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Background: Severe QT interval prolongation requires monitoring QTc intervals during anaesthesia with recommended therapeutic interventions at a threshold of 500 ms. The need for 12‐lead ECG and lack of standardisation limit such monitoring. We determined whether automated continuous intraoperative QTc monitoring with 5‐lead ECG measures QTc intervals comparable to 12‐lead ECG and whether the interpretation of QTc intervals depends on the correction formulae and the patient's sex. We compared intraoperative QTc times to QTc times from resting ECGs of a population from the same region, to substantiate the hypothesis that patients under general anaesthesia may need specific treatment thresholds. Methods: In this prospective observational study, intraoperative QT/QTc intervals were automatically recorded using 12 and 5‐lead ECG in 100 patients (44% males). QTc values were analysed for sex and formula‐specific aspects after correction for heart rate according to Bazett, Fridericia, Hodges, Framingham, Charbit and QTcRAS, and compared to a regional community‐based cohort. The level of significance was set to α = 0.05. Results: QT interval duration was not significantly different between 12‐lead and 5‐lead ECG (difference − 0.09 ms ± 8.5 ms, p = 0.793). The QTc interval duration significantly differed between the correction formulae (p < 0.001) and between sexes (p < 0.001). Mean intraoperative QTc duration was higher than in resting ECGs from a large community‐based population with the same regional background (438 vs. 417 ms). The incidence of prolonged values >500 ms significantly depended on the correction formula (p < 0.001) and was up to tenfold higher in women versus men. Conclusion: Intraoperative QTc interval measurement using a 5‐lead ECG is valid. Correction formulae and gender influence the intraoperative QTc interval duration and the incidence of pathologically prolonged values according to current limits. The consideration and definition of sex‐specific normal limits for QTc times under general anaesthesia, therefore, warrant further investigation. [ABSTRACT FROM AUTHOR]

Introduction: Early‐onset atrial fibrillation (AF) has already been observed in approximately 2% of patients with genetically proven long QT syndrome (LQTS). This frequency is higher than population‐based estimates of early‐onset AF. However, the concomitant expression of AF in LQTS is likely underestimated. The purpose of this study was to examine the clinical presentation, genetic background, and outcomes of a cohort of patients with LQTS and early‐onset AF referred to a single tertiary center. Methods: Twenty‐seven patients diagnosed with congenital LQTS were included in the study based on the documentation of early‐onset (age ≤50 years) clinical or subclinical AF episodes in all available medical records, including standard electrocardiograms, wearable monitor or cardiac implantable electronic devices. Results: Seventeen patients experienced clinical AF during the follow‐up period. Subclinical AF was detected in 10 patients through insertable or wearable cardiac monitors. In our series, the mean heart rate during AF episodes was found to be relatively low despite the patients' young age and the low or minimal effective doses of beta‐blockers used for QTc interval control. All patients exhibiting LQTS and early‐onset AF were genotype positive, carrying mutations in the KCNQ1 (66%), KCNH2, KCNE1, and SCN5A genes. Notably, most of these patients carried the same p.(R231C) mutation in the KCNQ1 gene (59%) and were from the same families, suggesting concurrent expression of familial AF and LQTS. Conclusion: LQTS patients are prone to developing clinical and subclinical AF, even at a younger age. The occurrence of early‐onset AF in the LQTS population could be more frequent than previously assumed. AF should be considered as a potential dysrhythmia related to LQTS. Our study emphasizes the importance of carefully researching clinical and/or subclinical episodes of AF through strict heart rhythm monitoring in the LQTS population. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors (ChEIs) are regularly used in Alzheimer's disease. Of the three ChEIs approved for dementia, donepezil is among the most prescribed drugs in the United States with nearly 6 million prescriptions in 2020; however, it is classified as a "known risk" QT interval‐prolonging medication (QTPmed). Given this claim is derived from observational data including single case reports, we aimed to evaluate high‐quality literature on the frequency and nature of proarrhythmic major adverse cardiac events (MACE) associated with donepezil. Methods: We searched Medline, Embase, International Pharmaceutical Abstracts, and Cochrane Central from 1996 onwards for randomized controlled trials (RCTs) involving patients age ≥18 years comparing donepezil to placebo. The MACE composite included mortality, sudden cardiac death, non‐fatal cardiac arrest, Torsades de pointes, ventricular tachyarrhythmia, seizure or syncope. Random‐effects meta‐analyses were performed with a treatment‐arm continuity correction for single and double zero event studies. Results: Sixty RCTs (n = 12,463) were included. Twenty‐five of 60 trials (n = 5886) investigated participants with Alzheimer's disease and 33 trials monitored electrocardiogram data. The mean follow‐up duration was 31 weeks (SD = 36). Mortality was the most commonly reported MACE (252/331, 75.8% events), the remainder were syncope or seizures, with no arrhythmia events. There was no increased risk of MACE with exposure to donepezil compared to placebo (risk ratio [RR] 1.08, 95% CI 0.88–1.33, I2 = 0%) and this was consistent in the subgroup analysis of trials including participants with cardiovascular morbidities (RR 1.14, 95% CI 0.88–1.47). Subgroup analysis suggested a trend toward more events with donepezil with follow‐up ≥52 weeks (RR: 1.32, 0.98–1.79). Conclusions: This systematic review with meta‐analysis found donepezil may not be arrhythmogenic. Donepezil was not associated with mortality, ventricular arrhythmias, seizure or syncope, although longer durations of therapy need more study. Further research to clarify actual clinical outcomes related to QTPmed is important to inform prescribing practices. [ABSTRACT FROM AUTHOR]

Aims: Patients with solid tumours were treated with the anti‐PD‐1 antibody dostarlimab in the Phase I GARNET trial. This study aimed to examine dostarlimab's effect on corrected QT (QTc) interval and the systemic concentration–QTc interval relationship. Methods: In GARNET Part 2B, patients received 500 mg dostarlimab every 3 weeks (Q3W) for four cycles, then 1000 mg Q6W. Triplicate 12‐lead ECGs were recorded and time‐matched pharmacokinetic (PK) samples collected at screening, on Day 1 of Cycles 1, 4, 5, 8, 12 (pre‐dose and 0.5 h after infusion end), and at treatment end. Concentration–change from baseline QTcF (ΔQTcF) analysis using a linear mixed effects model, summary statistics, incidence of clinically noteworthy ECG values and rhythm abnormalities were evaluated. Results: A total of 377 patients were considered for evaluation (n = 15 excluded from concentration–ΔQTcF). There was a non‐significant concentration–ΔQTcF relationship (0.001589 ms/μg/mL; P =.5906). Mean ΔQTcF increase was <6 ms (upper‐bound two‐sided 90% confidence interval [CI], <10 ms at all post‐dose timepoints). Highest geometric mean concentration was 414.1 μg/mL (Cycle 5 Day 1, 0.5 h) with predicted mean ∆QTcF of 3.064 ms (upper‐bound two‐sided 90% CI: 5.071). Mean QTcF prolongation (all concentrations) was 2.4 ms. QTcF prolongation ≥500 ms occurred in five patients (1.3%); 51 (13.6%) and nine patients (2.4%) had ΔQTcF ≥30 ms and ≥60 ms, respectively. Ten patients (2.7%) reported rhythm abnormalities. No U‐wave abnormalities, torsades de pointes, ventricular tachycardia or ventricular fibrillation/flutter were observed. Conclusions: Dostarlimab does not cause clinically significant QTcF prolongation exceeding the regulatory concern threshold. [ABSTRACT FROM AUTHOR]

