Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart.

OBJECTIVES: This study sought to 1) test the hypothesis that in the setting of bradycardia and drug-induced action potential prolongation, multiple foci of early afterdepolarizations (EADs) result in beat to beat changes in the origin and direction of the excitation wave front and are responsible for polymorphic arrhythmias; and 2) determine whether EADs may initiate nonstationary reentry, giving rise to the typical torsade de pointes (TDP) pattern. BACKGROUND: In the past, it has been difficult to associate EADs or reentry with the undulating electrocardiographic (ECG) patterns of TDP. METHODS: A voltage-sensitive dye was used for high resolution video imaging of electrical waves on the epicardial and endocardial surface of the Langendorff-perfused rabbit heart. ECG and monophasic action potentials from the right septal region were also recorded. Bradycardia was induced by ablation of the atrioventricular node. RESULTS: Perfusion of low potassium chloride Tyrode solution plus quinidine led to prolongation of the action potential and the QT interval. Eventually, EADs and triggered activity ensued, giving rise to intermittent episodes of polymorphic arrhythmia. In one experiment, triggered activity was followed by a long episode of vortex-like reentry with an ECG pattern characteristic of TDP. However, in most experiments, focal activity of varying origins and propagation patterns was observed. Triggered responses also showed varying degrees of local block. Similar results were obtained with E-4031. Burst pacing both at control conditions and in the presence of quinidine consistently led to vortex-like reentry whose ECG pattern resembled TDP. However, the cycle length of the arrhythmia with quinidine was longer than that for control ([mean +/- SEM] 194 +/- 12 vs. 132 +/- 8 ms, p < 0.03). CONCLUSIONS: Drug-induced polymorphic ventricular arrhythmias may result from beat to beat changes in wave propagation patterns initiated by EADs or EAD-induced nonstationary reentrant activity. In contrast, burst pacing-induced polymorphic tachycardia in the presence or absence of drugs is the result of nonstationary reentrant activity.

Electrotonic modulation of the T wave and cardiac memory.

Alterations in the sequence of ventricular activation (left bundle branch block occurring spontaneously or induced by atrial pacing; right ventricular pacing) were studied and shown to induce two opposite changes in the order of ventricular repolarization. One, which causes classic secondary T wave changes, occurs and disappears instantaneously, and is proportional in magnitude to the QRS complex but of opposite direction. The other, which requires a long time to reach its maximal effect and to be dissipated, shows the same direction as the abnormal QRS forces but becomes apparent only when normal activation is restored. The former is a well known consequence of prolongation of the activation time, but the latter appears to be modulated by electrotonic interactions occurring during cardiac activation, in such a way that repolarization is delayed in sites where depolarization begins, and accelerated in sites where depolarization terminates. Our study suggests that electrotonically modulated T wave changes show accumulation and memory, and may persist for days or weeks after the provoking stimulus (the change in the activation sequence) is discontinued. The fact that any shift of the activation sequence may produce "pseudoprimary" T wave changes that may persist long after cessation of the triggering factor has wide clinical implications. Electrotonic modulation of ventricular repolarization is a basic electrophysiologic mechanism that may account for several features of normal and abnormal T waves, and for the possible existence of a heart memory.

Spiral wave activity: a possible common mechanism for polymorphic and monomorphic ventricular tachycardias.

