 78.8, 103, and 153 ms, respectively). Thereby, cavutilide produces IhERG inhibition only when the cell is depolarized. During the same period of time, cavutilide produces greater block of IhERG when the cell is depolarized with 2 Hz frequency, if compared to 0.2 Hz. We suggest that, during the limited time after injection, cavutilide produces stronger inhibition of IKr in fibrillating atrium than in non-fibrillating ventricle. This leads to beneficial combination of antiarrhythmic effectiveness and low proarrhythmicity of cavutilide.

Cholinesterase inhibitors-associated torsade de pointes/QT prolongation: a real-world pharmacovigilance study.

Objective: Cholinesterase inhibitor (ChEIs) is the first-line drug for Alzheimer's disease (AD). Understanding torsade de pointes (TdP)/QT prolongation with different ChEIs is essential for its safe and rational administration. This study aimed to evaluate the correlation between different ChEIs and TdP/QT prolongation. Methods: All ChEIs related TdP/QT prolongation cases were retrieved from the FAERS database using standard MedDRA query (SMQ) from the first quarter of 2004 to the third quarter of 2022. Disproportionality and sensitivity analysis were used to determine the signal of TdP/QT prolongation related to ChEIs. Results: 557 cases of TdP/QT prolongation related to 3 ChEIs were searched by SMQ. The patients were mostly elderly people, with markedly more female than male. The signals of TdP/QT prolongation for ChEIs were detected by disproportionality analysis, and the signal of Donepezil was the strongest. The sensitivity analysis results indicate a robust and stable correlation between these signals with ChEIs. TdP/QT prolongation usually occurs within 1month after taking ChEIs. The drug with the highest frequency of combination with donepezil and galantamine is citalopram, and the drug with the highest frequency of combination with rivastigmine is atorvastatin. Conclusion: The signals of TdP/QT prolongation related to ChEIs were strong and stable. It is necessary to be vigilant about the TdP/QT prolongation of various ChEIs, especially in elderly women, the initial stage after taking ChEIs, and when ChEIs combining with drugs that could prolong the QT interval.

Assessment of Quinidine-Induced Torsades de Pointes Risks Using a Whole-Body Physiologically Based Pharmacokinetic Model Linked to Cardiac Ionic Current Inhibition.

The lethality of torsades de pointes (TdP) by drugs is one of main reasons that some drugs were withdrawn from the market. In order to assess drug-induced TdP risks, a model of cardiac ionic current suppression in human ventricular myocytes (ToR-ORd model), combined with the maximum effective free therapeutic plasma concentration or the maximum effective free therapeutic myocyte concentration was often used, with the latter proved to be more relevant and more accurate. We aimed to develop a whole-body physiologically-based pharmacokinetic (PBPK) model, incorporated with a human cardiomyocyte pharmacodynamic (PD) model, to provide a comprehensive assessment of drug-induced TdP risks in normal and specific scenarios. Quinidine served as an example to validate the PBPK-PD model via predicting plasma quinidine concentrations and quinidine-induced changes in QT interval (ΔQTc). The predicted plasma quinidine concentrations and ΔQTc values following oral administration or intravenous administration of quinidine were comparable to clinic observations. Visual predictive checks showed that most of the observed plasma concentrations and ΔQTc values fell within the 5th and 95th percentiles of simulations. The validated PBPK-PD model was further applied to assess the TdP risks using frequencies of early afterdepolarization and long-QT syndrome occurrence in 4 scenarios, such as therapeutic dose, supra-therapeutic dose, alkalosis, and hyperkalemia in 200 human subjects. In conclusion, the developed PBPK-PD model may be applied to predict the quinidine pharmacokinetics and quinidine-induced TdP risks in healthy subjects, but also simulate quinidine-induced TdP risks under disease conditions, such as hypokalemia and alkalosis.

