Mode of Action of a New Class IC Drug (ORG 7797) Against Atrial Fibrillation in Conscious Doges

Kirchhof, C; Wijffels, Maurits C.E.F.; Brugada, Josép; Planellas, Juan; Allessie, Maurits A.

doi:10.1097/00005344-199101000-00017

Cited by 48 publications

(26 citation statements)

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“…The importance of WL for the inducibility and stability of AF was initially studied by Rensma et al 10 and Kirchhof et al 11 They measured WL during pacing in the absence of AF. As shown in their studies, the antifibrillatory effects of several class I and III antiarrhythmic drugs were related to a prolongation by the minimal WL rather than a more pronounced effect on RP than on CV.…”

Section: Discussionmentioning

confidence: 99%

Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria

et al. 2003

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Background-This study aimed to assess the effects of pilsicainide, a pure sodium channel blocker, on electrophysiological action and wavefront dynamics during atrial fibrillation (AF). Methods and Results-In a newly developed model of isolated, perfused, and superfused canine atria (nϭ12), the right and left endocardia were mapped simultaneously by use of a computerized mapping system. AF was induced with 1 to 5 mol/L acetylcholine. The antifibrillatory actions of pilsicainide on AF cycle length (AFCL), refractory period (RP), conduction velocity (CV), excitable gap (EG), and the core of the mother rotor were studied. The RP was defined as the shortest coupling interval that could capture the fibrillating atrium. The EG was estimated as the difference between the AFCL and RP. At baseline, multiple wavefronts were observed. After 2.5 g/mL infusion of pilsicainide, all preparations showed irregular activity, and AF was terminated in 2 preparations. The AFCL and RP were prolonged, and CV was decreased significantly. The EG was widened (147%; PϽ0.01), and the core perimeter was increased (100%; PϽ0.01). Increasing the dosage either terminated AF (6 preparations) or converted to organized activity (ie, atypical atrial flutter) (4 preparations). On the maps, all "unorganized" AFs were terminated with the excitation of the core of the mother rotor by an outside wavefront, whereas in preparations with atrial flutter, pilsicainide did not terminate its activity. Conclusions-Widening

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Section: Discussionmentioning

confidence: 99%

Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria

et al. 2003

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“…Relation of Interruption of Atrial Flutter to the Wavelength Hypothesis Traditionally, it has been thought that the wavelength of excitation, defined as the product of the refractory period multiplied by the conduction velocity, has been very important in understanding the effects of antiarrhythmic drugs on reentrant rhythms. [41][42][43][44] In fact, over the years, and as summarized recently,44 it has been postulated that the effects of antiarrhythmic drugs on reentrant rhythms could be explained by their effects on the wavelength (ie, their effects on the product of conduction velocity and the refractory period). This hypothesis assumes (1) that any drug-induced slowing of conduction velocity that may occur is uniform; (2) that drug interruption of the reentrant rhythm occurs when a drug causes an increase in the wavelength such that the circulating reentrant wave front encounters tissue in the reentrant circuit that is not excitable because it is still refractory; and (3) that a drug that decreases conduction velocity (and thereby prolongs the cycle length of the reentrant rhythm -in our case, atrial flutter) is less likely or, in fact, unlikely to terminate the reentrant rhythm because it decreases the wavelength and therefore the degree of interaction between the head of the reentrant excitation wave front and the tail of refractoriness of the previous reentrant excitation wave front.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

et al. 1994

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BACKGROUND Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness. METHODS AND RESULTS The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133 +/- 9 to 172 +/- 27 milliseconds (P < .001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3 +/- 1.4 to 3.3 +/- 2.2 mA (P < .01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58 +/- 6 to 64 +/- 5 milliseconds (P < .005). Prolongation of the atrial effective refractory period from 166 +/- 20 to 174 +/- 24 milliseconds (P < .05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150 +/- 15 to 216 +/- 30 milliseconds (P < .001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9 +/- 8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction. CONCLUSIONS Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction.

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“…Initial studies suggested that AF termination was attributable to increased wavelength. [3][4][5]38 However, more recent work has shown that class I drugs can terminate AF while decreasing wavelength. 6,25 The experimental evidence is difficult to interpret because of accessory drug actions, including important K ϩ -channel blockade.…”

Section: Theoretical Aspectsmentioning

confidence: 99%

Mechanisms of Atrial Fibrillation Termination by Pure Sodium Channel Blockade in an Ionically-Realistic Mathematical Model

Kneller

Kalifa

Zou

et al. 2005

Circulation Research

130

117

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Abstract-The mechanisms by which Naϩ -channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na ϩ -channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na ϩ -current (I Na ) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I Na inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I Na inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I Na inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I Na inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I Na block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I Na inhibition in the mathematical model. We conclude that pure I Na inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org (Circ Res. 2005;96:e35-e47.) Key Words: atrial fibrillation Ⅲ mathematical model Ⅲ class I drugs Ⅲ sodium channels C lass I antiarrhythmic drugs terminate clinical atrial fibrillation (AF), but the electrophysiological mechanisms remain poorly understood. 1 AF is generally considered to be a re-entrant arrhythmia, and the stability of AF is classically related to the wavelength. 2 The wavelength (product of refractory period and conduction velocity [CV]) is thought to represent the minimum path length for re-entry and therefore to determine the size of functional re-entry circuits. 3 The most commonly accepted mechanism for antiarrhythmic drug termination of AF is drug-induced wavelength increases that reduce the number of circuits that the atria may accommodate.Experimental evidence has been presented suggesting that class I antiarrhythmic agents act on AF by changing the effective refractory period (ERP) and the wavelength. 2,4,5 Recent data have challenged established notions of antiarrhythmic drug action by showing that potent Na ϩ -channel blockers can terminate AF without increasing the wav...

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Mode of Action of a New Class IC Drug (ORG 7797) Against Atrial Fibrillation in Conscious Doges

Cited by 48 publications

References 0 publications

Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria

Widening of the Excitable Gap and Enlargement of the Core of Reentry During Atrial Fibrillation With a Pure Sodium Channel Blocker in Canine Atria

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

Mechanisms of Atrial Fibrillation Termination by Pure Sodium Channel Blockade in an Ionically-Realistic Mathematical Model

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