Torsades Research Articles

Comorbidities and use of proarrhythmic drugs in patients with torsade de pointes arrhythmia

Abstract Introduction Drug-induced long QT interval syndrome (LQTS) is a risk factor for torsade de pointes (TdP) ventricular arrhythmia. Combining several QT-prolonging drugs can also increase risk. Clinical decision support systems (CDSS) can help prescribers assess the risk for TdP associated with drugs. Use of combination of drugs and prevalence of other risk factors is not fully known in TdP . Purpose To describe 1) comorbidities (risk-diagnoses) 2) dispensed prescription drugs and their risk for TdP (risk-drugs) using two different CDSS. The hypothesis was that individuals with TdP had risk-diagnoses and used risk-drugs. Personalized decision regarding risk stratification and medication is important to prevent TdP. Methods Patients with first episode of TdP (ICD-10 I472.C) in the National Patient Register (NPR) between 2006 and 2018 were included in this retrospective register-based cohort study. Comorbidities within 5 years prior to the hospital care episode and at the time of TdP diagnosis were retrieved. Mortality was analyzed (National Cause of Death Register). Medications dispensed within 90 days prior to TdP were retrieved (Swedish Prescribed Drug Register). Drugs were classified using 2 different CDSS (Credible Meds and Janusmed Risk Profile). Individual medication data linked with Janusmed Risk Profile gave a risk score of combination of drugs according to an algorithm. Results 762 patients with TdP were identified, most were elderly (72% ≥65 years old), 50% females. After TdP, 31 patients (4.1%) died within 7 days, 61 (8.0%) within 30 days, 87 (11%) within 90 days. Five years prior to TdP 338 patients (44%) had ≥1 risk-diagnosis (heart failure, cardiomyopathies, acute/ chronic coronary syndromes, renal failure,liver disease, LQTS, ventricular arrhythmia and/or cardiac arrest). More males vs. females had risk-diagnoses (28% vs. 22%, p<0.0015). A median of 6 drugs (IQR 2-9) were dispensed. Anti-depressants and antiarrhythmics were the most common risk-drugs. According to Credible Meds, 192 (25%) patients used ≥1 drug with known risk, 51 patients (6.7%) ≥1 drug with possible risk and 208 patients (27%) ≥1 drug with conditional risk only. 470 patients (62%) had ≥1 risk-diagnosis and/or ≥ 1 risk-drug (known or possible risk). Another 88 patients had ≥1 risk-diagnosis and/or ≥1 risk-drug (conditional risk). Thus, 558 patients (73%) had ≥1 risk-diagnosis and/or ≥ 1 risk-drug (Credible Meds). Analysis of combination of drugs showed that 290 patients (38 %) had drugs with increased risk, 547 patients (72%) had ≥1 risk-diagnosis and/or a combined drugs associated with increased risk (Janusmed Risk Profile). Conclusion Prior to TdP approximately a third of patients were dispensed prescription drugs with proarrhythmic risk according to two different CDSS. Almost 75% of patients were dispensed drugs associated with proarrhythmic risk and/or had other proarrhythmic risk factors. Vigilance should be undertaken to modify risk factors to prevent TdP.Baseline characteristicsRisk-drugs dispensed prior to TdP

Significance of J wave with inverted ST-T polarity induced by ill-timed atrial premature beats and its association with Torsade de Pointes in patients with acute acquired long QT syndrome

Abstract Background When ventricular cardiomyocytes become depolarized during their relative refractory period (RRP), the amplitude of the action potential (AP) becomes lower than that of preceding AP, since some sodium channels are in their refractory state. If the membrane voltage does not reach a level high enough to activate voltage-dependent calcium channels, the AP duration becomes markedly shortened due to loss of AP dome. In patients with long QT syndrome (LQTS), intrinsic differences in AP duration and/or AP restitution kinetics exist between ventricular endocardium and epicardium. Thus, we hypothesized that atrial premature beats (APBs) can capture the RRP and amplify a transmural voltage gradient that manifests as a J wave with inverted ST-T polarity (APB-induced J wave). Purpose To investigate the prevalence of APB-induced J wave and examine the contribution to the development of Torsade de Pointes (TdP) in patients with acute acquired LQTS. Methods A total of 34 consecutive patients with acute acquired LQTS (14 men; median age, 69 years; median QTc, 645.5 ms) and documented TdP were enrolled. APBs were observed before the onset of TdP in 18 (52.9%) patients. The 34 patients were divided into 2 groups based on the presence or absence of APB-induced J wave with inverted ST-T polarity: APB-J wave group (n=8) and non-APB-J wave group (n=26). Results APB-J wave group constituted 23.5% (8/34) of the studied patients. There were no significant differences in clinical characteristics (sex, age and QTc) between the 2 groups. Macroscopic T-wave alternans was more frequently observed before TdP onset in APB-J wave group than non-APB-J wave group (75% vs 15.4%, p=0.003). The ill-timed APBs with J wave directly initiated TdP in all patients in APB-J wave group. APB-J wave group experienced TdP even after initiating conventional therapy more frequently than non-APB-J wave group (3.5 vs 1 event, p=0.04). Conclusions APB-induced J wave is observed in approximately one-fourth of acute acquired LQTS patients with TdP and is associated with an increased risk of TdP. Our observations suggest that APBs can amplify the transmural dispersion of repolarization manifested as a J wave.Figure1Figure2