Several mechanisms have been proposed to explain the electrocardiographic patterns observed during various forms of polymorphic ventricular tachycardias, including torsades de pointes. Such mechanisms include the coexistence of either multiple foci or multiple exit pathways from single foci giving rise to various forms of aberrant ventricular activation sequences. For example, the simultaneous firing of two widely spaced foci at slightly different frequencies has been used to explain the undulating electrocardiogram that is characteristic of torsades de pointes. However, in spite of some supporting experimental evidence, such an idea remains conjectural from the clinical point of view. Here I discuss a mechanism that has been proposed recently to explain both monomorphic and polymorphic patterns (including undulating patterns) of ventricular tachycardia. The hypothesis is derived from the theory of spiral wave activity in excitable media, and from recent experiments using high resolution optical mapping in isolated two-dimensional ventricular muscle preparations that demonstrate that spiral wave activity may account for self-sustaining reentrant activation. Such studies have led to the observation that the behavior of the spiral center, the core, plays a key role in determining the electrocardiographic manifestation of the arrhythmia. Indeed, a stationary position of the core results in a monomorphic pattern of activation. On the other hand, beat-to-beat changes in the core position (i.e., drifting) leads to irregular patterns of activation. In fact, when drifting occurs in one direction, it gives rise to a Doppler shift in the excitation period in such a way that two coexisting frequencies are manifest, one ahead of and one behind the drifting core. The activation frequency in the region ahead of the core is always higher than that behind the core. Under such conditions, electrocardiographic recordings of the activity demonstrate an undulating pattern, which resembles that of torsades de pointes. When the core drifts in various directions, a polymorphic pattern is manifest. Thus, depending on spiral core dynamics, monomorphic, undulating, or completely irregular patterns may be observed. Moreover, transitions between such patterns can also occur. For example, drifting spirals giving rise to polymorphic activation can become stationary and result in monomorphic activation as a result of anchoring of the core to a small discontinuity (e.g., an artery or small scar) in the tissue. Direct extrapolation of such results to clinical cases is not appropriate. However, the observations discussed in this article offer a new testable hypothesis in which a common mechanism is postulated for the electrocardiographic patterns associated with monomorphic and polymorphic tachycardias.

Electrophysiological mechanisms underlying rate-dependent changes of refractoriness in normal and segmentally depressed canine Purkinje fibers. The characteristics of post-repolarization refractoriness.

Tissues from diseased hearts are known to exhibit post-repolarization refractoriness and rate-dependent changes of the refractory period that are often inconsistent with changes in action potential duration. To examine the electrophysiological mechanisms responsible for such rate-dependent changes of the refractory period, a narrow inexcitable zone was created by superfusing the central segments of Purkinje fibers with an "ion-free" isotonic sucrose solution. The degree of conduction impairment could be finely regulated by varying the resistance of the extracellular shunt pathway. At intermediate or low levels of block, the refractory period remained unchanged or decreased, respectively, as the rate was increased. At relatively high levels of block, however, we observed marked increases of the refractory period in response to increases in the stimulation rate. The disparity of refractoriness between normally conducting fibers and fibers exhibiting discontinuous conduction characteristics and post-repolarization refractoriness increased dramatically as a function of increasing stimulation rate. With the aid of current clamp techniques, we demonstrate that the differential behavior is due to the interplay between rate-dependent changes in the restitution of excitability at the site beyond the depressed zone secondary to changes in passive and active membrane properties and in the intensity of local circuit current provided to that site by activity generated in the segment proximal to the zone of block. Our data suggest that rate-dependent changes of refractoriness in Purkinje tissue are principally governed by attendant changes in membrane resistance.

The effects of milrinone on conduction, reflection, and automaticity in canine Purkinje fibers.

Milrinone is a newly developed analogue of amrinone possessing potent positive inotropic action. Electrophysiologic actions of the drug have not been reported. In this study microelectrode techniques were used to assess the electrophysiologic effects of milrinone in canine false tendons homogeneously superfused with either normal or high-K Tyrode's solution and in Purkinje fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Milrinone (0.2 to 20 micrograms/ml) caused no major changes in the action potential characteristics, refractoriness, or conduction velocity in fibers exposed to normal Tyrode's solution, but markedly improved conduction and abbreviated or eliminated postrepolarization refractoriness in the ischemic gap preparations. The drug also exerted important effects on reflected reentry generated in these preparations. Depending on the initial level of block, milrinone (1) suppressed the arrhythmia, (2) shifted its frequency dependence, or (3) created the conditions that allowed reflection to occur. Similar results were obtained in homogeneously depressed fibers. At similar concentrations, milrinone caused a relatively small enhancement of automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may exert either antiarrhythmic or arrhythmogenic effects.

