Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig

Guns, Pieter-Jan; Johnson, Dan; Weltens, E; Lissens, J

doi:10.1016/j.vascn.2012.03.007

Cited by 30 publications

(31 citation statements)

References 44 publications

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“…This study suggests that hypokalemia-induced arrhythmogenicity may not be accounted for by the reversed relationships between the duration of electrical and mechanical systole, which have been reported to occur in other experimental models of electrical instability [6], [8]–[9]. Indeed, although hypokalemia was found to prolong repolarization and increase the occurrence of tachyarrhythmia in perfused guinea-pig and rabbit hearts, the duration of mechanical systole remained invariably longer compared to the QT interval, thereby contributing to the positive EM window, as assessed during both steady-state pacing and extrasystolic stimulations.…”

Section: Discussionmentioning

confidence: 56%

“…The EM window was calculated as the difference between the Q-P end interval and the QT interval on ECG, as described previously [6], [8]–[9], [26]. The measurements were performed both during steady-state pacing and extrasystolic stimulation (Figure 1).…”

Section: Methodsmentioning

confidence: 99%

“…Collectively, these changes lead to the negative EM window, wherein the QT interval exceeds the duration of ventricular contraction. The negative EM window is thought to facilitate the arrhythmic events, because the relatively long electrical systole (i.e., the QT interval) is associated with increased time for Ca 2+ entry and increased propensity to spontaneous sarcoplasmic reticulum Ca 2+ release; these changes may promote after-depolarizations, which act as triggers for tachyarrhythmia [6]–[9]. Accordingly, the negative EM window has been recently proposed as a novel preclinical marker of increased propensity to ventricular tachyarrhythmia (VT), especially in the setting of drug-induced prolongation of repolarization [6], [8]–[10].…”

Section: Introductionmentioning

confidence: 99%

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Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Osadchii

2014

PLoS ONE

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Normal hearts exhibit a positive time difference between the end of ventricular contraction and the end of QT interval, which is referred to as the electromechanical (EM) window. Drug-induced prolongation of repolarization may lead to the negative EM window, which was proposed to be a novel proarrhythmic marker. This study examined whether abnormal changes in the EM window may account for arrhythmogenic effects produced by hypokalemia. Left ventricular pressure, electrocardiogram, and epicardial monophasic action potentials were recorded in perfused hearts from guinea-pig and rabbit. Hypokalemia (2.5 mM K+) was found to prolong repolarization, reduce the EM window, and promote tachyarrhythmia. Nevertheless, during both regular pacing and extrasystolic excitation, the increased QT interval invariably remained shorter than the duration of mechanical systole, thus yielding positive EM window values. Hypokalemia-induced arrhythmogenicity was associated with slowed ventricular conduction, and shortened effective refractory periods, which translated to a reduced excitation wavelength index. Hypokalemia also evoked non-uniform prolongation of action potential duration in distinct epicardial regions, which resulted in increased spatial variability in the repolarization time. These findings suggest that arrhythmogenic effects of hypokalemia are not accounted for by the negative EM window, and are rather attributed to abnormal changes in ventricular conduction times, refractoriness, excitation wavelength, and spatial repolarization gradients.

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Section: Discussionmentioning

confidence: 56%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Osadchii

2014

PLoS ONE

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“…In LQT1 model, blockades of the slowed component of delayed rectifier potassium channel (I Ks ) (i.e. HMR1556, JNJ303) were used to trigger TdP (van der Linde et al, 2010;Guns et al, 2012b). Therefore, the difference of TdP episodes between the two models (LQT1 and LQT2) may be explained by severity of reduced repolarization reserve.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, an electromechanical window (EMW) has been proposed as an emerging biomarker for TdP liability in anesthetized dog and guinea pig model of acquired long QT syndrome type 1 (LQT1) (Guns et al, 2012a(Guns et al, , 2012bvan der Linde et al, 2010). While EMW has been shown to predict arrhythmias in the model of LQT1, it has not been evaluated in the setting of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS).…”

Section: Introductionmentioning

confidence: 99%

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

et al. 2017

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-The current regulatory guidelines recommend the use of QT interval to assess the risk of arrhythmogenic potential of new chemical entities. Recently, the electromechanical window (EMW), the difference in duration between electrical and mechanical systole, has been proposed as markers for druginduced torsades de pointes (TdP); however, data of EMW in short QT model are not available. This study aimed to characterize the EMW as a marker for drug-induced ventricular arrhythmias in anesthetized rabbit model of long QT syndrome type 2 (LQT2) and short QT syndrome (SQTS) infused with reference compounds known to lengthen or shorten QT intervals. After rabbits were anesthetized with isoflurane, body surface electrocardiograms and left ventricular pressure were recorded. The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5). The EMW in anesthetized rabbits ranged from 1.3 to 53.3 msec. All three drugs known to lengthen QT intervals prolonged QT and QTcF interval while the EMW was markedly decreased to negative values. Pinacidil significantly produced QT and QTcF shortening and significantly abbreviated the EMW (p < 0.05). This study demonstrated that the EMW is associated with QT intervals (p < 0.001). It is negative in the presence of QT-prolonging drugs while it is more positive in the presence of QT-shortening drugs. The results suggest that the EMW in anesthetized rabbits can be used in drug safety evaluation in addition to the QT interval.

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Cardiovascular Safety Assessment of New Chemical Entities: Current Perspective and Emerging Technologies

Tyagi

Sharma

2023

Biomedical Applications and Toxicity of Nanomaterials

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Negative electro-mechanical windows are required for drug-induced Torsades de Pointes in the anesthetized guinea pig

Cited by 30 publications

References 44 publications

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Impact of Hypokalemia on Electromechanical Window, Excitation Wavelength and Repolarization Gradients in Guinea-Pig and Rabbit Hearts

Characteristics of electromechanical window in anesthetized rabbit models of short QT and long QT syndromes

Cardiovascular Safety Assessment of New Chemical Entities: Current Perspective and Emerging Technologies

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