Mexiletine shortened QTc interval in an age-dependent manner but suppressed ventricular arrhythmias at all age in children with long QT syndrome type 8

Abstract Background long QT syndrome (LQTS) type 8 (LQT8) is caused by mutations in CACNA1C, a gene encoding the α-subunit of voltage-gated Ca2+ channels. Mexiletine is sodium channel blocker which is often utilized for patients with LQTS type 3. Recently, the potential QT shortening effect of mexiletine in patients with LQTS type 2, however the efficacy for LQT8 patients have not been elucidated sufficiently. Purpose The study aimed to examine the efficacy of mexiletine for LQT8 children. Methods and Results The study consisted of 5 LQT8 children diagnosed at age <18 years from 4 families (female n=2). Three cases diagnosed on the first day of life, others during school-aged period. The mean age at diagnosis was 3.8 ± 4.9 years. The CACNA1C mutations identified in the patients were R518C (Case No.1), R858H (No.2), M1476R (No3 and 4), and G402S (No.5). We analyzed response in 12-lead electrocardiogram (ECG) parameters to mexiletine (3mg/kg, Max 125mg) intravenous infusion over 10 minutes. 12-lead ECGs were recorded at rest and 10 minutes after infusion. Two of them were received in the school-age period (No.1 and 2), two were in the neonatal period (No.4 and 5), and another was twice in both periods (No.3). QTc was drastically shortened in school-aged children (No.1: 521/456ms, No.2: 691/556, No.3: 568/532ms), while 3 neonatal cases showed no QTc shortening (No.3: 481/479ms, No.4: 600/601ms, No.5: Pre 689ms/Post 714ms) (Figure). T wave alternans (TWA) that had occurred incessantly in the neonatal case No.4 dramatically suppressed a few seconds after mexiletine infusion. In addition, torsades de pointes (TdP) had been recorded in 2 cases (No.2 and 5). Then, case No.2 and 5 started combination therapy of oral mexiletine and β-blocker, and No.4 mexiletine therapy. They had no cardiac event during medication for several years, although case No.2 suffered recurrent cardiac events because of non-compliance to mexiletine. Conclusion Mexiletine shortened QTc interval in school-aged children with LQT8, but not in neonates. Regardless of QTc shortening, mexiletine successfully reduced TWA and TdP at all age of LQT8 children.Mexiletine infusion test

Ventricular arrhythmias occurring in myocardial infarction patients with acute ST-segment elevation within the first 24 hours after primary percutaneous coronary intervention and their prognostic value

Reperfusion therapy in myocardial infarction patients with acute ST-segment elevation significantly reduced the frequency of ventricular tachycardia and ventricular fibrillation, however, such arrhythmias still occur in 6-8% of patients, posing a threat to their lives.The aim of the study was to determine the nature of ventricular arrhythmias occurring in myocardial infarction patients with acute ST-segment elevation within the first 24 hours after primary percutaneous coronary intervention, and their prognostic value regarding the development of complications during the inpatient treatment phase. The study involved 82 individuals (mean age: 62,4±10,2 years; male: 69,23 (58,6-78,92)%, female: 30,77 (21,08-41,4)%). Within 24 hours after the infarct-related artery stenting, all patients underwent a 24-hour Holter ECG monitoring. The course of the disease was analyzed based on the presence of risk factors such as hypertension, diabetes mellitus, past COVID-19, and obesity. Ventricular rhythm disturbances were represented mainly by premature contractions. They occurred significantly more frequently in patients with arterial hypertension (883,71 (96,0; 986.0); p=0,02; p=0,03; p=0,02, compared to patients with a history of COVID-19, diabetes, and obesity, respectively) and in those with past COVID-19 (711,3 (125,0; 846,5); p=0,01; p=0,04, compared to indi­viduals with diabetes and obesity, respectively). Isolated premature ventricular complexes, pairs, triplets were recorded, and in individuals with arterial hypertension and past COVID-19 “runs” of ventricular extrasystoles and episodes of nonsustained monomorphic and even polymorphic ventricular tachycardia, such as Torsades de Pointes, (under the condition of combined risk factors) were noted; predominantly in these patients during the hospital phase such сom­plications as ventricular fibrillation and asystole,with sudden cardiac arrest developed. The obtained results is an evidence of electrical myocardial instability and indicate that myocardial infarction patients with acute ST-segment elevation, in addition to myocardial revascularization, require optimization of pharmacological treatment. The use of intravenous beta-blockers as part of complex treatment prevented the occurrence of life-threatening ventricular arrhythmias during the inpatient treatment phase.