Aims: Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation. Methods: Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated. Results: A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6–30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI = 7.1–28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI = 1.3–7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI = 0.8–4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1–488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI = 3.4–5.3) and 1.2 (95% CI = 0.8–1.6), respectively. Conclusion: The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD. [ABSTRACT FROM AUTHOR]

Levetiracetam (LEV), a well‐established anti‐seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to “pressure test” the CiPA approach with LEV and check the concordance of nonclinical core and follow‐up S7B assays with clinical and post‐marketing data. The following experiments were conducted with LEV (0.25–7.5 mM): patch clamp assays on hERG (acute or trafficking effects), NaV1.5, CaV1.2, Kir2.1, KV7.1/mink, KV1.5, KV4.3, and HCN4; in silico electrophysiology modeling (Virtual Assay® software) in control, large‐variability, and high‐risk human ventricular cell populations; electrophysiology measurements in human induced pluripotent stem cell (hiPSC)‐derived cardiomyocytes and dog Purkinje fibers; ECG measurements in conscious telemetered dogs after single oral administration (150, 300, and 600 mg/kg). Except a slight inhibition (<10%) of hERG and KV7.1/mink at 7.5 mM, that is, 30‐fold the free therapeutic plasma concentration (FTPC) at 1500 mg, LEV did not affect any other cardiac channels or hERG trafficking. In both virtual and real human cardiomyocytes, and in dog Purkinje fibers, LEV induced no relevant changes in electrophysiological parameters or arrhythmia. No QTc prolongation was noted up to 2.7 mM unbound plasma levels in conscious dogs, corresponding to 10‐fold the FTPC. Nonclinical assessment integrating CiPA assays shows the absence of QT prolongation and proarrhythmic risk of LEV up to at least 10‐fold the FTPC and the good concordance with clinical and postmarketing data, although this does not exclude very rare occurrence of QT prolongation cases in patients with underlying risk factors.Levetiracetam (LEV) QT‐ogram illustrates that no biologically relevant changes (>10% or 10 ms) in QT‐related biomarkers occur up to 10‐ to 30‐fold its free therapeutic plasma concentration (FTPC) in core and follow‐up CiPA/S7B nonclinical assays, and the good concordance of this nonclinical dataset with clinical data (TQT study). [ABSTRACT FROM AUTHOR]

Although metoclopramide has many adverse effects, torsade de pointes (TdP) is rare. We describe a fatal case of repeated ventricular fibrillation due to TdP following repeated administration of metoclopramide. Administration of multiple doses of metoclopramide over a short time to a patient with risk factors for TdP should be avoided. [ABSTRACT FROM AUTHOR]

We report a 28‐year‐old female patient with congenital type 2 long QT syndrome (LQTS) in which mexiletine shortened corrected QT interval (QTc) and effectively prevented refractory Torsade de Pointes (TdP) and ventricular fibrillation (VF). She developed TdP and VF, and was subsequently diagnosed with congenital type 2 LQTS. She had refractory TdP and VF every day despite medical therapy including β‐blocker. They were completely suppressed after the initiation of mexiletine with shorting of QTc interval. [ABSTRACT FROM AUTHOR]

Takotsubo cardiomyopathy (TCM) causes QT interval prolongation, potentially leading to a fatal arrhythmia. We report the first case of TCM associated with licorice‐induced pseudoaldosteronism causing fatal arrhythmia in an older patient on polypharmacy including yokukansan (TJ‐54) and galantamine. Polypharmacy should be resolved to prevent unexpected adverse events in older patients. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism predisposes patients to hypocalcemia. Patients with hypoparathyroidism are thus at risk of electrocardiographic abnormalities, including T‐wave alternans. T‐wave alternans is poorly understood and lacks uniform diagnostic criteria. Its presence suggests myocardial electrical instability, and it has become an important sign for identifying patients at high risk of malignant arrhythmias and sudden cardiac death. We report a rare case of T‐wave alternans with torsade de pointes due to hypocalcemia. The etiology of T‐wave alternans may easily be overlooked. It should thus be thoroughly investigated to avoid misdiagnosis and poor outcomes. [ABSTRACT FROM AUTHOR]

Drug‐induced QT prolongation, primarily antiarrhythmic drugs, is a common cause of torsade de pointes (TdP). Although there have been previous reports of drug‐induced TdP in patients, it has not been well documented when caused by citalopram during the pacemaker battery‐depletion phase. To improve delirium recognition, we report a case of citalopram‐induced TdP during the pacemaker battery‐depletion phase. An 84‐year‐old Chinese female was brought to the hospital presenting recurrent syncope. She lost consciousness and was admitted after her syncope TdP was documented. Her pacemaker was inspected and found to be operating in an extremely ineffective manner. Although she had prolonged QT interval after the pacemaker was replaced, she did not suffer another syncope attack, and ECG monitoring revealed no cardiac arrhythmia or TdP. During her admission, she was treated with citalopram for depression. Citalopram was discontinued when the QT interval shortened progressively. In this study, we described a case of citalopram‐induced TdP during the depletion phase of a pacemaker battery. This case should serve as a cautionary lesson to clinicians to avoid using citalopram during the pacemaker battery‐depletion phase. [ABSTRACT FROM AUTHOR]

The author discusses a study by K. A. Marill and colleagues in the issue which showed that some of the electrocardiographic (ECG) parameters accepted as high-risk markers for imminent torsade-de-pointes, are not as reliable as expected. Patients and controls in the study were matched for age, gender, and heart rate. Also cited are the influence of gender on risk, lessons to be learned from the study, and difficulties in predicting torsade-de-pointes in patients with QT prolongation.

Background: TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. Objective: Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real‐world healthcare setting. Methods: Case–control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow‐up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. Results: A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non‐white. The independent predictors of TdP were potassium concentration <3.6 mEq/L (OR = 10.6), prior history of atrial fibrillation/flutter (OR = 6.2), QTc >480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in‐hospital and 1‐year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. Conclusions: These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy. [ABSTRACT FROM AUTHOR]

An elderly Japanese woman developed acute decompensated heart failure caused by persistent atrial fibrillation (AF) and left ventricular systolic dysfunction. Approximately 6 days after starting intravenous administration of amiodarone (600 mg/day) for maintaining sinus rhythm after cardioversion of AF, electrocardiograms revealed a prolonged QT interval associated with torsade de pointes (TdP). The amiodarone-induced TdP disappeared after intravenous administration of landiolol plus magnesium and potassium, without discontinuation of amiodarone or overdrive cardiac pacing, although the prolonged QT interval persisted. To the best of our knowledge, this is the first report that landiolol could be effective for amiodarone-induced TdP. [ABSTRACT FROM AUTHOR]

Many volatile chemicals inhaled for a recreational high have a chemical structure similar to chloroform and may lead to Ikr blockade and subsequent torsades de pointes. This is one potential mechanism of action for huffing-associated sudden death. [ABSTRACT FROM AUTHOR]

