Idiopathic atrial fibrillation in dogs: electrophysiologic determinants and mechanisms of antiarrhythmic action of flecainide.

OBJECTIVES This study sought to determine the mechanisms of idiopathic atrial fibrillation and the atrial antifibrillatory action of flecainide in dogs. BACKGROUND In a small subset of dogs, sustained atrial fibrillation can be readily induced in the absence of vagal tone. The electrophysiologic mechanisms underlying this ability to sustain atrial fibrillation, and of flecainide action on the arrhythmia, are unknown. METHODS Six dogs with inducible sustained atrial fibrillation were studied before and after flecainide administration and compared with a control group of 10 dogs. RESULTS Dogs with atrial fibrillation differed in displaying more shortening of the atrial refractory period with increased rate, resulting in a significantly shorter refractory period and wavelength for reentry at rapid rates, and in increased regional dispersion in refractoriness. Activation maps during sustained fibrillation showed a mean (+/- SE) of 6.3 +/- 0.4 coexistent zones of reentry, compatible with short wavelengths, whereas in control dogs activation during self-limited atrial fibrillation was better organized, and the number of reentrant circuits was smaller. Quantitative analysis demonstrated significantly greater inhomogeneity of activation during atrial fibrillation in dogs with atrial fibrillation than in control animals. Flecainide terminated atrial fibrillation by increasing the duration and homogeneity of atrial refractoriness at rapid rates, thereby reducing the number of reentry circuits and the heterogeneity of activation. CONCLUSIONS The ability of atrial fibrillation to sustain itself resulted from enhanced rate-dependent shortening of atrial refractoriness and increased regional heterogeneity. Flecainide reversed these changes and restored sinus rhythm. These results suggest potential mechanisms of idiopathic atrial fibrillation and are pertinent to understanding the clinical actions of flecainide.

[1]  J J Gallagher,et al.  Techniques of intraoperative electrophysiologic mapping. , 1982, The American journal of cardiology.

[2]  S. Nattel,et al.  Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide. , 1994, Circulation.

[3]  S. Nattel,et al.  Rate-Dependent Changes in Intraventricular Conduction Produced by Procainamide in Anesthetized Dogs: A Quantitative Analysis Based on the Relation Between Phase 0 Inward Current and Conduction Velocity , 1989, Circulation Research.

[4]  G. Moe,et al.  On the multiple wavelet hypothesis o f atrial fibrillation. , 1962 .

[5]  A ROSENBLUETH,et al.  The mathematical formulation of the problem of conduction of impulses in a network of connected excitable elements, specifically in cardiac muscle. , 1946, Archivos del Instituto de Cardiologia de Mexico.

[6]  José Jalife,et al.  Cardiac electrophysiology and arrhythmias , 1985 .

[7]  D. Zipes,et al.  Effects of selective vagal and stellate ganglion stimulation of atrial refractoriness. , 1974, Cardiovascular research.

[8]  W. Giles,et al.  Contributions of a transient outward current to repolarization in human atrium. , 1989, The American journal of physiology.

[9]  E. Cowles Andrus,et al.  THE REFRACTORY PERIOD OF THE NORMALLY-BEATING DOG'S AURICLE; WITH A NOTE ON THE OCCURRENCE OF AURICULAR FIBRILLATION FOLLOWING A SINGLE STIMULUS , 1930, The Journal of experimental medicine.

[10]  K. Lie,et al.  The value of class IC antiarrhythmic drugs for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. , 1990, Journal of the American College of Cardiology.

[11]  M. Allessie,et al.  Vulnerability of rabbit atrium to reentry by hypoxia. Role of inhomogeneity in conduction and wavelength. , 1992, The American journal of physiology.

[12]  M. Allessie,et al.  Intra-atrial reentry as a mechanism for atrial flutter induced by acetylcholine and rapid pacing in the dog. , 1984, Circulation.

[13]  M. Shenasa,et al.  Evaluation of flecainide acetate in rapid atrial fibrillation complicating wolff‐parkinson‐white syndrome , 1985, Clinical cardiology.

[14]  S Nattel,et al.  Mechanism of flecainide's antiarrhythmic action in experimental atrial fibrillation. , 1992, Circulation research.

[15]  熊谷 浩一郎.  Electrophysiological properties in chronic lone atrial fibrillation , 1992 .

[16]  Allessie,et al.  Circus movement in rabbit atrial muscle as a mechanism of tachycardia. III. The "leading circle" concept: a new model of circus movement in cardiac tissue without the involvement of an anatomical obstacle. , 1977, Circulation research.