Quinidine-induced action potential prolongation, early afterdepolarizations, and triggered activity in canine Purkinje fibers. Effects of stimulation rate, potassium, and magnesium.

Early afterdepolarization (EAD)-induced triggered activity is thought to contribute to the cardiac arrhythmogenic effects of several class I antiarrhythmic agents. The combination of quinidine therapy, bradycardia, and hypokalemia is known to predispose to torsade de pointes, which is a form of atypical polymorphous ventricular tachycardia commonly associated with long QT intervals. Recent clinical reports have shown suppression of quinidine-induced torsade de pointes with intravenous administration of magnesium sulfate. To provide further understanding of these relations, we used standard microelectrode techniques to examine the time course of quinidine-induced action potential prolongation, EAD, and triggered activity development and the dependence of these changes on [K+]0, [Mg2+]0, and stimulation frequency in isolated Purkinje fiber preparations exposed to low concentrations of the drug. At slow stimulation rates, the quinidine-induced increase of action potential duration was slow to develop and failed to reach a steady state after 3 hours of exposure to the drug. EAD and EAD-induced triggered activity generally became apparent 70-90 minutes after adding the drug. Quinidine produced triggered activity in 10 of 22 preparations superfused with Tyrode's solution containing normal [K+]0 (3.5-4.0 mM) and in six other preparations when [K+]0 was reduced. In the presence of normal [K+]0, two types of EAD and triggered activity were distinguished. In four of 10 preparations, this activity arose from phase 2 of the action potential; in eight of 10, it was associated with phase 3; and in two experiments, both types were present in the same preparation. The incidence of both forms of triggered responses depended greatly on the rate of stimulation. Triggered activity arising from phase 3 was always manifest at rates considerably slower than those giving rise to phase 2 activity. Both forms of triggered activity were sensitive to changes in the extracellular concentration of potassium and magnesium. Lower-than-normal levels of these electrolytes facilitated the manifestation of triggered activity, whereas elevated levels suppressed or caused a shift in the frequency-dependence of the activity. Phase 2, but not phase 3, EADs were abolished in response to increased [Mg2+]0. The data show a clear congruity between the conditions that predispose to torsade de pointes in the clinic and the conditions under which quinidine may induce triggered activity and marked action potential prolongation in isolated Purkinje fibers.(ABSTRACT TRUNCATED AT 400 WORDS)

Spiral waves in two-dimensional models of ventricular muscle: formation of a stationary core.

Previous experimental studies have clearly demonstrated the existence of drifting and stationary electrical spiral waves in cardiac muscle and their involvement in cardiac arrhythmias. Here we present results of a study of reentrant excitation in computer simulations based on a membrane model of the ventricular cell. We have explored in detail the parameter space of the model, using tools derived from previous numerical studies in excitation-dynamics models. We have found appropriate parametric conditions for sustained stable spiral wave dynamics (1 s of activity or approximately 10 rotations) in simulations of an anisotropic (ratio in velocity 4:1) cardiac sheet of 2 cm x 2 cm. Initially, we used a model that reproduced well the characteristics of planar electrical waves exhibited by thin sheets of sheep ventricular epicardial muscle during rapid pacing at a cycle length of 300 ms. Under these conditions, the refractory period was 147 ms; the action potential duration (APD) was 120 ms; the propagation velocity along fibers was 33 cm/s; and the wavelength along fibers was 4.85 cm. Using cross-field stimulation in this model, we obtained a stable self-sustaining spiral wave rotating around an unexcited core of 1.75 mm x 7 mm at a period of 115 ms, which reproduced well the experimental results. Thus the data demonstrate that stable spiral wave activity can occur in small cardiac sheets whose wavelength during planar wave excitation in the longitudinal direction is larger than the size of the sheet. Analysis of the mechanism of this observation demonstrates that, during rotating activity, the core exerts a strong electrotonic influence that effectively abbreviates APD (and thus wavelength) in its immediate surroundings and is responsible for the stabilization and perpetuation of the activity. We conclude that appropriate adjustments in the kinetics of the activation front (i.e., threshold for activation and upstroke velocity of the initiating beat) of currently available models of the cardiac cell allow accurate reproduction of experimentally observed self-sustaining spiral wave activity. As such, the results set the stage for an understanding of functional reentry in terms of ionic mechanisms.

