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Background: We analyzed ventricular repolarization variability in genotyped long QT syndrome (LQTS) patients and in healthy volunteers (HV)., Method: The deltaT50, that is, the temporal variability of ventricular repolarization at 50% of the T-wave downslope, was analyzed every 15th minute on 175 and 390 Holter electrocardiogram (ECG) recordings from HV and genotyped LQTS patients, respectively. The average deltaT50 and QTcF were calculated in each subject., Results: DeltaT50 was 2.26 ± 0.71 ms (mean ± SD) in the HV and 5.74 ± 2.30 ms in the LQTS population (P < 0.0001). The sensitivity and specificity of QTcF (cutoff value 450 ms) to discriminate between the LQTS patients and the HV were 51.5% and 98.9%, and for deltaT50 (cutoff value 3 ms) 93.9% and 88.6%, respectively. The combination of both variables improved the diagnosis of the LQTS patients even further. Subgroups of LQTS patients at higher risk of cardiac events (with LQTS3, JLN, QTc > 500 ms or symptoms) had higher deltaT50 than subgroups at lower risk (with LQTS1, QTc < 450 ms or without symptoms). The variation in deltaT50 between day and night was concordant with the risk of symptoms; patients with LQTS1 had higher deltaT50 in the daytime and patients with LQTS3 had higher deltaT50 during the night., Conclusion: DeltaT50 more accurately distinguished between LQTS patients and HV than QTcF and was higher in LQTS patients with a higher risk of cardiac events. DeltaT50 can be used together with QTcF to improve the diagnosis in patients with the LQTS phenotype and tentatively also be of value for risk assessment in such patients., (©2012, Wiley Periodicals, Inc.)

Introduction: Accumulating evidence suggest that drug-induced QT prolongation per se poorly predicts repolarisation-related proarrhythmia liability. We examined whether beat-by-beat variability of the QT interval may be a complementary proarrhythmia marker to QT prolongation., Methods: Anaesthetised rabbits sensitized towards developing torsades de pointes (TdP) were infused for 30 min maximum with explorative antiarrhythmic compounds characterised as mixed ion channel blockers. Based on the outcome in this model the compounds were classified as having a low (TdPlow; n=5), intermediate (TdPintermediate; n=7) or high (TdPhigh; n=10) proarrhythmic potential. Dofetilide (n=4) was included as a representative of a selective IKr-blocking antiarrhythmic with known high proarrhythmic potential. QT interval prolongation and beat-by-beat QT variability (quantified as the short-term variability, STV) were continuously assessed during the infusion or up to the point where ventricular proarrhythmias were induced., Results: All compounds significantly prolonged the QT interval. For TdPlow and TdPhigh compounds the QT interval maximally increased from 169 ± 14 to 225 ± 28 ms (p<0.05) and from 186 ± 21 to 268 ± 42 ms (p<0.01), respectively. Likewise, in the dofetilide-infused rabbits the QT interval maximally increased from 177 ± 11 to 243 ± 25 ms (p<0.01). In contrast, whereas the STV in rabbits administered the TdPhigh compounds or dofetilide significantly increased prior to proarrhythmia induction (from 1.6 ± 0.4 to 10.5 ± 5.6 ms and from 1.6 ± 0.5 to 5.9 ± 1.8 ms, p<0.01) it remained unaltered in the TdPlow group (1.3 ± 0.6 to 2.2 ± 0.9 ms). In the TdPintermediate group, rabbits experiencing TdP had a similar maximal QT prolongation as the non-susceptible rabbits whereas the change in the STV was significantly different (from 0.9 ± 0.5 to 8.7 ± 7.3 ms vs 0.8 ± 0.3 to 2.5 ± 1.1 ms)., Discussion: It is concluded from the present series of experiments in a sensitive rabbit model of TdP that increased beat-by-beat QT interval variability precedes drug-induced TdP. In addition, assessment of this potential proarrhythmia marker may be useful in discriminating highly proarrhythmic compounds from compounds with a low proarrhythmic potential., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: The aim of the present study was to compare sensitivity in detecting the drug-induced QT interval prolongation in three dog models: conscious telemetered at sinus rhythm and conscious and anesthetized dogs during atrial pacing. The test substances used represent different chemical classes with different pharmacological and pharmacokinetic profiles., Method: Dofetilide and moxifloxacin were tested in all models, whereas cisapride and terfenadine were tested in the conscious telemetered and paced models. All substances were given as two consecutive 1.5-h intravenous infusions (infusions 1 and 2). The individual concentration-time courses of dofetilide, moxifloxacin, and cisapride were linked to the drug-induced effects on the QT interval and described with a pharmacokinetic-pharmacodynamic model to obtain an estimate of the unbound plasma concentrations at steady state that give a 10- and 20-ms drug-induced QT interval prolongation (CE10ms and CE20ms)., Results: In the conscious telemetered, conscious paced, and anesthetized dog models, the mean CE10ms values were 1.4, 4.0, and 2.5 nM for dofetilide and 1300, 1800, and 12,200 nM for moxifloxacin. For cisapride, the CE10ms values were 8.0 and 4.4 nM in the conscious telemetered and conscious paced dog models. The drug-induced QT interval prolongation during the last 30 min of infusions 1 and 2 was comparable in the conscious models, but smaller in the anesthetized dog model. Terfenadine displayed a marked delay in onset of response, which could only be detected by the extended ECG recording., Discussion: All dog models investigated detected QT interval prolongation after administration of the investigated test substances with similar sensitivity, except for a lower sensitivity in the anesthetized dogs following moxifloxacin administration. The conscious telemetered dog model was favorable, mainly due to the extended continuous ECG recording, which facilitated detection and quantification of delayed temporal differences between systemic exposure and drug-induced QT interval prolongation.

