QT prolongation, torsades des pointes, and cardiac arrest after 4 mg of IV ondansetron.

Ondansetron is a commonly used antiemetic in the emergency department despite a 2011 FDA warning regarding dose-related QTc prolongation and torsades des pointes (TdP). Cases of TdP from small ondansetron doses administered in the emergency department are lacking. A 41-year-old-woman with alcohol use disorder on no medications or supplements presented to an emergency department with one day of nausea, vomiting, and epigastric pain. Examination revealed a pulse of 77 beats/min and epigastric tenderness. The patient received 4 mg IV ondansetron, 30 mg IV ketorolac, and was placed on cardiac monitoring. ECG obtained one minute after ondansetron demonstrated premature ventricular contractions with QTc = 653 ms. Thirteen minutes after receiving ondansetron she suffered TdP and cardiac arrest. She received immediate CPR and IV epinephrine with successful defibrillation at one minute. She then received IV magnesium. Post-arrest ECGs demonstrated persistent QTc prolongation immediately and at three hours post-arrest. Laboratory studies, drawn prior to arrest, demonstrated hypokalemia (3.2 mEq/L), hypomagnesemia (1.3 mg/dL), and elevated lipase (4918 IU/L). She received no additional QT-prolonging agents. Transthoracic echocardiogram and troponins were normal; ECG intervals completely normalized within 12 h and she was discharged neurologically intact. The patient returned 18 months later with recurrent pancreatitis and similar electrolyte abnormalities; QT-prolonging drugs were avoided at that time and her course was uncomplicated. QT prolongation with subsequent torsades des pointes and cardiac arrest may occur in high-risk patients receiving small doses of ondansetron. Further studies are warranted to determine the safest antiemetic for use in the emergency department.

Torsade de pointes: A nested case-control study in an integrated healthcare delivery system.

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.

Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs.

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.

Translational Models and Tools to Reduce Clinical Trials and Improve Regulatory Decision Making for QTc and Proarrhythmia Risk (ICH E14/S7B Updates).

After multiple drugs were removed from the market secondary to drug-induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical-industry perspective making the case that "double-negative" nonclinical data (negative in vitro hERG and in vivo heart-rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double-negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double-negative nonclinical data could be used to reduce the number of "Thorough QT" (TQT) studies and reach a low-risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a "stage 2" of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc-prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double-negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

Arrhythmogenic foods - A growing medical problem.

Arrhythmogenic ingredients in our diet such as mushrooms, licorice, toxic honey, liquid protein drinks, etc. have long been recognized as rare but important considerations in the differential diagnosis of arrhythmias. Anecdotal reports of torsades de pointes (TdP), arrhythmias and/or sudden death and small studies in normal subjects have suggested that simple ingredients such as grapefruit juice or ingredients in energy drinks marketed as dietary supplements could have direct arrhythmogenic actions, especially in patients with congenital long QT syndrome (cLQTS). Two recent studies that employed the industry-standard "thorough QT" trial design leave no doubt that grapefruit juice and some energy drinks can prolong the QTc interval and to exceed 500 msec. in some patients with cLQTS, a threshold known to signal imminent danger. These reports raise numerous clinically important questions such as which other patients may be at risk of arrhythmias. For example, patients with multiple clinical risk factors for TdP (hypokalemia, bradycardia, female sex, etc.) may be at risk from these and possibly other dietary ingredients ingested by millions of people each day. It is essential that further research evaluate the safety of these and similar food products and that vulnerable patients, especially those with cLQTS, be warned of this serious and emerging threat.

Fragmented endocardial signals and early afterdepolarizations during torsades de pointes tachycardia.

