© 1996 American Heart Association, Inc.
Articles |
The Electrophysiological Mechanism of Ventricular Arrhythmias in the Long QT Syndrome
Tridimensional Mapping of Activation and Recovery Patterns
the Cardiology Division, Department of Medicine, State University of New York Health Science Center and Veterans Affairs Medical Center, Brooklyn.
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We have previously developed a canine in vivo model of the long QT syndrome (LQTS) using the neurotoxin anthopleurin A (AP-A), which acts by slowing sodium channel inactivation. The recent discovery of a genetic mutation in the cardiac sodium channel in some patients with the congenital LQTS, resulting in abnormal gating behavior similar to sodium channels exposed to AP-A, provides a strong endorsement of this animal model as a valid surrogate to the clinical syndrome of LQTS. In the present study, we conducted high-resolution tridimensional isochronal mapping of both activation and repolarization patterns in puppies exposed to AP-A that developed LQTS and polymorphic ventricular tachyarrhythmias (VTs). To map repolarization, we measured activation-recovery intervals (ARIs) using multiple unipolar extracellular electrograms. We demonstrated, for the first time in vivo, the existence of spatial dispersion of repolarization in the ventricular wall and differences in regional recovery in response to cycle-length changes that were markedly exaggerated after AP-A administration. Analysis of tridimensional activation patterns showed that the initial beat of polymorphic VT consistently arose as focal activity from a subendocardial site, whereas subsequent beats were due to successive subendocardial focal activity, reentrant excitation, or a combination of both mechanisms. Reentrant excitation was due to infringement of a focal activity on the spatial dispersion of repolarization, resulting in functional conduction block and circulating wave fronts. The polymorphic QRS configuration of VT in the LQTS was due to either changing the site of origin of focal activity, resulting in varying activation patterns, or varying orientations of circulating wave fronts.
Key Words: arrhythmia • ventricular tachycardia • mapping • reentry • early afterdepolarization
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Introduction |
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The LQTS is an electrophysiological entity characterized by prolongation of cardiac repolarization, reflected as a long QT interval in the surface ECG and the frequent occurrence of polymorphic VTs, sometimes with a twisting QRS morphology, better known as torsade de pointes.1 2 The LQTS can be either congenital, idiopathic, or acquired. Any pharmacological agent that can result in prolongation of the QT interval can cause the acquired LQTS in a certain number of individuals.3 The onset of torsade de pointes in the congenital and idiopathic LQTS is not necessarily bradycardia dependent, as is frequently the case in the acquired type, and the arrhythmia frequently occurs in the setting of increased adrenergic activity. These differences in clinical presentation have been cited by some investigators to suggest different electrophysiological mechanisms.2 However, the similarities between the congenital and acquired LQTS are compelling, since both are associated with a prolonged QT interval. Furthermore, indirect in vivo and in vitro evidence implicates EADs and dispersion of repolarization, sometimes as competing but often as complementary hypotheses, as mechanisms for torsade de pointes in both situations.3 4 5 The EAD hypothesis comes primarily from in vitro studies that show the development of EAD and EAD-induced triggered activity, preferentially in Purkinje fibers, under the influence of agents that prolong cardiac repolarization,6 7 8 and some authors have postulated EAD-induced reentry in the LQTS.9 The dispersion of repolarization hypothesis has been invoked on the basis of deductive analysis of the QT interval on the body surface and limited intracardiac recordings.10 11 12 The latter hypothesis has received strong support from recent studies that showed a marked heterogeneity of cell types found in the heart, believed to be based on putative differences in the expression of ion channels that control cardiac repolarization.13 14 15 However, it is not known whether differences of regional APDs observed in vitro approximate differences in the intact heart, where extensive cell-to-cell coupling would allow electrotonic interaction, which would minimize the differences in APD. The actual spatial dispersion of repolarization in vivo in the LQTS is not known in humans or in animal models.
