Static relationship of cycle length to reentrant circuit geometry.

BACKGROUND: Knowledge of the pathway common to both wave fronts in figure-8 reentrant circuits (ie, the isthmus) is of importance for catheter ablation to stop reentrant ventricular tachycardia. It was hypothesized that quantitative measures of reentry isthmus geometry were interrelated and could be correlated with tachycardia cycle length. METHODS AND RESULTS: A canine infarct model of reentrant ventricular tachycardia in the epicardial border zone with a figure-8 pattern of conduction was used for initial analysis (experiments in 20 canine hearts with monomorphic reentry). Sinus-rhythm and reentry activation maps were constructed, and quantitative (skeletonized) geometric parameters of the isthmus and border zone were measured from the maps. Regression equations were used to determine significant correlation relationships between skeletonized variables, which can be described as follows. Tachycardia cycle length, measured from the ECG R-R interval, increases with increasing isthmus length, width, narrowest width, angle with respect to muscle fibers, and circuit path length determined by use of sinus-rhythm measurements. After this procedure, in 5 test-set experiments, tachycardia cycle length measured from the R-R interval, in combination with regression coefficients calculated from initial experiments, correctly predicted isthmus geometry (mean estimated/actual isthmus overlap 70.5%). Also, the circuit path length determined with sinus-rhythm measurements correctly estimated the tachycardia cycle length (mean error 6.2+/-2.5 ms). CONCLUSIONS: Correlation relationships derived from measurements using reentry and sinus-rhythm activation maps are useful to assess isthmus geometry on the basis of tachycardia cycle length. Such estimates may improve catheter ablation site targeting during clinical electrophysiological study.

Effects of azimilide, a new class III antiarrhythmic drug, on reentrant circuits causing ventricular tachycardia and fibrillation in a canine model of myocardial infarction.

INTRODUCTION: Azimilide blocks the slow (I(Ks)) and fast (I(Kr)) components of the delayed rectifier potassium channel. It also has blocking effects on sodium (I(Na)) and calcium currents (I(CaL)). Its effects on reentrant circuits in infarct border zones causing ventricular tachyarrhythmias are unknown. METHODS AND RESULTS: Activation in reentrant circuits causing sustained ventricular tachycardia (SVT) and the initial polymorphic tachycardia that leads to ventricular fibrillation (VF) was mapped in the epicardial border zone (EBZ) of 4-day-old canine infarcts. Azimilide prolonged the effective refractory period (ERP) in both normal myocardium and EBZ, but reverse use-dependence in EBZ was prominent. Azimilide abolished SVT initiation by programmed electrical stimulation by prolonging the ERP at the site of stimulation either in normal or EBZ, preventing the occurrence of early premature impulses and the formation of lines of block in the EBZ necessary for formation of reentrant circuits. Azimilide prevented VF initiation by programmed electrical stimulation by causing conduction block of reentrant impulses in the EBZ during the initial beats of rapid polymorphic ventricular tachycardia, despite the reverse use-dependent effects on ERP. CONCLUSION: Azimilide has antiarrhythmic effects to prevent reentry causing SVT and VF in a canine infarct model.

Mechanisms for spontaneous changes in QRS morphology sometimes resembling torsades de pointes during reentrant ventricular tachycardia in a canine infarct model.

INTRODUCTION: Spontaneous changes in QRS morphology during sustained reentrant ventricular tachycardia, occurring gradually or abruptly, causing the tachycardia to be polymorphic, have been described in clinical cases. The purpose of this study was to determine the mechanism for such changes in a canine infarct model. METHODS AND RESULTS: Reentrant circuits were mapped in the epicardial border zone during sustained ventricular tachycardia in the canine heart, 4 days after left anterior descending coronary occlusion. In 10 tachycardias, there was either an abrupt change in QRS morphology or a gradual change that took up to 25 cycles. When the latter occurred, the ECG resembled torsades de pointes. Maps showed that the predominant mechanism for the change in QRS was a shift in the exit route by which the impulse left the reentrant circuit to activate the ventricles (9/10 tachycardias). Such shifts resulted from small changes in conduction velocity in segments of the circuit, either speeding or slowing, which modified the length of the functional lines of block. Movement of the circuit to a different region was responsible for the change in QRS in only one of these experiments, in which the reentrant mechanism also changed from functional to anatomic. CONCLUSION: Subtle changes in conduction in reentrant circuits can alter QRS morphology. Changes in the exit route from a stable reentrant circuit can cause the ECG characteristics to resemble torsades de pointes.