Introduction: Drug-induced QT interval prolongation may lead to ventricular arrhythmias. The aim of the study was to optimize QT interval data processing to quantify drug-induced QT interval prolongation in the telemetry instrumented conscious dog model., Methods: The test substances cisapride, dofetilide, haloperidol, and terfenadine and corresponding vehicles were given to male and female beagle dogs during two consecutive 90-min intravenous infusions. Cardiovascular parameters were recorded for 24 h and exposure to the drugs was measured. The delayed response in the QT interval after an abrupt change in heart rate was investigated. Eight mathematical models to describe the QT interval-heart rate relationship were compared and different sets of covariates were used to quantify the drug-induced effect on the QT interval., Results: After an abrupt decrease in heart rate, a 75% adaptation of the QT interval was reached after 54+/-9 s. A linear model was preferred to correct the drug-induced effect on the QT interval for heart rate, vehicle effect, serial correlation, plasma concentration and time of day. All test substances significantly prolonged the QT interval., Discussion: To optimize the processing of QT interval data, the delay in QT interval response after an abrupt change in heart rate should be considered. The QT interval-heart rate relationship and vehicle response were individual-specific and corrections were therefore made individually. When estimating the drug-induced effect on the QT interval it is considered advantageous to use plasma concentration as a covariate, as well as adjusting for vehicle effect and serial correlation in measurements. The conscious dog model detected significant increases in the QT interval for all test substances investigated.

Introduction: To assure drug safety, the investigation of the relationship between plasma concentration and drug-induced prolongation of the QT interval of the ECG is a challenge in drug discovery. For this purpose, dofetilide was utilized to demonstrate the benefits of characterizing the complete time course of concentrations and effect in conscious beagle dogs in the assessment of drug safety., Method: On two separate occasions, four male and two female beagle dogs were given vehicle or the test substance, dofetilide (0.25 mumol/kg), over a 3-h intravenous infusion. Cardiovascular parameters, including QT intervals, were recorded for 24-h using radiotelemetry. The QT interval was corrected individually for heart rate, vehicle treatment, and serial correlation (QT(c)). Exposure (plasma concentration) to dofetilide was measured and described by a two-compartment model. The individual concentration-time course of dofetilide was linked to the QT(c) interval via an effect compartment and a pharmacodynamic E(max) model, to account for the observed hysteresis., Results: Dofetilide induced a concentration-dependent increase in the QT(c) interval, with an EC(50) of 9 nM (3-30 nM, 95% C.I.) and an E(max) of 59+/-9 ms. A hysteresis loop was observed by plotting plasma concentrations vs. QT interval in time order, indicating a delay in onset of effect. It was found to have an equilibrium half-life of 11+/-8 min. Based on the parameters potency and E(max), a representation was made of the drug-induced changes to the QT interval., Discussion: An effect compartment model was found to accurately mimic the QT interval prolongation following administration of the test substance, dofetilide. The assessment of the individual concentration-effect relationship and confounding factors such as hysteresis might provide a better prediction of the safety profiles of new drug candidates.