We have previously developed an in vivo canine model of LQTS using the neurotoxins AP-A7 and ATX-II.16 These agents act by slowing sodium channel inactivation, resulting in a sustained inward current during the plateau and prolongation of APD.17 18 Recently, a genetic mutation has been reported in patients with the autosomal dominant LQTS for the gene that encodes for the voltage-gated sodium channel 
subunit (SCN5A).19 The mutant channels were shown to generate a sustained inward current during depolarization,20 quite similar to the sodium channels exposed to AP-A or ATX-II.17 These recent findings provide a strong endorsement of the animal model as a valid surrogate to the clinical syndrome. The model combines features of both the congenital LQTS (ion channel abnormality) and acquired LQTS (onset of ventricular arrhythmias is frequently bradycardia dependent). More intriguing are the recent preliminary clinical observations showing that the onset of torsade de pointes in the LQ3 patient with a mutant sodium channel occurs at rest or during sleep rather than during exercise, possibly in association with relative bradycardia.21 On the basis of our previous in vitro and in vivo observations in this model, we proposed that the initial beat of a torsade de pointes tachycardia is an EAD-triggered impulse originating from Purkinje fibers, whereas subsequent beats could be due to either successive EADs or reentrant excitation.7 The present study was designed to provide validation of this hypothesis.
In the present study, high-resolution tridimensional isochronal mapping of both activation and repolarization patterns was performed in dogs that were exposed to AP-A and developed bradycardia-dependent LQTS and VTs. To map repolarization patterns, ARIs were measured using multiple extracellular unipolar electrograms.22 To obtain higher resolution for isochronal mapping, 10- to 12-week-old puppies were used.
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Surgical Preparation
The present study was approved by the Animal Studies Subcommittee of the local institutional review board and conformed to the guiding principles of the Declaration of Helsinki. Experiments were performed on 9 purpose-bred mongrel puppies, 10 to 12 weeks old, weighing 3.5 to 5.0 kg. Puppies were preanesthetized with sodium thiopental (17.5 mg/kg IV) via the cephalic vein. Puppies were then intubated and anesthetized with 1.0% to 2.0% isoflurane (vaporized in 100% O2) via a positive ventilation anesthesia machine (F500, The Forreger Co). Catheters were inserted into the femoral vein for administration of fluids and drugs and the femoral artery to monitor blood pressure. ECG leads I, aVF, and V1 and blood pressure (Statham transducer, Gould, Inc) were continuously monitored on a physiological recorder (VR12, PPG Industries). The heart was exposed through a midsternotomy, and a pericardial cradle was constructed. During the experiment, the core temperature was monitored using an electronic thermometer (Yellow Springs Instrument Co) and maintained constant at 37°C by the use of a thermostatically controlled thermal blanket and heat lamp. Warm (37°C) saline was applied intermittently to the heart to moisten the epicardium and prevent surface cooling. AP-A was administered as an intravenous bolus of 50 µg/kg followed by a maintenance dose of 1.0 µg/kg per minute.7 To slow the heart rate, vagal stimulation was accomplished by insertion of polyimide-coated silver wires (75-µm diameter), exposed 2 to 3 mm at the tip, into the right and left cervical vagosympathetic trunks. Square pulses of 0.3 ms were delivered at 0.1 to 3 V and a frequency of 20 Hz. On completion of the experiment, the animal was euthanized by electrical induction of ventricular fibrillation and extirpation of the heart under general anesthesia.
Recording Electrodes and Electrode Localization
Sixty-four plunge needle electrodes were used for tridimensional mapping of the whole ventricle. Needle electrodes were fabricated with 50-µm-diameter polyimide-coated tungsten wires contained within a 21-gauge stainless steel needle. Left ventricular plunge electrodes contained six to eight unipolar electrodes, each pole separated by 1 mm. Right ventricular electrodes contained three or four unipolar electrodes, each separated by 1 mm. The septal electrodes contained 10 unipolar electrodes grouped in pairs, each pole separated by 1 mm and each pair separated by 2 mm. The most proximal electrode was located 
0.5 mm from the epicardial surface. Plunge electrodes were placed throughout the heart in the left ventricle, right ventricle, and septum; the distance between plunge electrodes was 4 to 9 mm. After termination of the experiment, each plunge electrode was removed and carefully replaced by a labeled map-tack pin in the exact electrode site. After the heart was removed, 10% methanol-free formalin was infused via the left and right coronary ostia and then placed in 10% formalin for at least 24 hours. After fixation in formalin, a detailed epicardial map was made by placing clear cellophane over the surface of the fixed heart and tracing the location of the labeled pins in relation to each other and to anatomic landmarks. The pins were replaced by small color-coated plastic brush bristles to facilitate sectioning. The heart was then cut transversely into five slices 5 to 7 mm in thickness. The outline of each slice was traced carefully to show the exact insertion site and direction of each electrode, as well as the site of the most distant bipole pair. The tracings were then enlarged for later tridimensional isochronal map construction.
