Dofetilide Promotes Repolarization Abnormalities in Perfused Guinea-pig Heart

Osadchii, Oleg E.

doi:10.1007/s10557-012-6405-1

Cited by 19 publications

(32 citation statements)

References 47 publications

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“…Steepened electrical restitution may facilitate significant beat‐to‐beat alterations in action potential duration in the presence of fast beating rates, thus precipitating ventricular fibrillation . In this study, the maximum restitution slope was found to be significantly increased by procainamide ( Figure e ), which is in line with changes determined previously upon infusion of selective I Kr blocker such as dofetilide . In contrast, neither steady‐state APD 90 nor the steepness of electrical restitution was affected by lidocaine, a selective I Na blocker ( Figure b,d,f ).…”

Section: Discussionsupporting

confidence: 91%

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Osadchii

2013

Fundamemntal Clinical Pharma

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Procainamide is class Ia Na(+) channel blocker that may prolong ventricular repolarization secondary to inhibition of IK r , the rapid component of the delayed rectifier K(+) current. In contrast to selective IN a blockers such as lidocaine, procainamide was shown to produce arrhythmogenic effects in the clinical setting. This study examined whether pro-arrhythmic responses to procainamide may be accounted for by drug-induced repolarization abnormalities including impaired electrical restitution kinetics, spatial gradients in action potential duration (APD), and activation-to-repolarization coupling. In perfused guinea-pig hearts, procainamide was found to prolong the QT interval on ECG and left ventricular (LV) epicardial monophasic APD, increased the maximum slope of electrical restitution, enhanced transepicardial APD variability, and eliminated the inverse correlation between the local APD and activation time values determined at distinct epicardial recording sites prior to drug infusion. In contrast, lidocaine had no effect on electrical restitution, the degree of transepicardial repolarization heterogeneities, and activation-to-repolarization coupling. Spontaneous episodes of monomorphic ventricular tachycardia were observed in 57% of procainamide-treated heart preparations. No arrhythmia was induced by lidocaine. In summary, this study suggests that abnormal changes in repolarization may contribute to pro-arrhythmic effects of procainamide.

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Section: Discussionsupporting

confidence: 91%

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Osadchii

2013

Fundamemntal Clinical Pharma

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“…Proarrhythmic modifications of ventricular repolarization by dofetilide were analysed in experimental studies. Consistent with spatial heterogeneities in the distribution of I Kr , dofetilide was found to produce non‐uniform lengthening of APD and/or the refractory period in canine, rabbit, and guinea‐pig hearts (Osadchii 2012c; 2012d, 2014c: studies IV, V, and X, respectively) . Over the transepicardial plane, dofetilide evokes a greater APD lengthening in LV than RV chamber, an effect that contributes to attenuated RV‐to‐LV activation–repolarization coupling, as evidenced by markedly reduced slope of the local APD‐to‐activation time linear relationships (Fig.…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 73%

“…This change results in increased epicardial dispersion of repolarization time in dofetilide‐treated heart preparations, both during regular pacing and in extrasystolic beats (Osadchii 2014c: study X) . Across the LV wall, dofetilide provokes a greater prolongation of refractory periods at the endocardium compared to the epicardium, thus increasing the transmural dispersion of refractoriness (Osadchii 2012c, 2012d: studies IV and V, respectively) . Two other important attributes of dofetilide‐induced arrhythmogenicity appear to be the steepened electrical restitution, and abnormal temporal relations between ventricular APD and refractory period.…”

Section: Arrhythmogenic Responses To Antiarrhythmic Drugsmentioning

confidence: 99%

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Osadchii

2017

Acta Physiologica

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In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia. Cardiac electrical instability attributed to abnormal repolarization relies on the complex interplay between a provocative arrhythmic trigger and vulnerable arrhythmic substrate, with a central role played by the excessive prolongation of ventricular action potential duration, impaired intracellular Ca handling, and slowed impulse conduction. This review outlines the electrical activity of ventricular myocytes in normal conditions and cardiac disease, describes classical electrophysiological mechanisms of cardiac arrhythmia, and provides an update on repolarization-related surrogates currently used to assess arrhythmic propensity, including spatial dispersion of repolarization, activation-repolarization coupling, electrical restitution, TRIaD (triangulation, reverse use dependence, instability, and dispersion), and the electromechanical window. This is followed by a discussion of the mechanisms that account for the dependence of arrhythmic vulnerability on the location of the ventricular pacing site. Finally, the review clarifies the electrophysiological basis for cardiac arrhythmia produced by hypokalaemia, and gives insight into the clinical importance and pathophysiology of drug-induced arrhythmia, with particular focus on class Ia (quinidine, procainamide) and Ic (flecainide) Na channel blockers, and class III antiarrhythmic agents that block the delayed rectifier K channel (dofetilide).

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“…Experiments in these systems have demonstrated different arrhythmic risk markers, such as increased TDR given by the maximum APD difference across the myocardial wall [48], increased critical interval for re-excitation given by the APD-ERP difference [23], [49], [50], [51], shortened λ and reduced λ-TRIAD (which is based on λ and repolarization properties of triangulation, reverse use dependence, instability and dispersion: TRIaD) [52]. The clinical marker traditionally used for predicting arrhythmic risk has been QT c [53].…”

Section: Introductionmentioning

confidence: 99%

Electrophysiological mechanisms of long and short QT syndromes

Tse

Chan

Keung

et al. 2017

IJC Heart & Vasculature

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The QT interval on the human electrocardiogram is normally in the order of 450 ms, and reflects the summated durations of action potential (AP) depolarization and repolarization of ventricular myocytes. Both prolongation and shortening in the QT interval have been associated with ventricular tachy-arrhythmias, which predispose affected individuals to sudden cardiac death. In this article, the molecular determinants of the AP duration and the causes of long and short QT syndromes (LQTS and SQTS) are explored. This is followed by a review of the recent advances on their arrhythmogenic mechanisms involving reentry and/or triggered activity based on experiments conducted in mouse models. Established and novel clinical risk markers based on the QT interval for the prediction of arrhythmic risk and cardiovascular mortality are presented here. It is concluded by a discussion on strategies for the future rational design of anti-arrhythmic agents.

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Dofetilide Promotes Repolarization Abnormalities in Perfused Guinea-pig Heart

Cited by 19 publications

References 47 publications

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Procainamide and lidocaine produce dissimilar changes in ventricular repolarization and arrhythmogenicity in guinea‐pig

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

Electrophysiological mechanisms of long and short QT syndromes

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