Introduction: For patients using QTc prolonging medications, the health care system is challenged to mitigate the risk of drug‐induced long‐QT syndrome (DiLQTS) and sudden cardiac death (SCD). Community pharmacists (CPs) receive QTc alerts when dispensing but intervene infrequently. Personal electrocardiogram (ECG) monitors are a new, inexpensive technology that could provide additional patient risk information to identify individuals with a prolonged QTc interval in real time. Objectives: (1) Describe QTc interval‐prolonging medications, QTc interval calculations, and associated interventions and prescriber responses for a CP‐delivered QTc interval assessment program, and (2) Describe patient satisfaction with the service. Methods: A prospective study of 9‐month duration in three community pharmacies in Iowa. CPs were trained to measure QTc interval using the KardiaMobile ECG monitor. English‐speaking patients aged ≥18 years were recruited to have a 30 seconds ECG tracing if the CP received a computer QTc‐related alert or had concern about QTc effect/interaction. CPs used professional judgment regarding prescriber contact but were required to contact the prescriber if the QTc interval was prolonged (>470 ms males, >480 ms females). Results: There were 53 patients who met study criteria and participated in the service. Mean age was 55.1 years, 38 (72%) were female, and 19 (36%) received newly prescribed QTc interval‐prolonging medications. A computer‐generated QTc alert was present for 36 (68%) of participants. CPs contacted a prescriber for 6 (11%) patients regarding concern for DiLQTS (mean QTc 495 ms). Of these six instances, three had QTc prolongation requiring mandatory prescriber contact (mean QTc 529 ms). Prescriber contact resulted in medication changes for 3 (50%) patients. Conclusion: CPs were able to measure QTc interval, identify patients at risk for DiLQTS, and make accepted medication therapy recommendations related to QTc prolongation. CP assessment of QTc interval may be a useful approach to improve risk stratification of individuals at risk of DiLQTS and SCD. Trial registration: Clinical Trials.gov Identifier: NCT04000542. [ABSTRACT FROM AUTHOR]

We report a 77‐year‐old human on renal dialysis for end‐stage renal disease with heart failure and atrial fibrillation (AF) complicated by a high ventricular frequency. The underlying disease was thought as tachycardia‐induced‐cardiomyopathy. Intravenous infusion of amiodarone was initiated, and direct current cardioversion succeeded in converting AF to sinus rhythm. Then, excessive increases in the QT and Tpeak‐Tend (Tp‐e) intervals were seen and hypokalemia induced by hemodialysis led to the development of numerous episodes of torsades de pointes (TdP). Magnesium repletion was effective in preventing TdP, while Tp‐e intervals returned to the previous values 2 days after the discontinuation of amiodarone. [ABSTRACT FROM AUTHOR]

QTc interval prolongation can lead to life‐threatening complications such as Torsade de Pointes (TdP), ventricular tachycardia (VT) and sudden cardiac death (SCD). It can occur with tyrosine kinase inhibitors (TKIs) but comparative real‐world analyses on the incidence and complication rates are scarce. We retrospectively reviewed all cancer patients treated with TKI therapy at Mayo Clinic between January 2005 and December 2018 and had at least two ECGs (before and after TKI). For each TKI type, we determined the administration rate and incidence of QTc prolongation. QTc prolongation was defined as a corrected QT interval (by Fridericia formula) ≥450 ms in men and ≥470 ms in women. A total of 618 cancer patients were included with 902 TKI administrations, of which 654 (72.5%) were accounted for by pazopanib, sunitinib, imatinib, nilotinib and dasatinib. QTc prolongation (any grade) was reported in 28.8%, most commonly with nilotinib (38.7%) and dasatinib (41.7%). A QTc interval ≥500 ms and a QTc increase ≥60 ms was documented in 46 and 63 administrations, respectively. Life‐threatening toxicity was seen in 14 cases (5.4% of QTc prolongation cases) including VT in 9, SCD in 3 and TdP in two administrations. The response to QTc prolongation was: discontinuation in 68%, dose reduction in 13.5%, temporary hold in 8.1% and no action in 10.4%. In conclusion, QTc prolongation with TKI therapy is very common (∼1/3 of cases) and in 5% (1.7% overall) associated with life‐threatening complications. These data support recommendations for careful ECG monitoring in cancer patients undergoing TKI therapy. What's new?: While tyrosine kinase inhibitors (TKIs) are superior cancer therapies and increase the efficacy of classical chemotherapeutics, significant toxicities limit their use. Among these, QTc prolongation represents a major concern, though real‐world clinical data are sparse. Here, among 618 cancer patients treated with TKIs at the Mayo Clinic, approximately one‐third experienced QTc prolongation, and this was noted in particular with BCR‐ABL and VEGF TKIs. Overall, high‐grade QTc prolongations were observed in one‐fifth of patients. About 5 percent of patients had life‐threatening complications. These data highlight the importance of QTc interval monitoring and reduction of contributing factors during TKI therapy. [ABSTRACT FROM AUTHOR]

Computer-generated Bazett-corrected QT (QTcB) algorithms are common in clinical practice and can rapidly identify repolarization abnormalities, but accuracy is variable. This report highlights marked rate-corrected QT (QTc) interval prolongation not detected by the computer algorithm. A 26-year-old woman with anorexia nervosa was admitted with severe hypokalemia and ventricular ectopy. Computer-generated QTcB was 485 ms, while manual adjudication yielded a QTcB of 657 ms and a Fridericia-corrected QT (QTcF) interval of 626 ms using digital calipers. Computer-generated QTc intervals may aid in clinical decision-making. However, accuracy is variable, particularly in the setting of ectopy, and requires manual verification. [ABSTRACT FROM AUTHOR]

Background: Torsade de pointes is a form of polymorphic ventricular tachycardia associated with heart rate–corrected QT (QTc) interval prolongation. With approximately 24–61% of critically ill patients experiencing QTc interval prolongation, a predictive tool to identify high‐risk patients could assist in the monitoring and management in the intensive care unit (ICU). The Tisdale et al. Risk Score (TRS) is a predictive tool that was developed and validated in a cardiac critical care unit. Objectives: The objective of this study was to evaluate the predictive validity (sensitivity and specificity) and likelihood ratios of the TRS in a medical ICU. Methods: This was a longitudinal, retrospective, cohort study of consecutive patients who met the inclusion criteria from October 2017 to June 2018 with a sample size of 264 patients. The sample size was derived based on the number of TRS covariates and an exploratory variable. Baseline characteristics and risk factors were documented from electronic health records. The first occurrence of QTc interval prolongation, defined as a QTc interval > 500 ms or an increase ≥ 60 ms above baseline, was the primary endpoint. Main Results: The sensitivity and specificity of the TRS for low‐risk patients against the moderate‐risk and high‐risk patients were 97% (95% CI 91–99%) and 16% (95% CI 11–23%), respectively. These results corresponded to a positive likelihood ratio of 1.15 (95% CI 1.07–1.24) and a negative likelihood ratio of 0.20 (95% CI 0.06–0.65). Conclusions: In conclusion, the TRS showed a high sensitivity, making it useful in identifying patients at risk of developing QTc interval prolongation. Furthermore, patients categorized as low risk by the tool can be considered as having minimal risk of developing QTc interval prolongation. Given the tool's low specificity, it does not reliably identify all patients at low risk of QTc interval prolongation. [ABSTRACT FROM AUTHOR]

