Action Potential Alternans and Irregular Dynamics in Quinidine‐Intoxicated Ventricular Muscle Cells Implications for Ventricular Proarrhythmia

BackgroundCardiac cells display rate-dependent beat-to-beat variations in action-atential duration (APD), action potential amplitude (APA), and excitability during periodic stimulation. We hypothesized that quinidine causes a marked increase in the variability of APD, APA, and excitability of ventricular cells isolated from quinidine-toxic, arrhythmic ventricles. Methods and ResultsAction potentials were recorded from right ventricular endocardial tissues (2× 1 cm, <2 mm thick) isolated from dogs in which ventricular tachycardia and ventricular fibrillation (VT/VF) were induced with intravenous quinidine (80-100 mg/kg) over a 5-hour period in vivo (n=7). As the basic cycle length (BCL) of stimulation was progressively shortened, rate-dependent variations in APD and APA occurred. The initial dynamic change was alternans of APD and APA that could be either in or out of phase between two cells. The magnitude of alternans was a function of the BCL and the strength of the stimulation current. At critically short BCLs, irregular APD and APA behavior emerged in the quinidine-intoxicated cells. In control cells (n=16) isolated from three nontreated dogs, APD and APA remained constant at all BCLs tested (2,000-300 msec). Quinidine increased the slope of the APD restitution curve compared with control. The observed quinidine APD restitution curve was fitted with a biexponential equation, and computer simulation using the fitted restitution curve reproduced the aperiodic APD seen in the quinidine toxic cells during periodic stimulation. Thus, the observed irregular APD behavior was predictable from the restitution curve. ConclusionsQuinidine toxicity increases the temporal and spatial variability of APD and APA in the ventricle that may promote the initiation of reentrant VT/VF in vivo. The slope of the APD restitution curve provides a method to quantitate inhomogeneities in repolarization time and could be a useful marker for proarrhythmia.

[1]  R. Tieleman,et al.  DISPERSION OF REFRACTORINESS AS A CAUSE OF VENTRICULAR ARRHYTHMIAS IN PATIENTS WITH MITRAL-VALVE PROLAPSE , 1994 .

[2]  W Peters,et al.  Cellular Mechanisms of Differential Action Potential Duration Restitution in Canine Ventricular Muscle Cells During Single Versus Double Premature Stimuli , 1992, Circulation.

[3]  E. Rowland,et al.  Dispersion of monophasic action potential duration: demonstrable in humans after premature ventricular extrastimulation but not in steady state. , 1992, Journal of the American College of Cardiology.

[4]  L. Glass,et al.  Evolution of rhythms during periodic stimulation of embryonic chick heart cell aggregates. , 1991, Circulation research.

[5]  W. Karplus,et al.  The simplified-FitzHugh-Nagumo model with action potential duration restitution: effects on 2D wave propagation , 1991 .

[6]  C. Luo,et al.  A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. , 1991, Circulation research.

[7]  L. Glass,et al.  A unified model of atrioventricular nodal conduction predicts dynamic changes in Wenckebach periodicity. , 1991, Circulation research.

[8]  Y. Nakamura,et al.  Quantitative indices of dispersion of refractoriness for identification of propensity to re-entrant ventricular tachycardia in a canine model of myocardial infarction. , 1991, Cardiovascular research.

[9]  S Yasui,et al.  Significance of discordant ST alternans in ventricular fibrillation. , 1990, Circulation.

[10]  J Jalife,et al.  Nonlinear dynamics of rate-dependent activation in models of single cardiac cells. , 1990, Circulation research.

[11]  Dante R. Chialvo,et al.  Sustained vortex-like waves in normal isolated ventricular muscle. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T J Lewis,et al.  Chaotic dynamics in an ionic model of the propagated cardiac action potential. , 1990, Journal of theoretical biology.

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

[14]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[15]  D. Chialvo,et al.  Low dimensional chaos in cardiac tissue , 1990, Nature.

[16]  J Jalife,et al.  Supernormal excitability as a mechanism of chaotic dynamics of activation in cardiac Purkinje fibers. , 1990, Circulation research.

[17]  H. Tanaka,et al.  Time- and voltage-dependent block of the delayed K+ current by quinidine in rabbit sinoatrial and atrioventricular nodes. , 1989, The Journal of pharmacology and experimental therapeutics.

[18]  J. C. Bailey,et al.  Action potential duration alternans in dog Purkinje and ventricular muscle fibers. Further evidence in support of two different mechanisms. , 1989, Circulation.

[19]  H. Karagueuzian,et al.  Comparative Electrophysiologic, Antiarrhythmic, and Proarrhythmic Effects of Quinidine and Dihydroquinidine: In Vivo and In Vitro Studies , 1989 .

[20]  M Delmar,et al.  Slow Recovery of Excitability and the Wenckebach Phenomenon in the Single Guinea Pig Ventricular Myocyte , 1989, Circulation research.

[21]  M Delmar,et al.  Ionic Basis and Analytical Solution of the Wenckebach Phenomenon in Guinea Pig Ventricular Myocytes , 1989, Circulation research.

