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While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses I Kr , I Na and I Ca,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit I Kr , but it may not suppress I Na or I Ca in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca 2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion and reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged the frequency-corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations, blocked I Kr in isolated cardiomyocytes (Class III effects), and reduced the maximum rate of depolarization ( V max ) at cycle lengths smaller than 1000 ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent reentry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

Background: Drugs belonging to diverse therapeutic classes can prolong myocardial refractoriness or slow conduction. These drugs may be effective and well-tolerated, but the risk of sudden cardiac death from torsades de pointes (TdP) remains a major concern. The corrected QT interval has significant limitations when used for risk stratification. Measurement of global electrical heterogeneity (GEH) could help identify the substrate vulnerable to drug-induced ventricular arrhythmias., Objective: The purpose of this study was to improve risk stratification for drug-induced TdP by measuring GEH on the electrocardiogram (ECG)., Methods: We analyzed ECG data from a case-control study of patients with a history of drug-induced TdP as well as age- and sex-matched controls. Vectorcardiograms were constructed from ECGs. GEH was measured via the spatial ventricular gradient (SVG) vector (magnitude, azimuth, and elevation). Log odds coefficients for TdP were estimated using multivariable logistic regression., Results: Among 17 cases (47% male; age 58.9 ± 12.5 years) and 17 controls (29% male; age 61.0 ± 12.2 years), 34 ECGs were analyzed. SVG azimuth was significantly different between cases and controls (3.4 vs 22.0 degrees, respectively; P = 0.02). After adjusting for sex and QTc interval, odds of TdP increased by a factor of 3.2 for each 1 SD change in SVG azimuth from the control group mean (95% confidence interval 1.07-9.14; P = .04). QTc was not significant in the multivariable analysis (P = .20)., Conclusion: SVG azimuth is correlated with a history of drug-induced TdP independent of QTc. GEH measurement may help identify patients at high risk for drug-induced arrhythmias., (Copyright © 2020 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients initiated on sotalol and dofetilide require inpatient monitoring and dose adjustments due to risks of corrected QT (QTc) prolongation and Torsades de pointes (TdP). Patients may receive higher initial doses than recommended due to close monitoring by specialized practitioners. The objective of this study was to describe prescribing practices of sotalol and dofetilide and to compare safety outcomes between standard and nonstandard dosing strategies., Methods: This was a single-center retrospective analysis of adult inpatients who underwent sotalol or dofetilide initiation between June 1, 2015, and August 1, 2018. The end points of this study included the percentage of patients who received standard and nonstandard dosing, incidence of QTc prolongation (≥500 milliseconds or ≥15% from baseline), incidence of TdP, and dose reduction or medication discontinuation., Results: A total of 379 patients (195 sotalol and 184 dofetilide) were included in this analysis. There were 110 (56.4%) patients in the sotalol group and 111 (58.4%) patients in the dofetilide group that received nonstandard initial dosing. Nonstandard dosing was associated with a greater incidence of QTc prolongation compared to standard dosing (57.5% vs 43.0%, P = .005). Only one patient in the nonstandard dosing group experienced TdP. Patients initiated on nonstandard dosing required dose reduction or therapy discontinuation (37.6% vs 23.4%, P = .003) more frequently., Conclusion: Higher than recommended initial doses of sotalol or dofetilide were associated with higher incidence of QTc prolongation and more frequent therapy modification.

Introduction: The Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative differentiates torsadogenic risk of 28 drugs affecting ventricular repolarization based on multiple in vitro human derived ionic currents. However, a standardized prospective assessment of the electrophysiologic effects of these drugs in an integrated in vivo preclinical cardiovascular model is lacking. This study questioned whether QTc interval prolongation in a preclinical in vivo model could detect clinically reported QTc prolongation and assign torsadogenic risk for ten CiPA drugs., Methods: An acute intravenous administered ascending dose anesthetized dog cardiovascular model was used to assess QTc prolongation along with other electrocardiographic (PR, QRS intervals) and hemodynamic (heart rate, blood pressures, left ventricular contractility) parameters at plasma concentrations spanning and exceeding clinical exposures. hERG current block potency was characterized using IC 50 values from automated patch clamp., Results: All eight drugs eliciting clinical QTc prolongation also delayed repolarization in anesthetized dogs at plasma concentrations within four-fold clinical exposures. In vitro QTc safety margins (defined based on clinical C max values/plasma concentrations eliciting statistically significant QTc prolongation in dogs) were lower for high vs intermediate torsadogenic risk drugs. In comparison, hERG IC 10 values represented as total drug concentrations were better predictors of preclinical QTc prolongation than hERG IC 50 values., Conclusion: There was good concordance for QTc prolongation in the anesthetized dog model and clinical torsadogenic risk assignment. QTc assessment in the anesthetized dog remains a valuable part of a more comprehensive preclinical integrated risk assessment for delayed repolarization and torsadogenic risk as part of a global cardiovascular evaluation., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Sotalol, a Vaughan-Williams Class III antiarrhythmic medication, is used to manage atrial arrhythmias. Due to its QT-prolonging effect and subsequent increased risk of torsade de pointes, many centers admit patients during the initial dosing period. Despite its widespread use, little information is available regarding dosing protocols during this period. In this multicenter investigation, dosing protocols in patients initiating sotalol therapy were examined to identify predictors of successful sotalol initiation. Over a 4-year period, patients admitted to 5 hospitals in the United States for inpatient telemetry monitoring during initiation for nonresearch purposes were enrolled. A 3-day course of 5 of 6 doses of sotalol was considered successful completion of the loading protocol. Of the 213 enrolled patients, over 90% were successfully discharged on sotalol. Significant bradycardia, ineffectiveness, and excessive QT prolongation were reasons for failed completion. Absence of a dose adjustment was a strong predictor of successful initiation (odds ratio: 6.6, 95% confidence interval: 1.3-32.7, P = .02). Hypertension, use of a calcium channel blocker, use of a separate β-blocker, and presence of a pacemaker were predictors of dose adjustments. Marginal structural models (ie, inverse probability weighting based on probability of a dose adjustment) verified that these factors also predicted successful initiation via preventing any dose adjustment and suggests that considering these factors may result in a higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication. The study findings suggest that factors predicting need for dose adjustment can be used to identify patients who could undergo outpatient initiation. Prospective studies are needed to verify this approach.