A 23‐year‐old female had been suffering from recurrent syncopal episodes during sleep since her childhood. She had a family history of sudden death and her QTc interval was remarkably prolonged to 537 ms A Holter ECG revealed torsade de pointes, corresponding to syncope. She was started on mexiletine and her QTc interval shortened. Her symptoms were controlled after β‐blockers and Ca‐blockers were added. A genetic analysis with a next generation sequencer identified a frameshift mutation at the C terminus of the KCNH2 gene. Here we present a type 2 long QT syndrome case in which mexiletine was effective. [ABSTRACT FROM AUTHOR]

The antidiarrheal over‐the‐counter drug loperamide is increasingly being used to control opioid withdrawal or for opioid abuse. Taking many times above the normally recommended dose is dangerous with cardiovascular, respiratory, and neurological adverse events. Cytochrome P‐450 (CYP)2C8, CYP3A, and P‐glycoprotein inhibitors can increase the plasma and central nervous system concentrations and radically alter the risk profile of loperamide. Online forums suggest using over‐the‐counter metabolic enzyme blockers to enhance the effects. Public health options include switching over‐the‐counter loperamide to blister packs (the FDA‐preferred method), making loperamide only available by prescription, or moving the product behind the pharmacy counter. Although naloxone may ameliorate the neurological and respiratory adverse events, it is ineffective at reversing loperamide‐induced arrhythmias. Even magnesium might provide less efficacy in loperamide‐induced Torsade de Pointes necessitating the use of cardiac pacing and electrical cardioversion. [ABSTRACT FROM AUTHOR]

BACKGROUND: The exponential increase in the number of medications associated with clinically important prolongation of the heart rate‐corrected QT interval (QTc) places older adults at increased risk of arrhythmias including life‐threatening torsade de pointes (TdP) and sudden death. Risk factors, other than age older than 65 years and female sex, include multiple concurrent drugs that prolong QTc and a variety of underlying predisposing conditions. Although electronic medical records and pharmacy dispensing systems can alert clinicians to the risk of QTc‐prolonging therapy, more than 95% of safety alerts are overridden, and many systems have deactivated QTc drug interaction alerts. The clinical consequences, magnitude of the effect, mitigation strategies, and recommended monitoring are not well defined for nursing facility (NF) residents. DESIGN: Narrative review. SETTING: NFs in the United States. PARTICIPANTS: NF residents. RESULTS: Medications known to prolong QTc include selected anti‐infectives, antidepressants, urinary anticholinergics, antipsychotics, and cholinesterase inhibitors (eg, donepezil), used commonly in NFs. Drug‐drug interactions are a risk when adding a medication that exaggerates the effect or inhibits the metabolism of a QTc‐prolonging medication. The vast majority of patients in whom TdP is induced by noncardiac drugs have risk factors that are easily identifiable. CONCLUSIONS: Recommendations are provided to improve standardization and use of drug interaction alerts, evaluate the risk of QTc‐prolonging drugs in older adults receiving generally lower doses, validate a QTc risk score addressing complex multimorbidity, garner evidence to guide clinical decision making, avail NFs of access to electrocardiograms and interpretive recommendations, and develop standards of practice for hosting risk discussions with residents and their families. J Am Geriatr Soc, 1–8, 2019. [ABSTRACT FROM AUTHOR]

The article offers information on case study of 2-year-old boy visited hospital because he suffered from bronchitis. It mentions the patient's bradycardia; performed an electrocardiogram (ECG) and significant bradycardia and QT prolongation were confirmed. A medical history taken from the mother revealed that she was found to be positive for the anti-Ro/SSA antibody and the patient had been noted as having severe bradycardia during fetal period in another institution.

Prolongation of the heart rate–corrected QT (QTc) interval increases the risk for torsade de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors that include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of two or more QTc interval‐prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP. Investigators have utilized the field of predictive analytics, which generates predictions using techniques including data mining, modeling, machine learning, and others, to develop methods of risk quantification and prediction of QTc interval prolongation. Predictive analytics have also been incorporated into clinical decision support (CDS) tools to alert clinicians regarding patients at increased risk of developing QTc interval prolongation. The objectives of this article are to assess the effectiveness of predictive analytics for identification of patients at risk of drug‐induced QTc interval prolongation and to discuss the efficacy of incorporation of predictive analytics into CDS tools in clinical practice. A systematic review of English‐language articles (human subjects only) was performed, yielding 57 articles, with an additional 4 articles identified from other sources; a total of 10 articles were included in this review. Risk scores for QTc interval prolongation have been developed in various patient populations including those in cardiac intensive care units (ICUs) and in broader populations of hospitalized or health system patients. One group developed a risk score that includes information regarding genetic polymorphisms; this score significantly predicted TdP. Development of QTc interval prolongation risk prediction models and incorporation of these models into CDS tools reduce the risk of QTc interval prolongation in cardiac ICUs and identify health system patients at increased risk for mortality. The impact of these QTc interval prolongation predictive analytics on overall patient safety outcomes, such as TdP and sudden cardiac death relative to the cost of development and implementation, requires further study. [ABSTRACT FROM AUTHOR]

Key points: T‐wave alternans (TWA) and T‐wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre‐existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re‐entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. Abstract: T‐wave alternans (TWA) and irregular beat‐to‐beat T‐wave variability or T‐wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization‐mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre‐existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L, resulted in a tissue‐scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re‐entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate‐induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions. [ABSTRACT FROM AUTHOR]

Abstract: Since its initial description by Jervell and Lange‐Nielsen in 1957, the congenital long QT syndrome (LQTS) has been the most investigated cardiac ion channelopathy. Although congenital LQTS continues to remain the domain of cardiologists, cardiac electrophysiologists, and specialized centers, the by far more frequent acquired drug‐induced LQTS is the domain of all physicians and other members of the health care team who are required to make therapeutic decisions. This report will review the electrophysiological mechanisms of LQTS and torsade de pointes, electrocardiographic characteristics of acquired LQTS, its clinical presentation, management, and future directions in the field. [ABSTRACT FROM AUTHOR]

Rationale, aims, and objectives Prolongation of the corrected QT (QTc) interval is associated with increased morbidity and mortality. The association between QTc interval-prolonging medications (QTPMs) and risk factors with magnitude of QTc interval lengthening is unknown. We examined the contribution of risk factors alone and in combination with QTPMs to QTc interval lengthening. Method The Atherosclerosis Risk in Communities study assessed 15 792 participants with a resting, standard 12-lead electrocardiogram and ≥1 measure of QTc interval over 4 examinations at 3-year intervals (1987-1998). From 54 638 person-visits, we excluded participants with QRS ≥ 120 milliseconds (n = 2333 person-visits). We corrected the QT interval using the Bazett and Framingham formulas. We examined QTc lengthening using linear regression for 36 602 person-visit observations for 14 160 cohort members controlling for age ≥ 65 years, female sex, left ventricular hypertrophy, QTc > 500 milliseconds at the prior visit, and CredibleMeds categorized QTPMs (Known, Possible, or Conditional risk). We corrected standard errors for repeat observations per person. Results Eighty percent of person-visits had at least one risk factor for QTc lengthening. Use of QTPMs increased over the 4 visits from 8% to 17%. Among persons not using QTPMs, history of prolonged QTc interval and female sex were associated with the greatest QTc lengthening, 39 and 12 milliseconds, respectively. In the absence of risk factors, Known QTPMs and ≥2 QTPMs were associated with modest but greater QTc lengthening than Possible or Conditional QTPMs. In the presence of risk factors, ≥2 QTPM further increased QTc lengthening. In combination with risk factors, the association of all QTPM categories with QTc lengthening was greater than QTPMs alone. Conclusion Risk factors, particularly female sex and history of prolonged QTc interval, have stronger associations with QTc interval lengthening than any QTPM category alone. All QTPM categories augmented QTc interval lengthening associated with risk factors. [ABSTRACT FROM AUTHOR]