Mechanisms of resetting reentrant circuits in canine ventricular tachycardia.

BACKGROUND: Resetting has been used to characterize reentrant circuits causing clinical tachycardias. METHODS AND RESULTS: To determine the mechanisms of resetting, sustained ventricular tachycardia was induced in dogs with 4-day-old myocardial infarctions by programmed stimulation. Premature stimulation was accomplished from multiple regions within reentrant circuits; resetting curves were constructed and compared with activation maps. Monotonically increasing responses, or a "mixed" response (increasing portion preceded by a flat portion), occurred. All reentrant circuits had a fully excitable gap. Interval-dependent conduction delay and concealed retrograde penetration led to increased resetting response curves. CONCLUSIONS: Multiple mechanisms revealed by mapping cause resetting of reentrant circuits.

Remodeling of cardiac gap junctions: the relationship to the genesis of ventricular tachycardia.

Cardiac gap junctions are responsible for normal conduction properties of the ventricles. Alteration in gap junction distribution (remodeling) in ischemic heart disease is likely to be an important cause of life threatening ventricular arrhythmias.

New mechanism of antiarrhythmic drug action: increasing L-type calcium current prevents reentrant ventricular tachycardia in the infarcted canine heart.

BACKGROUND: We studied whether increasing L-type calcium current has antiarrhythmic effects. METHODS AND RESULTS: Reentrant circuits in the epicardial border zone (EBZ) of healing canine infarcts were mapped during sustained ventricular tachycardia. The cardiac-specific L-type calcium current enhancer Bay Y5959 prevented initiation of sustained ventricular tachycardia in 7 of 14 experiments. Bay Y5959 caused slowing of conduction in areas of slow nonuniform conduction in reentrant circuits; block eventually occurred. Conduction was not affected in other regions of the circuits or in more normal areas of the EBZ, nor was the EBZ effective refractory period changed. Bay Y5959 also improved conduction of premature impulses so that lines of unidirectional block necessary for VT initiation were not formed, an effect not related to a change in the effective refractory period at the site of block. CONCLUSIONS: Block of conduction caused by enhanced L-type calcium current in reentrant circuits may result from a decreased gap junctional conductance consequent to an increase in intracellular calcium. An increase in L-type calcium current may improve conduction of premature impulses.

Relationship of specific electrogram characteristics during sinus rhythm and ventricular pacing determined by adaptive template matching to the location of functional reentrant circuits that cause ventricular tachycardia in the infarcted canine heart.

INTRODUCTION: It would be advantageous, for ablation therapy, to localize reentrant circuits causing ventricular tachycardia by quantifying electrograms obtained during sinus rhythm (SR) or ventricular pacing (VP). In this study, adaptive template matching (ATM) was used to localize reentrant circuits by measuring dynamic electrogram shape using SR and VP data. METHODS AND RESULTS: Four days after coronary occlusion, reentrant ventricular tachycardia was induced in the epicardial border zone of canine hearts by programmed electrical stimulation. Activation maps of circuits were constructed using electrograms recorded from a multichannel array to ascertain block line location. Electrogram recordings obtained during SR/VP then were used for ATM analysis. A template electrogram was matched with electrograms on subsequent cycles by weighting amplitude, vertical shift, duration, and phase lag for optimal overlap. Sites of largest cycle-to-cycle variance in the optimal ATM weights were found to be adjacent to block lines bounding the central isthmus during reentry (mean 61.1% during SR; 63.9% during VP). The distance between the mean center of mass of the ten highest ATM variance peaks and the narrowest isthmus width was determined. For all VP data, the center of mass resided in the isthmus region occurring during reentry. CONCLUSION: ATM high variance measured from SR/VP data localizes functional block lines forming during reentry. The center of mass of the high variance peaks localizes the narrowest width of the isthmus. Therefore, ATM methodology may guide ablation catheter position without resorting to reentry induction.