BACKGROUND: Bradycardia-induced torsade de pointes (TdP) tachycardia in patients with spontaneous high-degree atrioventricular block (AVB) is common. The aim of this study was to analyze endocardial recordings during TdP in spontaneous high-degree AVB in humans to better understand the electrophysiological mechanisms underlying this phenomenon. METHODS: The study group consisted of 5 patients with typical episodes of TdP during spontaneous high-degree AVB. A standard (USCI) temporary bipolar endocardial catheter positioned at the apex of the right ventricle (RV) and bipolar chest leads from two precordial leads V1 and V4 were used to record the tracings during TdP. RESULTS: The presence of a wide spectrum of fragmentations was noted on endocardial electrograms (EGMs), which were invisible on the surface electrocardiogram (ECG) tracing. Endocardial signals indicated that TdP started in the proximity of the RV apex, since the local EGM began prior to the QRS complex on the surface ECG. Early afterdepolarizations (EADs) were observed in 2 out of 5 cases confirming a common opinion about the mechanism of TdP. However, this phenomenon was not observed in 3 other patients suggesting that the arrhythmia was the result of a different mechanism originating in proximity to the RV apex. CONCLUSIONS: This work demonstrated early endocardial signals in the RV apex during TdP associated with high-degree AVB in humans, and exhibits a spectrum of fragmented signals in this area occurring on a single or multiple beats. These fragmentations indicate areas of poor conduction and various degrees of intramyocardial block, and therefore a new mechanism of TdP tachycardia in some patients with spontaneous high-degree AVB.

Point of View: Electrophysiological Endpoints Differ When Comparing the Mode of Action of Highly Successful Anti-arrhythmic Drugs in the CAVB Dog Model With TdP.

In the anaesthetized, chronic atrioventricular block (CAVB) dog, ventricular ectopic beats and Torsade de pointes arrhythmias (TdP) are believed to ensue from an abrupt prolongation of ventricular repolarization and increased temporal dispersion of repolarization, quantified as short-term variability (STV). These TdP stop spontaneously or, when supported by substantial spatial dispersion of repolarization (SDR), degenerate into ventricular fibrillation. However, most studies involving ventricular arrhythmias do not quantify SDR by means of an electrophysiological parameter. Therefore, we reviewed the effects of 4 highly effective anti-arrhythmic drugs (flunarizine, verapamil, SEA-0400, and GS-458967) on the repolarization duration and associated STV. All drugs were tested as anti-arrhythmic strategies against TdP in CAVB dogs, their high anti-arrhythmic efficacy was defined as suppressing drug-induced TdP in 100% of the experiments. This comparison demonstrates that even though the anti-arrhythmic outcome was similar for all drugs, distinct responses of repolarization duration and associated STV were observed. Moreover, the aforementioned and commonly adopted electrophysiological parameters were not always sufficient in predicting TdP susceptibility, and additional quantification of the SDR proved to be of added value in these studies. The variability in electrophysiological responses to the different anti-arrhythmic drugs and their inconsistent adequacy in reflecting TdP susceptibility, can be explained by distinct modes of interference with TdP development. As such, this overview establishes the separate involvement of temporal and spatial dispersion in ventricular arrhythmogenesis in the CAVB dog model and proposes SDR as an additional parameter to be included in future fundamental and/or pharmaceutical studies regarding TdP arrhythmogenesis.

Cardiologist's point of view: Novel ECG biomarkers and in silico models for proarrhythmic risk prediction: Are we ready?

The CiPA initiative is well underway, but in its early stages. Are we ready for it? There are several issues that bear on the success of this multidisciplinary effort related to (1) the final testing paradigm that will result, (2) the way in which discrepancies in test methods will be handled, (3) commercialization of the testing methods, (4) quantitative understanding of arrhythmia risk of the 6 non-hERG channels being tested, (5) validity of the CiPA drug list, and (6) ultimate clinical validation.

AV-block and conduction slowing prevail over TdP arrhythmias in the methoxamine-sensitized pro-arrhythmic rabbit model.

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.

T-type calcium current contributes to escape automaticity and governs the occurrence of lethal arrhythmias after atrioventricular block in mice.