[22]  C. Antzelevitch,et al.  Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Effects of stimulation rate, potassium, and magnesium. , 1989, Circulation.

[23]  M. Franz,et al.  Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. , 1988, The Journal of clinical investigation.

[24]  M J Lab,et al.  Electrophysiological alternans and restitution during acute regional ischaemia in myocardium of anaesthetized pig. , 1988, The Journal of physiology.

[25]  D. Roden,et al.  Quinidine delays IK activation in guinea pig ventricular myocytes. , 1988, Circulation research.

[26]  H. Karagueuzian,et al.  Relation of monophasic action potential recorded with contact electrode to underlying transmembrane action potential properties in isolated cardiac tissues: a systematic microelectrode validation study. , 1988, Cardiovascular research.

[27]  J. Salata,et al.  Effects of Quinidine on Action Potentials and Ionic Currents in Isolated Canine Ventricular Myocytes , 1988, Circulation research.

[28]  M. Fishbein,et al.  Cellular electrophysiologic characteristics of surviving subendocardial fibers in chronically infarcted right ventricular myocardium susceptible to inducible sustained ventricular tachycardia. , 1987, American heart journal.

[29]  G. Sawicki,et al.  Effects of quinidine sulfate on the balance among active and passive cellular properties that comprise the electrophysiologic matrix and determine excitability in sheep Purkinje fibers. , 1987, Circulation research.

[30]  J Toyama,et al.  Effects of activation sequence and anisotropic cellular geometry on the repolarization phase of action potential of dog ventricular muscles. , 1987, Circulation.

[31]  M. Hiraoka,et al.  Effects of quinidine on plateau currents of guinea-pig ventricular myocytes. , 1986, Journal of molecular and cellular cardiology.

[32]  M. Fishbein,et al.  Coronary venous retroinfusion of procainamide: a new approach for the management of spontaneous and inducible sustained ventricular tachycardia during myocardial infarction. , 1986, Journal of the American College of Cardiology.

[33]  N. El-Sherif,et al.  Reentrant ventricular arrhythmias in the late myocardial infarction period in the dog. 13. Correlation of activation and refractory maps. , 1985, Circulation research.

[34]  B F Hoffman,et al.  Action Potential Prolongation and Induction of Abnormal Automaticity by Low Quinidine Concentrations in Canine Purkinje Fibers Relationship to Potassium and Cycle Length , 1985, Circulation research.

[35]  M. Fishbein,et al.  Spontaneous ventricular tachycardia associated with isolated right ventricular infarction, one day after right coronary artery occlusion in the dog: studies on the site of origin and mechanism. , 1985, American heart journal.

[36]  B. Surawicz,et al.  Cycle length-dependent action potential duration in canine cardiac Purkinje fibers. , 1984, The American journal of physiology.

[37]  B. Surawicz,et al.  Characteristics and Possible Mechanism of Ventricular Arrhythmia Dependent on the Dispersion of Action Potential Durations , 1983, Circulation.

[38]  H. Swinney.  Observations of order and chaos in nonlinear systems , 1983 .

[39]  C Antzelevitch,et al.  Characteristics of Reflection as a Mechanism of Reentrant Arrhythmias and Its Relationship to Parasystole , 1980, Circulation.

[40]  M. Allessie,et al.  Circus Movement in Rabbit Atrial Muscle as a Mechanism of Tachycardia: II. The Role of Nonuniform Recovery of Excitability in the Occurrence of Unidirectional Block, as Studied with Multiple Microelectrodes , 1976, Circulation research.

[41]  J. Nolasco,et al.  A graphic method for the study of alternation in cardiac action potentials. , 1968, Journal of applied physiology.

[42]  J. Cummings,et al.  Quinidine Syncope: Paroxysmal Ventricular Fibrillation Occurring during Treatment of Chronic Atrial Arrhythmias , 1964, Circulation.

[43]  R. W. Joyner,et al.  Cellular mechanisms of delayed recovery of excitability in ventricular tissue. , 1991, The American journal of physiology.

[44]  M. Arnsdorf.  Cardiac excitability, the electrophysiologic matrix and electrically induced ventricular arrhythmias: order and reproducibility in seeming electrophysiologic chaos. , 1991, Journal of the American College of Cardiology.

[45]  M. Yamaki,et al.  Significance ofDiscordant STAlternans inVentricular Fibrillation , 1990 .

[46]  L Glass,et al.  Phase-locked rhythms in periodically stimulated heart cell aggregates. , 1988, The American journal of physiology.

[47]  R J Cohen,et al.  Electrical alternans and cardiac electrical instability. , 1988, Circulation.

[48]  Joseph M. Smith,et al.  Electrical alternans andcardiac electrical instability , 1988 .

[49]  L. Glass,et al.  From Clocks to Chaos: The Rhythms of Life , 1988 .

[50]  D. Chialvo,et al.  Non-linear dynamics of cardiac excitation and impulse propagation , 1987, Nature.

[51]  B. Katzung,et al.  Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. , 1984, Annual review of pharmacology and toxicology.

[52]  Thomas Lewis,et al.  NOTES UPON ALTERNATION OF THE HEART , 1911 .