Противодементные лекарственные средства и синдром удлиненного интервала QT

Aim. Analysis and systematization of the results of domestic and foreign studies of drug-induced QT prolongation and the risk of Torsade de Pointes (TdP) associated with the use of antidementia drugs to update the knowledge of practicing neurologists about the possibility of predicting and preventing life-threatening cardiac adverse drug reactions. Key points. Dementia is a syndrome that accompanies various neurodegenerative diseases, which causes significant maladjustment and disability in the patient. Anti-dementia drugs are used to slow down the progression of dementia which require long-term (lifelong) appointment. Therefore, the safety profile of these drugs is important in practice, in particular such conditions as the long QT syndrome and the development of ventricular tachycardia (TdP). The authors searched for full-text domestic and foreign publications (full-text versions of original articles, clinical cases, systematic reviews, meta-analyses, Cochrane reviews) in Russian and English, available in knowledge-intensive bibliographic databases (eLIBRARY, PubMed, Scopus, Springer, ClinicalKeys, OxfordPress, Google Scholar, MedCredit, DrugBank, PharmGKB), by keywords and their combinations. The study was conducted in accordance with the requirements for the PRISMA 2022 systematic review. The search depth is 10 years (2013–2023). Conclusion. The systematic review demonstrated the variable effect of antidementia drugs on the processes of repolarization and depolarization of the ventricular myocardium: shortening of the QT interval, no effect, borderline prolongation of the QT interval, prolongation of the QT interval. Donepezil has the lowest cardiac safety profile. Studies of galantamine have yielded conflicting results. The lowest risk of QT prolongation and TdP development was observed with rivastigmine and memantine. There is insufficient data on the cardiac safety of the new generation of antidementia drugs: aducanumab, lecanemab and donanemab. Keywords: antidementia drugs, adverse drug reactions, dementia, prolongation of the QT interval, cardiotoxicity, long QT syndrome, Torsade de Pointes, ventricular tachycardia, sudden cardiac death.

Quercetin is a foe in the heart by targeting the hERG potassium channel.

Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism. hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination. Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 μM quercetin. Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication.

Advanced integration of 2DCNN-GRU model for accurate identification of shockable life-threatening cardiac arrhythmias: a deep learning approach.

Cardiovascular diseases remain one of the main threats to human health, significantly affecting the quality and life expectancy. Effective and prompt recognition of these diseases is crucial. This research aims to develop an effective novel hybrid method for automatically detecting dangerous arrhythmias based on cardiac patients' short electrocardiogram (ECG) fragments. This study suggests using a continuous wavelet transform (CWT) to convert ECG signals into images (scalograms) and examining the task of categorizing short 2-s segments of ECG signals into four groups of dangerous arrhythmias that are shockable, including ventricular flutter (C1), ventricular fibrillation (C2), ventricular tachycardia torsade de pointes (C3), and high-rate ventricular tachycardia (C4). We propose developing a novel hybrid neural network with a deep learning architecture to classify dangerous arrhythmias. This work utilizes actual electrocardiogram (ECG) data obtained from the PhysioNet database, alongside artificially generated ECG data produced by the Synthetic Minority Over-sampling Technique (SMOTE) approach, to address the issue of imbalanced class distribution for obtaining an accuracy-trained model. Experimental results demonstrate that the proposed approach achieves high accuracy, sensitivity, specificity, precision, and an F1-score of 97.75%, 97.75%, 99.25%, 97.75%, and 97.75%, respectively, in classifying all the four shockable classes of arrhythmias and are superior to traditional methods. Our work possesses significant clinical value in real-life scenarios since it has the potential to significantly enhance the diagnosis and treatment of life-threatening arrhythmias in individuals with cardiac disease. Furthermore, our model also has demonstrated adaptability and generality for two other datasets.

Analysis of cardiohemodynamic and electrophysiological effects of morphine along with its toxicokinetic profile using the halothane-anesthetized dogs.

Although morphine has been used for treatment-resistant dyspnea in end-stage heart failure patients, information on its cardiovascular safety profile remains limited. Morphine was intravenously administered to halothane-anesthetized dogs (n=4) in doses of 0.1, 1 and 10 mg/kg/10 min with 20 min of observation period. The low and middle doses attained therapeutic (0.13 µg/mL) and supratherapeutic (0.97 µg/mL) plasma concentrations, respectively. The low dose hardly altered any of the cardiovascular variables except that the QT interval was prolonged for 10-15 min after its start of infusion. The middle dose reduced the preload and afterload to the left ventricle for 5-15 min, then decreased the left ventricular contractility and mean blood pressure for 10-30 min, and finally suppressed the heart rate for 15-30 min. Moreover, the middle dose gradually but progressively prolonged the atrioventricular conduction time, QT interval/QTcV, ventricular late repolarization period and ventricular effective refractory period without altering the intraventricular conduction time, ventricular early repolarization period or terminal repolarization period. A reverse-frequency-dependent delay of ventricular repolarization was confirmed. The high dose induced cardiohemodynamic collapse mainly due to vasodilation in the initial 2 animals by 1.9 and 3.3 min after its start of infusion, respectively, which needed circulatory support to treat. The high dose was not tested further in the remaining 2 animals. Thus, intravenously administered morphine exerts a rapidly appearing vasodilator action followed by slowly developing cardiosuppressive effects. Morphine can delay the ventricular repolarization possibly through IKr inhibition in vivo, but its potential to develop torsade de pointes will be small.

