Relationship of clinical adverse event reports to models of arrhythmia risk.

A vital aspect of the drug discovery and development process is the identification and filtering of drugs with high risk of dangerous adverse events. Torsade de Pointes (TdP) is one example of an adverse event that requires thorough in vitro and in vivo drug screening. This is because TdP, a tachycardic ventricular arrhythmia, can develop into fatal cardiac events if left unresolved and has been missed during drug development with profound consequences. These factors led to the development of pre-clinical screening guidelines based on the presence of drug induced QT prolongation (QTp), which has been linked to TdP. These guidelines have high sensitivity, but low specificity, as they tend to predict QTp, which precedes TdP events but does not always lead to TdP. Computational models have the potential to improve these prediction methods by bridging the gaps between preclinical and clinical data. This study proposes the use of adverse event reports obtained from the FDA Adverse Event Reporting System as a representation of clinical TdP risk. By incorporating these reports into computational models, a more accurate risk prediction may be developed.

Machine-Learning Prediction of Drug-Induced Cardiac Arrhythmia: Analysis of Gene Expression and Clustering.

A marked delay in the electrical repolarization of heart ventricles is characterized by prolongation of the Q-T wave (QT) interval on a surface electrocardiogram. Such a delay can lead to potentially life-threatening cardiac arrhythmia (torsades de pointes). Such prolongation is also a widely accepted cardiac safety biomarker in drug development. Current preclinical drug-safety assays include patch clamp analysis to evaluate drug-related blockade of cardiac repolarizing ion currents. Recently reported patch clamp assay results have shown predictive sensitivities and specificities in the ranges of 64%-82% and 75%-88%, respectively. In this project, we use a support vector machine classifier to find mean sensitivities and specificities of 85% and 90%, respectively, across 77 drug subclassifications. Clustering by gene expression profile similarities shows that drugs known to prolong the QT interval do not always form distinct groups, but the number of groups is limited. The most common biological network links associated with these groups involve genes linked with fatty acid metabolism, G proteins, intracellular glutathione, immune responses, apoptosis, mitochondrial function, electron transport, and mitogen-activated protein kinases. These results suggest that machine-learning analysis of gene expression and clustering may augment cardiac safety predictions for improving drug-safety assessments.

Electrophysiological measurements that can explain and guide temporary accelerated pacing to avert (re)occurrence of torsade de pointes arrhythmias in the canine chronic atrioventricular block model.

BACKGROUND: Pacing at higher rates is known to suppress torsade de pointes (TdP) arrhythmias. Nevertheless, exact application and mechanism need further clarification. In the anesthetized canine chronic atrioventricular block model, ventricular remodeling is responsible for a high and reproducible incidence of TdP upon a challenge with dofetilide. OBJECTIVE: We used this model to investigate by what mechanism accelerated pacing averts TdP and what repolarization parameter could be used to guide temporary accelerated pacing (TAP). METHODS: Ten dogs with repetitive TdP after administration of dofetilide when paced at 60 beats/min were selected. In a serial experiment, TAP was initiated at 100 beats/min after the first ectopic beat. Electrocardiogram and right and left ventricular (LV) monophasic action potential durations (MAPDs) were recorded. In a subset, vertical dispersion was determined with a duodecapolar catheter. Temporal dispersion was quantified as short-term variability (STV). Arrhythmias were quantified with the arrhythmia score. RESULTS: The increase in repolarization parameters observed after administration of dofetilide was counteracted by TAP (eg, LV MAPD from 381 ± 94 ms back to 310 ± 17 ms; P < .05). Temporal dispersion (STVLVMAPD) increased from 0.69 ± 0.37 to 2.59 ± 0.96 ms (P < .05) after administration of dofetilide and back to 1.15 ± 0.54 ms (P < .05) with TAP. This was accompanied by suppression of recurrent TdP in 7 of 10 dogs (P < .05) and a trend toward reduction in vertical (spatial) dispersion from 56 ± 25 to 31 ± 4 ms (P = .06). In those dogs, seconds after capture of TAP, almost all ectopy disappeared, causing a decrease in arrhythmia score from 21 ± 12 to 4 ± 3 (P < .05). CONCLUSION: TAP is effective in averting TdP by decreasing spatial and temporal measures of repolarization. Increase in temporal dispersion (STV) can guide TAP.