Background and Purpose: K v 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of K v 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model., Experimental Approach: LUF7244 was tested in vitro for (a) increasing human I Kv11.1 and canine I Kr and (b) decreasing dofetilide-induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block., Key Results: LUF7244 (0.5-10 μM) concentration dependently increased I Kv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on I KIR2.1 , I Nav1.5 , I Ca-L , and I Ks , doubled I Kr , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg -1 ·15 min -1 ) in dogs with sinus rhythm was not proarrhythmic and shortened, non-significantly, repolarization parameters (QTc: -6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide-induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 μM after chronic atrioventricular block., Conclusions and Implications: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of K v 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Purpose: There is a significant variation in the clinical approach of initiation and dose adjustment of dofetilide in atrial fibrillation (AF). Excessive QT prolongation could predispose patients to torsades de pointes (TdP), which can be fatal., Methods: We performed a retrospective case-control study at Mayo Clinic Rochester (January 1, 2003 to December 31, 2016). "TdP risk" cases were defined as patients on dofetilide therapy for AF with subsequent TdP or excessive QTc prolongation requiring dose reduction or discontinuation (N = 31). A control group was matched 1:1 with cases by age, gender, year of admission, and dofetilide dose (N = 31)., Results: Using multivariate regression analysis, independent predictors of TdP risk included baseline QTc exceeding recommendations (adjusted odd ratio [AOR] 4.57; P = 0.023); underlying AF with rapid ventricular rate (AOR 16.95; P = 0.004); and diuretic therapy for acute heart failure (AOR 8.42; P = 0.007). Poor inter-observer agreement was identified among QT interval measurement in patients with AF and rapid ventricular rate compared to those in rate controlled AF or sinus rhythm. TdP risk cases receiving diuretics for acute heart failure had a significant decline in creatinine clearance than controls, although serum electrolytes and replacement did not differ among the two groups., Conclusions: Excessive QTc prolongation and AF with rapid ventricular rate at time of dofetilide initiation (likely due to difficulty in measuring QT intervals), and diuretic therapy for acute heart failure were independent factors for dofetilide-related TdP risk. Based on these data, possible preventive strategies could be adapted for safety protocols among hospitalized patients.

Despite proven effectiveness in treating tachyarrhythmias, sotalol is proarrhythmic and can cause torsades de pointes. Given the emergence of studies that show no benefit from rhythm control strategies in managing atrial fibrillation, as well as the introduction of nonpharmacological approaches to treating arrhythmias, we felt it necessary to ascertain if there was any role for sotalol given its side effects. Review of the literature regarding sotalol use in the prevention and treatment of supraventricular and ventricular tachyarrhythmias seems to show that more effective and safer agents and nonpharmacological alternatives are currently available. However, sotalol still seems to be useful in preventing supraventricular tachyarrhythmias postcardiac surgery and in reverting hemodynamically stable sustained ventricular tachycardias in the setting of coronary artery disease. Its role in the prevention of tachyarrhythmias in the setting of arrhythmogenic right ventricular cardiomyopathy requires further investigation.