Dynamic changes in electrogram morphology at functional lines of block in reentrant circuits during ventricular tachycardia in the infarcted canine heart: a new method to localize reentrant circuits from electrogram features using adaptive template matching.

INTRODUCTION: Fractionated, low-amplitude or long-duration electrograms have limited specificity for locating reentrant circuits causing ventricular tachycardia (VT). In this study a new method is described, adaptive template matching (ATM), based on the quantification of beat-to-beat changes in electrograms, for locating functional reentrant circuits that are relatively stable and cause monomorphic VT. METHODS AND RESULTS: Monomorphic VTs were induced in 4-day-old infarcted canine hearts by programmed stimulation and reentrant circuits mapped in the epicardial border zone with a 196 or 312 bipolar electrode array. For ATM analysis, a template electrogram from each electrode, during an early cycle, was matched with all subsequent (input) electrograms at the same site by weighting the inputs of amplitude, duration, average baseline, and phase lag. The mean square error (MSE) between template and input was the criterion used to adapt the weights, and was also a measure of changes in electrogram shape that occur from cycle to cycle. The variance of each of the weighting parameters at all electrode sites were plotted on a representation of the electrode array, and the location of the functional lines of block bounding the central common pathway of reentrant circuits with figure-of-eight characteristics, overlaid on the ATM map. Peaks of high variance were found to be coincident with functional lines of block during all tachycardia episodes. CONCLUSION: Specific beat-to-beat changes in electrograms occur at functional lines of block in reentrant circuits that can be quantified by ATM analysis, suggesting that these regions might be located without activation mapping. The method might be useful to guide ablation catheter position.

Location of diastolic potentials in reentrant circuits causing sustained ventricular tachycardia in the infarcted canine heart: relationship to predicted critical ablation sites.

BACKGROUND: The complete reentrant circuit for ablation of reentrant ventricular tachycardia (VT) in humans can rarely be localized by mapping. As a result, surrogate markers, such as diastolic electrical activity, subsequently confirmed by entrainment, have been used. However, ablation at those sites has had variable efficacy. The reasons for this variability are not clear. METHODS AND RESULTS: We correlated activation maps of reentrant circuits in the epicardial border zone of 4-day old infarcted dog hearts with the corresponding ECGs for 45 VTs to determine the regions of the reentrant circuits activated during diastole. In VTs with a figure-8 reentrant pattern, the center point of the central common pathway, the part of the circuit critical for the maintenance of reentry, was activated in early diastole in 32 of 35 VTs (91.4%), in late diastole in 1 (2.9%), and in systole in 2 (5.7%). Regions outside the circuit were rarely activated in diastole. In 10 VTs, the reentrant circuit was characterized by a single reentrant loop. In these circuits, no one region was predicted to be critical for maintenance of reentry, and a segment of the circuits was activated during diastole. However, regions peripheral to the circuit were also activated during diastole. CONCLUSIONS: The pattern of reentrant activation determines the specificity of diastolic activity for locating critical sites for ablation of VT.

Mechanisms for spontaneous termination of monomorphic, sustained ventricular tachycardia: results of activation mapping of reentrant circuits in the epicardial border zone of subacute canine infarcts.

OBJECTIVES: The objective of this study was to determine why sustained ventricular tachycardias (VT) sometimes stop without outside intervention. BACKGROUND: Sustained, monomorphic VT in patients with ischemic heart disease is often caused by reentrant excitation. These tachycardias can degenerate into rapid polymorphic rhythms or occasionally terminate spontaneously. METHODS: Sustained VT was induced by programmed stimulation in dog hearts 4 to 5 days after ligation of the left anterior descending coronary artery. Activation in reentrant circuits in the epicardial border zone of the infarct was mapped using 192 to 312 bipolar electrodes. RESULTS: Spontaneous termination of sustained VT always occurred when the reentrant wave front blocked in the central common pathway in reentrant circuits with a figure-of-eight configuration. Two major patterns of termination were identified from activation maps of the circuits that were not distinguishable from each other on the surface electrocardiogram: 1) Abrupt termination was not preceded by any change in the pattern of activation or cycle length. It could occur at different locations within the central common pathway, was not related to the directions of the muscle fiber orientation and was not caused by a short excitable gap. 2) Termination caused by premature activation (after a short cycle) either resulted from shortening of the functional lines of block around which the reentrant impulse circulated or was caused by wave fronts originating outside the reentrant circuit. In only one episode were oscillations of cycle length associated with termination. CONCLUSIONS: The mechanisms for termination of reentry in functional circuits causing VT are different from those in anatomic circuits where oscillatory behavior precedes termination.