Rate dependence and supernormality in excitability of guinea pig papillary muscle.

It is well known that in most cardiac tissues an increase in rate results in a decrease of excitability and, eventually, conduction block. We used microelectrode techniques to evaluate the rate and time dependence of excitation latency in 27 isolated guinea pig papillary muscles (GPPM). Latency was measured as the interval between the stimulus onset and action potential upstroke. When the intensity of current was just suprathreshold, prolongation of the basic cycle length (BCL) from 300 to 1,000 ms produced an increase in latency or failure of excitation. Such behavior was observed with extracellular as well as intracellular stimulation. Rate-dependent changes in latency were maximal during the first 10-20 s following the rate change and reached a steady state in approximately 200 s. Application of premature beats revealed the presence of a "supernormal phase" in which latency abbreviated. Strength-interval and strength-duration curves demonstrated that changes in excitability accurately paralleled those observed in latency. Hence, supernormal excitability at the end of the phase 3 repolarization was consistently observed in all ventricular muscle experiments. Deceleration-induced decrease of excitability was attended by hyperpolarization, increase of action potential upstroke velocity (Vmax) and action potential amplitude, and decrease in membrane resistance. Our data suggest that paradoxical rate-related changes of excitability in GPPM are the result of changes in the passive membrane properties. Under conditions of depressed conductivity, this particular behavior may account for the occurrence of bradycardia-dependent block.

Sustained vortex-like waves in normal isolated ventricular muscle.

Sustained reentrant excitation may be initiated in small (20 x 20 x less than 0.6 mm) preparations of normal ventricular muscle. A single appropriately timed premature electrical stimulus applied perpendicularly to the wake of a propagating quasiplanar wavefront gives rise to circulation of self-sustaining excitation waves, which pivot at high frequency (5-7 Hz) around a relatively small "phaseless" region. Such a region develops only very low amplitude depolarizations. Once initiated, most episodes of reentrant activity last indefinitely but can be interrupted by the application of an appropriately timed electrical stimulus. The entire course of the electrical activity is visualized with high temporal and spatial resolution, as well as high signal-to-noise ratio, using voltage-sensitive dyes and optical mapping. Two- and three-dimensional graphics of the fluorescence changes recorded by a 10 x 10 photodiode array from a surface of 12 x 12 mm provide sequential images (every msec) of voltage distribution during a reentrant vortex. The results suggest that two-dimensional vortex-like reentry in cardiac muscle is analogous to spiral waves in other biological and chemical excitable media.

Electrotonic inhibition and active facilitation of excitability in ventricular muscle.