Current inotropic agents in heart failure therapy associate with low benefit and significant adverse effects, including ventricular arrhythmias. Istaroxime, a novel Na + /K + -transporting ATPase inhibitor, also stimulates SERCA2a activity, which would confer improved inotropic and lusitropic properties with less proarrhythmic effects. We investigated hemodynamic, electrophysiological and potential proarrhythmic and antiarrhythmic effects of istaroxime in control and chronic atrioventricular block (CAVB) dogs sensitive to drug-induced Torsades de Pointes arrhythmias (TdP). In isolated normal canine ventricular cardiomyocytes, istaroxime (0.3-10 μM) evoked no afterdepolarizations and significantly shortened action potential duration (APD) at 3 and 10 μM. Istaroxime at 3 μg/kg/min significantly increased left ventricular (LV) contractility (dP/dt+) and relaxation (dP/dt-) respectively by 81 and 94% in anesthetized control dogs (n = 6) and by 61 and 49% in anesthetized CAVB dogs (n = 7) sensitive to dofetilide-induced TdP. While istaroxime induced no ventricular arrhythmias in control conditions, only single ectopic beats occurred in 2/7 CAVB dogs, which were preceded by increase of short-term variability of repolarization (STV) and T wave alternans in LV unipolar electrograms. Istaroxime pre-treatment (3 μg/kg/min for 60 min) did not alleviate dofetilide-induced increase in repolarization and STV, and mildly reduced incidence of TdP from 6/6 to 4/6 CAVB dogs. In six CAVB dogs with dofetilide-induced TdP, administration of istaroxime (90 μg/kg/5 min) suppressed arrhythmic episodes in two animals. Taken together, inotropic and lusitropic properties of istaroxime in CAVB dogs were devoid of significant proarrhythmic effects in sensitive CAVB dogs, and istaroxime provides a moderate antiarrhythmic efficacy in prevention and suppression of dofetilide-induced TdP., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We analyzed torsadogenic and pharmacokinetic profile of E-4031 using chronic atrioventricular block dogs. E-4031 in intravenous doses of 0.03, 0.1 and 0.3 mg/kg over 10 min prolonged QT/QTc, and increased short-term variability of QT in a dose-related manner (n = 4), resulting in onset of torsade de pointes in 1 animal after the middle dose and 4 animals after the high dose, while it attained peak plasma concentrations of 16.5, 60.5 and 182.5 ng/mL at 10 min after their start of administration, respectively (n = 2). These results bridge the gap of information between in vitro proarrhythmia assay and clinical observation in human subjects., (Copyright © 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Background and Purpose: Enhanced late sodium current (late I Na ) in heart failure and long QT syndrome type 3 is proarrhythmic. This study investigated the antiarrhythmic effect and mode of action of the selective and potent late I Na inhibitor GS-458967 (GS967) against Torsades de Pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog., Experimental Approach: Electrophysiological and antiarrhythmic effects of GS967 were evaluated in isolated canine ventricular cardiomyocytes and CAVB dogs with dofetilide-induced early afterdepolarizations (EADs) and TdP, respectively. Mapping of intramural cardiac electrical activity in vivo was conducted to study effects of GS967 on spatial dispersion of repolarization., Key Results: GS967 (IC 50 ~200nM) significantly shortened repolarization in canine ventricular cardiomyocytes and sinus rhythm (SR) dogs, in a concentration and dose-dependent manner. In vitro, despite addition of 1μM GS967, dofetilide-induced EADs remained present in 42% and 35% of cardiomyocytes from SR and CAVB dogs, respectively. Nonetheless, GS967 (787±265nM) completely abolished dofetilide-induced TdP in CAVB dogs (10/14 after dofetilide to 0/14 dogs after GS967), while single ectopic beats (sEB) persisted in 9 animals. In vivo mapping experiments showed that GS967 significantly reduced spatial dispersion of repolarization: cubic dispersion was significantly decreased from 237±54ms after dofetilide to 123±34ms after GS967., Conclusion and Implications: GS967 terminated all dofetilide-induced TdP without completely suppressing EADs and sEB in vitro and in vivo, respectively. The antiarrhythmic mode of action of GS967, through the reduction of spatial dispersion of repolarization, seems to predominantly impede the perpetuation of arrhythmic events into TdP rather than their initiating trigger., (© 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The hypothesis of the study is that Torsades de pointes (TdP) history can be better identified using T-wave morphology compared to Fridericia-corrected QT interval (QTcF) at baseline. ECGs were recorded at baseline and during sotalol challenge in 20 patients with a history of TdP (+TdP) and 16 patients without previous TdP (-TdP). The QTcF and T-wave morphology combination score (MCS) were calculated. At baseline, there was no significant difference in QTcF between the groups (+TdP: QTcF = 446 ± 9 ms; -TdP: QTcF = 431 ± 9 ms, P = 0.27). In contrast, MCS was significantly different between the groups at baseline (+TdP: MCS = 1.07 ± 0.095; -TdP: MCS = 0.74 ± 0.07, P = 0.012). Both QTcF and MCS could be used to discriminate between +TdP and -TdP after sotalol but only MCS reached statistical significance at baseline. Combining QTcF with MCS provided a significantly larger difference between groups than QTcF alone., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Anti-atrial fibrillatory, proarrhythmic and cardiodepressive profiles of dronedarone were analyzed using the halothane-anesthetized beagle dogs (n = 4) to create a standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of dronedarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s attained the peak plasma concentrations of 61 and 1248 ng/mL, respectively, reflecting sub- to supra-therapeutic ones. The low dose decreased the left ventricular contraction and mean blood pressure, which were enhanced at the high dose. The high dose also decreased the heart rate and cardiac output, but increased the total peripheral resistance and left ventricular end-diastolic pressure, showing its potent cardiodepressive profile. Moreover, the high dose delayed the atrioventricular nodal and intraventricular conductions in addition to the ventricular repolarization, suggesting its inhibitory action on the Ca 2+ , Na + and K + channels in the in situ heart, respectively. The high dose also prolonged the effective refractory period 1.9 times greater in the atrium than in the ventricle, explaining its clinically demonstrated efficacy against the atrial arrhythmias. Dronedarone significantly prolonged the T peak -T end in a dose-related manner with a tendency to prolong the terminal repolarization period and J-T peak c, indicating considerable risk to induce torsade de pointes. No significant change was detected in the P-wave duration by either dose, indicating the lack of effect on the atrial Na + channel in vivo. The current experimental protocol and the results of dronedarone can be used as a guide for safety pharmacological evaluation of new anti-atrial fibrillatory drugs.

Several risk factors for development of a potentially fatal ventricular arrhythmia, torsade de pointes, have been observed, including female gender. However, in most investigations, only few torsade events were included and/or rarely were postdose heart rate corrected QT (QTc) measurements included, as a surrogate of drug exposure. We developed a multivariate logistic regression model using data from 22,214 patients (33% women) with 84 torsade events (56% women) to evaluate the relationship between risk factors for torsade using data from four anti-arrhythmic drug development programs. Before model development, we evaluated different QT/QTc postdose metrics (average, maximum, etc.) to determine which QT metric should be included into the model. The developed multivariate model showed that, after accounting for known risk factors for torsade and postdose QTc, that female gender remained a significant risk factor for torsade., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

A systematic review was conducted for all published case reports on drug-induced torsade de pointes (TdP) in elderly (≥80 years) patients to study if the administration of the offending agent was reckless. Overall, 61 reports on drug-induced TdP in patients aged 80-97 years were included in the analysis. Non-modifiable risk factors for drug-induced TdP (e.g. acute coronary syndrome, female gender and congestive heart failure), modifiable risk factors (e.g. hypokalemia, severe hypomagnesemia and digitalis toxicity) and reckless administration of a QT interval-prolonging agent (e.g. despite a known QT interval prolongation or a history of TdP, together with other QT interval prolonging agents in higher than recommended doses) were recorded in each case. Overall, 54 (88.5%) patients had non-modifiable risk factors for drug-induced TdP and 21 (34.4%) patients had modifiable risk factors. The administration of the offending agent was reckless in one half (n = 31; 50.8%) of the patients. The most prevalent reckless administration of a QT interval-prolonging agent was together with other QT interval-prolonging agents (n = 16; 51.6%) or despite QT interval prolongation (n = 8; 25.8%). In conclusion, although risk factors for drug-induced TdP are prevalent in elderly patients with drug-induced TdP, in approximately 50% of patients it appeared following a reckless administration of a QT interval-prolonging agent. In this population physicians should particularly avoid administration of two or more QT interval-prolonging agents simultaneously or administration of a QT interval-prolonging agent despite QT interval prolongation.