Impact of Hydroxychloroquine, on QTC Interval, in Patients with Rheumatologic Diseases

Background: Hydroxychloroquine (HCQ) has been historically used for treatment of autoimmune diseases and more recently, it is used for treatment of COVID-19 patients. Using HCQ in COVID-19 patients resulted in corrected QT(QTc) prolongation which has potential to deteriorate into Torsades de Pointes and sudden cardiac death. As it is used chronically by rheumatologic patients so this study was designed to establish effect of HCQ on QTc in rheumatic patients. Methods: A cross sectional comparative study conducted in Rheumatology Department Shaikh Zayed hospital, Lahore. Non-probability consecutive sampling technique was used. Duration of study was 169 days. 45 patients used HCQ for three months and 45 patients did not use HCQ. ECG was done at induction in the study and after three months. Serum calcium, potassium and magnesium were also checked at onset. QTc was calculated by Bazett’s formula. Results: QTc did not raise in 21(46%) patients, in both groups. QTc raised between 1- 50msec in 20(44.4%) and 23(51.1%) patients in HCQ exposed and unexposed patients, respectively. QTc rise more than 50msec in 4(8.88%) and 1(2.2%) patient in HCQ exposed and unexposed patients, respectively (p-value=0.344). The QTc change is associated with heart rate showing 75.0% chances of increased QTc among those with increased heart rate. Conclusion: HCQ did not increase QTc interval in 46% study. 8.88% of HCQ exposed population and 2.22% of HCQ unexposed population had significant change in QTc. However, no adverse cardiac events were observed in study duration

MOXIFLOXACIN INDUCED QT INTERVAL PROLONGATION: A RISK TO TORSADE DE POINTES IN ELDERLY PATIENTS

Background: Quinolones are notorious for QT interval prolongation and sometimes carry risks for development of Torsade de Pointes. Objective of this study was to determine the effect of moxifloxacin on QT interval prolongation on electrocardiogram. Methods: It was a cross-sectional study, conducted in Medical Department of Mardan, Medical Complex, Mardan, from January to December 2021. Moxifloxacin was given for treatment of different ailments to 57 patients after approval of study protocols from Ethical Committee of Gajju Khan Medical College/Bacha Khan Medical Complex Swabi. Their baseline ECGs, second ECG on its Tmax and third set of ECGs were recorded, in triplicates, on 48 hours of treatment. QTc was calculated using Bazett’s formula either using lead II or alternatively AVR, AVF, V5, V6, or V4, leads. Moxifloxacin was administered in recommended doses. Results: Of the 57 patients, 24 patients (42%) showed QTC prolongation (prolonged QTc: For male >450 ms, and for female >470 ms); and 19 patients (33%) reached to the limits for a risk (Patients with QTc >500 ms or QTc change over baseline >60 ms) for development of Torsade de pointes. Remaining 14 patients (25%) faced no complications. Statistically significant changes were observed for both male and female patients (p<0.05). However, QT prolongation was sustained for 48 hours in female only. Conclusion: Moxifloxacin produced significant changes in QTc particularly in elderly patients. Mean changes in QTc on 48 hours were prolonged in females than males. Pak J Physiol 2023;19(4):11–4

Effect of Flecainide and Ibutilide Alone and in Combination to Terminate and Prevent Recurrence of Atrial Fibrillation.