INTRODUCTION: The effects of subthreshold electrical pulses on the response to subsequent stimulation have been described previously in experimental animal studies as well as in the human heart. In addition, previous studies in cardiac Purkinje fibers have shown that diastolic excitability may decrease after activity (active inhibition) and, to a lesser extent, following subthreshold responses (electrotonic inhibition). However, such dynamic changes in excitability have not been explored in isolated ventricular muscle, and it is uncertain whether similar phenomena may play any role in the activation patterns associated with propagation abnormalities in the myocardium. METHODS AND RESULTS: Experiments were performed in isolated sheep Purkinje fibers and papillary muscles, and in enzymatically dissociated guinea pig ventricular myocytes. In all types of preparations introduction of a conditioning subthreshold pulse between two suprathreshold pulses was followed by a transient decay in excitability (electrotonic inhibition). The degree of inhibition was directly related to the amplitude and duration of the conditioning pulse and inversely related to the postconditioning interval. Yet, inhibition could be demonstrated long after (> 1 sec) the end of the conditioning pulse. Electronic inhibition was found at all diastolic intervals and did not depend on the presence of a previous action potential. In Purkinje fibers, conditioning action potentials led to active inhibition of subsequent responses. In contrast, in muscle cells, such action potentials had a facilitating effect (active facilitation). Electrotonic inhibition and active facilitation were observed in both sheep ventricular muscle and guinea pig ventricular myocytes. Accordingly, during repetitive stimulation with pulses of barely threshold intensity, we observed: (1) bistability (i.e., with the same stimulating parameters, stimulus:response patterns were either 1:1 or 1:0, depending on previous history), and (2) abrupt transitions between 1:1 and 1:0 (absence of intermediate Wenckebach-like patterns). Simulations utilizing an ionic model of cardiac myocytes support the hypothesis that electrotonic inhibition in well-polarized ventricular muscle is the result of partial activation of IK following subthreshold pulses. On the other hand, active facilitation may be the result of an activity-induced decrease in the conductance of IK1. CONCLUSION: Diastolic excitability of well-polarized ventricular myocardium may be transiently depressed following local responses and transiently enhanced following action potentials. On the other hand, diastolic excitability decreases during quiescence. Active facilitation and electrotonic inhibition may have an important role in determining the dynamics of excitation of the myocardium in the presence of propagation abnormalities.

Spatiotemporal irregularities of spiral wave activity in isolated ventricular muscle.

Voltage-sensitive dyes and high resolution optical mapping were used to analyze the characteristics of spiral waves of excitation in isolated ventricular myocardium. In addition, analytical techniques, which have been previously used in the study of the characteristics of spiral waves in chemical reactions, were applied to determine the voltage structure of the center of the rotating activity (ie, the core). During stable spiral wave activity local activation occurs in a periodic fashion (ie, 1:1 stimulus: response activation ratio) throughout the preparation, except at the core, which is a small elongated area where the activity is of low voltage and the activation ratio is 1:0. The voltage amplitude increases gradually from the center of the core to the periphery. In some cases, however, regular activation patterns at the periphery may coexist with irregular local activation patterns near the core. Such a spatiotemporal irregularity is attended by variations in the core size and shape and results from changes in the core position. The authors conclude that functionally determined reentrant activity in the heart may be the result of spiral waves of propagation and that local spatiotemporal irregularities in the activation pattern are the result of changes in the core position.

Stationary and drifting spiral waves of excitation in isolated cardiac muscle.

Excitable media can support spiral waves rotating around an organizing centre. Spiral waves have been discovered in different types of autocatalytic chemical reactions and in biological systems. The so-called 're-entrant excitation' of myocardial cells, causing the most dangerous cardiac arrhythmias, including ventricular tachycardia and fibrillation, could be the result of spiral waves. Here we use a potentiometric dye in combination with CCD (charge-coupled device) imaging technology to demonstrate spiral waves in the heart muscle. The spirals were elongated and the rotation period, Ts, was about 180 ms (3-5 times faster than normal heart rate). In most episodes, the spiral was anchored to small arteries or bands of connective tissue, and gave rise to stationary rotations. In some cases, the core drifted away from its site of origin and dissipated at a tissue border. Drift was associated with a Doppler shift in the local excitation period, T, with T ahead of the core being about 20% shorter than T behind the core.

Technical features of a CCD video camera system to record cardiac fluorescence data.