Rationale: Drug-induced prolongation of the corrected QT interval (QTc) may lead to serious and potentially life-threatening ventricular tachyarrhythmia, such as torsades de pointes (Tdp), which is worthy of clinical attention. Here, we report 1 case of Tdp after a coadministration of fluoxetine and amiodarone., Patient Concerns: A 62-year-old Chinese male who placed with the implanted cardioverter-defibrillator (ICD) appeared the QTc prolongation and Tdp after the concurrent administration of fluoxetine and amiodarone., Diagnoses: Torsades de pointes (Tdp)., Interventions: The patient was treated with magnesium and potassium immediately. Her ICD-brady pacing mode was reprogrammed to 90 bpm. Meanwhile, both of fluoxetine and amiodarone were discontinued., Outcomes: The further episodes of Tdp were prevented. After a few days, the QTc gradually decreased without clinically significant arrhythmias., Lessons: The present case demonstrates that a potential drug-drug interaction (DDI) may lead to a life-threatening drug adverse reaction (ADR) especially in special subjects. Therefore, clinicians should closely monitor the electrocardiogram (ECG) when QTc-prolonging agents are given to patients with cardiac abnormalities, and avoid combining 2 QTc-prolonging drugs.

Background: Although dofetilide labeling states that the drug must be initiated or reinitiated with continuous electrocardiographic monitoring and in the presence of trained personnel, the risks of dofetilide reloading justifying repeat hospitalization have not been investigated., Methods and Results: Patients admitted for dofetilide reloading for atrial arrhythmias were retrospectively reviewed. The need for dose adjustment and the incidence of torsades de pointes (TdP) were identified. The incidence of TdP in dofetilide reloading was compared with patients admitted for dofetilide initial loading. Of 138 patients admitted for dofetilide reloading for atrial arrhythmias, 102 were reloaded at a previously tolerated dose, 30 with a higher dose from a previously tolerated dose and 2 at a lower dose; prior dosage was unknown in 4 patients. Dose adjustment or discontinuation was required in 44 patients (31.9%). No TdP occurred in the same dose reloading group, but TdP occurred in 2 patients admitted to increase dofetilide dosage (0% versus 6.7%; P =0.050). Dofetilide dose adjustment or discontinuation was required in 30 of 102 patients (29.4%) reloaded at a previously tolerated dose and in 11 of 30 patients (36.7%) admitted for an increase in dose., Conclusions: Although no TdP occurred in patients admitted to reload dofetilide at the same dose as previously tolerated, dosage adjustments or discontinuation was frequent and support the need for hospitalization for dofetilide reloading. Patients admitted for reloading with a higher dose tended to be at higher risk for TdP than patients reloaded at a prior tolerated dose., (© 2017 American Heart Association, Inc.)

Background and Purpose: Several rabbit proarrhythmia models have been developed using genetic or pharmacological methods to suppress the slow component of delayed rectifier K + currents in the ventricle, leading to reduction of the repolarization reserve. Here we have characterized a novel rabbit in vivo proarrhythmia model with severe bradycardia caused by acute atrioventricular block (AVB)., Experimental Approach: Bradycardia was induced in isoflurane-anaesthetized rabbits by inducing AVB with catheter ablation, and the ventricle was electrically driven at 60 beats min -1 throughout the experiment except when extrasystoles appeared. We assessed the effects of two antiarrhythmics, two quinolone antibiotics and one antipsychotic drug, which were chosen as positive drugs (dofetilide, sparfloxacin and haloperidol) and negative drugs (amiodarone and moxifloxacin) for induction of Torsades de Pointes (TdP)., Key Results: In our model, TdP arrhythmias appeared with high reproducibility after i.v. dofetilide (10-100 μg·kg -1 ) in five out of six rabbits, sparfloxacin (30 mg·kg -1 ) in three out of six rabbits and haloperidol (0.3-3 mg·kg -1 ) in two out of six rabbits. The lethal arrhythmias repeatedly appeared and were accompanied with prolongation of the QT interval and early afterdepolarization-like phenomena. Neither amiodarone (0.3-10 mg·kg -1 , n = 6) nor moxifloxacin (3-30 mg·kg -1 , n = 6) induced such arrhythmias, even when QT intervals were prolonged., Conclusions and Implications: These results suggest that our model of the unremodelled and bradycardic heart of the anaesthetized rabbit is a useful test system for the detection of drug-induced TdP arrhythmias., (© 2017 The British Pharmacological Society.)