Data Acquisition and Isochronal Mapping
Unipolar electrograms were acquired using three variable-gain 128-channel multiplexed data acquisition systems (DSC 2000, INET Corp), allowing simultaneous recording of up to 384 signals. Each electrogram was amplified and filtered with a fixed high-pass setting of 0.05 Hz and an adjustable low-pass setting of 500 to 1000 Hz. The analog data were digitized with 12-bit resolution at a sampling rate of 1000 to 2000 samples per second per channel. The digitized signals were then stored on hard disk on an IBM-compatible computer system (486PC, Touche Co). Where indicated, digitized electrograms were further filtered off-line. Up to 384 unipolar electrograms could be recorded, from which 192 bipolar electrograms could be synthesized off-line, by taking the arithmetic difference between two neighboring unipolar recording sites. The timing of selected landmarks in each activation and recovery complex was automatically computed and stored for later analysis. Activation times were determined using previously published criteria.23 24 25 Computer-generated isochrones of activation were derived from the activation time data and delineated by closed contours at 10- to 20-ms intervals beginning with the earliest detected time of activation. For the whole-ventricle activation maps, zones of functional unidirectional conduction block were identified using previously defined criteria.23 24 25 A continuous line, or surface, was drawn through these regions and was defined as a zone of functional conduction block.23
ARIs
Unipolar signals were low-pass–filtered using a digital eight-pole Butterworth filter (frequency cutoff, 50 Hz) before computation of temporal derivatives. ARI was defined as the interval between the time of minimum first derivative (Vmin) of the QRS and the maximum first derivative (Vmax) of the T wave of unipolar electrograms.21 Computer-generated isochrones of recovery were derived from the ARIs and were delineated by closed contours at 10- to 20-ms intervals beginning with the shortest ARI.
Previous experimental studies have shown that ARIs derived from unipolar electrograms reasonably approximate the local ERP.21 26 27 28 29 However, in the presence of AP-A, there is compelling evidence that large differences in repolarization occur over short distances. Since none of the previous studies analyzed ARIs in the presence of large spatial differences in repolarization, we decided to perform an analysis of the relationship of ARI to refractoriness during control and in the presence of AP-A in order to validate the technique of ARI determination in this model. The relation between ARI and ERP was determined at multiple sites within the ventricle using two different high-resolution tridimensional grids. The first grid consisted of a 4x4x6 cube arrangement of unipolar recording sites (Fig 1A
). This was accomplished by insertion of 16 plunge electrodes through a rigid acetyl plate that was sutured in place at different epicardial sites. Plunge recording electrode needles were inserted through the plate at 2-mm spacing in a 4x4 array. Each needle contained six polyimide-coated 50-µm tungsten wires separated by 1 mm. A 3x3x3 cube arrangement of unipolar stimulation sites was made by insertion of nine plunge electrodes, introduced through the rigid plate, midway between each group of four plunge recording needles, at 2-mm spacing. Plunge stimulating electrode needles were constructed in a manner similar to that for the recording electrode except that the plunge stimulating electrode contained three polyimide-coated silver wires (75-µm diameter) spaced 2.0 mm apart. ERPs were measured at the eight recording sites surrounding each stimulating electrode. A distance of 1.44 mm separated the stimulating electrode from each of the eight surrounding recording electrodes in an attempt to avoid virtual cathode effects.30 31
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The second grid consisted of eight plunge electrodes; each consisted of six recording sites 1 mm apart inserted through a rigid acetyl plate and arranged in a circle with a 2-mm radius around a single 6-mm plunge stimulating electrode (Fig 1B
). The large unipolar cathodal surface resulted in whole-field stimulation.32 This arrangement allowed simultaneous determination of ERPs at multiple recording sites across the left ventricular wall.