A charge-coupled device (CCD) camera was used to acquire movies of transmembrane activity from thin slices of sheep ventricular epicardial muscle stained with a voltage-sensitive dye. Compared with photodiodes, CCDs have high spatial resolution, but low temporal resolution. Spatial resolution in our system ranged from 0.04 to 0.14 mm/pixel; the acquisition rate was 60, 120, or 240 frames/sec. Propagating waves were readily visualized after subtraction of a background image. The optical signal had an amplitude of 1 to 6 gray levels, with signal-to-noise ratios between 1.5 and 4.4. Because CCD cameras integrate light over the frame interval, moving objects, including propagating waves, are blurred in the resulting movies. A computer model of such an integrating imaging system was developed to study the effects of blur, noise, filtering, and quantization on the ability to measure conduction velocity and action potential duration (APD). The model indicated that blurring, filtering, and quantization do not affect the ability to localize wave fronts in the optical data (i.e., no systematic error in determining spatial position), but noise does increase the uncertainty of the measurements. The model also showed that the low frame rates of the CCD camera introduced a systematic error in the calculation of APD: for cutoff levels > 50%, the APD was erroneously long. Both noise and quantization increased the uncertainty in the APD measurements. The optical measures of conduction velocity were not significantly different from those measured simultaneously with microelectrodes. Optical APDs, however, were longer than the electrically recorded APDs. This APD error could be reduced by using the 50% cutoff level and the fastest frame rate possible.

Effects of pacing on stationary reentrant activity. Theoretical and experimental study.

It is well known that electrical pacing may either terminate or change the rate and/or ECG appearance of reentrant ventricular tachycardia. However, the dynamics of interaction of reentrant waves with waves initiated by external pacing are poorly understood. Prevailing concepts are based on simplistic models in which propagation occurs in one-dimensional rings of cardiac tissue. Since reentrant activation in the ventricles occurs in two or three dimensions, such concepts might be insufficient to explain the mechanisms of pacing-induced effects. We used numerical and biological models of cardiac excitation to explore the phenomena, which may take place as a result of electrical pacing during functionally determined reentry. Computer simulations of a two-dimensional array of electrically coupled FitzHugh-Nagumo cells were used to predict the response patterns expected from thin slices of sheep ventricular epicardial muscle, in which self-sustaining reentrant activity in the form of spiral waves was consistently initiated by premature stimulation and monitored by means of video mapping techniques. The results show that depending on their timing and shape, externally induced waves may collide with the self-sustaining spiral and result in one of three possible outcomes: (1) direct annihilation of the spiral, (2) multiplication of the spiral, or (3) shift of the spiral center (ie, core). Multiplication and shift of the spiral core were attended by changes in rate and morphology of the arrhythmia as seen by "pseudo-ECGs." Furthermore, delayed termination (ie, termination of the activity one to three cycles after the stimulus) occurred after both multiplication and shift of the spiral center. Both numerical predictions and experimental results support the hypothesis that whether a pacing stimulus will terminate a reentrant arrhythmia or modify its ECG appearance depends on whether the interactions between the externally induced wave and the spiral wave result in the de novo formation of one or more "wavebreaks." The final outcome depends on the stimulus parameters (ie, position and size of the electrodes and timing of the stimulus) as well as on the position of the newly formed wavebreak(s) in relation to that of the original wave.

Spatiotemporal periodicity during atrial fibrillation in the isolated sheep heart.