Short-term variability (STV), to quantify beat-to-beat variability of repolarization, is a surrogate parameter that reliably identifies proarrhythmic risk in preclinical models. Examples include not only the use in the chronic atrioventricular block (CAVB) dog model whereby it was developed but also in vulnerable patients with heart failure or drug-induced long QT syndrome. In the CAVB dog model, STV can specifically distinguish between safe and unsafe drugs in proarrhythmic screening. Conversely, this dog model also offers the possibility to evaluate antiarrhythmic strategies in a setting of Torsades de Pointes (TdP) induction with a standard IKr inhibitor. The different antiarrhythmic interventions studied in suppression and prevention of drug-induced TdP in vivo in the CAVB dog model and in vitro in canine ventricular cardiomyocytes are described in this overview. We provide evidence that STV predicts the magnitude of antiarrhythmic effect against TdP better than other repolarization parameters in both suppression and prevention conditions. Moreover, suppression and prevention experiments revealed the same level of antiarrhythmic efficacy, whereas cellular experiments seem more sensitive in comparison with drug testing in vivo. Together, these observations suggest that STV could be used as a consistent indicator to rank efficacy of antiarrhythmic interventions in a number of conditions.

Background: Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated., Methods and Results: All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow-up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long-term follow-up (255 patient-years; mean, 447 days; interquartile range, 201-779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty-eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow-up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect., Conclusions: Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT-prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Competing Interests: I have read and understood BMJ policy on declaration of interests and declare that we have no competing interests.

Background: Although atrial fibrillation (AF) is the most common abnormal heart rhythm and its prevalence continues to rise, there is a marked paucity of effective and safe antiarrhythmic drugs for AF. This study was done to test whether combined use of dofetilide and mexiletine exhibits not only a synergistic effect on AF suppression but also a safer profile in drug-induced ventricular proarrhythmias., Methods and Results: The effects of dofetilide plus mexiletine on atrial effective refractory period (ERP), AF inducibility, QT, and QT-related ventricular arrhythmias were studied using the isolated arterially perfused rabbit atrial and ventricular wedge preparations. Dofetilide or mexiletine alone mildly to moderately prolonged atrial ERP, but their combined use produced a markedly rate-dependent increase in atrial ERP. Dofetilide (3 nmol/L) plus mexiletine (10 μmol/L) increased the ERP by 28.2% from 72.2±5.7 to 92.8±5.9 ms (n=9, P <0.01) at a pacing rate of 0.5 Hz and by 94.5% from 91.7±5.2 to 178.3±12.0 ms (n=9, P <0.01) at 3.3 Hz. Dofetilide plus mexiletine strongly suppressed AF inducibility. On the other hand, dofetilide at 10 nmol/L produced marked QT and T p-e prolongation, steeper QT-BCL and T p-e -BCL slopes, and induced early afterdepolarizations and torsade de pointes in the ventricular wedges. Mexiletine at 10 μmol/L reduced dofetilide-induced QT and T p-e prolongation, QT-BCL and T p-e -BCL slopes, and abolished early afterdepolarizations and torsade de pointes., Conclusions: In rabbits, combined use of dofetilide and mexiletine not only synergistically increases atrial ERP and effectively suppresses AF inducibility, but also markedly reduces QT liability and torsade de pointes risk posed by dofetilide alone., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Introduction: To study the conditions leading to the initiation and termination of drug induced Torsade de pointes (TdP) along with QT prolongation., Methods: A 2D anisotropic transmural section of the ventricular myocardium is modeled using the TP06 equations and the cells are interconnected with gap junction conductances (GJC). The tissue is remodeled by reducing the repolarization reserve (by increasing calcium current (I CaL )) of all cells thus making them vulnerable to development of early after depolarizations (EADs)., Results: Clinical risk conditions like decreased potassium current (I Kr ), bradycardia, hypokalemia and short-long-short (SLS) triggering sequences are included in the tissue. A pseudo-electrocardiogram is created to realize the intensity of remodeling required in presence of risk factors to initiate TdP. On initiating TdP, the effect of increasing GJC and decreasing I CaL is shown to terminate a non-self-limiting TdP., Conclusion: Without the inclusion of underlying increase in I CaL along with risk factors, TdP cannot be initiated., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Anti-atrial fibrillatory and proarrhythmic potentials of amiodarone were simultaneously analyzed by using the halothane-anesthetized beagle dogs (n = 4) in order to begin to prepare standard protocol for clarifying both efficacy and adverse effects of anti-atrial fibrillatory drugs. Intravenous administration of 0.3 mg/kg of amiodarone hydrochloride decreased the heart rate and mean blood pressure. Additional administration of 3 mg/kg of amiodarone hydrochloride prolonged the QT interval besides the effects observed by the low dose, whereas it showed 1.6 times larger prolongation in the effective refractory period of the atrium than that of the ventricle, which may explain its clinical efficacy against atrial arrhythmias. However, no significant change was detected by either dose in the early repolarization assessed by corrected J-T peak or the late repolarization done by T peak -T end in the electrocardiogram, although the former tended to be shortened and the reverse was true for the latter. Lack of prolongation in the early repolarization will make it feasible to better understand why amiodarone lacks proarrhythmic potential in spite of the QT-interval prolongation. Thus, these results of amiodarone obtained by current protocol may become a guidance on assessing efficacy and adverse effects of new anti-atrial fibrillatory drugs in vivo.

The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na+ current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca2+ current (ICaL) caused by a decrease in Ca2+-dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.

Torsades de pointes (TdP) is a characteristic polymorphic ventricular arrhythmia associated with delayed ventricular repolarization as evidenced on the surface electrocardiogram by QT interval prolongation. It typically occurs in self-limiting bursts, causing dizziness and syncope, but may occasionally progress to ventricular fibrillation and sudden death. Acquired long QT syndromes are mainly caused by cardiac disease, electrolyte abnormalities or exposure to drugs that block rectifying potassium channels, especially IKr. Management of TdP or marked QT prolongation includes removal or correction of precipitants, including discontinuation of culprit drugs and institution of cardiac monitoring. Electrolyte abnormalities and hypoxia should be corrected, with potassium concentrations maintained in the high normal range. Immediate treatment of TdP is by intravenous administration of magnesium sulphate, terminating prolonged episodes using electrical cardioversion. In refractory cases of recurrent TdP, the arrhythmia can be suppressed by increasing the underlying heart rate using isoproterenol (isoprenaline) or transvenous pacing. Other interventions are rarely needed, but there are case reports of successful use of lidocaine or phenytoin. Anti-arrhythmic drugs that prolong ventricular repolarization should be avoided. Some episodes of TdP could be avoided by careful prescribing of QT prolonging drugs, including an individualized assessment of risks and benefits before use, performing baseline and periodic electrocardiograms and measurement of electrolytes, especially during acute illnesses, using the lowest effective dose for the shortest possible time and avoiding potential drug interactions. These steps are particularly important in those with underlying repolarization abnormalities and those who have previously experienced drug-induced TdP., (© 2015 The British Pharmacological Society.)