Background Due to its availability, atenolol is the primary beta-blocker used in Australia for children with long QT syndrome. There is limited data on long-term follow-up of its use. Methods A single-tertiary-center, retrospective, observational study investigating all children and adolescents who had genetically proven long QT syndrome type 1 (LQT1) and type 2 (LQT2) was conducted. Their pretreatment exercise tests were evaluated for QTc intervals into the recovery phase of exercise. Results Eighty six patients were identified (LQT1, 67, and LQT2, 19) from 2004 to 2014. The majority (86%) of patients were initially referred for family screening. Atenolol was administered at a mean dose of 1.58 ± 0.51 mg/kg/day. During the median follow-up period of 4.29 years, only one proband developed ventricular arrhythmia whilst taking atenolol, No patient had cardiac arrest or aborted cardiac arrest. With respect to side effects of atenolol, only two patients had intolerable side effects necessitating changes of medication. Evaluation of exercise tests (pretreatment) demonstrated that corrected QT (QTc) intervals at 2–3 min into the recovery phase of exercise were significantly prolonged for LQT1 patients. LQT1 patients with transmembrane mutation had longer QTc intervals than their C-terminus mutation counterparts, reaching statistical significance at 3 min into the recovery phase of exercise. Conclusions Atenolol is an effective treatment for genetically proven LQT1 and LQT2 children and adolescents, with good tolerability. In LQT1 patients, QTc intervals at 2–3 min into the recovery phase of exercise were significantly prolonged, particularly in patients with transmembrane mutations. [ABSTRACT FROM AUTHOR]

A 76-year-old man who had been diagnosed with long-QT syndrome type 2 had frequent syncopal attacks. The electrocardiogram was monitored, and frequent torsades de pointes (TdP) was detected despite administration of conventional medications: oral propranolol, verapamil, intravenous magnesium sulfate, verapamil, and lidocaine. In contrast, 2 μg/kg/min landiolol could completely suppress TdP. Subsequently, an implantable cardioverter defibrillator was placed, and he was diagnosed with silent myocardial ischemia using myocardial perfusion scintigraphy and coronary angiography. This is the first case report wherein landiolol effectively suppressed TdP due to long-QT syndrome with silent myocardial ischemia. [ABSTRACT FROM AUTHOR]

Inhibition of the human ether-a-go-go-related gene (hERG) K+ channel by drugs leads to QT prolongation on the electrocardiogram and can result in serious cardiac arrhythmia. For this reason, screening of drugs on hERG is mandatory during the drug development process. Patch clamp electrophysiology in a defined physiological saline solution (PSS) represents the standard method for assaying drug effects on the channel. To make the assay more translatable to clinical studies, we have conducted whole-cell patch clamping of hERG using pure human serum as the extracellular medium. Pure human serum had little effect on the hERG channel waveform or the current-voltage relationship when compared to PSS. hERG current recordings were highly stable in serum at room temperature, but prolonged recordings at the physiological temperature required prior heat inactivation of the serum. Compared to PSS, the IC50 values, conducted at room temperature, of the classic hERG blocking drugs cisapride, moxifloxacin, and terfenadine were shifted to the right by an extent predicted by their known plasma protein binding, but we did not detect any differences in IC50s between male and female serum. Total plasma levels of these drugs associated with clinical QT prolongation corresponded to small (<15%) inhibition of hERG current in pure serum suggesting that minor inhibition of the channel leads to observable pharmacodynamic effects. Conducting whole-cell patch clamping of hERG in human serum has the potential to make the assay more translatable to clinical studies and improve its predictive value for safety testing. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims: Few studies have investigated linezolid (LZD)-associated cardiotoxicity. This study explored the potential association between LZD and QT interval prolongation., Methods: Adverse event reports of QT interval prolongation associated with LZD from the Food and Drug Administration Adverse Event Reporting System from January 2013 to December 2021 were analysed and the reporting odds ratio (ROR) with 95% confidence intervals were calculated., Results: A total of 6738 adverse event reports of LZD as the primary and secondary suspected drug were obtained from the database, including 192 reports with electrocardiogram QT prolonged (QTp), and the ROR value was 26.1 (95% CI = 22.6-30.2). There were 8 reports of long QT syndrome, ROR 14.2 (95% CI = 7.1-28.5); 5 reports of torsade de pointes, ROR 3.2 (95% CI = 1.3-7.6); and 5 reports of ventricular tachycardia, ROR 1.9 (95% CI = 0.8-4.5). Subgroup analysis revealed that patients with tuberculosis treated with LZD had a higher reporting rate among all QTp reports, exhibiting an odds ratio of 330.0 (95% CI = 223.1-488.1). The odds ratios of QTp associated with LZD treatments in patients with and without tuberculosis were 4.2 (95% CI = 3.4-5.3) and 1.2 (95% CI = 0.8-1.6), respectively., Conclusion: The study showed an association between LZD and QT interval prolongation. In the report on patients with tuberculosis, the incidence of QTp was higher when treated with LZD., (© 2022 British Pharmacological Society.)

Efavirenz Induced QTc Interval Prolongation Background Efavirenz (EFV) has been associated with torsade de pointes despite marginal QT interval lengthening. Since EFV is metabolized by the cytochrome P450 (CYP) 2B6 enzyme, we hypothesized that EFV would lengthen the rate-corrected QT (QTcF) interval in carriers of the CYP2B6*6 decreased functional allele. Objective The primary objective of this study was to evaluate EFV-associated QT interval changes with regard to CYP2B6 genotype and to explore mechanisms of QT interval lengthening. Methods EFV was administered to healthy volunteers (n = 57) as a single 600 mg dose followed by multiple doses to steady-state. Subjects were genotyped for known CYP2B6 alleles and ECGs and EFV plasma concentrations were obtained serially. Whole-cell, voltage-clamp experiments were performed on cells stably expressing hERG and exposed to EFV in the presence and absence of CYP2B6 expression. Results EFV demonstrated a gene-dose effect and exceeded the FDA criteria for QTcF interval prolongation in CYP2B6*6/*6 carriers. The largest mean time-matched differences ∆∆QTcF were observed at 6 hours (14 milliseconds; 95% CI [1; 27]), 12 hours (18 milliseconds; 95% CI [-4; 40]), and 18 hours (6 milliseconds; 95% CI [-1; 14]) in the CYP2B6*6/*6 genotype. EFV concentrations exceeding 0.4 μg/mL significantly inhibited outward hERG tail currents (P < 0.05). Conclusions This study demonstrates that homozygous carriers of CYP2B6*6 allele may be at increased risk for EFV-induced QTcF interval prolongation via inhibition of hERG. [ABSTRACT FROM AUTHOR]