Olanzapine Versus Quetiapine: Corrected QT Changes in Critically Ill Patients.

Olanzapine and quetiapine are frequently administered atypical antipsychotic medications and their effects on the corrected QT (QTc) in the critically ill population remain understudied. The objective of this study was to compare the impact of olanzapine and quetiapine on QTc changes in critically ill patients. This was a single-center, retrospective analysis. Adult patients admitted to the intensive care unit (ICU) from January 2023 through July 2023 were included if they received ≥2 doses of either olanzapine or quetiapine within a 48-hour period and had one QTc evaluated within 48 hours of antipsychotic initiation. The major endpoint was a composite of the incidence of QTc prolongation (defined as QTc > 500 ms or QTc > 60 ms above baseline) following antipsychotic initiation. Univariable and multivariable analyses were performed to identify risk factors for QTc prolongation. There was no statistical difference in the major composite endpoint between patients in the olanzapine and quetiapine groups (8/83 [9.6%] vs 19/129 [14.7%]; P = .28). The incidence of QTc > 500 ms (7/244 [2.9%] vs 20/427 [4.7%]; P = .25) and change from baseline >60 ms (5/244 [2.0%] vs 17/427 [4.0%]; P = .26) were not statistically different between the olanzapine and quetiapine groups, respectively. There were no occurrences of Torsades de Pointes or extrapyramidal symptoms in either group. The results of this study suggest olanzapine and quetiapine may have similar impact on QTc prolongation in critically ill patients. These findings could contribute to safer prescribing practices in the ICU.

Explainable artificial intelligence (XAI) to find optimal in-silico biomarkers for cardiac drug toxicity evaluation

The Comprehensive In-vitro Proarrhythmia Assay (CiPA) initiative aims to refine the assessment of drug-induced torsades de pointes (TdP) risk, utilizing computational models to predict cardiac drug toxicity. Despite advancements in machine learning applications for this purpose, the specific contribution of in-silico biomarkers to toxicity risk levels has yet to be thoroughly elucidated. This study addresses this gap by implementing explainable artificial intelligence (XAI) to illuminate the impact of individual biomarkers in drug toxicity prediction. We employed the Markov chain Monte Carlo method to generate a detailed dataset for 28 drugs, from which twelve in-silico biomarkers of 12 drugs were computed to train various machine learning models, including Artificial Neural Networks (ANN), Support Vector Machines (SVM), Random Forests (RF), XGBoost, K-Nearest Neighbors (KNN), and Radial Basis Function (RBF) networks. Our study’s innovation is leveraging XAI, mainly through the SHAP (SHapley Additive exPlanations) method, to dissect and quantify the contributions of biomarkers across these models. Furthermore, the model performance was evaluated using the test set from 16 drugs. We found that the ANN model coupled with the eleven most influential in-silico biomarkers namely dVmdtrepol,dVmdtmax,APD90,APD50,APDtri,CaD90,CaD50,Catri,CaDiastole,qInward,andqNet\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\frac{dVm}{dt}_{repol}, \\frac{dVm}{dt}_{max}, {APD}_{90}, {APD}_{50}, {APD}_{tri}, {CaD}_{90}, {CaD}_{50}, {Ca}_{tri}, {Ca}_{Diastole}, qInward, and qNet$$\\end{document} showed the highest classification performance among all classifiers with Area Under the Curve (AUC) scores of 0.92 for predicting high-risk, 0.83 for intermediate-risk, and 0.98 for low-risk drugs. We also found that the optimal in silico biomarkers selected based on SHAP analysis may be different for various classification models. However, we also found that the biomarker selection only sometimes improved the performance; therefore, evaluating various classifiers is still essential to obtain the desired classification performance. Our proposed method could provide a systematic way to assess the best classifier with the optimal in-silico biomarkers for predicting the TdP risk of drugs, thereby advancing the field of cardiac safety evaluations.

