Vernakalant in an Experimental Model of Pacing-Induced Heart Failure: Lack of Proarrhythmia Despite Prolongation of Repolarization

Frommeyer, Gerrit; Grotthoff, Jochen Schulze; Fischer, Christina; Bogossian, Harilaos; Reinke, Florian; Kochhäuser, Simon; Dechering, Dirk G.; Fehr, Michael; Milberg, Peter; Eckardt, Lars

doi:10.1016/j.cardfail.2014.07.013

Cited by 12 publications

(7 citation statements)

References 28 publications

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“…147 Polyunsaturated fatty acids have been shown to reduce beat-to-beat variability and, therefore, mediate a beneficial antiarrhythmic effect. 46 Stable temporal dispersion of repolarization was also observed after application of ranolazine, 115 vernakalant, 138,139 or amiodarone or dronedarone 19,31 in intact and failing hearts. Furthermore, additional application of ranolazine induced a significant reduction in temporal dispersion of repolarization in hearts pretreated with sotalol.…”

Section: Spatial Dispersion Of Repolarizationmentioning

confidence: 60%

“…138 For all three drugs, these findings were preserved in the presence of nonischaemic chronic heart failure. 115,139 The potential beneficial effect of a reduction in spatial dispersion of repolarization in the setting of acquired LQTS was observed by administration of polyunsaturated fatty acids, 46 the L-type calcium current inhibitor verapamil, 140 or selective inhibition of the sodiumcalcium exchanger with the compound SEA0400. 18 Again, the antiarrhythmic effect of verapamil or of selective inhibition of the sodium-calcium exchanger was preserved in the setting of chronic heart failure.…”

Section: Spatial Dispersion Of Repolarizationmentioning

confidence: 99%

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Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

2015

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Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

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Section: Spatial Dispersion Of Repolarizationmentioning

confidence: 60%

Section: Spatial Dispersion Of Repolarizationmentioning

confidence: 99%

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

2015

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“…Experimental studies in isolated rabbit hearts presented a safe electrophysiologic profile despite significant prolongation of myocardial repolarization . These results were confirmed in an experimental model of pacing‐induced chronic heart failure . Based on these findings, vernakalant may also have a protective effect SQTS.…”

Section: Introductionmentioning

confidence: 56%

“…15 These results were confirmed in an experimental model of pacing-induced chronic heart failure. 16 Based on these findings, vernakalant may also have a protective effect SQTS.…”

Section: Ranolazine and Vernakalant Prevent Ventricular Arrhythmias Imentioning

confidence: 95%

Ranolazine and Vernakalant Prevent Ventricular Arrhythmias in an Experimental Whole‐Heart Model of Short QT Syndrome

Frommeyer

Ellermann

Dechering

et al. 2016

Cardiovasc electrophysiol

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“…The post‐repolarization refractoriness is considered an antiarrhythmic change, because it protects the heart from premature activation in early diastole, which would otherwise trigger VT. Therefore, antiarrhythmic agents that produce a greater increase in ERP compared to an increase in APD 90 , can be an effective therapy for preventing VT …”

Section: Electrical Activity Of Ventricular Cellsmentioning

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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Vernakalant in an Experimental Model of Pacing-Induced Heart Failure: Lack of Proarrhythmia Despite Prolongation of Repolarization

Cited by 12 publications

References 28 publications

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms

Ranolazine and Vernakalant Prevent Ventricular Arrhythmias in an Experimental Whole‐Heart Model of Short QT Syndrome

Role of abnormal repolarization in the mechanism of cardiac arrhythmia

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