Abstract: We present a case of sudden cardiac arrest 7 hours after radiofrequency ablation of the atrioventricular junction for symptomatic permanent atrial fibrillation unresponsive to medical therapy. The Holter monitoring revealed a progressive increasing of QT interval after the procedure, highlighting the repolarization instability after acute changes in heart rates associated with modification of ventricular activation, leading to occurrence of short coupling interval ventricular extra beats and finally to a “torsade de pointes.” This illustration underlines the need to program a relatively rapid ventricular rate first weeks after junction ablation, especially in case of rapid ventricular rate prior to the procedure, as well as the role of continuous ECG and QT interval monitoring during hospital stay. [ABSTRACT FROM AUTHOR]

Background: Little is known about time-dependent changes in QT dynamics after initiation of atrial fibrillation (AF) and after restoration of sinus rhythm (SR) in patients with paroxysmal AF. Methods: Beat-to-beat QT and RR intervals in CM5 lead were measured automatically in 13 patientswith both AF and SR on the single 24-hour Holter electrocardiology recording. QT-RR relation was analyzed at six periods of time: 1 hour before AF onset (Pre0-1h), 0-1 hour and 4-5 hours after AF onset (AF0-1h and AF4-5h), and 0-1 hour, 2-3 hours, and 4-5 hours after the restoration of SR (SR0-1h, SR2-3h, and SR4-5h). Results: QT-RR slope was gradually decreased after AF onset and gradually returned to the baseline level after restoration of SR. The slope became greater at SR4-5h than at AF4-5h and AF0-1h. In patients receiving antiarrhythmic drugs (AADs; n=5), QT-RR slope was greater at SR4-5h than in those not receiving AADs (n = 8). Conclusion: In patients with paroxysmal AF, bradycardia-dependent QT prolongation was attenuated during AF, and was corrected and gradually augmented along with continuation of SR, especially in patients receiving AADs. This could increase the risk of developing torsade de pointes. [ABSTRACT FROM AUTHOR]

Aim To assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, corrected QT interval (QTc) prolongation or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone. Design Retrospective pharmacoepidemiological study. Setting Adverse drug events reported spontaneously to the FDA between 1969 and June 2011 originating in 196 countries (71% events from the United States). Cases Adverse event cases mentioning methadone ( n = 14 915) or buprenorphine ( n = 7283) were evaluated against all other adverse event cases ( n = 4 796 017). Measurements The primary outcome was the composite of ventricular arrhythmia or cardiac arrest. The secondary outcome was the composite of QTc prolongation or torsade de pointes. The proportional reporting ratio (PRR) was used to identify disproportionate reporting defined as a PRR > 2, χ2 error > 4, with ≥ 3 cases. Findings There were 132 (1.8%) ventricular arrhythmia/cardiac arrest and 19 (0.3%) QTc prolongation/torsade de pointes cases associated with buprenorphine compared with 1729 (11.6%) ventricular arrhythmia/cardiac arrest and 390 (2.6%) QTc prolongation/torsade de pointes cases involving methadone. PRRs associated with buprenorphine were not significant for ventricular arrhythmia/cardiac arrest (1.10, 95%, confidence interval (0.93-1.31, χ2 = 1.2) or QTc prolongation/torsade de pointes (1.03, 95% CI = 0.66-1.62, χ2 = 0.01), but were for methadone (7.20, 95% CI = 6.88-7.52, χ2 = 8027; 10.7, 95% CI = 9.66-11.8, χ2 = 1538, respectively). Conclusion In spontaneously reported adverse events, methadone is associated with disproportionate reporting of cardiac arrhythmias, whereas buprenorphine is not. Although these findings probably reflect clinically relevant differences, a causal connection cannot be presumed and disproportionality analysis cannot quantify absolute risk per treatment episode. Population-based studies to definitively quantify differential incidence rates are warranted. [ABSTRACT FROM AUTHOR]

Dronedarone is a promising, relatively new antiarrhythmic agent characterized by structural similarities to amiodarone but without amiodarone's severe organ toxicity. The proarrhythmic potential of dronedarone, however, is of increasing concern. We describe a 76-year-old woman who had been receiving dronedarone 400 mg twice/day to prevent recurrent atrial tachycardia with rapid ventricular response. Several months later, she came to the emergency department with decompensated congestive heart failure and episodes of atrial tachycardia; digoxin 0.5 mg and furosemide 40 mg were administered intravenously. Thereafter nonsustained torsade de pointes (TdP) tachycardia occurred. She was transferred to the intensive care unit where a dose of amiodarone 150 mg was administered intravenously by mistake. Thereafter, the patient showed sustained TdP necessitating cardiac resuscitation. Dronedarone was discontinued, and digoxin and amiodarone were not administered again. Under dronedarone a relevant QT prolongation was documented that was additionally augmented after concomitant treatment with digoxin and amiodarone. Use of the Naranjo adverse drug reaction probability scale indicated a probable adverse drug reaction to dronedarone (score of 7). To our knowledge, this is the first case report of a patient who experienced TdP tachycardias while receiving dronedarone therapy in connection with a worsening of heart failure and possible drug interactions with digoxin and amiodarone. Clinicians should be aware of this potential adverse drug reaction and perform repeated heart rate-corrected QT ( QTc) interval measurements as well as screening for congestive heart failure in patients receiving dronedarone therapy. [ABSTRACT FROM AUTHOR]

Anesthesia in the Methoxamine-Sensitized Rabbit Introduction The methoxamine-sensitized rabbit model is widely used to screen drugs for proarrhythmic properties, especially repolarization-dependent TdP arrhythmias. With the change of anesthesia and/or sensitizing agent, conduction disturbances have been reported as well. Therefore, we compared currently available in-house anesthetics in order to preserve arrhythmia sensitivity and preclude conduction disturbances. Methods and Results Rabbits were randomly assigned to 3 groups: (1) 35 mg/kg ketamine + 5 mg/kg xylazine; (2) 0.5 mL/kg hypnorm + 3 mg/kg midazolam; (3) 35 mg/kg ketamine + 20 mg/kg propofol. Anesthesia was maintained by 1.5% isoflurane. Concomitant infusion of methoxamine (17 μg/kg/min for 40 minutes) and dofetilide (10 μg/kg/min for 30 minutes) was used to induce arrhythmias. Sole methoxamine infusion exclusively decreased HR in groups 1 and 3. Dofetilide lengthened repolarization, followed in time by PQ/QRS prolongation, second-degree AV block, and subsequently TdP arrhythmias. TdP was seen in 80%, 0%, and 33% of the rabbits in groups 1, 2, and 3, respectively. Decreasing the dose of dofetilide to 5 μg/kg/min in ketamine/xylazine anesthetized rabbits resulted in a drop in TdP incidence (25%) while conduction disturbances persisted. Flunarizine (n = 6) suppressed all TdP arrhythmias while conduction disturbances remained present. Conclusion TdP incidence in the methoxamine-sensitized rabbit could be dramatically influenced by anesthesia, drug dose, and flunarizine, while conduction slowing remained present. Thus, conduction slowing seems to be the integral outcome in this model. [ABSTRACT FROM AUTHOR]