Torsades de Pointes electrical storm in children with KCNH2 mutations

Congenital long QT syndrome (LQTS) is a genetic heart disorder, which may lead to life-threatening arrhythmias, especially in children. Here, we reported two children who were initially misdiagnosed with epilepsy and experienced Torsades de Pointes (TdP) cardiac electrical storm (ES). Through whole exome sequencing (WES), we identified two Potassium voltage-gated channel subfamily H member 2 (KCHN2) mutations (c.1841 C > T and c.1838 C > T) respectively in a 6-year-old boy and a 13-year-old girl. Clinical data indicated that the QT interval was significantly prolonged, the T-wave pattern of chest V5-V6 leads and limb leads were inverted. Our study suggests that patients with epilepsy, especially those refractory epilepsy with atypical features, need comprehensive evaluation of cardiovascular function. KCNH2 mutation in pore region, QT interval prolongation and T wave inversion are high risk factors for ES. For LQT2 patients with ES, Nadolol and left cardiac sympathetic denervation are indicated, sometimes with an ICD.

6692 Proarrhythmic Risk Of Hypoglycemia; A Case Of Insulin-Induced Hypoglycemia Provoking Torsade De Pointes-Cardiac Arrest

Abstract Disclosure: A.M. San Hernandez: None. A. Adelkhanova: None. H. Ashraf: None. J. Aguayo Herrera: None. M.F. Siddiqui: None. Introduction: Torsade de Pointes is a life-threatening polymorphic ventricular tachycardia which is associated with QTc prolongation caused by medications, metabolic and electrolyte abnormalities. Very few cases of hypoglycemia causing QTc prolongation and Torsades de Pointes have been reported in the literature. Although the mechanism is unclear, the effects of low blood glucose have been proposed to induce a sympathetic response, hypokalemia and calcium disturbances. We report a case of an insulin-induced hypoglycemia causing Torsades de Pointes cardiac arrest, highlighting the proarrhythmic risk of hypoglycemia. Case presentation: A 57-year-old female with a history of Insulin-dependent Type 2 Diabetes Mellitus (DM) was brought in by EMS due to severe symptomatic hypoglycemia (POC blood glucose of 30 mg/dL), requiring treatment with dextrose. Patient reported reduced oral intake due to vomiting for 1 week and continued insulin administration without self-monitoring of blood glucose. Laboratory work up on presentation revealed severe hypoglycemia VBG= 55 mg/dL and mild hypomagnesemia Mg=1.4mg/dL (Ref Range 1.7-2.2mg/dl) which was treated. There was no hypokalemia or hypocalcemia. ECG showed sinus rhythm with prolonged QTc interval of 573ms and non-specific ST changes.Few hours later, patient developed torsades de pointes, requiring ACLS resuscitation. ROSC was achieved after two rounds of CPR. Patient received dextrose infusion to maintain euglycemic state. She was not taking any QTc prolonging medication. There was no history of autoimmune disease. Except for hypoglycemia, no other metabolic abnormality could be identified. Cardiac and pulmonary etiologies of cardiac arrest were ruled out. Post-ROSC ECG showed sinus tachycardia with normalization of QTc to 454ms. Thus, Insulin-induced hypoglycemia was appointed as the main culprit for her cardiac arrest, in the setting of QTc prolongation. Patient received diabetes self-management and hypoglycemia education. Conclusion: Several studies support strong correlation between hypoglycemia and arrhythmic events during bedtime in people with diabetes “The dead in bed syndrome”. Hypoglycemia causes an acquired long QT syndrome independent of other risk factors such as cardiac autonomic neuropathy. Possible mechanisms include; sympathoadrenal activation, which regulates potassium, calcium and chloride channels or altered autonomic regulation caused by hypoglycemia itself regardless of the effect of insulin or hypokalemia. QT prolongation is a risk factor for sudden cardiac death by causing torsades de pointes ventricular tachycardia (VT).People with insulin dependent diabetes are at high risk of hypoglycemia and should be cautioned about the proarrhythmic risk of hypoglycemia. Education is crucial, and Continuous glucose monitor (CGM) is a valuable tool to be use in such a patient population. Presentation: 6/3/2024

6966 A Rhythmic Life-Threatening Enigma Unveiled: KCNH2 Mutation-Associated Torsades de Points Unmasking Primary Hyperaldosteronism in Cardiological Realm