Background and Purpose: The present study was undertaken to investigate an effect of dofetilide, a potent arrhythmic blocker of the voltage-gated K(+) channel, hERG, on cardiac autonomic control. Combined with effects on ardiomyocytes, these properties could influence its arrhythmic potency., Experimental Approach: The short-term variability of beat-to-beat QT interval (STVQT ), induced by dofetilide is a strong surrogate of Torsades de pointes liability. Involvement of autonomic modulation in STVQT was investigated in healthy cynomolgus monkeys and beagle dogs by power spectral analysis under conditions of autonomic blockade with hexamethonium., Key Results: Increase in STVQT induced by dofetilide in monkeys and dogs was closely associated with an enhancement of endogenous heart rate and QT interval high-frequency (HF) oscillations. These effects were fully suppressed under conditions of autonomic blockade with hexamethonium. Ventricular arrhythmias, including Torsades de pointes in monkeys, were prevented in both species when HF oscillations were suppressed by autonomic blockade. Similar enhancements of heart rate HF oscillations were found in dogs with other hERG blockers described as causing Torsades de pointes in humans., Conclusions and Implications: These results demonstrate for the first time that beat-to-beat ventricular repolarization variability and ventricular arrhythmias induced by dofetilide are dependent on endogenous HF autonomic oscillations in heart rate. When combined with evidence of hERG-blocking properties, enhancement of endogenous HF oscillations in heart rate could constitute an earlier and more sensitive biomarker than STVQT for Torsades de pointes liability, applicable to preclinical regulatory studies conducted in healthy animals., (© 2015 The British Pharmacological Society.)

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., (© 2015 Pharmacotherapy Publications, Inc.)

Dofetilide is an effective antiarrhythmic agent for conversion of atrial fibrillation and atrial flutter as well as maintenance of sinus rhythm in appropriately selected patients. However, as with other antiarrhythmic agents, proarrhythmia is a known adverse effect. The risk of dofetilide induced torsade de pointes (Tdp) is low when used with strict dosing criteria guided by renal function, QT interval and concomitant drug therapy. Benefit from dofetilide use must be individualized and weighed against the side effects and the role of other available treatment options. In this review, we discuss the underlying mechanism, risk factors and precautionary measures to avoid dofetilide induced QT prolongation and ventricular tachycardia/Tdp. We suggest a scheme for the management of QT prolongation, ventricular arrhythmia and Tdp as well., (Copyright © 2013 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Ventricular arrhythmia induced by drugs (pro-arrythmia) is an uncommon event, whose occurrence is unpredictable but potentially fatal. The ability of a variety of medications to induce these arrhythmias is a significant problem facing the pharmaceutical industry. Genetic variants have been shown to play a role in adverse events and are also known to influence an individual's optimal drug dose. This review provides an overview of the current understanding of the role of genetic variants in modulating the risk of drug induced arrhythmias., (© 2013 The British Pharmacological Society.)

Since information regarding the effects of pH on the extent of nifekalant-induced repolarization delay and torsades de pointes remains limited, we assessed it with a Langendorff heart model of guinea pigs. First, we investigated the effects of pH change from 7.4 to 6.4 on the bipolar electrogram simulating surface lead II ECG, monophasic action potential (MAP), effective refractory period (ERP), and terminal repolarization period (TRP) and found that acidic condition transiently enhanced the ventricular repolarization. Next, we investigated the effects of pH change from 6.4 to 7.4 in the presence of nifekalant (10 μM) on the ECG, MAP, ERP, TRP, and short-term variability (STV) of MAP90 and found that the normalization of pH prolonged the MAP90 and ERP while the TRP remained unchanged, suggesting the increase in electrical vulnerability of the ventricle. Meanwhile, the STV of MAP90 was the largest at pH 6.4 in the presence of nifekalant, indicating the increase in temporal dispersion of repolarization, which gradually decreased with the return of pH to 7.4.Thus, a recovery period from acidosis might be more dangerous than during the acidosis, because electrical vulnerability may significantly increase for this period while temporal dispersion of repolarization remained increased.

Aims: A prolonged QT interval is associated with increased risk of Torsades de pointes (TdP) and may be fatal. We sought to investigate the extent to which clinical covariates affect the change in QT interval among 'real-world' patients treated with sotalol and followed in an electronic medical record (EMR) system., Methods and Results: We used clinical alerts in our EMR system to identify all patients in whom a new prescription for sotalol was written (2001-11). Rate-corrected QT (QTc) was calculated by Bazett's formula. Correlates of sotalol-induced change in the QTc interval and sotalol discontinuation were examined using linear and logistic regression, respectively. Overall, 541 sotalol-exposed patients were identified (n = 200 women, 37%). The mean first sotalol dose was 86 ± 39 mg, age 64 ± 13 years, and BMI 30 ± 7 kg/m(2). Atrial fibrillation/flutter was the predominant indication (92.2%). After initial exposure, the change in the QTc interval from baseline was highly variable: ΔQTc after 2 h = 3 ± 42 ms (P = 0.17) and 11 ± 37 ms after ≥48 h (P < 0.001). Multivariable linear regression analysis identified female gender and age, reduced left ventricular ejection fraction, high sotalol dose, hypertrophic cardiomyopathy, and loop diuretic co-administration as correlates of increased ΔQTc at ≥48 h (P < 0.05 for all). Within 3 days of initiation, 12% discontinued sotalol of which 31% were because of exaggerated QTc prolongation. One percent developed TdP., Conclusion: In this EMR-based cohort, the increase in QTc with sotalol initiation was highly variable, and multiple clinical factors contributed. These data represent an important step in ongoing work to identify real-world patients likely to tolerate long-term therapy and reinforces the utility of EMR-based cohorts as research tools.