Characteristics of the temporal and spatial excitable gap in anisotropic reentrant circuits causing sustained ventricular tachycardia.

The excitable gap of a reentrant circuit has both temporal (time during the cycle length that the circuit is excitable) and spatial (length of the circuit that is excitable at a given time) properties. We determined the temporal and spatial properties of the excitable gap in reentrant circuits caused by nonuniform anisotropy. Myocardial infarction was produced in canine hearts by ligation of the left anterior descending coronary artery. Four days later, reentrant circuits were mapped in the epicardial border zone of the infarcts with a multielectrode array during sustained ventricular tachycardia induced by programmed stimulation. During tachycardia, premature impulses were initiated by stimulation at sites around and in the reentrant circuits, and their conduction characteristics in the circuit were mapped. All circuits had a temporal excitable gap in at least part of the circuit, which allowed premature impulses to enter the circuit. Completely and partially excitable segments of the temporal gap were identified by measuring conduction velocity of the premature impulses; conduction was equal to the native reentrant wave front in completely excitable regions and slower than the reentrant wave front in partially excitable regions. In some circuits, a temporal gap existed throughout the circuit, permitting the entire circuit to be reset over a range of premature coupling intervals, although the size of the gap varied at different sites. In other circuits, the gap became so small at local sites that even though premature impulses could enter the circuit, the circuit could not be reset. Premature impulses could terminate reentry in circuits that could be reset or not. We also found a significant spatial gap, which was identified by determining the distance between the head of the circulating wave front, which could be located on the activation map, and its tail, which was the site most distal from the head as located by the site of entry of the premature wave front into the circuit. The spatial gap could also vary in different parts of the circuit. Therefore, nonuniform anisotropic reentrant circuits have both a temporal and spatial excitable gap with fully and partially excitable components that change in different parts of the circuit.

Mechanisms causing sustained ventricular tachycardia with multiple QRS morphologies: results of mapping studies in the infarcted canine heart.

BACKGROUND: Sustained reentrant ventricular tachycardias (VTs) with different QRS morphologies have been observed to occur spontaneously and during programmed stimulation in human hearts. We determined mechanisms that can cause tachycardias with multiple morphologies in a canine model of myocardial infarction by mapping reentrant circuits. METHODS AND RESULTS: Reentrant VT with multiple QRS morphologies was induced in 11 canine hearts with 4-day-old infarcts. Comparison of activation maps of the reentrant circuits in the epicardial border zone associated with each morphology indicated two basic mechanisms. Less frequently, VTs of different morphologies in the same heart were caused by reentrant circuits in different regions of the infarct. Most commonly, the reentrant circuits associated with different morphologies were in the same region. Three different factors caused different exit routes from circuits in the same region, leading to the multiple morphologies. (1) The reentrant wave front for each morphology rotated around the same line of block but in different directions. (2) Reentrant circuits associated with each morphology were similar, but there were small changes in the extent of the central line of block. (3) Reentrant circuits with completely different sizes and shapes caused different morphologies. CONCLUSIONS: In this canine model, tachycardias with multiple morphologies most commonly arise from reentrant circuits in the same region of the infarct, suggesting that most often only one area has electrophysiological properties necessary to sustain reentry.

Cellular electrophysiologic mechanisms of cardiac arrhythmias.