BACKGROUND: When complete atrioventricular block (AVB) occurs, infranodal escape rhythms are essential to prevent bradycardic death. The role of T-type Ca(2+) channels in pacemaking outside the sinus node is unknown. We investigated the role of T-type Ca(2+) channels in escape rhythms and bradycardia-related ventricular tachyarrhythmias after AVB in mice. METHODS AND RESULTS: Adult male mice lacking the main T-type Ca(2+) channel subunit Cav3.1 (Cav3.1(-/-)) and wild-type (WT) controls implanted with ECG telemetry devices underwent radiofrequency atrioventricular node ablation to produce AVB. Before ablation, Cav3.1(-/-) mice showed sinus bradycardia (mean±SEM; RR intervals, 148±3 versus 128±2 ms WT; P<0.001). Immediately after AVB, Cav3.1(-/-) mice had slower escape rhythms (RR intervals, 650±75 versus 402±26 ms in WT; P<0.01) but a preserved heart-rate response to isoproterenol. Over the next 24 hours, mortality was markedly greater in Cav3.1(-/-) mice (19/31; 61%) versus WT (8/26; 31%; P<0.05), and Torsades de Pointes occurred more frequently (73% Cav3.1(-/-) versus 35% WT; P<0.05). Escape rhythms improved in both groups during the next 4 weeks but remained significantly slower in Cav3.1(-/-). At 4 weeks after AVB, ventricular tachycardia was more frequent in Cav3.1(-/-) than in WT mice (746±116 versus 214±78 episodes/24 hours; P<0.01). Ventricular function remodeling was similar in Cav3.1(-/-) and WT, except for smaller post-AVB fractional-shortening increase in Cav3.1(-/-). Expression changes were seen post-AVB for a variety of genes; these tended to be greater in Cav3.1(-/-) mice, and overexpression of fetal and profibrotic genes occurred only in Cav3.1(-/-). CONCLUSIONS: This study suggests that T-type Ca(2+) channels play an important role in infranodal escape automaticity. Loss of T-type Ca(2+) channels worsens bradycardia-related mortality, increases bradycardia-associated adverse remodeling, and enhances the risk of malignant ventricular tachyarrhythmias complicating AVB.

The ketogenic diet and the QT interval.

Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms.

[Clinical characteristics of 52 patients with torsade de points associated with acquired QT prolongation].

OBJECTIVE: Risk factors, ECG characteristics and treatment options of patients with Torsade de Points associated with acquired QT prolongation are summarized in this study. METHOD: Using "torsade de points" and "QT prolongation" as the keywords to search the inpatients database from 1990 - 2010 of Fuwai hospital, 52 eligible patients were included in this analysis. RESULTS: Structural heart diseases were found in 67.3% and electrolyte disorders in 59.6% patients, 36.5% patients received diuretic therapy and 28.8% received antiarrhythmic drugs which might induce prolonged QT interval. The mean QTc was (571 ± 93) ms and (456 ± 50) ms before and after treatment. All patients received potassium and magnesium supplement. Isoproterenol was used in 32.7% patients. 13.5% patients received temporary pacing therapy. CONCLUSIONS: Torsade de points and acquired QT interval prolongation was often associated with electrolyte disorders and drugs causing QT prolongation. ECG and QTc should be intensively monitored for high risk patients. Early awareness of the warning signs might contribute to early recognition and proper treatment of patients with Torsade de Points associated with acquired QT prolongation.

Ventricular rate adaptation: a novel, rapid, cellular-based in-vitro assay to identify proarrhythmic and torsadogenic compounds.

INTRODUCTION: Delayed cardiac repolarization is an established risk factor for proarrhythmia and Torsades-de-Pointes (TdeP) that is typically measured in vitro during slow, regular stimulation. We have developed an alternative, novel, and rapid cellular-based approach for predicting drug-induced proarrhythmia that detects changes in electrical refractoriness based on mechanical responses (measured optically) during increasingly rapid trains of stimulation interspersed with pauses (mimicking the clinically observed short-long-short (SLS) stimulation sequence associated with the TdeP initiation). METHODS: Acutely isolated rabbit ventricular myocytes were superfused and electrically stimulated using an accelerating pacing protocol (APP) consisting of 12 consecutive pacing segments (10 beats per segment) with incrementally faster cycle lengths; trains were separated by pauses to identify loss of stimulus capture as well as to mimic clinically observed SLS sequences. Drug effects were evaluated based on a myocyte's ability to contract during progressively faster pacing segments (rate-adaptation); the earliest rate during which the myocyte fails to respond (longest cycle length with incomplete capture (CLIC)) was used to quantify electrophysiologic effects. RESULTS: Torsadogenic drugs known to delay repolarization during slow stimulation prolonged CLIC and dramatically limited the ability to respond to progressively rapid stimulation. The recognized proarrhythmic compounds E-4031, cisapride, grepafloxacin, and haloperidol rapidly prolonged CLIC at and above therapeutic concentrations in a concentration-dependent manner, while negative controls (captopril, indomethacin, and loratidine) do not affect rate-adaptation. DISCUSSION: Ventricular rate adaptation represents a novel approach for rapidly detecting drugs with torsadogenic risk using rapid rhythms that are typically not employed when evaluating proarrhythmic risk. This method is well suited for detecting and avoiding potential cardiac liabilities early in drug discovery ("frontloading") prior to final selection of candidate drugs.

Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent.

Ibutilide is a class III antiarrhythmic agent indicated for cardioversion of atrial fibrillation and atrial flutter to sinus rhythm (SR). The most serious complication of ibutilide is torsades de pointes (TdP). Magnesium has been successfully used for the treatment of TdP, but its use as a prophylactic agent for this arrhythmia has not yet been established. The present study investigated whether high dose of magnesium would increase the safety and efficacy of ibutilide administration. A total of 476 patients with atrial fibrillation or atrial flutter who were candidates for conversion to SR were divided into 2 groups. Group A consisted of 229 patients who received ibutilide to convert atrial fibrillation or atrial flutter to SR. Group B consisted of 247 patients who received an intravenous infusion of 5 g of magnesium sulfate for 1 hour followed by the administration of ibutilide. Then, another 5 g of magnesium were infused for 2 additional hours. Of the patients in groups A and B, 154 (67.3%) and 189 (76.5%), respectively, were converted to SR (p = 0.033). Ventricular arrhythmias (sustained, nonsustained ventricular tachycardia, and TdP) occurred significantly more often in group A than in group B (7.4% vs 1.2%, respectively, p = 0.002). TdP developed in 8 patients (3.5%) in group A and in none (0%) in group B (p = 0.009). The administration of magnesium (despite the high doses used) was well tolerated. In conclusion, the administration of high doses of magnesium probably makes ibutilide a much safer agent, and magnesium increased the conversion efficacy of ibutilide.

Un caso de QT largo y torsades de pointes por ciprofloxacino / No disponible

No disponible

Life-threatening Torsades de Pointes resulting from "natural" cancer treatment.

INTRODUCTION: Nonradioactive cesium chloride (CsCl) is used by some alternative medicine advocates as a treatment for cancer. The therapy was proven to be neither safe nor effective. Chronic use of CsCl has resulted in cases with severe cardiotoxicity. CASE REPORT: A 65-year-old lady presented to our hospital's accident and emergency department with recurrent syncope attacks. Electrocardiogram monitoring showed QT prolongation and transient Torsades de Pointes (TDP) ventricular tachycardia. She was taking anticancer naturopathic drugs for 6 weeks before admission. One of her naturopathic drugs was subsequently confirmed containing 89% CsCl by weight. Besides conventional treatment of QT prolongation and TDP, the patient was given a 4-week course of oral Prussian blue to enhance gastrointestinal elimination of cesium. The serum half-life of cesium was reduced from 61.7 to 29.4 days after the use of Prussian blue. QT prolongation was normalized in 27 days. DISCUSSION: To our knowledge, this is the first published case of nonradioactive cesium poisoning treated with Prussian blue. A transient rise in serum cesium level was observed during Prussian blue therapy. Possible explanations for this observation include poor drug compliance during outpatient treatment and redistribution of cesium from body stores. CONCLUSION: Nonradioactive CsCl poisoning can result in severe cardiotoxicity with QT prolongation and TDP ventricular tachycardia. The key points in the management of nonradioactive cesium poisoning include cessation of cesium exposure, vigorous electrolytes replacement, and oral Prussian blue therapy.

QT interval prolongation, torsade de pointes and renal disease.

