Methods and limitations of an experimental model of long QT syndrome

Weissenburger, Jacques; Chézalviel, F.; Davy, Jean‐Marc; Lainée, Pierre; Guhennec, C.; Penin, E.; Engel, Franck; Cynober, Luc; Motté, G; Cheymol, G

doi:10.1016/0160-5402(91)90051-6

Cited by 32 publications

(11 citation statements)

References 22 publications

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“…Sotalol is a class III antiarrhythmic agent known to produce torsades de pointes in man and EAD on Purkinje fibres, an effect related to the block of potassium currents. The cumulated amount of sotalol administered (7.8 mg/kg for 3 h) in the present study is higher than the 6 mg/kg infused in 1 hour during our previous work on a conscious dog model of torsades de pointes [4]. In that study the baseline cycle length was 1600 msec (AV block) and QT interval was 315 msec, a value significantly shorter than the 369 Ϯ 13 msec we measured in the present model (baseline of D-sotalol group at 1500 msec).…”

Section: Discussioncontrasting

confidence: 58%

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Weissenburger

Noyer

Cheymol

et al. 1999

Clin Experimental Allergy

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Observations of torsades de pointes during therapy with terfenadine and astemizole has raised concern about the cardiac safety of non-sedating H1-antagonist agents. We compared cetirizine, another compound of that class, to D-sotalol and to astemizole in a model of acquired long QT syndrome. Open-chest surgery was performed in adult beagle dogs anaesthetized with halothane and thiopental. Bradycardia was produced with beta-adrenergic blockade and sinus node crush. Four left ventricular intramyocardial unipolar monophasic action potentials (MAP) were recorded during atrial pacing at basic cycle lengths (BCL) 400-1500 msec, before and during three successive 1-h drug infusions (0.14, 0.45 and 1.4 mg/kg/h for astemizole and cetirizine and 1.1, 2.2 and 4.5 mg/kg/h for D-sotalol). Dose- and bradycardia-dependent prolongations of MAP duration (MAPD) were produced by D-sotalol (P < 0.001) and astemizole (P < 0.001) but not by cetirizine. At BCL 1500 ms, the three infusions of astemizole prolonged endocardial MAPD from 323 +/- 8 msec (mean +/- SE) at baseline to 343 +/- 10, 379 +/- 13 and 468 +/- 26 msec, respectively (n = 9). Sotalol prolonged that MAPD from 339 +/- 6 msec to 377 +/- 7, 444 +/- 15 and 485 +/- 24 msec (n = 7). In contrast, cetirizine did not prolong MAPD: 341 +/- 8 msec at baseline Vs 330 +/- 8, 324 +/- 9 and 323 +/- 11 msec (n = 9). Drug-induced increase in transmural dispersion reached +79 +/- 19 msec after astemizole, +59 +/- 21 msec after D-sotalol and only +7 +/- 11 msec after cetirizine. Runs of ventricular tachycardias and torsades de pointes occurred during dose three of astemizole (5/9 dogs) and D-sotalol (4/7 dogs) but never during cetirizine. In the present model, astemizole and D-sotalol but not cetirizine prolonged MAPD and transmural dispersions of repolarization and produced torsades de pointes. These results suggest that the halothane-anaesthetized bradycardic dog could be a valuable model to discriminate drugs for their class III effects and proarrhythmic potencies.

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Section: Discussioncontrasting

confidence: 58%

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Weissenburger

Noyer

Cheymol

et al. 1999

Clin Experimental Allergy

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“…Pacing electrodes are placed, and the dogs are followed for 2 to 4 months to allow for bradycardia‐induced ventricular remodeling 53 . In one version of this model, the dogs' susceptibility to torsades de pointes is further increased by using furosemide to induce hypokalemia 54 …”

Section: Whole Heart and Related Studiesmentioning

confidence: 99%

Drug‐Induced Torsades de Pointes and Implications for Drug Development

Fenichel¹,

Malík

Antzelevitch

et al. 2004

Cardiovasc electrophysiol

308

200

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Torsades de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently developed understanding of the underlying electrophysiology allows better estimation of the drug‐induced risks and explains the failures of older approaches through the surface ECG. This article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug‐induced repolarization changes, their preclinical and clinical evaluation, and the risk‐to‐benefit interpretation of drug‐induced torsades de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsades within drug development programs. Individual sections of the text discuss the techniques and limitations of methods directed at drug‐related ion channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and interpretation of human ECGs obtained in clinical studies. The final section of the text discusses drug‐induced torsades within the larger evaluation of drug‐related risks and benefits. (J Cardiovasc Electrophysiol, Vol. 15, pp. 475‐495, April 2004)

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“…2,11,12 In those AVB dogs, reproducible TdP could be induced by pacing with short/long/short sequence or class III antiarrhythmic drugs, but the spontaneous TdP episode and the incidence of sudden cardiac death were relatively low (22% and 10%, respectively). 2,8,11,12 In this study, 24 of 34 AVB rabbits (71%) developed TdP spontaneously, and all of the 25 noneuthanized rabbits died suddenly. The difference of TdP incidence between rabbit and dog models may depend on the degree of QT prolongation (see below).…”

Section: High Incidence Of Tdp In a Rabbit Model With Chronic Avbmentioning

confidence: 99%

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

et al. 2002

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Background-The ionic basis of acquired QT prolongation and torsade de pointes (TdP) unrelated to drugs is not fully understood. Methods and Results-We created a rabbit model with chronic complete atrioventricular block (AVB) (nϭ34), which showed prominent QT prolongation (by 120%), high incidence of spontaneous TdP (71%), and cardiac hypertrophy. Patch-clamp experiments were performed in left ventricular myocytes from 9 rabbits (8 with TdP, 1 without TdP) at Ϸ21 days of AVB and from 8 sham-operated controls with sinus rhythm. Action potential duration was prolonged in AVB myocytes compared with control (ϩ61% at 0.5 Hz, ϩ21% at 3 Hz). Both rapidly and slowly activating components of the delayed rectifier K ϩ current (I Kr and I Ks ) in AVB myocytes were significantly smaller than in control by 50% and 55%, respectively. There was no significant difference in Ca 2ϩ -independent transient outward current (I to1 ). L-type Ca 2ϩ current (I Ca,L ) in control and AVB myocytes was similar in peak amplitude, but the half voltage for activation was shifted to the negative direction (5.9 mV) in AVB myocytes. Voltage dependence of I Ca,L inactivation was not different in control and AVB myocytes. The inward rectifier K ϩ current (I K1 ) significantly increased in AVB myocytes compared with control. Conclusions-In the rabbit, chronic AVB leads to prominent QT prolongation and high incidence of spontaneous TdP. Downregulation of both I Kr and I Ks in association with altered I Ca,L activation kinetics may underlie the arrhythmogenic ventricular remodeling.

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Methods and limitations of an experimental model of long QT syndrome

Cited by 32 publications

References 22 publications

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Electrophysiological effects of cetirizine, astemizole and d‐sotalol in a canine model of long QT syndrome

Drug‐Induced Torsades de Pointes and Implications for Drug Development

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

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