The ERP at each site was measured as follows: diastolic threshold was determined at the stimulation site during a basic driven rate (S1-S1) using an increasing current in steps of 0.05 mA. Once the diastolic threshold was determined, the current level was increased to 1.5 times diastolic threshold. Data were accepted if the maximum diastolic threshold was 
0.6 mA. This ensured that the stimulating current amplitude did not exceed 0.9 mA, thus avoiding virtual cathode effects beyond the interelectrode spacing.30 31 Although stimulation in the tridimensional heart may not produce a perfectly cylindrical field effect, the small currents were used to minimize errors in the shape of the wave front. Premature stimuli (S2) were introduced at increasing intervals (10 ms), beginning with a short coupling interval, after a train of eight basic driven beats. The local electrograms surrounding each stimulus site were displayed on a digital storage oscilloscope (3001A, Norland Corp). Once there was successful propagation of S2, the drive-train length was then increased to 50 beats to ensure a steady state of refractoriness and recovery. The premature coupling interval, S1-S2, was decreased by 20 ms and then again introduced at increasing coupling intervals (5 to 10 ms) until propagation occurred. The ERP of the surrounding sites was defined as the longest S1-S2 interval that failed to evoke a locally propagated response. ERPs were determined at a basic CL of 1000 in control and during AP-A infusion. The relationships between ERPs and ARIs were statistically compared by linear regression analysis.
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Effects of AP-A on Tridimensional ARIs
Fig 2
shows eight unipolar electrograms recorded along the epicardial-endocardial axis from the basal anterolateral left ventricular wall. The most endocardial site (electrode 1) was located 0.5 mm from the endocardial surface; the most epicardial site (electrode 8) was located 0.5 mm from the epicardial surface. Recordings were obtained during control and after AP-A. Sinus bradycardia was maintained at a CL of 1100 to 1150 ms by vagal stimulation. AP-A resulted in marked prolongation of the QT interval of the surface ECG as well as the local QT intervals. The lower panel shows the occurrence of a three-beat run of VT (V1 to V3). Note that the first ectopic beat, V1, failed to conduct to electrodes 1 to 6 but conducted to the two most epicardial sites (electrodes 7 and 8). Also note that after V1 there was marked shortening of the QT intervals, which allowed conduction of the second ectopic beat, V2, to all eight electrodes.
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Fig 3 illustrates the calculation of local ARIs and the first temporal derivative of the eight unipolar electrograms shown in Fig 2 of the sinus beats, marked by asterisks, during control (left panel) and after AP-A (right panel). During control, there was a gradual increase of ARIs from subepicardial to midmyocardial zones, followed by a slight decrease at subendocardial sites. The total dispersion of ARIs was 37 ms across a 7-mm distance, and the maximum dispersion was 20 ms between contiguous sites 4 and 5. After AP-A, the ARIs increased 2.5 times throughout the heart. The total dispersion of ARI across the epicardial-endocardial axis increased from 37 to 103 ms. The difference between contiguous electrodes increased in a nonuniform fashion. For example, there was no dispersion between electrodes 1 and 2, but a significant ARI increase of 42 ms occurred between electrodes 4 and 5. The shorter ARIs at the two subepicardial sites (electrodes 7 and 8) explained the ability of the activation wave front of V1 to conduct to these sites, as shown in Fig 2. Conversely, the ARIs at electrodes 1 to 6 extended beyond the arrival of the activation wave front during V1, resulting in conduction block at those sites.
