Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhythmic Effects of Quinidine in a Model of Short QT Syndrome

Milberg, Peter; Tegelkamp, Regina; Osada, Nani; Schimpf, Rainer; Wolpert, Christian; Breithardt, Günter; Borggrefe, Martin; Eckardt, Lars

doi:10.1111/j.1540-8167.2007.00813.x

Cited by 94 publications

(81 citation statements)

References 34 publications

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“…This is consistent with previous studies in which the use of ATP sensitive "openers" of potassium channel (I K-ATP ) has been shown to be associated with VF (Chi et al, 1990;Lu et al, 2008;Padrini et al, 1992). It is known that I K-ATP openers shorten action potential duration so that the effective refractory period is abbreviated (Milberg et al, 2007). Pinacidil has also been shown to increase maximal transmural dispersion of repolarization between left and right ventricles in canine wedge preparation (Extramiana and Antzelevitch, 2004).…”

Section: Discussionsupporting

confidence: 91%

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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Section: Discussionsupporting

confidence: 91%

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

et al. 2017

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“…Thus far, only quinidine has been shown to affect QT intervals and electrophysiology testing outcome. 109 …”

Section: Prognosis and Therapymentioning

confidence: 99%

Sudden Cardiac Arrest Without Overt Heart Disease

Modi

Krahn

2011

Circulation

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“…12 This phenomenon, known as post-repolarization refractoriness, was demonstrated to be a slow process that could greatly outlast full repolarization. 13 Since the deactivation kinetics of the slow component of the delayed rectifier current, I Ks , are an important determinant of post-repolarization refractoriness, 12 it seems reasonable to hypothesize that the spatially distributed wavebreaks and intermittent block processes that are frequently observed at the exceedingly high frequencies of cardiac fibrillation are the result, in part, of the inherent spatial heterogeneities in I Ks distribution. To our knowledge, the role of the delayed rectifier currents in rotor dynamics and fibrillation frequency has received very little attention.…”

Section: Ionic Basis Of Fibrillatory Conduction: Role Of I Ksmentioning

confidence: 99%

Cardiac fibrillation: From ion channels to rotors in the human heart

Vaquero¹,

Calvo²,

Jalife³

2008

Heart Rhythm

158

134

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Cardiac fibrillation is one of the most important causes of morbidity and mortality in the developed world, but its mechanisms are still a matter of debate. Not only is the role of certain ion channels currently being unraveled, but also investigators are starting to gather evidence for the dynamics and molecular mechanisms of both atrial (AF) and ventricular (VF) fibrillation in humans. In this brief review, we evaluate the available evidence for the separate roles played by individual sarcolemmal ion channels in AF and VF, assessing the clinical relevance of such findings. Importantly, while human data support the idea that rotors are a crucial mechanism for fibrillation maintenance in both the atria and the ventricles, there are clear inherent differences between the two chamber types, particularly in regards to the role of specific ion channels in fibrillation. But there are also similarities. This knowledge, together with new information on the changes that take place during disease evolution and between structurally normal and diseased hearts may enhance our understanding of fibrillatory processes pointing to new pharmacological or interventionist approaches to improve disease outcomes.

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Reduction of Dispersion of Repolarization and Prolongation of Postrepolarization Refractoriness Explain the Antiarrhythmic Effects of Quinidine in a Model of Short QT Syndrome

Cited by 94 publications

References 34 publications

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

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

Sudden Cardiac Arrest Without Overt Heart Disease

Cardiac fibrillation: From ion channels to rotors in the human heart

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