Torsade de pointes is a form of polymorphic ventricular tachycardia occurring in a setting of prolonged QT interval on surface electrocardiogram. Several non-antiarrhythmic drugs including antibiotic and antipsychotic agents have been shown to prolong cardiac repolarization predisposing to torsade de pointes ventricular tachycardia. Blockade of the delayed rectifier (repolarising) potassium current and drug interactions with inhibitors of the cytochromes P450 (CYP)-mediated metabolism are the most common underlying mechanisms. Many antiarrhythmic drugs have been also implicated in prolonging QT interval and triggering torsades de pointes, especially during chronic therapy or in case of acute high dose toxicity. Progressive renal disease is associated from the earliest stages with increased QT interval and dispersal and with an increased risk of cardiovascular death, specifically sudden death. It has also been reported that cCorrected QT (QTc) interval prolongation and torsade de pointes are associated with end-stage renal disease (ESRD) and that they can be a cause of sudden death in ESRD. We present a case of torsade de pointes in a 82-year-old Italian woman with chronic renal failure.

Chronic methadone therapy complicated by torsades de pointes: a case report.

Methadone is commonly used by patients presenting to the Emergency Department (ED). The common, acute side effects of central nervous system depression and respiratory depression are easily recognizable by treating physicians as attributable to methadone; however, the cardiac toxicity of chronic methadone use recently has only been recognized. Both chronic use of large doses and a recent increase in the daily dose of methadone have been associated with QT prolongation and subsequent development of torsades de pointes. We describe the case of a 40-year-old woman whose methadone dose recently had been increased to 135 mg per day. She then presented to the ED with symptomatic torsades de pointes. She was stabilized in the ED by cardioversion and infusions of magnesium sulfate and lidocaine. The markedly prolonged corrected QT interval significantly shortened after discontinuing methadone. Inpatient cardiology evaluation found no other cause for the dysrhythmia. She was definitively treated with reduction of the daily methadone dose and an implanted cardioverter-defibrillator.

Action potential experiments complete hERG assay and QT-interval measurements in cardiac preclinical studies.

INTRODUCTION: The ICHS7B guideline focused on hERG and QT assays, although other factors have also been linked with the induction of severe arrhythmias. Thus, the aim of the present study was to demonstrate that two in vitro action potential recordings constitute convincing models of predictive drug-induced Torsades de pointes (TdP) and re-entry arrhythmias. METHODS: The effects of D,L-sotalol, flecainide and quinidine were investigated on potassium (hERG) and sodium (Na(V)1.5) currents transfected in HEK-293 cells to determine the repercussion of the blockade of these currents on rabbit Purkinje fibre (PF) and atrial action potentials. Atrial conduction velocity was also investigated as a model of re-entry arrhythmias. RESULTS: hERG channels were blocked by D,L-sotalol, quinidine and flecainide (IC(50): 69, 0.33 and 0.74 micromol/L, respectively). D,L-sotalol (30 micromol/L) induced reverse-use dependent increases in action potential duration (APD(90): +31.7% and +81.2% at 1 and 0.2 Hz) and triangulation (APD(90-40): +34.7% and +73.6% at 1 and 0.2 Hz) in PF but not in atria. Quinidine (10 micromol/L) also increased APD(90) (+14.5% and +68.5% at 1 and 0.2 Hz) and APD(90-40) (+73.3% and +152.1% at 1 and 0.2 Hz) in PF. Flecainide (10 micromol/L) shortened APD(90) in PF (-26.0% and - 22.2% at 1 and 0.2 Hz). Quinidine and flecainide blocked Na(V)1.5 channels by 32.3% and 73.1%, respectively, and produced decreases in dV/dt(max) which were more marked in atria (-20.4% and -31.9%) compared to PF (-12.8% and 22.4%) at 1 Hz. Finally, quinidine and flecainide decreased atrial conduction speed by 14.6% and 30.8%, respectively. CONCLUSION: Results obtained with flecainide demonstrate that use of the hERG channel alone should not be considered as a useful single assay. Rabbit Purkinje fiber action potentials can be considered as a comparable model for detection of reverse-use dependent APD prolongation and triangulation whereas the rabbit atria can be considered as a useful model for detection of sodium channel blockade associated with decreases in dV/dt(max) and conduction velocity.