[17]  S Nattel,et al.  Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. , 1990, Circulation.

[18]  J. Agmon,et al.  Diagnosis and characteristics of lone atrial fibrillation. , 1989, Chest.

[19]  E. Pritchett,et al.  Flecainide acetate treatment of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation: dose-response studies. The Flecainide Supraventricular Tachycardia Study Group. , 1991, Journal of the American College of Cardiology.

[20]  S. Nattel,et al.  Electrophysiological Effects of α‐Adrenergic Stimulation , 1990, Pacing and clinical electrophysiology : PACE.

[21]  Ishioninomiya.  Direct Evidence of Nonuniform Distribution of Vagal Effects on Dog Atria , 1966 .

[22]  S Nattel,et al.  Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness. , 1993, Circulation.

[23]  Y. Asano,et al.  On the mechanism of termination and perpetuation of atrial fibrillation. , 1992, The American journal of cardiology.

[24]  M. Allessie,et al.  Length of Excitation Wave and Susceptibility to Reentrant Atrial Arrhythmias in Normal Conscious Dogs , 1988, Circulation research.

[25]  E. Pritchett,et al.  Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrhythmic therapy. A multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Flecainide Supraventricular Tachycardia Study Group. , 1989, Circulation.

[26]  G. Dobb,et al.  Reversion of recent-onset atrial fibrillation to sinus rhythm by intravenous flecainide. , 1991, The American journal of cardiology.

[27]  H E HOFF,et al.  Cholinergic factor in auricular fibrillation. , 1955, Journal of applied physiology.

[28]  J A ABILDSKOV,et al.  Nonuniform distribution of vagal effects on the atrial refractory period. , 1958, The American journal of physiology.

[29]  J M de Bakker,et al.  Increased dispersion of "refractoriness" in patients with idiopathic paroxysmal atrial fibrillation. , 1992, Journal of the American College of Cardiology.

[30]  W. Rheinboldt,et al.  A COMPUTER MODEL OF ATRIAL FIBRILLATION. , 1964, American heart journal.

[31]  S Nattel,et al.  Delayed rectifier outward current and repolarization in human atrial myocytes. , 1993, Circulation research.

[32]  M. Allessie,et al.  Mode of Action of a New Class IC Drug (ORG 7797) Against Atrial Fibrillation in Conscious Doges , 1991, Journal of cardiovascular pharmacology.

[33]  B. Fermini,et al.  Mechanism of flecainide's rate-dependent actions on action potential duration in canine atrial tissue. , 1993, The Journal of pharmacology and experimental therapeutics.

[34]  I. V. Van Gelder,et al.  Efficacy and safety of flecainide acetate in the maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter. , 1989, The American journal of cardiology.

[35]  P. Coumel,et al.  Failure in the rate adaptation of the atrial refractory period: its relationship to vulnerability. , 1982, International journal of cardiology.

[36]  J. Walker,et al.  The effects of acetylcholine in the heart‐lung preparation including the production of auricular fibrillation , 1955, The Journal of physiology.

[37]  M. Allessie,et al.  Quantification of spatial inhomogeneity in conduction and initiation of reentrant atrial arrhythmias. , 1990, The American journal of physiology.

[38]  D C Harrison,et al.  Antiarrhythmic drug classification: new science and practical applications. , 1985, The American journal of cardiology.

[39]  S. Nattel,et al.  Effects of flecainide on the rate dependence of atrial refractoriness, atrial repolarization and atrioventricular node conduction in anesthetized dogs. , 1992, Journal of the American College of Cardiology.

[40]  M. Jenkins,et al.  Efficacy and safety of flecainide acetate for atrial tachycardia or fibrillation. , 1987, The American journal of cardiology.

[41]  R. Fenici,et al.  Cardiac biopsy in patients with "primary" atrial fibrillation. Histologic evidence of occult myocardial diseases. , 1991, Chest.

[42]  W C Sealy,et al.  Epicardial mapping in the Wolff-Parkinson-White syndrome. , 1975, Circulation.

[43]  T. Colatsky,et al.  Block of delayed rectifier potassium current, IK, by flecainide and E-4031 in cat ventricular myocytes. , 1990, Circulation.

[44]  M. Allessie,et al.  Experimental evaluation of Moe's multiple wavelet hypothesis of atrial fibrillation , 1985 .