Hyperglycemia and subsequent torsades de pointes with marked QT prolongation during refeeding.

OBJECTIVE: A fatal cardiac complication can occasionally present in malnourished patients during refeeding; this is known as refeeding syndrome. However, to our knowledge, hyperglycemia preceding torsades de pointes with QT prolongation during refeeding has not been reported. In the present study, we present a case in which hyperglycemia preceded torsades de pointes with QT prolongation during refeeding. The aim of this study was to determine the possible mechanism underlying QT prolongation during refeeding and indicate how to prevent it. METHODS: A 32-y-old severely malnourished woman (body mass index 14.57 kg/m2) was admitted to the intensive care unit of our institution after resuscitation from cardiopulmonary arrest due to ventricular fibrillation. She was diagnosed with anorexia nervosa. Although no obvious electrolyte abnormalities were observed, her blood glucose level was 11 mg/dL. A 12-lead electrocardiogram at admission showed sinus rhythm with normal QT interval (QTc 0.448). RESULTS: Forty mL of 50% glucose (containing 20 g of glucose) was intravenously injected, followed by a drip infusion of glucose to maintain blood glucose level within normal range. After 9 h, the patient's blood glucose level increased to 569 mg/dL. However, after 38 h, an episode of marked QT prolongation (QTc 0.931) followed by torsades de pointes developed. CONCLUSIONS: Hyperglycemia during refeeding can present with QT prolongation; consequently, monitoring blood glucose levels may be useful in avoiding hyperglycemia, which can result in QT prolongation. Furthermore, additional monitoring of QT intervals using a 12-lead electrocardiogram should allow the early detection of QT prolongation when glucose solution is administered to a malnourished patient with (severe) hypoglycemia.

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.

Rechanneling the cardiac proarrhythmia safety paradigm: a meeting report from the Cardiac Safety Research Consortium.

This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration-sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance.

KN-93, A CaMKII inhibitor, suppresses ventricular arrhythmia induced by LQT2 without decreasing TDR.

Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 µmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 µmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.

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.

[Magnesium metabolism and therapeutic strategy in cardiovascular disease].

Many epidemiological and clinical analysis have reported the relation between Mg and cardiovascular disease. Hypomagnesemia may be triggering mechanisms for ischemic heart disease, arrhythmias after open heart surgery, serious arrhythmias such as Torsades de Pointes (TdP) , and the negative feed back in congestive heart failure. Supplemental and therapeutic Mg infusion have been reported to reduce the mortality in acute myocardial infarction and having the cardioprotective effect after infarction (controversial) . It is also reported to reduce the incidence of arrhythmias after heart surgery, terminate the serious arrhythmias such as TdP, and improve the negative feed back in congestive heart failure. Magnesium metabolisms in cardiovascular disease are not necessarily clear. We expect the precise analysis of Mg actions and attractive Mg therapy in clinical literature.

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.

[First experience of clinical use of new class III antiarrhythmic agent niferidil in patients with persistent atrial fibrillation and flutter].

The aim of the study was to evaluate the efficacy and safety of administered intravenously niferidil in doses 10, 20 and 30 mkg per kg in patients with persistent atrial fibrillation (AF) and flutter (AFL) for pharmacological cardioversion. The study included 30 patients (22 male) with persistent AF (n = 28) and AFL (n = 2) without structural heart diseases with median arrhythmia duration 6.1 +/- 4.8 months (2 weeks to 24 months). Niferidil was administered as 3 bolus injections (10 mkg per kg each) performed with the interval of 15 minutes. Antiarrhythmic efficacy of niferidil in dose of 10 mkg per kg was 60%, in dose of 20 mkg per kg it was 70%, and in dose of 30 mkg per kg reached 90% prespectively. The part of the patients, in whom QTc prolongation exceeded potentionally dangerous value of 500 mc, was 22.2% (6 of 27). None of the patients developed proarrhythmic side effect as torsade de pointes.

