Mortality Following Ventricular Arrhythmia Suppression by Encainide, Flecainide, and Moricizine After Myocardial Infarction

The nonlinear spatial redundancy and the linear spatial correlation function were used to investigate to what extent nonlinearity was involved in the coupling of atrial regions and how organization in activation patterns of sustained atrial fibrillation (AF) had been modified by administration of the class IC agent cibenzoline in the experimental model of sustained AF in instrumented conscious goats.Electrograms were measured in five goats during sustained AF and when the fibrillation interval had been prolonged to about 25%, 50% and 85% (CIB25, CIB50, CIB85) with respect to control. The nonlinear association length and linear correlation length were estimated along the principle axes of two-dimensional correlation maps estimated from the spatial redundancy and the spatial correlation function, respectively.The estimated short axis association length in the right atrium increased already shortly after the start of infusion (CIB25, +61%), and remained significantly different from control during the experiment, including the effects of non-simultaneous interaction. At CIB85 the association length had almost become twice as long with respect to control (increase from 16 to 29 mm, +89%), while in the left atrium changes were less pronounced (increase from 9 to 12 mm, +32%). The linearized association length which was estimated using multivariate surrogate data increased more gradually and was less sensitive to changes in spatial organization. The results of the spatial correlation analysis suggest that the druginduced nonlinearity in the spatio-temporal dynamics of sustained AF is related to activation patterns which are characterized by extended uniformly propagating fibrillation wavefronts (AF type I).We conclude that cibenzoline enhanced the spatial organization of sustained AF associated with a transition from type II to type I AF activation patterns. This may destabilize the perpetuation of AF since an increase in association length is equivalent to a reduction of atrial tissue mass available to support reentrant circuits. The results are consistent with the hypothesis that larger association lengths result from fewer and larger reentrant circuits. It is argued that effects of diminished curvature of fibrillation wavefronts are anti-arrhythmic under conditions of suppressed excitability imposed by cibenzoline. Termination of AF may be mediated by a mechanism resembling a bifurcation of the dynamics which sets in when the ends of fractionated wavefronts cannot sufficiently curve anymore to maintain a positive balance of newly generated wavelets needed to sustain AF.

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“…For instance, adverse effects like pro-arrhythmia have recently been recognized in clinical drug trials (Epstein et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Spatial Correlation Analysis of the Pharmacological Conversion of Sustained Atrial Fibrillation in Conscious Goats by Cibenzoline

Hoekstra

Diks

Allessie

et al. 2000

Archives of Physiology and Biochemistry

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“…9 A third drug, moricizine, continued to be tested in CAST-II, but this also did not reduce SCD and may have increased it. 10,11 …”

Section: Learning From Historymentioning

confidence: 99%

Pharmacology and Toxicology of Nav1.5-Class 1 Antiarrhythmic Drugs

Roden

2014

Cardiac Electrophysiology Clinics

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SYNOPSIS Although cardiac sodium channel blocking drugs can exert antiarrhythmic actions, they can also provoke life-threatening arrhythmias through a variety of mechanisms. This review addresses the way in which drugs interact with the channel, and how these effects translate to clinical beneficial or detrimental effects. A further understanding of the details of channel function and of drug-channel interactions may lead to the development of safer and more effective antiarrhythmic therapies.

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“…The findings of Cardiac Arrhythmia Suppression Trial (CAST) [56] have taught clinicians imperative lessons in terms of safety of intervention. Although class I antiarrhythmic agents effectively suppress ventricular arrhythmia, they induce greater rates of sudden cardiac death, and all of these agents cause mortality [57].…”

Section: Efficacy and Safety Of Pharmacologic Interventions Of Depresmentioning

confidence: 99%

Depression and ischemic heart disease: Overview of the evidence and treatment implications

Jiang

Blumenthal²

2003

Curr Psychiatry Rep

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Mortality Following Ventricular Arrhythmia Suppression by Encainide, Flecainide, and Moricizine After Myocardial Infarction

Cited by 151 publications

References 19 publications

Spatial Correlation Analysis of the Pharmacological Conversion of Sustained Atrial Fibrillation in Conscious Goats by Cibenzoline

Spatial Correlation Analysis of the Pharmacological Conversion of Sustained Atrial Fibrillation in Conscious Goats by Cibenzoline

Pharmacology and Toxicology of Nav1.5-Class 1 Antiarrhythmic Drugs

Depression and ischemic heart disease: Overview of the evidence and treatment implications

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