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Fig 4 illustrates the relation between ARI and ERP determined by field stimulation from a central stimulating electrode as shown in Fig 1B. The six unipolar electrograms were recorded 1 mm apart along the epicardial-endocardial axis from a left ventricular anterobasal paraseptal site. The most endocardial site (electrode 1) was located 0.5 mm from the endocardial surface, and the most epicardial site (electrode 6) was located 0.5 mm from the epicardial surface. Recordings were obtained after AP-A infusion. The first unipolar complex in each of the five panels represents the last S1 beat in a train of 50 cycles at a CL of 1000 ms. The second complex is the premature stimulus S2. The S1-S2 coupling intervals were increased in 10-ms steps. Note that at the 460-ms coupling interval, there was a failure of response at all six sites (Fig 4, far left panel), whereas at the 540-ms coupling interval, S2 conducted to all sites (Fig 4, far right panel). At intermediate coupling intervals, there was a variable response depending on the duration of the ARI at each site. The ARIs at each site varied slightly (<10 ms) during successive ERP determinations. The ERP value determined by the extrastimulus technique correlated with the computed ARI interval at each site within ±15 ms. Fig 4 illustrates the presence of a steep gradient of both ARI and ERP between the two subendocardial and the two contiguous midmyocardial sites as well as between the latter and the two subepicardial sites. On the other hand, there was little dispersion of refractoriness between the two subepicardial sites (electrodes 5 and 6) and a modest dispersion of refractoriness between the two subendocardial sites (electrodes 1 and 2). The steepest gradient of both ARI (59 ms) and ERP (50 ms) was across the 1-mm distance between subepicardial site 5 and midmyocardial site 4 as well as between subendocardial site 2 and midmyocardial site 3 (57- and 50-ms dispersion of ARI and ERP, respectively).
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Fig 5 illustrates the correlation between ERP and ARI at a pacing CL of 1000 ms following AP-A infusion from 116 data points obtained from three different experiments. The correlation between the two measurements was significant (r=.99).
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Microelectrode studies in transmural preparations have shown that subepicardial, midmyocardial, and subendocardial cells respond differently to changes in CL.13 33 Midmyocardial M cells had the steepest APD-CL relationship, followed by transitional cells. The least steep relationship was observed in subepicardial and subendocardial cells. We studied the relationship between ARI and CL at steady state across the left ventricular free wall both during control conditions and during AP-A infusion. The difference in the ARI-CL relation along the epicardial-endocardial axis was markedly exaggerated during AP-A infusion. This is illustrated in Fig 6, which shows eight transmural unipolar electrograms recorded across the basolateral wall of the left ventricle. The electrodes were spaced regularly at 1.0 mm. The most endocardial electrode (electrode 1) was located 0.5 mm from the endocardial surface, whereas the most epicardial electrode (electrode 8) was located 0.5 mm from the epicardial surface. Recordings were obtained during a constant AP-A infusion at four CLs (400, 600, 1000, and 1400 ms). To maintain a constant supraventricular rhythm at 1000 to 1400 ms, the sinus node was crushed, and atrial pacing was applied during graded vagal stimulation. Measurements of ARIs (shown to the right of each electrogram) were made after a stable ARI was obtained at each CL. At a CL of 400 ms, no significant difference in ARI was found across the left ventricular wall. At 600 ms, ARIs at midmyocardial sites lengthened more compared with subepicardial and subendocardial sites. At 1000 ms, and especially at 1400 ms, ARIs at midmyocardial sites 3 to 6 were significantly longer than at subepicardial and subendocardial sites. At 1400 ms, the total dispersion across the endocardial-epicardial axis increased to 151 ms. There was an increase of 52 ms between subepicardial electrodes (sites 8 and 7) and a steeper gradient of 67 ms between site 6 and midmyocardial site 5. There was a shortening of ARI of 47 ms between sites 4 and 3 and of 41 ms between sites 2 and 3.
