Electrophysiologic Mechanisms of Antiarrhythmic Efficacy of a Sotalol and Class Ia Drug Combination: Elimination of Reverse Use Dependence

Lee, Douglas S.; Newman, David; Ham, Miney; Dorian, Paul

doi:10.1016/s0735-1097(96)00423-8

Cited by 29 publications

(7 citation statements)

References 32 publications

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“…However, we did not find prognostic relevance of ERP/APD ratio or APD, nor a correlation to inducibility, despite successful prediction of prognosis by inducibility itself. In previous studies ERP/APD ratios have been investigated mainly to assess the actions of antiarrhythmic drugs [37]. Koller et al found that the introduction of additional extrastimuli changes the fixed relation between ERP and APD, a finding which we could confirm [10].…”

Section: Discussionsupporting

confidence: 54%

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

et al. 2013

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BackgroundAn action potential duration (APD) restitution curve with a steep slope ≥1 has been associated with increased susceptibility for malignant ventricular arrhythmias. We aimed to evaluate the “restitution hypothesis” and tested ventricular APD restitution slope as well as effective refractory period (ERP)/APD ratio for long-term prognostic value in patients with ischemic (ICM) or dilated cardiomyopathy (DCM).Methodology/Principal FindingsMonophasic action potentials were recorded in patients with ICM (n = 32) and DCM (n = 42) undergoing routine programmed ventricular stimulation (PVS). Left ventricular ejection fraction was 32±7% and 28±9%, respectively. APD and ERP were measured at baseline stimulation (S1) and upon introduction of one to three extrastimuli (S2–S4). ERP/APD ratios and the APD restitution curve were calculated and the maximum restitution slope was determined. After a mean follow-up of 6.1±3.0 years, the combined end-point of mortality and and/or implantable cardioverter-defibrillator shock was not predicted by restitution slope or ERP/APD ratios. Comparing S2 vs. S3 vs. S4 extrastimuli for restitution slope (1.5±0.6 vs. 1.4±0.4 vs. 1.3±0.5; p = NS), additional extrastimuli did not lead to a steepening restitution slope. ERP/APD ratio decreased with additional extrastimuli (0.98±0.09 [S1] vs. 0.97±0.10 [S2] vs. 0.93±0.11 [S3]; p = 0.03 S1 vs. S3). Positive PVS was strongly predictive of outcome (p = 0.006).Conclusions/SignificanceNeither ventricular APD restitution slope nor ERP/APD ratios predict outcome in patients with ICM or DCM.

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Section: Discussionsupporting

confidence: 54%

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

et al. 2013

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“…PRR will be present when an action potential-prolonging drug, e.g., sotalol, is combined with a sodium channel blocker, e.g., mexiletine. PRR could therefore also contribute to the antiarrhythmic effects of such combinations of antiarrhythmic drugs (Breithardt et al, 1981;Chezalviel-Guilbert et al, 1995;Lee et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

Kirchhof¹,

Degen²,

Franz³

et al. 2003

J Pharmacol Exp Ther

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It is still incompletely understood why amiodarone is such a potent antiarrhythmic drug. We hypothesized that chronic amiodarone treatment produces postrepolarization refractoriness (PRR) without conduction slowing and that PRR modifies the induction of ventricular arrhythmias. In this study, the hearts of 15 amiodarone-pretreated (50 mg/kg p.o. for 6 weeks) rabbits and 13 controls were isolated and eight monophasic action potentials were simultaneously recorded from the epicardium and endocardium of both ventricles. Steady-state action potential duration (APD), conduction times, refractory periods, and dispersion of action potential durations were determined during programmed stimulation and during 50-Hz burst stimuli, and related to arrhythmia inducibility. Amiodarone prolonged APD by 12 to 15 ms at pacing cycle lengths of 300 to 600 ms (p Ͻ 0.05) but did not significantly increase conduction times or dispersion of APD. Amiodarone prolonged refractoriness more than action potential duration, resulting in PRR (refractory period Ϫ APD at 90% repolarization, 14 Ϯ 10 ms, p Ͻ 0.05 versus controls). PRR curtailed the initial sloped part of the APD restitution curve by 20%. During burst stimulation, pronounced amiodarone-induced PRR (40 Ϯ 15 ms, p Ͻ 0.05 versus controls) reduced the inducibility of ventricular arrhythmias (p Ͻ 0.05 versus controls). Furthermore, in 35% of bursts only monomorphic ventricular tachycardias and no longer ventricular fibrillation were inducible in amiodarone-treated hearts (p Ͻ 0.05 versus controls). Chronic amiodarone treatment prevents ventricular tachycardias by inducing PRR without much conduction slowing, thereby curtailing the initial part of APD restitution. PRR without conduction slowing is a desirable feature of drugs designed to prevent ventricular arrhythmias.The need to prevent frequent appropriate discharges of implantable defibrillators, the side effects of long-term defibrillator therapy, and the increasing economic constraints in several health care systems have reemphasized the need for antiarrhythmic agents that prevent ventricular arrhythmias. Chronic amiodarone treatment reduces recurrent ventricular tachyarrhythmias (Connolly, 1999) and, in contrast to other antiarrhythmic agents, including potassium channel blockers, does not increase mortality or sudden death rates (Echt et al., 1991;Singh et al., 1995;Waldo et al., 1996;Wyse et al., 2001). Therefore, amiodarone is one of the few remaining treatment options to prevent recurrent ventricular arrhythmias (Connolly, 1999). Although amiodarone blocks multiple ion currents in the heart (Kamiya et al., 2001;Maltsev et al., 2001), the electrophysiological effects by which amiodarone exerts this unique antiarrhythmic action are not well understood.A series of premature stimuli applied at the shortest possible coupling interval allow earlier capture of each consecutive stimulus. This shortening of the effective refractory period (ERP) is not only caused by rate-dependent decrease in action potential duration (APD) bu...

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“…Dofetilide is not Food and Drug Administration approved for use in VAs and is not available in many parts of the world. Limited experience is also present with combinations of sotalol and either quinidine or procainamide, [145] or amiodarone plus mexiletine plus either quinidine or procainamide [146].…”

Section: Pharmacological Therapy For Ventricular Tachycardia With Strmentioning

confidence: 99%

EHRA/HRS/APHRS expert consensus on ventricular arrhythmias

Pedersen¹,

Kay²,

Kalman³

et al. 2014

Journal of Arrhythmia

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Electrophysiologic Mechanisms of Antiarrhythmic Efficacy of a Sotalol and Class Ia Drug Combination: Elimination of Reverse Use Dependence

Abstract: The combination of low dose sotalol and a class Ia agent greatly prolongs refractoriness. The magnitude of the effect increases at shorter coupling intervals.

Cited by 29 publications

References 32 publications

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

Amiodarone-Induced Postrepolarization Refractoriness Suppresses Induction of Ventricular Fibrillation

EHRA/HRS/APHRS expert consensus on ventricular arrhythmias

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