A 7-year-old boy presented at our hospital with syncope. At birth, electrocardiography had shown a long QT interval with torsade de pointes (TdP). Congenital long QT syndrome (LQTS) had been diagnosed by genetic testing, and was successfully controlled with oral propranolol. At age 7, TdP had recurred with syncope. Electrocardiography revealed a prominent long QT interval with T-wave alternans. The propranolol dose was increased, but TdP remained uncontrolled. A cardioverter-defibrillator (ICD) was implanted epicardially, and TdP completely resolved with atrial pacing. We report this rare case of ICD implantation in a child with LQTS. [ABSTRACT FROM AUTHOR]

Background: The gene KCNE1 encodes the β‐subunit of cardiac voltage‐gated K+ channels and causes long QT syndrome (LQTS). LQTS is characterized by the prolongation of QT interval and lethal arrhythmias such as torsade de pointes (TdP). A KCNE1 polymorphism, D85N, has been shown to modify the phenotype of LQTS through a loss‐of‐function effect on both KCNQ1 and KCNH2 channels when co‐expressed and reconstituted in a heterologous expression system. Methods: A screening for the D85N polymorphism was performed in 355 LQTS families with mutations in KCNQ1, KCNH2, or SCN5A. Among the probands who had a heterozygous status with the polymorphism, we focused on a family with a KCNH2 mutation (E58K), a N‐terminal missense mutation, and examined the clinical significance of this polymorphism. We also conducted biophysical assays to analyze the effect of the polymorphism in mammalian cells. Results: In 355 probands, we found 14 probands (3.9%) who had a heterozygous compound status with the D85N polymorphism. In the family with a KCNE1‐D85N polymorphism and a KCNH2‐E58K mutation, the proband and her daughter carried both the KCNH2 mutation and the KCNE1‐D85N polymorphism. They experienced repetitive syncope and TdP. Two sons of the proband had either KCNH2‐E58K mutation or KCNE1‐D85N, but were asymptomatic. Biophysical assays of KCNE1‐D85N with KCNH2‐E58K variants produced a larger reduction in the reconstituted IKr currents compared to co‐expression with wild‐type KCNE1. Conclusions: The KCNE1‐D85N polymorphism modified the clinical features of LQTS patients. [ABSTRACT FROM AUTHOR]

Ibandronate-Induced Proarrhythmia Introduction Bisphosphonates, including ibandronate, are used in the prevention and treatment of osteoporosis. Methods and Results We report a case of suspected ibandronate-associated arrhythmia, following a single dose of ibandronate in a 55-year-old female. ECG at presentation revealed frequent ectopy and QT/QTc interval prolongation; at follow-up 9 months later the QT/QTc intervals were normalized. Proarrhythmic potential of ibandronate was assessed with a combination of in vivo and in vitro approaches in canines and canine ventricular myocytes. We observed late onset in vivo repolarization instability after ibandronate treatment. Myocytes superfused with ibandronate exhibited action potential duration (APD) prolongation and variability, increased early afterdepolarizations (EADs) and reduced Ito (P < 0.05), with no change in IKr. Ibandronate-induced APD changes and EADs were prevented by inhibition of intracellular calcium cycling. Ibandronate increased sarcoplasmic reticulum calcium load; during washout there was an increase in calcium spark frequency and spontaneous calcium waves. Computational modeling was used to examine the observed effects of ibandronate. While reductions in Ito alone had modest effects on APD, when combined with altered RyR inactivation kinetics, the model predicted effects on APD and SR Ca2+ load consistent with observed experimental results. Conclusion Ibandronate may increase the susceptibility to ventricular ectopy and arrhythmias. Collectively these data suggest that reduced Ito combined with abnormal RyR calcium handling may result in a previously unrecognized form of drug-induced proarrhythmia. [ABSTRACT FROM AUTHOR]

BACKGROUND AND PURPOSE The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the IKr-blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. EXPERIMENTAL APPROACH Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. KEY RESULTS During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. CONCLUSIONS AND IMPLICATIONS In the canine CAVB model, ventricular remodelling and IKr block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide-induced TdP. [ABSTRACT FROM AUTHOR]

This review aims to clarify the underlying risk of arrhythmia associated with the use of macrolides and fluoroquinolones antibiotics. Torsades de pointes (TdP) is a rare potential side effect of fluoroquinolones and macrolide antibiotics. However, the widespread use of these antibiotics compounds the problem. These antibiotics prolong the phase 3 of the action potential and cause early after depolarization and dispersion of repolarization that precipitate TdP. The potency of these drugs, as potassium channel blockers, is very low, and differences between them are minimal. Underlying impaired cardiac repolarization is a prerequisite for arrhythmia induction. Impaired cardiac repolarization can be congenital in the young or acquired in adults. The most important risk factors are a prolonged baseline QTc interval or a combination with class III antiarrhythmic drugs. Modifiable risk factors, including hypokalemia, hypomagnesemia, drug interactions, and bradycardia, should be corrected. In the absence of a major risk factor, the incidence of TdP is very low. The use of these drugs in the appropriate settings of infection should not be altered because of the rare risk of TdP, except among cases with high-risk factors. [ABSTRACT FROM AUTHOR]

ABSTRACT Purpose Emergency department (ED) patients receive medications that place them at risk for adverse events, including drug-induced prolongation of the QT interval, which can lead to Torsade de Pointes and sudden cardiac death. We report the frequency of prescription and co-prescription of QT-prolonging medications in US EDs and factors associated with high-risk prescribing practices. Methods We analyzed the ED component of the National Hospital Ambulatory Medical Care Survey for 1995 through 2009. Yearly rates of visits involving the prescription of QT-prolonging medications were determined. Multivariate regression analyses identified factors associated with the prescription of two or more QT-prolonging medications. Results Approximately 16.5 million visits annually (15.0%) involved prescription of a QT-prolonging drug, with 1.7 million (1.6%) involving multiple prescriptions. Visits associated with QT-prolonging drugs more than doubled over the study period (10.4% to 22.2%). Diphenhydramine, azithromycin, and ondansetron were most frequently implicated (46.1% of cases). The most commonly prescribed combination was diphenhydramine and famotidine, both QT-prolonging medications available over-the-counter. Female gender and older age were associated with co-prescription of QT-prolonging medications. The rate of EKG screening among visits associated with QT-prolonging drug combinations was low (20.9%), but more common than among visits without a QT-prolonging drug (OR 1.3; 95% CI 1.2-1.5). Conclusion Use of QT-prolonging medications is increasing in EDs nationally. A small number of agents account for a large proportion of these visits and may represent an area for targeted screening or monitoring interventions in the ED. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A 38-year-old obese woman presented with recurrent polymorphic ventricular tachycardia secondary to persistent hypokalemia necessitating more than 40 DC shocks. All endocrine investigations for hypokalemia were negative with impression of 'mysterious hypokalemia.' On repeated inquiry, a hidden history of licorice use was elicited causing persistent hypokalemia. The case highlights a life threatening complication of licorice use. In addition, it reiterates the importance of repeated history taking in a patient with undiagnosed hypokalemia and torsade de pointes which avoided a device therapy. [ABSTRACT FROM AUTHOR]