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Fig 7, left, shows composite data of ARI distribution collected from 12 unipolar plunge needle recordings in the basal lateral wall of the left ventricle in a 4x10-mm section during control (top) and constant AP-A infusion (bottom). Each plunge needle contained eight unipolar electrodes spaced regularly at 1 mm. ARI measurements were grouped into bins and plotted as a function of the electrode location along the epicardial-endocardial axis. The differences between groups were analyzed by ANOVA. During both control and AP-A, ARIs increased at longer CLs. During control, at 400- and 600-ms CL, ARIs were slightly longer in midmyocardial zones, but the difference was not statistically significant. At 1000 ms, midmyocardial ARIs were longer compared with subepicardial and subendocardial ARIs, but the difference was significant only between midmyocardial and subepicardial zones. At 1400 ms, the difference between ARIs at midmyocardial zones and both subepicardial and subendocardial zones was statistically significant. After AP-A, ARIs increased two to three times compared with control at similar CLs. The steepest increase occurred at midmyocardial zones. At 600 ms, ARIs were slightly longer in midmyocardial zones, but the differences were not statistically significant. At 1000 and 1400 ms, a significant increase in ARIs was apparent in midmyocardial electrodes 3 to 6 compared with both subendocardial electrodes 1 and 2 and subepicardial electrodes 7 and 8. There was, however, marked variation in ARI dispersion at the two transitional zones between midmyocardial sites and both subepicardial and subendocardial sites. Differences in ARIs of up to 80 ms (at a CL of 1400 to 1500 ms) between contiguous sites, 1.0 mm apart, at the transition zone were not uncommon.
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To further illustrate the distribution of ARI across the ventricular wall, a group analysis was performed from which the percentage change in ARI was plotted for 400- and 1500-ms CLs in the presence of AP-A. ARI values in each experiment were normalized to the epicardial ARI at the shortest CL (400 ms) for each needle to account for differences between experiments. Data shown in Fig 7, right, are from five experiments, and all recordings were obtained from approximately the same region in the basolateral wall of the left ventricle. At 400 ms, there was little difference across the epicardial-endocardial axis. However, pacing at 1500 ms resulted in a 270% to 331% increase in ARI from 400 ms. The effect was greatest in the midmyocardium. The ARI relation showed a steep transition with distance from epicardium to midmyocardium and a more gradual change from midmyocardium to endocardium. Fig 7 illustrates, for the first time, the in vivo counterpart to the in vitro observations of Sicouri and Antzelevitch.33
ECG Characteristics of Ventricular Arrhythmias
Two ECG characteristics are usually associated with ventricular arrhythmias in the LQTS. One is the characteristic QRS morphology of the VT,1 and the second is a short-long cardiac sequence that frequently precedes the onset of the tachyarrhythmia.34 35 To satisfy the description of torsade de pointes as originally reported by Dessertenne,1 the axis of the QRS complex must change direction after a certain number of complexes as if the complex rotated around the baseline. The phasic variation of the polarity and amplitude of the QRS complexes may be apparent only if several synchronous surface ECG leads are recorded. The short-long cardiac cycle sequence is usually the result of a premature ventricular response and the compensatory pause following that response, respectively.34 35
Figs 8 and 9 show recordings from experiments 2 and 3 (see Table) that illustrate the ECG characteristics of ventricular arrhythmias induced by AP-A. Fig 8 shows ECG lead I during control and after AP-A administration. A slow sinus or low atrial rhythm at a CL of 1600 to 1800 ms was maintained by vagal stimulation. AP-A resulted in marked prolongation of the QT interval (from 310 ms during control to 620 to 640 ms after AP-A at a similar CL). Panels B through E of Fig 8 represent sequential recordings obtained 10 to 14 minutes after AP-A administration. Panel B shows the occurrence of a ventricular bigeminal rhythm. The ventricular premature beats occurred at the end of the prolonged QT interval at a coupling interval of 620 ms. In panel C, after a period of bigeminal rhythm, a long coupled ventricular premature beat initiated a six-beat run of nonsustained polymorphic VT at an average CL of 250 ms. Panel D illustrates a similar sequence of bigeminal rhythm followed by a 12-beat run of nonsustained VT at an average CL of 235 ms. Although the QRS axis of the last beat changed direction, the arrhythmia did not last long enough to illustrate the characteristic torsade de pointes morphology. In panel E, the ventricular escape rhythm was in the form of a slow ventricular escape beat followed by a ventricular premature beat, one of which initiated a fast polymorphic VT that required direct-current shock to restore sinus rhythm.