Cardiac arrhythmias are caused by alterations in the electrophysiologic properties of the cardiac cells, which affect the characteristics of the transmembrane potentials. The electrophysiologic properties that cause arrhythmias are automaticity, triggered activity, and reentrant excitation. Each of these mechanisms is described in terms of the characteristics of the transmembrane potentials and how these influence the appearance of the arrhythmia on the electrocardiogram.

Mechanisms for absence of inverse relationship between coupling intervals of premature impulses initiating reentrant ventricular tachycardia and intervals between premature and first tachycardia impulses.

BACKGROUND: During initiation of tachycardias by programmed stimulation (PES), an inverse relationship between the coupling interval of the premature impulse (V1V2) and the interval between the premature impulse and the first impulse of tachycardia (V2T1) has been proposed to be a specific indicator of reentry. However, an inverse relationship has not always been observed during initiation of clinical reentrant ventricular tachycardias (VTs). METHODS AND RESULTS: Reentrant VT was initiated by PES in twelve 4-day-old infarcted dog hearts. The relationship between V1V2 and V2T1 was always direct. Mapping of the epicardial border zone (EBZ) indicated that initiation of VT was secondary to functional orthodromic block of V2, propagation of V2 around the line of block, and antidromic propagation through the original location of the block. In 7 dogs, the line of orthodromic block and the pathway of orthodromic propagation were similar for different V1V2 coupling intervals. Orthodromic conduction time around the line to its distal side was longer at shorter V1V2 intervals, but a shorter antidromic delay in the area of unidirectional block for shorter V1V2 intervals, possibly reflecting small changes in the conduction pathway involving deeper layers of the EBZ, resulted in shorter V2T1 intervals. In the other 5 dogs, the orthodromic conduction pathway of V2 around the line of block changed markedly, with a shorter pathway for shorter V1V2 intervals resulting in shorter V2T1 intervals. CONCLUSIONS: An inverse relationship between V1V2 and V2T1 is not a specific indicator of functional reentry.

Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia.

BACKGROUND: Slow, nonuniform conduction caused by abnormal gap-junctional coupling of infarct-related myocardium is thought to be a component of the arrhythmogenic substrate. The hypothesis that changes in gap-junctional distribution in the epicardial border zone (EBZ) of healing canine infarcts define the locations of reentrant ventricular tachycardia (VT) circuits was tested by correlating activation maps of the surviving subepicardial myocardial layer with immunolocalization of the principal gap-junctional protein, connexin43 (Cx43). METHODS AND RESULTS: The EBZ overlying 4-day-old anterior infarcts in three dogs with inducible VT and three noninducible dogs was mapped with a high-resolution electrode array and systematically examined by standard histology and confocal immunolocalization of Cx43. The thickness of the EBZ was significantly less in the hearts with (538 +/- 257 microns) than without (840 +/- 132 microns; P < .05) VT. At the interface with the underlying necrotic cells, the EBZ myocardium showed a marked disruption of gap-junctional distribution, with Cx43 labeling abnormally arrayed longitudinally along the lateral surfaces of the cells. In the EBZ of all hearts, the disrupted Cx43 labeling extended part of the way to the epicardial surface, with the most superficial epicardial myocytes having the normal transversely orientated pattern. Only in the hearts with inducible VT did the disorganization extend through the full thickness of the surviving layer at sites correlating with the location of the central common pathways of the figure-of-8 reentrant VT circuits. CONCLUSIONS: Altered gap-junctional distribution is part of the early remodeling of myocardium after infarction, and by defining the location of the common central pathway of the reentrant VT circuits, it may be a determinant of VT susceptibility.

Electrophysiological effects of flecainide on anisotropic conduction and reentry in infarcted canine hearts.