Marked prolongation of the QT interval on the electrocardiogram associated with the polymorphic ventricular tachycardia Torsades de Pointes is a serious adverse event during treatment with antiarrhythmic drugs and other culprit medications, and is a common cause for drug relabeling and withdrawal. Although clinical risk factors have been identified, the syndrome remains unpredictable in an individual patient. Here we used genome-wide association analysis to search for common predisposing genetic variants. Cases of drug-induced Torsades de Pointes (diTdP), treatment tolerant controls, and general population controls were ascertained across multiple sites using common definitions, and genotyped on the Illumina 610k or 1M-Duo BeadChips. Principal Components Analysis was used to select 216 Northwestern European diTdP cases and 771 ancestry-matched controls, including treatment-tolerant and general population subjects. With these sample sizes, there is 80% power to detect a variant at genome-wide significance with minor allele frequency of 10% and conferring an odds ratio of ≥2.7. Tests of association were carried out for each single nucleotide polymorphism (SNP) by logistic regression adjusting for gender and population structure. No SNP reached genome wide-significance; the variant with the lowest P value was rs2276314, a non-synonymous coding variant in C18orf21 (p  =  3×10(-7), odds ratio = 2, 95% confidence intervals: 1.5-2.6). The haplotype formed by rs2276314 and a second SNP, rs767531, was significantly more frequent in controls than cases (p  =  3×10(-9)). Expanding the number of controls and a gene-based analysis did not yield significant associations. This study argues that common genomic variants do not contribute importantly to risk for drug-induced Torsades de Pointes across multiple drugs.

Methadone maintenance treatment (MMT) is commonly used for chronic pain control and for substitution in heroin addicts undergoing rehabilitation. Methadone is known to prolong QT interval and sometimes cause torsade de pointes (TdP) and ventricular fibrillation (VF). Treatment of TdP by antiarrhythmic drugs that prolong QT interval may worsen TdP. To our knowledge, worsening of methadone-induced TdP by amiodarone has not been reported before. We describe here a case of methadone-induced TdP that deteriorated into ventricular fibrillation upon treatment with intravenous (IV) amiodarone and resolved after discontinuation of amiodarone and treatment with IV magnesium, potassium, and lidocaine.

Dofetilide is a class III antiarrhythmic agent approved for the maintenance of sinus rhythm in patients with persistent atrial fibrillation (AF). The goal of this study was to determine if chemical cardioversion (CCV) suggests a greater sensitivity to dofetilide and, therefore, portends a higher risk of proarrhythmia. We analyzed 99 consecutive patients with persistent AF who were loaded on dofetilide before cardioversion. CCV occurred after 2 ± 1.5 doses of dofetilide in 46 patients whereas electrical cardioversion (ECV) was required in the remaining 53 patients after 4.7 ± 1.3 doses. During index hospitalization, there were higher rates of dofetilide discontinuation because of QT prolongation or torsades de pointes (TdP) in the CCV group compared with the ECV group (24% vs 2%, p = 0.001). All patients with CCV requiring drug discontinuation converted after a single dose of dofetilide. Additionally, all 3 patients with TdP were in the CCV group. Furthermore, 15 of the 21 patients with CCV (71%) who converted after the first dose of dofetilide developed significant QT prolongation, requiring dose adjustment or discontinuation of drug. Among patients discharged on drug, AF recurrence and drug discontinuation rates were similar between groups at 2-year follow-up. In patients hospitalized for initiation of dofetilide, CCV occurs in almost 50% and is associated with higher rates of pathologic QT prolongation and TdP compared with those who require ECV. Once discharged on dofetilide, safety and efficacy is similar in both groups. In conclusion, patients with CCV may require closer monitoring for proarrhythmia., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.

The drug-induced Torsade de Pointes (TdP) tachycardia is a known regulatory problem which led to the concept of the so-called thorough QT (TQT) studies now required for practically every new pharmaceutical compound. This review summarizes the concept of the TQT studies, their statistical evaluation, and related pharmacodynamic /pharmacokinetic modeling. The review also lists suggestions of how to make TQT studies more efficient and how to improve the interpretation of clinical data obtained during drug development to identify drugs prone to TdP induction more effectively., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We report a case of macroscopic T-wave alternans occurring 30 min before the onset of amiodarone-induced torsade de pointes, illustrating a means to monitor for proarrhythmia.

Objectives: This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS)., Background: Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS., Methods: This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study., Results: The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4))., Conclusions: These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Study Objective: To characterize the frequency and type of cardiac events, including torsade de pointes, associated with dronedarone and its structural analog, amiodarone, outside of the clinical trial setting., Design: Retrospective analysis., Data Source: Spontaneous reports in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database generated between July 1, 2009, and June 30, 2011., Measurements and Main Results: All reports of adverse events during the study period were reviewed to identify cardiac events associated with any approved drug in the United States. The type and number of cardiac events associated with dronedarone and amiodarone were determined. Active ingredients were identified using the Drugs@FDA database, and the Medical Dictionary for Regulatory Activities (MedDRA) was used to aggregate related adverse events. To avoid redundant reporting, all statistics were generated in reference to unique case identifiers. Dronedarone was associated with more adverse cardiovascular event reports than amiodarone (810 vs 493 reports) during the study period. Dronedarone was also associated with the most reports of torsade de pointes of any approved drug in the United States (37 reports), followed by amiodarone (29 reports). Reports of ventricular arrhythmias and cardiac arrest (138 vs 113 reports) as well as heart failure (179 vs 126 reports) were more common with dronedarone than amiodarone., Conclusion: Dronedarone was associated with reports of ventricular arrhythmia, cardiac arrest, and torsade de pointes in clinical practice. Whether this observation accounts for the increased risk of fatal arrhythmia observed in a recent prospective trial requires further investigation., (© 2012 Pharmacotherapy Publications, Inc. All rights reserved.)