Abstract Disclosure: S. Dejprapasorn: None. N. Nopparatana: None. S. Soonthornpun: None. R. Leelawattana: None. N. Kietsiriroje: None. S. Limumpornpetch: None. T. Nilmoje: None. W. Lohawijarn: None. T. Wongsuttipakorn: None. P. Choochuen: None. P. Limumpornpetch: None. Introduction: Primary hyperaldosteronism (PA) is characterized by hypertension and hypokalemia. However, its ability to masquerade life-threatening Torsades de Pointes makes it an unusual and dismissed diagnosis, revealing the link between PA and serious arrythmia. Clinical Case A 30-year-old female experienced three episodes of palpitations, followed by syncope. Upon admission, her blood pressure was 147/87 mmHg. ECG showed prolonged QT intervals with potassium level was 2.6 mmol/L (3.5-5.0 mmol/L). Continuous cardiac monitoring captured Torsades de Pointes. Despite potassium replacement, long QT still persisted. Pathogenic variant, c.2592+1G>A, within KCNH2 was discovered. Aldosterone concentration showed 69.65 ng/dL (9.70-62.60 ng/dL) and plasma renin activity was 0.12 ng/mL/h (1.50-5.70 ng/mL/h). Aldosterone-to-renin ratio was 580. Aldosterone post 4-h saline infusion test was 31.71 ng/dL which were consistent with PA. Adrenal unenhanced CT scan identified bilateral adrenal nodules (right 1.3 cm, left 1.1 cm). After receiving a cardioverter-defibrillator and spironolactone, the patient has had no palpitations, and their potassium level has remained normal. Clinical lessons: PA rarely presents ventricular arrhythmia. KCNH2 mutation may link between long QT syndrome (LQTS) and PA arises. LQTS type 2 is attributable to KCNH2 mutations, impacting potassium channel subunits crucial for adjusting currents during sympathetic activation. This is essential for shortening the QT interval with increasing heart rate. KCNH2 mutations disrupt this process, prolonging the QT interval and heightening the risk of arrhythmias. Aldosterone synthesis relies on calcium signaling triggered by potassium currents. Adrenal cortex hosts approximately 90 potassium channels genes, including KCNJ5 and KCNH2. Mutations in gene can disrupt the calcium signaling cascade, leading to excessive aldosterone production. While KCNJ5 mutation is well-documented in PA, the potential correlation between KCNH2 mutations and a similar mechanism remains unexplored in clinical reports to date. This case highlights the importance of a thorough comprehension of genetic cause contributing to pathogenesis of PA with complex clinical presentations. Presentation: 6/1/2024

12609 Navigating The Therapeutic Challenge Of Post-surgical Hypoparathyroidism And Refractory Hypocalcemia

Abstract Disclosure: D. Fawcett: None. A. Domingo: None. Introduction: Post-surgical hypoparathyroidism poses a challenge due to calcium metabolism disturbances, ranging from mild to life-threatening complications. Despite advancements, vigilant monitoring and tailored interventions are vital for optimizing outcomes. Refractory hypocalcemia, resistant to standard therapies, underscores the need for specialized care to prevent prolonged hospitalization and morbidity. Case description: A 68-year-old woman with a history of Graves' disease and parathyroid carcinoma underwent total thyroidectomy and parathyroidectomy in January 2024. She presented to the emergency department for the second time with a recurrence of bilateral hand and perioral paresthesias, along with numbness, tingling, and weakness throughout her body. Notably, she had a prior hospital admission with similar symptoms and was discharged on calcium carbonate, magnesium, calcitriol, and vitamin D3. Vital signs were not provided. Initial laboratory workup revealed a calcium level of 4.3, with corrected calcium at 5.8, and magnesium levels at 1.8, supplemented with magnesium oxide. A 24-hour urine calcium test, vitamin D, and malabsorptive workup for celiac disease were unremarkable. Immunoglobulin A was low; however, tissue transglutaminase IgA and anti-gliadin antibodies were negative. An electrocardiogram showed a normal sinus rhythm with QT prolongation to 570 ms. Despite resuming her home regimen, her calcium level remained low, prompting initiation of calcium infusion. Consultations with endocrinology and nephrology were made, necessitating close monitoring and uptitration of calcium and vitamin D supplements for achievement and maintenance of low normal calcium levels. High doses of 3g TID of calcium and calcitriol 2mcg PO TID allowed for symptom control and discharge with outpatient follow-up with endocrinology and nephrology. Conclusion: Supplemental therapy with calcium and vitamin D analogues is standard for managing post-surgical hypoparathyroidism. Early identification and adequate management prevent hypocalcemia-related complications, including tetany, seizures, and cardiovascular anomalies such as QTc prolongation, as seen in our patient, which can result in torsade de pointes. Multidisciplinary care alongside nephrology was paramount. Serum calcium should be maintained in the low normal range, and 24-hour urine calcium excretion should also be closely monitored. Daily hydrochlorothiazide can be used to prevent hypercalciuria. In recurrent cases, as in our patient, titration of calcium and vitamin D analogues is imperative. Long-term consequences, including renal dysfunction, osteoporosis, and increased cardiovascular risk, underscore the necessity for timely diagnosis and management. Presentation: 6/2/2024

On the relationship between hERG inhibition and the magnitude of QTc prolongation: An in vitro to clinical translational analysis