BACKGROUND: The class IC antiarrhythmic drug flecainide has been shown to be ineffective for the treatment of ventricular arrhythmias in some patients who have had a prior myocardial infarction and sometimes even provoke arrhythmias (proarrhythmic effect). Since some ventricular tachycardias may be caused by anisotropic reentry, we determined the effects of flecainide on this mechanism for reentry in infarcted canine hearts in order to determine possible causes for its clinical effects. METHODS AND RESULTS: The effects of flecainide were determined on ventricular tachycardia induced by programmed electrical stimulation in dogs with healing myocardial infarction 4 days after coronary artery occlusion. Activation in the reentrant circuits causing tachycardia was mapped with a 196-channel computerized mapping system. We found that flecainide converted inducible unsustained ventricular tachycardia to inducible sustained ventricular tachycardia by modifying conduction in the reentrant circuit. In general, by slowing conduction, the reentrant wave front did not block after flecainide, leading to perpetuation of reentrant excitation. When sustained ventricular tachycardia could be induced before the drug, flecainide prolonged the coupling interval of premature impulses necessary to induce tachycardia by lengthening the line of block and slowing conduction around it. Flecainide also slowed the rate of the tachycardia but did not terminate it. The anisotropic reentrant circuits were modified so that the central common pathway of "figure-of-eight" circuits was narrowed and lengthened due to extension of the lines of block that bounded the pathways. Extension of the lines of block resulted from depression of conduction in the direction transverse to the long axis of the myocardial fiber bundles caused by flecainide. Flecainide also slowed conduction in the longitudinal direction in part of the circuits. The depressant effects of flecainide on both longitudinal and transverse anisotropic conduction were quantified by pacing from the center of the electrode array and it was found, contrary to predictions, that transverse conduction was depressed as much as longitudinal conduction. CONCLUSIONS: Flecainide slows conduction in both the longitudinal and transverse direction relative to the orientation of the myocardial fibers. This enables sustained reentry to occur more easily. Flecainide does not cause conduction block in crucial regions of reentrant circuits (central common pathway) and therefore does not prevent reentrant tachycardia in healing infarcts.

Prediction of the location and time of spontaneous termination of reentrant ventricular tachycardia for radiofrequency catheter ablation therapy.

Ventricular tachycardia caused by reentrant excitation can lead to cardiac arrest and sudden death. Drug treatment and surgical procedures have been used with limited effectiveness. Catheter ablation methods are more promising because they are less invasive than surgery. Although ablation has come to be highly effective in the treatment of supraventricular tachycardias, the overall success rate remains low for ventricular tachycardias, which may be due in part to an inaccurate localization of the reentrant pathway. The authors hypothesize that a site in the myocardium exists that is critical for the maintenance or reentry and that when ablated, will result in permanent cessation of the tachycardia. The authors also hypothesize that this is the same site where the reentrant impulse blocks during spontaneous termination of tachycardia. A series of experiments has been designed to determine if there are specific properties of extracellular electrograms recorded from reentrant circuits that would enable the circuits to be identified without activation maps and, more specifically, allow the site of block causing spontaneous termination to be localized. For quantitative analysis of electrograms, a paradigm is developed to characterize electrogram morphology using a canine infarct model. Changes in morphology (shape, size, and location of signal deflections) can be considered (1) motions of a coordinate system and/or (2) conformational changes of shape. To a first approximation, stationarity over short time segments is assumed so that the motions and conformations can be parameterized. These parameters were extracted for 50 cardiac cycles during an episode of nonsustained ventricular tachycardia, in which 196-bipolar electrode pairs were positioned in an array format across the epicardial surface of the heart. The results of these studies of changes in electrogram morphology suggest that during cycles 5 to 49 of ventricular tachycardia, in many electrograms near the circuit, the cycle length increases linearly, the amplitude increases, and the duration of activation decreases. During cycles 50 to 54, the cycle length increases much more markedly, the amplitude decreases, and the duration of activation increases. These observations suggest that cycle lengthening may be an important property of some spontaneous terminations, and moreover that other morphologic characteristics are affected differently at different stages of cycle lengthening. Further, all motion parameters tended to oscillate from cycle to cycle in either an alternans pattern or longer oscillation. The variations in morphology were typically only a few percent from cycle to cycle. Such variability would not be evident using only ruler-and-caliper measurements made by hand because of the lack of precision and the sheer volume of data. It is expected that this approach for characterization of electrogram morphology will be extremely useful clinically to (1) increase speed and accuracy of ablation site selection and (2) reduce multichannel electrogram recording complexity during ablation site selection.