Introduction: A number of predisposing factors have been suggested to be contributing to drug-induced torsade de pointes (TdP) arrhythmias: short-long-short (SLS) sequence, bradycardia, timing of drug administration, anaesthesia, ventricular remodelling, and altered ventricular activation due to ventricular ectopic beats (SLS) or idioventricular rhythm (IVR). Chronic atrio-ventricular (AV)-block (CAVB) dogs are susceptible to dofetilide-induced TdP., Methods and Results: In 32 anaesthetized animals, the relevance of ventricular remodelling for TdP susceptibility was studied by dofetilide [0.025 mg/kg/5 min intravenously (iv)] during bradycardia in the presence (CAVB, n= 18) or absence [acute atrio-ventricular block (AVB), n= 32] of ventricular remodelling. In sub-protocols, the possible pro-arrhythmic effects of timing of dofetilide administration: prior to (n= 11), or after creation of AVB (n= 9) and relevance of SLS pacing (n= 17) was investigated during IVR. Dofetilide was also given after AVB when the activation of the ventricles was normal: pacing (1000 ms) from the high septum (n= 7) or abnormal but fixed from the left ventricular apex (n= 5). Torsade de pointes inducibility was defined as reproducible (≥ 3 times) occurrence. In acute AV block (AAVB), dofetilide did not induce TdP spontaneously (0 of 32), whereas TdP was seen in 10 out of 18 serially tested dogs in CAVB (P< 0.001). The other factors: timing of dofetilide (0 of 11 vs. 0 of 9), SLS pacing (0 of 17 vs. 1 of 17), or ventricular activation (0 of 7 vs. 0 of 5) did not increase TdP susceptibility. Beat-to-beat variability of repolarization increased after ventricular remodelling and was highest prior to TdP induction., Conclusion: In AAVB dogs, TdP is not spontaneously seen, whereas it is present in CAVB. This implies that ventricular remodelling is a prerequisite for TdP induction in this model.

Background: Drug-induced long-QT syndrome (diLQTS) is an adverse drug effect that has an important impact on drug use, development, and regulation. We tested the hypothesis that common variants in key genes controlling cardiac electric properties modify the risk of diLQTS., Methods and Results: In a case-control setting, we included 176 patients of European descent from North America and Europe with diLQTS, defined as documented torsades de pointes during treatment with a QT-prolonging drug. Control samples were obtained from 207 patients of European ancestry who displayed <50 ms QT lengthening during initiation of therapy with a QT-prolonging drug and 837 control subjects from the population-based KORA study. Subjects were successfully genotyped at 1424 single-nucleotide polymorphisms (SNPs) in 18 candidate genes including 1386 SNPs tagging common haplotype blocks and 38 nonsynonymous ion channel gene SNPs. For validation, we used a set of cases (n=57) and population-based control subjects of European descent. The SNP KCNE1 D85N (rs1805128), known to modulate an important potassium current in the heart, predicted diLQTS with an odds ratio of 9.0 (95% confidence interval, 3.5-22.9). The variant allele was present in 8.6% of cases, 2.9% of drug-exposed control subjects, and 1.8% of population control subjects. In the validation cohort, the variant allele was present in 3.5% of cases and in 1.4% of control subjects., Conclusions: This high-density candidate SNP approach identified a key potassium channel susceptibility allele that may be associated with the rare adverse drug reaction torsades de pointes.

Background: Dronedarone (D) is developed to maintain sinus rhythm in patients suffering from atrial fibrillation. The aim of the present study was to investigate, whether dronedarone also has an antiarrhythmic potential in the ventricle and to elucidate the mechanisms for its low proarrhythmic potential in an experimental whole heart model., Methods and Results: Thirty-five rabbits underwent chronic treatment with D (n = 15; 50 mg · kg(-1) · d(-1)) and amiodarone (A; n = 20; 50 mg · kg(-1) · d(-1)). Hearts were perfused on a Langendorff apparatus. Results were compared with hearts acutely treated with sotalol (S; 50-100 μM; n = 14). A 12-lead electrocardiogram and up to 8 ventricular epi- and endocardial monophasic action potentials showed a significant prolongation of QT interval (D: +24 milliseconds, A: +28 milliseconds, S: +35 milliseconds (50 μM), +56 milliseconds (100 μM); P < 0.02) compared with baseline. In contrast to D and A, S led to a significant increase in dispersion of repolarization and exhibited reverse use dependence. D, A, and S increased refractory period, resulting in a significant increase in postrepolarization refractoriness (effective refractory period minus action potential duration; D = +12 milliseconds; A = +14 milliseconds; S = +25 milliseconds; P < 0.05). S led to a triangular action potential configuration, whereas D and A caused a fast phase 3 prolongation. After lowering of potassium concentration, 50% of S-treated hearts showed torsade de pointes, in contrast to an absence of torsade de pointes in D and A., Conclusions: Prolongation of myocardial repolarization and postrepolarization refractoriness by D may act antiarrhythmic. A fast phase 3 repolarization in the absence of both increased dispersion of repolarization and reverse use dependence prevents proarrhythmia.