Study Objectives To measure concordance between different intensive care unit ( ICU) clinicians and a consensus group of electrophysiology ( EP) cardiologists for use of a common rate-corrected QT interval ( QTc)-prolonging medication in cases containing different potential risk factor(s) for torsade de pointes (TdP). Design Prospective case-based evaluation. Setting Academic medical center with 320 beds. Subjects Medical house staff ( MDs) and ICU nurses ( RNs) from one center and select critical care pharmacists ( PHs). Intervention Completion of a survey containing 10 hypothetical ICU cases in which patients had agitated delirium for which a psychiatrist recommended intravenous haloperidol 5 mg every 6 hours. Each case contained different potential risk factor(s) for TdP in specific combinations. A group of five EP cardiologists agreed that haloperidol use was safe in five cases and not safe in five cases. Measurements and Main Results For each case, participants were asked to document whether they would administer haloperidol, to provide a rationale for their decision, and to state their level of confidence in that decision. Most clinicians (92 of 115 [80%]) invited to participate completed the cases. Among the five cases where EP cardiologists agreed that haloperidol was not safe, 29% of respondents felt that haloperidol was safe. Conversely, in the five cases where EP cardiologists felt haloperidol was safe, 21% of respondents believed that it was not safe. Overall respondent- EP cardiologist agreement for haloperidol use across the 10 cases was moderate (κ = 0.51). MDs and PHs were in agreement with the EP cardiologists more than RNs (p=0.03). Interprofessional variability existed for the TdP risk factors each best identified. Clinician confidence correlated with EP cardiologist concordance for MDs (p=0.002) and PHs (p=0.0002), but not for RNs (p=0.69). Conclusion When evaluating use of a QTc interval-prolonging medication, ICU clinicians often fail to identify the TdP risk factors that EP cardiologists feel should prevent its use. Clinician- EP cardiologist concordance varies by the specific risk factor(s) for TdP and the ICU professional conducting the assessment. [ABSTRACT FROM AUTHOR]

Background and Purpose Zolpidem, a short-acting hypnotic drug prescribed to treat insomnia, has been clinically associated with acquired long QT syndrome ( LQTS) and torsade de pointes ( TdP) tachyarrhythmia. LQTS is primarily attributed to reduction of cardiac human ether-a-go-go-related gene ( hERG)/ IKr currents. We hypothesized that zolpidem prolongs the cardiac action potential through inhibition of hERG K+ channels. Experimental Approach Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record hERG currents from Xenopus oocytes and from HEK 293 cells. In addition, hERG protein trafficking was evaluated in HEK 293 cells by Western blot analysis, and action potential duration ( APD) was assessed in human-induced pluripotent stem cell ( hiPSC)-derived cardiomyocytes. Key Results Zolpidem caused acute hERG channel blockade in oocytes ( IC50 = 61.5 μM) and in HEK 293 cells (IC50 = 65.5 μM). Mutation of residues Y652 and F656 attenuated hERG inhibition, suggesting drug binding to a receptor site inside the channel pore. Channels were blocked in open and inactivated states in a voltage- and frequency-independent manner. Zolpidem accelerated hERG channel inactivation but did not affect I- V relationships of steady-state activation and inactivation. In contrast to the majority of hERG inhibitors, hERG cell surface trafficking was not impaired by zolpidem. Finally, acute zolpidem exposure resulted in APD prolongation in hiPSC-derived cardiomyocytes. Conclusions and Implications Zolpidem inhibits cardiac hERG K+ channels. Despite a relatively low affinity of zolpidem to hERG channels, APD prolongation may lead to acquired LQTS and TdP in cases of reduced repolarization reserve or zolpidem overdose. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine)1 B/1 D agonists are vasoconstrictors that can affect coronary and cerebral arteries. Retrosternal chest, arm, and jaw pain following triptan use is generally attributed to 'triptan sensations' and dismissed as noncardiac. However, triptans narrow normal coronary arteries and occasionally trigger vasospasm. They are contraindicated in atherosclerotic vascular disease. Part 1 of this review examines the relationship of medications used in migraine with the likelihood of causing vasospasm or vasoconstriction, and the triggering of cardiac arrhythmias. We report an illustrative case of polymorphic ventricular tachyarrhythmia, electrocardiogram changes consistent with cardiac ischemia, and acquired corrected QT interval lengthening following oral sumatriptan in a 53-year-old migraineur without risk factors for coronary artery disease ( CAD). Extensive evaluation revealed insignificant single coronary vessel atherosclerosis and coronary artery vasospasm on ergonovine challenge. The report highlights the hidden risk that may underlie a 'triptan sensation' and the possible association of the vasospastic features of Raynaud's phenomenon, migraine headaches, and coronary vasospasm. Part 1 discusses the risks for Torsade de Pointes, vasospasm, and ischemia, with a review and discussion of case reports of triptan-associated cardiovascular events in migraineurs with and without CAD risk factors or documented CAD; of the epidemiology and studies of triptans, vasospasm, and cardiovascular morbidity; and of the relationship of variant angina, migraine, and vasospastic disease. In the second part of this review, headache medications and their propensity for corrected QT prolongation will be summarized. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine)1 B/1 D agonists can vasoconstrict coronary and cerebral arteries. Chest, jaw, and arm discomfort, so-called 'triptan sensations,' are often felt to be noncardiac. In Part 1 of this review, the relationship of triptans, coronary artery narrowing, and spasm was discussed, along with a case of a 53-year-old woman without cardiac risk factors who developed polymorphic ventricular tachycardia and cardiac ischemia with acquired corrected QT ( QTc) interval prolongation following oral sumatriptan. In Part 2 of this review, headache medications, drug-drug interactions, QTc prolongation, and cardiac arrhythmias are appraised and discussed. Triptans, cardiac arrhythmias, and ischemia by prescribing information are summarized. The reader is provided tables on QTc prolongation by medication. The problem of QTc prolongation with a variety of headache medications at conventional doses, including triptans, serotonin reuptake inhibitors (selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors), other antidepressants, antihistamines, and antinauseants should lead to proactively obtaining electrocardiograms and more vigilant surveillance of headache patients. This may be the place to start in protecting patients from these cardiac adverse events. [ABSTRACT FROM AUTHOR]

Concerns over cardiac side effects are the largest single cause of compound attrition during pharmaceutical drug development. For a number of years, biophysically detailed mathematical models of cardiac electrical activity have been used to explore how a compound, interfering with specific ion-channel function, may explain effects at the cell-, tissue- and organ-scales. With the advent of high-throughput screening of multiple ion channels in the wet-lab, and improvements in computational modelling of their effects on cardiac cell activity, more reliable prediction of pro-arrhythmic risk is becoming possible at the earliest stages of drug development. In this paper, we review the current use of biophysically detailed mathematical models of cardiac myocyte electrical activity in drug safety testing, and suggest future directions to employ the full potential of this approach. LINKED ARTICLE This article is commented on by Gintant, pp. 929-931 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02096.x [ABSTRACT FROM AUTHOR]