BACKGROUND: The activation patterns that underlie the irregular electrical activity during atrial fibrillation (AF) have traditionally been described as disorganized or random. Recent studies, based predominantly on statistical methods, have provided evidence that AF is spatially organized. The objective of this study was to demonstrate the presence of spatial and temporal periodicity during AF. METHODS AND RESULTS: We used a combination of high-resolution video imaging, ECG recordings, and spectral analysis to identify sequential wave fronts with temporal periodicity and similar spatial patterns of propagation during 20 episodes of AF in 6 Langendorff-perfused sheep hearts. Spectral analysis of AF demonstrated multiple narrow-band peaks with a single dominant peak in all cases (mean, 9.4+/-2.6 Hz; cycle length, 112+/-26 ms). Evidence of spatiotemporal periodicity was found in 12 of 20 optical recordings of the right atrium (RA) and in all (n=19) recordings of the left atrium (LA). The cycle length of spatiotemporal periodic waves correlated with the dominant frequency of their respective optical pseudo-ECGs (LA: R2=0.99, slope=0.94 [95% CI, 0.88 to 0.99]; RA: R2=0.97, slope=0.92 [95% CI, 0.80 to 1.03]). The dominant frequency of the LA pseudo-ECG alone correlated with the global bipolar atrial EG (R2=0.76, slope=0.75 [95% CI, 0.52 to 0.99]). In specific examples, sources of periodic activity were seen as rotors in the epicardial sheet or as periodic breakthroughs that most likely represented transmural pectinate muscle reentry. However, in the majority of cases, periodic waves were seen to enter the mapping area from the edge of the field of view. CONCLUSIONS: Reentry in anatomically or functionally determined circuits forms the basis of spatiotemporal periodic activity during AF. The cycle length of sources in the LA determines the dominant peak in the frequency spectra in this experimental model of AF.

Spiral waves of excitation underlie reentrant activity in isolated cardiac muscle.

The mechanism of reentrant ventricular tachycardia was studied in computer simulations and in thin (approximately 20 x 20 x 0.5-mm) slices of dog and sheep ventricular epicardial muscle. A two-dimensional matrix consisting of 96 x 96 electrically coupled cells modeled by the FitzHugh-Nagumo equations was used to analyze the dynamics of self-sustaining reentrant activity in the form of elliptical spiral waves induced by premature stimulation. In homogeneous anisotropic media, spirals are stationary and may last indefinitely. However, the presence of small parameter gradients may lead to drifting and eventual termination of the spiral at the boundary of the medium. On the other hand, spirals may anchor and rotate around small discontinuities within the matrix. Similar results were obtained experimentally in 10 preparations whose electrical activity was monitored by means of a potentiometric dye and high-resolution optical mapping techniques; premature stimulation triggered reproducible episodes of sustained or nonsustained reentrant tachycardia in the form of spiral waves. As a rule, the spirals were elongated, with the major hemiaxis parallel to the longitudinal axis of the cells. The period of rotation (183 +/- 68 msec [mean +/- SD]) was longer than the refractory period (131 +/- 38 msec) and appeared to be determined by the size of the spiral's core, which was measured using a newly devised "frame-stack" plot. Drifting of spiral waves was also observed experimentally. Drift velocity was 9.8% of the velocity of wave propagation. In some cases, the core became stationary by anchoring to small arteries or other heterogeneities, and the spiral rotated rhythmically for prolonged periods of time. Yet, when drift occurred, spatiotemporal variations in the excitation period were manifested as a result of a Doppler effect, with the excitation period ahead of the core being 20 +/- 6% shorter than the excitation period behind the core. As a result of these coexisting frequencies, a pseudoelectrocardiogram of the activity in the presence of a drifting spiral wave exhibited "QRS complexes" with an undulating axis, which resembled those observed in patients with torsade de pointes. The overall results show that spiral wave activity is a property of cardiac muscle and suggest that such activity may be the common mechanism of a number of monomorphic and polymorphic tachycardias.

Wave-front curvature as a cause of slow conduction and block in isolated cardiac muscle.