There is a need for improved approaches to rhythm control therapy of atrial fibrillation (AF). The effectiveness of flecainide (1.5 µmol/L) and ibutilide (20 nmol/L), alone and in combination, to cardiovert and prevent AF recurrence was studied in canine-isolated coronary-perfused right atrioventricular preparations. We also examined the safety of the combination of flecainide (1.5 µmol/L) and ibutilide (50 nmol/L) using canine left ventricular wedge preparations. Sustained AF (>1 hour) was inducible in 100%, 60%, 20%, and 0% of atria in the presence of acetylcholine alone, acetylcholine+ibutilide, acetylcholine+flecainide, and acetylcholine+ibutilide+flecainide, respectively. When used alone, flecainide and ibutilide cardioverted sustained AF in 40% and 20% of atria, respectively, but in 100% of atria when used in combination. Ibutilide prolonged atrial and ventricular effective refractory period by 15% and 8%, respectively, at a cycle length of 500 ms (P<0.05 for both). Flecainide increased the effective refractory period in atria by 27% (P<0.01) but by only 2% in the ventricles. The combination of the 2 drugs lengthened the effective refractory period by 42% in atria (P<0.01) but by only 7% (P<0.05) in the ventricles. In left ventricular wedges, ibutilide prolonged QT and Tpeak-Tend intervals by 25 and 55%, respectively (P<0.05 for both; cycle length, 2000 ms). The addition of flecainide (1.5 µmol/L) partially reversed these effects (P<0.05 for both parameters versus ibutilide alone). Torsades de Pointes score was relatively high with ibutilide alone and low with the drug combination. In our experimental model, a combination of flecainide and ibutilide significantly improves cardioversion and prevents the recurrence of AF compared with monotherapies with little to no risk for the development of long-QT-mediated ventricular proarrhythmia.

An Update on Hypomagnesemia and Hypermagnesemia

Magnesium is an essential element with a pleiotropic role in human biology. Despite tight intestinal and renal regulation of its balance, insufficient intake can finally result in hypomagnesemia, which is a proxy of intracellular deficiency. Conditions such as diabetes, cancer, and infections are often associated with hypomagnesemia, which mostly predicts an unfavorable outcome. The effects of hypomagnesemia can either be direct and include neurological and cardiovascular symptoms or indirect, taking a mechanistic role in inflammation, endothelial dysfunction, and oxidative stress. The indication for intravenous magnesium as a treatment of torsades de pointes and pre-eclampsia is unrefuted, but new indications of peroral or intravenous supplementation, albeit with less supporting evidence, have emerged suggesting, respectively, an attenuation of vascular calcification in chronic kidney disease and improved rate control in atrial fibrillation. Other potential beneficial properties of magnesium, which were claimed by observational data, such as lipid lowering and renal protection, were not, or only partially, investigated in randomized controlled trials. Thus, the role of peroral supplementation of mild chronic asymptomatic hypomagnesemia should be separated from the more targeted prescription of magnesium in specific study populations. (Severe) hypermagnesemia is potentially life-threatening and occurs almost uniformly in subjects with severe renal failure exposed to either supplements or to magnesium-containing cathartics or antacids. Moderate hypermagnesemia is very common in pre-eclamptic women treated with intravenous magnesium. For most (but not all) studied endpoints, mild hypermagnesemia yields a survival benefit. Long-lasting concerns about the potential negative effects of mild hypermagnesemia on bone physiology and structure have so far not been unequivocally demonstrated to be troublesome.

Drug-induced QT prolongation and torsade de pointes: a real-world pharmacovigilance study using the FDA Adverse Event Reporting System database.

Introduction: Drug-induced QT prolongation and (or) Torsade de Pointes (TdP) is a well-known serious adverse reaction (ADR) for some drugs, but the widely recognized comprehensive landscape of culprit-drug of QT prolongation and TdP is currently lacking. Aim: To identify the top drugs reported in association with QT prolongation and TdP and provide information for clinical practice. Method: We reviewed the reports related to QT prolongation and TdP in the FDA Adverse Event Reporting System (FAERS) database from January 1, 2004 to December 31, 2022, and summarized a potential causative drug list accordingly. Based on this drug list, the most frequently reported causative drugs and drug classes of QT prolongation and TdP were counted, and the disproportionality analysis for all the drugs was conducted to in detect ADR signal. Furthermore, according to the positive-negative distribution of ADR signal, we integrated the risk characteristic of QT prolongation and TdP in different drugs and drug class. Results: A total of 42,713 reports in FAERS database were considered to be associated with QT prolongation and TdP from 2004 to 2022, in which 1,088 drugs were reported as potential culprit-drugs, and the largest number of drugs belonged to antineoplastics. On the whole, furosemide was the most frequently reported drugs followed by acetylsalicylic acid, quetiapine, citalopram, metoprolol. In terms of drug classes, psycholeptics was the most frequently reported drug classes followed by psychoanaleptics, analgesics, beta blocking agents, drugs for acid related disorders. In disproportionality analysis, 612 drugs showed at least one positive ADR signals, while citalopram, ondansetron, escitalopram, loperamide, and promethazine were the drug with the maximum number of positive ADR signals. However, the positive-negative distribution of ADR signals between different drug classes showed great differences, representing the overall risk difference of different drug classes. Conclusion: Our study provided a real-world overview of QT prolongation and TdP to drugs, and the presentation of the potential culprit-drug list, the proportion of reports, the detection results of ADR signals, and the distribution characteristics of ADR signals may help understand the safety profile of drugs and optimize clinical practice.