Assessing the magnitude of QTc prolongation is crucial in drug development due to its association with Torsades de Pointes. Inhibition of the hERG channel, pivotal in cardiac repolarization, is a key factor in evaluating this risk. In this study, the relationship between hERG inhibition and QTc prolongation magnitude was investigated, with the aim to derive simple guidance on the required hERG margin to avoid a large (>20 ms) QTc prolongation. MethodsData from literature and FDA sources were searched for compounds with hERG IC50 values alongside clinical QTc data with paired plasma concentrations, or compounds demonstrating a clinical concentration-QTc relationship. Relationships between hERG inhibition, hERG IC50 margin to unbound plasma Cmax, and QTc prolongation magnitude were calculated. ResultsAnalysis of 148 clinical QTc observations from 98 compounds revealed that compounds associated with QTc prolongation >10 ms typically exhibited hERG margins of ≤33-fold, while those exceeding 20 ms were generally associated with margins of ≤24-fold. QTc increases above 10 ms were not observed at hERG margins >100-fold. Based on 53 clinical concentration-QTc datasets, modest hERG inhibition levels of ~4–6 % correlated with a 10 ms QTc prolongation, while ~10–13 % inhibition corresponded to a 20 ms prolongation. ConclusionsThis study enhances understanding of the relationship between hERG inhibition and QTc prolongation magnitude, by conducting analysis across a wide range of 98 compounds. This information can be used to determine the optimal hERG margin, particularly for drug discovery projects with limited scope to completely design-out hERG activity.

Mechanisms underlying the spontaneous termination of torsades de pointes in an experimental model of long QT syndrome

BackgroundTorsades de pointes (TdP) represent a complex polymorphic ventricular tachycardia. While the triggering mechanisms of early afterdepolarization and increased dispersion of repolarization are well investigated, the sudden self-limiting termination remains poorly understood. ObjectiveThe purpose of this study was to perform analysis of TdP to investigate factors causing spontaneous termination. MethodsWe used a large data set from Langendorff experiments in isolated rabbit hearts in which drug-induced QT prolongation, bradycardia, and hypokalemia provoke TdP. We included 427 episodes with typical TdP characteristics of polymorphic self-terminating beats and twisting QRS complexes occurring in the presence of abnormal QT prolongation due to various different QT-prolonging drugs. The use of 8 monophasic action potential catheters allowed the characterization of action potential duration, configuration, and dispersion of repolarization beyond the capabilities of the surface electrocardiogram. To identify possible mechanisms of arrhythmia termination, the initial, midpoint, and terminal 3 ventricular complexes were analyzed for each episode. ResultsAn abrupt decrease in spatial dispersion over the course of a TdP episode was identified as a precursor for termination of TdP. Within the last 3 beats, a sudden significant decrease in the dispersion of repolarization was observed as a predictor of termination. In parallel, there was a decrease in action potential duration (action potential duration at 90% repolarization) before termination. Also, a change in action potential configuration (action potential duration at 90% repolarization/action potential duration at 50% repolarization ratio) in terms of the loss of action potential dome with a restitution of action potential triangulation was observed. ConclusionIn >400 TdP episodes, homogenization of myocardial repolarization with the recovery of an action potential configuration determines the termination of TdP episodes.

Drug-induced torsadogenicity prediction model: An explainable machine learning-driven quantitative structure-toxicity relationship approach

Drug-induced Torsade de Pointes (TdP), a life-threatening polymorphic ventricular tachyarrhythmia, emerges due to the cardiotoxic effects of pharmaceuticals. The need for precise mechanisms and clinical biomarkers to detect this adverse effect presents substantial challenges in drug safety assessment. In this study, we propose that analyzing the physicochemical properties of pharmaceuticals can provide valuable insights into their potential for torsadogenic cardiotoxicity. Our research centers on estimating TdP risk based on the molecular structure of drugs. We introduce a novel quantitative structure-toxicity relationship (QSTR) prediction model that leverages an in silico approach developed by adopting the 4R rule in laboratory animals. This approach eliminates the need for animal testing, saves time, and reduces cost. Our algorithm has successfully predicted the torsadogenic risks of various pharmaceutical compounds. To develop this model, we employed Support Vector Machine (SVM) and ensemble techniques, including Random Forest (RF), Extreme Gradient Boosting (XGBoost), and Categorical Boosting (CatBoost). We enhanced the model's predictive accuracy through a rigorous two-step feature selection process. Furthermore, we utilized the SHapley Additive exPlanations (SHAP) technique to explain the prediction of torsadogenic risk, particularly within the RF model. This study represents a significant step towards creating a robust QSTR model, which can serve as an early screening tool for assessing the torsadogenic potential of pharmaceutical candidates or existing drugs. By incorporating molecular structure-based insights, we aim to enhance drug safety evaluation and minimize the risks of drug-induced TdP, ultimately benefiting both patients and the pharmaceutical industry.