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.

Minimizing repolarization-related proarrhythmic risk in drug development and clinical practice.

Proarrhythmia, the development of new or worse arrhythmias in response to drug therapy, is a major limitation to the development and use of new drugs. There are different types of drug-induced proarrhythmia, including long-QT syndrome (LQTS), short-QT syndrome and proarrhythmia related to Na+-channel blockade/conduction impairment. By far the most important form of proarrhythmia at present is drug-induced LQTS and its associated characteristic tachyarrhythmia, torsades de pointes (TdP). TdP arises when cellular action potentials (APs) are excessively prolonged, leading to arrhythmogenic afterdepolarizations, especially early afterdepolarizations (EADs), which trigger complex re-entry in a substrate involving increased transmural dispersion of repolarization. In vitro screening, increasingly involving high-throughput assays, is used to assess potential candidate molecules and eliminate potentially problematic structures at an early stage of development. The most commonly used screening assays assess drug block of the K+ current carried by human ether-à-go-go (hERG) subunits, corresponding to the rapid delayed-rectifier K+ channel, the overwhelmingly most common target of TdP-inducing drugs. In addition, the effects of drugs on AP duration or the in vivo equivalent, QT interval, are often assessed in animal models. Methods available for repolarization-related proarrhythmic risk assessment include in vitro (Langendorff-perfused rabbit or guinea pig hearts) and in vivo models (such as alpha-adrenoceptor-stimulated rabbits, rabbits with reduced repolarization reserve due to block of slow delayed-rectifier current, animals with chronic atrioventricular block or animals with cardiac remodelling caused by congestive heart failure). In silico modelling may be helpful for molecular design of non-hERG blocking candidates and for optimization of compound selection (at the molecular and pharmacological profile levels). Finally, clinical evaluation of effects on electrocardiographic intervals (particularly QT) and cardiac rhythm are often needed, both prior to drug approval and after successful introduction on the market (postmarketing surveillance). The successful avoidance of proarrhythmic complications is a shared responsibility of the innovative pharmaceutical industry, regulatory authorities, partners in the clinical drug development phase and practicing physicians. This paper reviews the principal forms of proarrhythmia and the methods that can be used to minimize the risk of proarrhythmia in drug development and clinical practice, with particular emphasis on the most common and problematic form, acquired LQTS.

Pharmacological enhancement of cardiac gap junction coupling prevents arrhythmias in canine LQT2 model.

Gap junctions contribute to the transmural heterogeneity of repolarization in the normal heart and under conditions of prolonged QT interval in the diseased heart. This study examined whether enhancing of gap junction coupling can reduce transmural dispersion of repolarization (TDR) and prevent torsade de pointes (TdP) in a canine LQT2 model. Canine left ventricular wedge preparations were perfused with delayed rectifier potassium current (IKr) blocker d-sotalol to mimic LQT2 and the antiarrhythmic peptide 10 (AAP10) was used as a gap junction coupling enhancer. As compared with the control group, the LQT2 group had significantly augmented TDR and higher incidence of TdP associated with increased nonphosphorylated connexin 43 (Cx43). AAP10 prevented augmentation of TDR and induction of TdP while rescuing Cx43 phosphorylation. There was no significant change in the quantity and spatial distribution of Cx43. These data indicate that gap junction enhancer AAP10 can prevent augmentation of TDR and suppress TdP by preventing dephosphorylation of Cx43 in a LQT2 model.

Methadone-associated Q-T interval prolongation and torsades de pointes.

PURPOSE: The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided. SUMMARY: Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible. CONCLUSION: Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary.

Ultrafast sodium channel block by dietary fish oil prevents dofetilide-induced ventricular arrhythmias in rabbit hearts.