We have investigated the role of wave-front curvature on propagation by following the wave front that was diffracted through a narrow isthmus created in a two-dimensional ionic model (Luo-Rudy) of ventricular muscle and in a thin (0.5-mm) sheet of sheep ventricular epicardial muscle. The electrical activity in the experimental preparations was imaged by using a high-resolution video camera that monitored the changes in fluorescence of the potentiometric dye di-4-ANEPPS on the surface of the tissue. Isthmuses were created both parallel and perpendicular to the fiber orientation. In both numerical and biological experiments, when a planar wave front reached the isthmus, it was diffracted to an elliptical wave front whose pronounced curvature was very similar to that of a wave front initiated by point stimulation. In addition, the velocity of propagation was reduced in relation to that of the original planar wave. Furthermore, as shown by the numerical results, wave-front curvature changed as a function of the distance from the isthmus. Such changes in local curvature were accompanied by corresponding changes in velocity of propagation. In the model, the critical isthmus width was 200 microns for longitudinal propagation and 600 microns for transverse propagation of a single planar wave initiated proximal to the isthmus. In the experiments, propagation depended on the width of the isthmus for a fixed stimulation frequency. Propagation through an isthmus of fixed width was rate dependent both along and across fibers. Thus, the critical isthmus width for propagation was estimated in both directions for different frequencies of stimulation. In the longitudinal direction, for cycle lengths between 200 and 500 milliseconds, the critical width was < 1 mm; for 150 milliseconds, it was estimated to be between 1.3 and 2 mm; and for the maximum frequency of stimulation (117 +/- 15 milliseconds), it was > 2.5 mm. In the transverse direction, critical width was between 1.78 and 2.32 mm for a basic cycle length of 200 milliseconds. It increased to values between 2.46 and 3.53 mm for a basic cycle length of 150 milliseconds. The overall results demonstrate that the curvature of the wave front plays an important role in propagation in two-dimensional cardiac muscle and that changes in curvature may cause slow conduction or block.

Vortex shedding as a precursor of turbulent electrical activity in cardiac muscle.

In cardiac tissue, during partial blockade of the membrane sodium channels, or at high frequencies of excitation, inexcitable obstacles with sharp edges may destabilize the propagation of electrical excitation waves, causing the formation of self-sustained vortices and turbulent cardiac electrical activity. The formation of such vortices, which visually resembles vortex shedding in hydrodynamic turbulent flows, was observed in sheep epicardial tissue using voltage-sensitive dyes in combination with video-imaging techniques. Vortex shedding is a potential mechanism leading to the spontaneous initiation of uncontrolled high-frequency excitation of the heart.

Nonstationary vortexlike reentrant activity as a mechanism of polymorphic ventricular tachycardia in the isolated rabbit heart.

BACKGROUND: Ventricular tachycardia may result from vortexlike reentrant excitation of the myocardium. Our general hypothesis is that in the structurally normal heart, these arrhythmias are the result of one or two nonstationary three-dimensional electrical scroll waves activating the heart muscle at very high frequencies. METHODS AND RESULTS: We used a combination of high-resolution video imaging, electrocardiography, and image processing in the isolated rabbit heart, together with mathematical modeling. We characterized the dynamics of changes in transmembrane potential patterns on the epicardial surface of the ventricles using optical mapping. Image processing techniques were used to identify the surface manifestation of the reentrant organizing centers, and the location of these centers was used to determine the movement of the reentrant pathway. We also used numerical simulations incorporating Fitzhugh-Nagumo kinetics and realistic heart geometry to study how stationary and nonstationary scroll waves are manifest on the epicardial surface and in the simulated ECG. We present epicardial surface manifestations (reentrant spiral waves) and ECG patterns of nonstationary reentrant activity that are consistent with those generated by scroll waves established at the right and left ventricles. We identified the organizing centers of the reentrant circuits on the epicardial surface during polymorphic tachycardia, and these centers moved during the episodes. In addition, the arrhythmias that showed the greatest movement of the reentrant centers displayed the largest changes in QRS morphology. The numerical simulations showed that stationary scroll waves give rise to monomorphic ECG signals, but nonstationary meandering scroll waves give rise to undulating ECGs characteristic of torsade de pointes. CONCLUSIONS: Polymorphic ventricular tachycardia in the healthy, isolated rabbit heart is the result of either a single or paired ("figure-of-eight") nonstationary scroll waves. The extent of the scroll wave movement corresponds to the degree of polymorphism in the ECG. These results are consistent with our numerical simulations that showed monomorphic ECG patterns of activity for stationary scroll waves but polymorphic patterns for scroll waves that were nonstationary.