Inhibition of hERG K channels by verapamil at physiological temperature: Implications for the CiPA initiative

The Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative reassesses using the inhibition of hERG potassium channels by drugs as the major determinant for the potential to cause drug-induced Torsades de Pointes (TdP) cardiac arrhythmias. Here we report our findings on the next phase of CiPA: Determination of hERG inhibitory properties using the standard CiPA-defined data acquisition protocol, here called the standard protocol, at physiological temperature (37 degrees Celsius). To do this, we measured inhibition of hERG1a potassium channels stably expressed in HEK293 cells by the small molecule verapamil, using manual whole-cell patch-clamp electrophysiology recordings with the standard protocol, which is characterized, in part, by a series of 10 s duration voltage steps to 0 mV, ultimately leading to a cumulative recording time of approximately 30 min. Using the standard protocol, we measured an IC50 for verapamil of 225 nM, a Hill coefficient of 1, and time constant of inhibition at 0 mV of 0.64 s. But, using the standard protocol resulted in a very low (5 %) experimental success rate per cell, which had low practicality for future experiments. To address the 5 % success rate, we generated a revised protocol characterized, in part, by a series of 3 s duration voltage steps to 0 mV, leading to a cumulative recording time of approximately 10 min. Using the revised protocol, we found an IC50 for verapamil of 252 nM, a Hill coefficient of 0.8, and time constant of inhibition at 0 mV of 0.67 s. The values measured with the revised protocol were similar to those measured using the standard protocol and, furthermore, our success rate using the revised protocol rose to 25 %, an increase of 5-fold over the standard protocol, and more in line with the success rate for biophysical studies. In summary, we captured key pharmacological data for subsequent analysis in CiPA using a revised protocol with an increased success rate and an overall enhanced feasibility and practicality. We propose that the revised protocol may be more pragmatic for generation of some hERG channel drug inhibition data for CiPA and other regulatory sciences.

Assessment of QTc-interval Prolonging Medication Utilization and Associated Potential Drug-Drug Interactions in Hospitalized Cardiac Patients: A Cross-Sectional Study in Cardiology

Background: Several medications are linked to QTc-interval prolongation and torsades de pointes (TdP), a risk that is more common among hospitalized patients due to polypharmacy and associated QTc-interval-prolonging drug-drug interactions (QTc-pDDIs). Objective: This study aimed to identify the prevalence of QTc-interval-prolonging drug (QTc-Drug) utilization and QTc-pDDIs among postoperative cardiac patients admitted to the National Institute of Cardiovascular Diseases (NICVD). Method: We conducted a cross-sectional study at the NICVD, reviewing patients' medication charts for the use of QTc-Drugs and QTc-pDDIs. The CredibleMeds list was used to identify drugs associated with QTc-interval prolongation, while Micromedex Drug-Int.® and Lexicomp Interact® were utilized to screen for QTc-pDDIs. Results: A total of 384 patients, with an average age of 48.9 ± 13.9 years, were included in the study. On average, patients used 10.3 ± 1.7 medications. Of the 3,956 medications prescribed, 22.9% were QTc-Drugs. The most frequently used QTc-Drug classes were diuretics (69.3%), anti-emetics (61.5%), and proton pump inhibitors (51.0%). Overall, 99.7% of patients received at least one QTc-Drug. The most frequent QTc-pDDI was ciprofloxacin-domperidone (7.6%), classified as major by Micromedex and a category B interaction by Lexicomp. Conclusion: The prevalence of QTc-Drugs was very high among postoperative cardiac patients, with nearly all patients (99.7%) receiving at least one QTc-Drug. The most common QTc-pDDI was ciprofloxacin-domperidone (7.6%), identified as a major interaction by Micromedex and a category B interaction by Lexicomp. Category X (contraindicated) QTc-pDDIs should be avoided in hospitalized patients.

Safety analysis of fluoroquinolone drugs in elderly patients over 65 based on FAERS