Several epidemiologic and clinical studies show that following myocardial infarction, dietary supplements of omega-3 polyunsaturated fatty acids (omega3FA) reduce sudden death. Animal data show that omega3FA have antiarrhythmic properties, but their mechanisms of action require further elucidation. The effects of omega3FA supplementation were studied in female rabbits to analyze whether their antiarrhythmic effects are due to a reduction of triangulation, reverse use-dependence, instability, and dispersion (TRIaD) of the cardiac action potential (TRIaD as a measure of proarrhythmic effects). In Langendorff-perfused hearts challenged by a selective rapidly activating delayed rectifier potassium current inhibitor that has been shown to exhibit proarrhythmic effects (dofetilide; 1 to 100 nM), omega3FA pretreatment (30 days; n=6) prolonged the plateau phase of the monophasic action potential; did not slow the terminal fast repolarization; reduced the dofetilide-induced prolongation of the action potential duration; reduced dofetilide-induced triangulation; and reduced dofetilide-induced reverse use-dependence, instability of repolarization, and dispersion. Dofetilide reduced excitability in omega3FA-pretreated hearts but not in control hearts. Whereas torsades de pointes (TdP) were observed in five out of six in control hearts, none were observed in omega3FA-pretreated hearts. Docosahexaenoic acid (DHA) inhibited the sodium current with ultrafast kinetics. Dietary omega3FA supplementation markedly reduced dofetilide-induced TRIaD and abolished dofetilide-induced TdP. Ultrafast sodium channel block by DHA may account for the antiarrhythmic protection of the dietary supplements of omega3FA against dofetilide-induced proarrhythmia observed in this animal model.

Calmodulin antagonist W-7 prevents sparfloxacin-induced early afterdepolarizations (EADs) in isolated rabbit purkinje fibers: importance of beat-to-beat instability of the repolarization.

INTRODUCTION: The occurrence of early afterdepolarizations (EADs) has been related to the incidence of torsades de pointes in drug-induced long QT (LQT). The generation of EADs may be facilitated by Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase). METHODS AND RESULTS: In the present study, we investigated a possible involvement of Ca(2+)/Calmodulin dependent protein kinase in the generation of sparfloxacin-induced EADs in isolated rabbit Purkinje fibers by means of a calmodulin antagonist W-7. EADs were evident in 8 of the 10 preparations perfused with sparfloxacin at 1 x 10(-4) M and stimulated at 0.2 Hz. The induction of EADs by sparfloxacin was associated with a large prolongation of the duration of the action potential (APD), an increase in the triangulation, and the short-term instability of the repolarization. CaM kinase blockade with the calmodulin antagonist W-7 inhibited sparfloxacin-induced EADs in a concentration-dependent manner (EADs were induced in 3 of 10, 1 of 10, and 0 of 8 preparations in the presence of W-7 at 5 x 10(-7) M, 5 x 10(-6) M, and 5 x 10(-5) M, respectively; P < 0.01 at 5 x 10(-6) M and 5 x 10(-5) M). The inhibition of sparfloxacin-induced EADs by W-7 at 5 x 10(-7) M and 5 x 10(-6) M was associated with a significant decrease in the beat-to-beat instability but not associated with a significant shortening of the APD and reduction of V(max). CONCLUSION: The present findings support the hypothesis that CaM kinase may be a proarrhythmic signaling molecule and demonstrate that CaM kinase may be involved in the generation of EADs in drug-induced LQT and enhanced beat-to-beat instability of repolarization is essential for the genesis of EADs in rabbit in vitro.

An overview of QT interval assessment in safety pharmacology.

Medicinal products that prolong cardiac repolarization unintentionally, as assessed in terms of prolongation of the QT interval of the electrocardiogram, may trigger a potentially fatal arrhythmia called torsade de pointe (TDP). This lethal risk necessitates a detailed preclinical evaluation before initiating clinical trials. There are two different and complementary approaches to assess the potential of drugs to cause QT interval prolongation. The in vivo approach provides information on the potential of the compound to prolong the QT interval under near-physiological conditions. It is mostly descriptive and not explanatory in terms of mechanisms of action. The in vitro approach provides much more mechanistic information, but is far removed from the clinical situation. While both approaches appear to possess reasonable predictive value, the results may depend largely on the experimental conditions employed. This unit reviews these issues and discusses a strategy aimed at understanding the problems associated with this cardiovascular risk.

Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization: does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes?

BACKGROUND: The present study examined pacing site-dependent changes in QT interval and transmural dispersion of repolarization (TDR) and their potential role in the development of torsade de pointes (TdP). METHODS AND RESULTS: In humans, the QT interval, JT interval, and TDR were measured in 29 patients with heart failure during right ventricular endocardial pacing (RVEndoP), biventricular pacing (BiVP), and left ventricular epicardial pacing (LVEpiP). In animal experiments, pacing site--dependent changes in ventricular repolarization were examined with a rabbit left ventricular wedge preparation in which action potentials from endocardium and epicardium could be simultaneously recorded with a transmural ECG. In humans, LVEpiP and BiVP led to significant QT and JT prolongation. LVEpiP also enhanced TDR. Frequent R-on-T extrasystoles generated by BiVP and LVEpiP but completely inhibited by RVEndoP occurred in 4 patients, of whom 1 developed multiple episodes of nonsustained polymorphic ventricular tachycardia and another suffered incessant TdP. In rabbit experiments, switching from endocardial to epicardial pacing produced a net increase in QT interval and TDR by 17+/-5 and 22+/-5 ms, respectively (n=6, P<0.01), without parallel increases in ventricular transmembrane action potential durations. Epicardial pacing facilitated transmural propagation of early afterdepolarization, leading to the development of R-on-T extrasystoles and TdP in the presence of action potential duration-prolonging agents. CONCLUSIONS: LVEpiP and BiVP increase QT, JT, and TDR by altering the transmural sequence of activation of the intrinsically heterogeneous ventricular myocardium. Our data suggest that the resultant exaggeration of arrhythmic substrates can lead to the development of TdP in a subset of patients.

Chronic amiodarone evokes no torsade de pointes arrhythmias despite QT lengthening in an animal model of acquired long-QT syndrome.

BACKGROUND: Amiodarone is an effective antiarrhythmic drug rarely associated with torsade de pointes arrhythmias (TdP). The noniodinated compound dronedarone could resemble amiodarone and be devoid of the adverse effects. In the dog with chronic complete atrioventricular (AV) block (CAVB) and acquired long-QT syndrome, the electrophysiological and proarrhythmic properties of the drugs were compared after 4 weeks of oral treatment. METHODS AND RESULTS: Amiodarone (n=7, 40 mg. kg(-1). d(-1)) and dronedarone (n=8, 20 mg/kg BID) were started at 6 weeks of CAVB (baseline). Six dogs served as controls. Surface ECGs and endocardially placed monophasic action potential catheters in the left (LV) and right (RV) ventricles were recorded to assess QTc time, action potential duration (APD), interventricular dispersion (DeltaAPD=LV APD minus RV APD), early afterdepolarizations (EADs), ectopic beats, and TdP. Both amiodarone (+21%) and dronedarone (+31%) increased QTc time. Amiodarone showed no increase in DeltaAPD in 4 of 7 dogs, whereas dronedarone augmented DeltaAPD in 7 of 8 animals. After dronedarone, TdP occurred in 4 of 8 dogs with the highest DeltaAPD (105+/-20 ms). TdP was never seen with amiodarone, not even in the dogs that had DeltaAPD values comparable to those with dronedarone. Furthermore, a difference existed in EADs and ectopic activity incidence (dronedarone 3 of 8; amiodarone 0 of 7), which was also seen during an epinephrine challenge. CONCLUSIONS: In the CAVB dog model, both amiodarone and dronedarone prolong QT time (class III effect). The absence of TdP with amiodarone seems to be related to homogeneous APD lengthening in the majority of dogs and the lack of EADs and/or ventricular ectopic beats in all.