High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model.

Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog. Methods: Dofetilide (25μg/kg in 5min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats/minute for 2min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60retro). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDRcubic). Results: In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 ± 33 vs. 0 ± 0, p < 0.05 and vs. 12.5 ± 25 and 25 ± 50, both p > 0.05). The reduction in TdP score was reflected by a significant decrease in SDRcubic (125 ± 46ms before TdP vs. 49 ± 18ms during RVA100, p < 0.05), and SDR was smaller than in the RVA60retro animals (101 ± 52ms, p < 0.05 vs. RVA100). Conclusion: In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.

Long-term QT prolongation in monkeys after doxorubicin administration at doses similar to breast cancer therapy.

Studies in small animals and human patients have suggested that anthracyclines may prolong cardiac repolarization, or at least inhibit repolarization reserve, predisposing to QT prolongation and dangerous arrhythmias such as Torsades de pointes. This association in humans is difficult to confirm due to multiple confounding variables such as the presence of other medications and concurrent illness. Identify a long-term association between anthracycline administration and repolarization prolongation in nonhuman primates, which can be measured as prolonged QT/QTc intervals on surface electrocardiogram. Five female African Green monkeys (AGMs) aged 13 ± 1 years received Doxorubicin (Dox) at doses similar to women treated for breast cancer (30-60 mg/m2/biweekly IV, total cumulative dose: 240 mg/m2) and underwent 12-lead electrocardiogram (ECG) before and 15 weeks after the final dose of Dox treatment. A blinded paired analysis was performed on ECG derived heart rate (HR), QRS, QT and QT corrected for HR (QTc) interval durations. After Dox, all monkeys exhibited increased QT (BL: 323.2 ± 27.4 ms vs. Post-Dox: 366.4 ± 18.7 ms, p = 0.002) and QTc (BL: 440.2 ± 22.8 ms vs. Post-Dox: 500.8 ± 22.0 ms, p = 0.009) intervals, without any significant changes in HR or QRS duration (p = 0.92 and p = 0.47 respectively). AGMs treated with Dox exhibited long-term QT and QTc prolongation, along with the expected cardiotoxicity (LVEF decrease). While similar findings were shown in small animal studies, confounders make human association difficult to prove. Our finding provides a valuable intermediary step, showing direct effect of Dox on repolarization in nonhuman primates.

Transvenous Pacemaker Placement: A Review for Emergency Clinicians

BackgroundTransvenous pacemaker placement is an integral component of therapy for severe dysrhythmias and a core skill in emergency medicine. ObjectiveThis narrative review provides a focused evaluation of transvenous pacemaker placement in the emergency department setting. DiscussionTemporary cardiac pacing can be a life-saving procedure. Indications for pacemaker placement include hemodynamic instability with symptomatic bradycardia secondary to atrioventricular block and sinus node dysfunction; overdrive pacing in unstable tachydysrhythmias, such as torsades de pointes; and failure of transcutaneous pacing. Optimal placement sites include the right internal jugular vein and left subclavian vein. Insertion first includes placement of a central venous catheter. The pacing wire with balloon is then advanced until electromechanical capture is obtained with the pacer in the right ventricle. Ultrasound can be used to guide and confirm lead placement using the subxiphoid or modified subxiphoid approach. The QRS segment will demonstrate ST segment elevation once the pacing wire tip contacts the endocardial wall. If mechanical capture is not achieved with initial placement of the transvenous pacer, the clinician must consider several potential issues and use an approach to evaluating the equipment and correcting any malfunction. Although life-saving in the appropriate patient, complications may occur from central venous access, right heart catheterization, and the pacing wire. ConclusionsAn understanding of transvenous pacemaker placement is essential for emergency clinicians.