ABSTRACT Objective This study investigates adverse drug event (ADE) reports from the FAERS related to FQs drugs in patients aged 65 and older. The findings aim to guide the rational clinical use of these drugs in elderly patients. Methods We employed Reporting Odds Ratio (ROR) and Proportional Reporting Ratio (PRR) methods to analyze ADE reports for the representative FQ drugs from Q1 2015 to Q4 2023, covering 36 quarters. Results The analysis identified 6883 ADE cases for ciprofloxacin, 5866 for levofloxacin, 1498 for moxifloxacin, and 317 for ofloxacin. Moxifloxacin showed higher incidences of Cardiac disorders and Psychiatric disorders ADEs (4.01%, 23.11%). Ciprofloxacin and levofloxacin showed higher ADE rates in musculoskeletal and connective tissue diseases (20.18% and 26.97%) compared to moxifloxacin (3.62%) and ofloxacin (9.25%). Additionally, moxifloxacin and ofloxacin showed higher ADE rates for eye disorders (10.61% and 15.03%). Conclusion Different FQs exhibit varying ADE profiles across cardiovascular, vascular and lymphatic, renal and urinary, psychiatric, musculoskeletal and connective tissue, and ocular systems. Patients with underlying systemic diseases should avoid FQs with higher ADE risks for their conditions. Personalized medication plans for elderly patients should also be strengthened.

Association of anxiolytic drugs with Torsade de Pointes: a pharmacovigilance study of the Food and Drug Administration Adverse Event Reporting System.

This study aimed to determine the association of Torsade de Pointes (TdP) with anxiolytic drugs and present a detailed overview of anxiolytic-induced cases of TdP reported to the Food and Drug Administration Adverse Event Reporting System (FAERS). All cases of anxiolytic-induced TdP (n = 260) between 1990 and 2020 were retrieved from the FAERS database using the Preferred Term 'Torsade de Pointes, code: 10044066' from the Medical Dictionary for Regulatory Activities (MedDRA version 22). Four data-mining algorithms were used for disproportionality analysis: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC). Anxiolytics with ≥3 TdP cases were included. Of a total of eight drugs, this study identified seven signals of TdP, of which six signals were new, namely for alprazolam, bromazepam, lorazepam, meprobamate, midazolam, and oxazepam. Based on disproportionality analysis, among new signals, the highest risk of TdP was observed with bromazepam and midazolam. Alprazolam showed the lowest risk for TdP, while diazepam did not reach significant disproportionality. This study identified six new signals of TdP among anxiolytic drugs, so warranting stringent clinical studies to ascertain the actual risk of TdP and ensure patient safety. This study is registered at ClinicalTrials.gov (NCT.gov ID: NCT04293432).

The Incidence of Torsades de Pointes With Perioperative Triple Antiemetic Administration.

The safety of triple antiemetic therapy consisting of ondansetron, haloperidol, and a steroid, to surgical patients is unknown. To determine the incidence of torsade de pointes (TdP) or death following perioperative administration of triple antiemetic therapy. 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. 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). 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.

Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors.

During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.

Exploring the correlation between cardiovascular adverse events and antidepressant use: A retrospective pharmacovigilance analysis based on the FDA Adverse Event Reporting System database

BackgroundThe high comorbidity and mutually reinforcing relation between depression and cardiovascular disease have raised concerns about the cardiovascular risk of antidepressants. To gain a better understanding of this correlation, we performed a comprehensive evaluation regarding the types and degrees of cardiovascular adverse events (AEs) associated with 37 commonly prescribed antidepressants. MethodsAE reports from January 2004 to December 2023 were retrieved from the FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis was performed to identify antidepressant-related cardiovascular signals using the reporting odds ratio, proportional reporting ratio, and information component. Influencing factors of cardiovascular death, including age, sex, antidepressant choice, and concomitant medication, were explored. The underlying mechanisms of antidepressant-associated cardiovascular risk related to neurotransmitter transporters/receptors were further explored. ResultsThe use of antidepressants was associated with eight categories of Standardized MedDRA Queries of cardiovascular events. Different antidepressants exerted varying types and degrees of cardiovascular risks along with contributions to death in reports with cardiovascular AEs. Among them, monoamine oxidase inhibitors had the highest risk of developing six cardiovascular event categories: torsades de pointes (TdP)/QT prolongation, hypertension, cardiac arrhythmias, cardiomyopathy, pulmonary hypertension, and ischaemic heart disease. Age, male and the use of 24 types of antidepressants and concomitant medications were positively correlated with death in cardiovascular AEs. The highest risk associated with antidepressants was found in amoxapine (OR = 5.00 [2.13, 11.75], P < 0.001), followed by moclobemide (OR = 3.66 [1.85, 7.24], P < 0.001). Correlation analysis indicated the occurrence of antidepressant-related TdP/QT prolongation, hypertension and cardiomyopathy was associated with the binding and uptake inhibition of dopamine and norepinephrine transporters as well as their selectivity over serotonin transporters. ConclusionThe retrospective analysis revealed that cardiovascular AEs were connected with antidepressant use, and the binding/uptake inhibitory potency and selectivity of neurotransmitters of antidepressants played an important role, providing a preliminary basis for further in-depth study of antidepressant-related cardiovascular toxicity. However, as an exploratory study, prospective studies are needed to validate our findings in the future.