Objective: The aim was to study factors contributing to torsade de pointes in the acquired long QT syndrome., Methods: Anaesthetised rabbits or cats were given a continuous infusion of methoxamine and the class III agent almokalant (at a rate of 5 or 25 nmol.kg-1.min-1, respectively) and the effects on incidence of torsade de pointes and QT dispersion were examined. Effects of almokalant on action potentials recorded from Purkinje fibres and ventricular cells of rabbits and cats were also studied., Results: "High rate" infusion of almokalant prolonged the QTc interval [from 162(SEM 6.2) ms to 211 (5.3) ms, p < 0.001] and initiated torsade de pointes in 9/10 rabbits after a dose of 391(116.3) nmol.kg-1. During "low rate" infusion, 1/8 rabbits developed torsade de pointes (p = 0.0029) despite infusion of 900 nmol.kg-1 almokalant and QTc prolongation from 162(3.6) ms to 230(12.6) ms (p < 0.01). In eight separate rabbits given the high rate infusion of almokalant, seven developed torsade de pointes and the QTc dispersion increased from 15(1.7) ms to 32(5.6) ms (p < 0.05). In six rabbits given the low rate infusion, none developed torsade de pointes (p = 0.0023), and the QTc dispersion was unaltered. In six cats, high rate infusion induced a QT interval lengthening from 241(6.0) ms to 349(8.0) ms (p < 0.001), but in only one cat was torsade de pointes initiated and preceded by a marked increase in QT dispersion (from 22 ms to 78 ms). In vitro, almokalant caused a marked lengthening of the action potential duration and early afterdepolarisations in Purkinje fibres but not in ventricular muscle cells of the rabbit. In the cat, however, almokalant induced a homogeneous prolongation of the action potential duration in both cell types, and early afterdepolarisations were never observed., Conclusions: The rate of infusion of repolarisation delaying agents may influence the dispersion of repolarisation and play a decisive role in the initiation of torsade de pointes.

Background: Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorphous ventricular tachyarrhythmias (PVTs) (i.e., torsade de pointes). We have studied whether the potassium channel opener pinacidil and two of its pyridylcyanoguanidine analogues (P1075 and P1188) have any antiarrhythmic effects on clofilium-induced PVTs and triggered responses in rabbits in vivo and in vitro., Methods and Results: Anesthetized rabbits were pretreated with propranolol (2 mumol/kg i.v.) and subsequently given a concomitant intravenous infusion of clofilium (63 nmol/kg/min for maximally 15 minutes) and the alpha 1-agonist methoxamine (70 nmol/kg/min). In vehicle-pretreated rabbits (n = 19), clofilium invariably induced PVTs, which closely resembled torsade de pointes and were preceded by a marked prolongation of the QTU interval (27 +/- 2.4%, p less than 0.001). In a separate group of seven rabbits in which monophasic action potentials were recorded from the left ventricular endocardium, the tachyarrhythmia was preceded by deflections consistent with early afterdepolarizations (EADs) of the plateau repolarization phase of the monophasic action potentials. Intravenous administration of the pyridylcyanoguanidines in doses reducing mean arterial blood pressure by 25 or 50 mm Hg, respectively, was associated with a dose-dependent attenuation in the occurrence of clofilium-induced PVTs. In the pinacidil-pretreated rabbits (0.41 mumol/kg or 1.86 mumol/kg i.v.), the occurrence of PVTs was reduced from seven of seven rabbits to five of six and to three of seven rabbits (p = 0.035 versus vehicle-pretreated controls), respectively. In rabbits pretreated with the low dose of P1075 (0.01 mumol/kg i.v.), PVT occurrence was reduced from six of six rabbits to two of six rabbits (p = 0.030), whereas in six rabbits given the high dose of P1075 (0.13 mumol/kg), no PVTs appeared (p = 0.001). When the sulfonylurea glibenclamide (10 mumol/kg i.v.) was administered to rabbits before P1075 (0.13 mumol/kg) was infused, clofilium induced PVTs in five of six rabbits (not significantly different from the incidence in the vehicle-pretreated rabbits). Pretreatment with P1188 (4.36 mumol/kg or 11.88 mumol/kg i.v.) caused a reduction in the occurrence of PVT from six of six rabbits to five of six and to none of six rabbits (p = 0.001), respectively. In the six animals pretreated with the high dose of P1188 in which no clofilium-induced arrhythmias were elicited, glibenclamide (20 mumol/kg i.v.) was injected after the entire dose of clofilium had been administered. In these rabbits, premature ventricular systoles and PVTs appeared within a few minutes in five and four of the animals, respectively. In contrast to the pyridylcyanoguanidines, diltiazem pretreatment (0.9 mumol/kg i.v., decreasing arterial pressure by 50 mm Hg) did not attenuate PVT occurrence (five of six rabbits). Acute administration of P1075 (0.13 mumol/kg) during recurrent attacks of PVTs abruptly regularized the rhythm in 12 of 13 animals and diminished EADs observed in monophasic action potentials recorded from the left ventricular endocardium. In in vitro experiments, action potentials were simultaneously recorded from rabbit Purkinje fibers and ventricular muscle cells. Clofilium markedly prolonged action potential duration in Purkinje fibers but not in ventricular muscle cells, and eventually, bradycardia-dependent EADs and triggered activity were elicited. P1075 completely abolished EADs and triggered activity in all (six of six) experiments. Glibenclamide antagonized the suppressive effect of P1075; hence, EADs and triggered responses reappeared and resembled those present before P1075., Conclusions: These results suggest that ATP-sensitive potassium channel activat, Background: Earlier observations have indicated that repolarization-delaying agents may, under certain circumstances, have the propensity to induce polymorp