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Fig 9 was obtained from experiment 3 and illustrates ECG recordings of leads I, aVF, and V1 during control (panel A) and 9 to 12 minutes after AP-A administration (panels B through E). A slow sinus rhythm at a CL of 1000 to 1200 ms was maintained by vagal stimulation. AP-A resulted in marked prolongation of the QT interval. Panel B shows the occurrence of a ventricular bigeminal rhythm followed by couplets and triplets. Panel C, obtained 30 s later, shows a six-beat polymorphic VT at an average CL of 320 ms. Although the QRS configuration reversed polarity between the second and third beats and once again between the fifth and sixth beats, the arrhythmia is better described as polymorphic rather than a torsade de pointes VT. Note that the QRS configuration of the couplets, the first two beats of the triplets in panel B, and the first two beats of the six-beat VT run in panel C are identical in all three surface leads. The recordings in panels D and E, obtained 30 s later, are continuous and show the presence of an atrial bigeminal rhythm and the onset of a fast torsade de pointes VT that required direct-current shock to restore sinus rhythm.
Activation Patterns During Polymorphic VT
Fig 10 is a diagrammatic tridimensional illustration of recording sites from a typical puppy heart cut transversely into five sections, oriented with the basal section on top and the apical section on bottom, and labeled 1 to 5. The position of each plunge needle electrode is indicated in the figure. Figs 11 through 16 illustrate the tridimensional activation patterns from experiment 3 shown in Fig 9. The puppy was 10 weeks old and weighed 4.8 kg. Thirty minutes was allowed for stabilization of the recordings after insertion of the plunge electrodes. Similar to the experience of other investigators,36 37 needle insertion, per se, did not result in any significant alteration of electrophysiological or hemodynamic parameters. After control recordings, AP-A was administered as an intravenous bolus of 50 µg/kg followed by a maintenance dose of 1.0 µg/kg per minute.
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Fig 11 illustrates the tridimensional isochronal activation patterns of the sinus beat and the following six-beat VT shown in Fig 9C. The isochrones are drawn as closed contours at 10-ms intervals for the sinus beat (S in the figure) and 20-ms intervals for the ventricular beats (V1 to V6). Conduction block between electrodes is represented in the maps by heavy solid lines. The map of the sinus beat showed an early breakthrough at the subendocardial left septal region in the second and third sections, whereas the last ventricular activation occurred after 38 ms at the basal posterior left ventricular epicardium. Earliest activation during V1 occurred simultaneously at two separate subendocardial septal sites in sections 2 and 5 (marked by asterisks). The total ventricular activation time was 80 ms. In section 5, functional conduction block occurred on the left side near the earliest site of origin, forcing the activation wave front to circulate in a clockwise direction. With the exception of a small zone at the left ventricular apex, the last region to be activated at the 80-ms isochrone was the right ventricular free wall. This activation pattern could explain the R-wave configuration of the QRS complex of this beat in lead V1. The V2 beat also had two separate subendocardial sites of earliest activation (marked by asterisks in sections 2 and 5). The earliest subendocardial site in section 5 was only 2 mm away from the earliest site during the V1 beat. In contrast to the V1 beat, the total activation time of the V2 beat was much longer (158 ms). This explains the longer QRS duration of this beat in the surface leads (see Fig 9C). Functional conduction block developed between the anterior septum and the right ventricular free wall, forcing late circular activation of the right ventricle. This activation pattern conforms with the R-wave configuration in surface lead V1. The sites of origin and ventricular activation patterns of the V1 and V2 beats were identical to those of the couplet and the first two beats of the triplets in Fig 9B.
The earliest activation during ventricular beats V3 to V5 occurred at very close subendocardial septal sites in section 4 (marked by asterisks in Fig 11). The total ventricular activation time of each of the three beats ranged from 80 to 85 ms, and the activation pattern was largely similar between the three beats (almost identical for beats V4 and V5). Septal activation during the three beats was generally in a right to left direction, and most of the left ventricle was activated late. The tridimensional activation pattern of ventricular beats V3 to V5 could explain the largely similar QRS configuration in surface leads (almost identical for beats V4 and V5) as well as the fact that all three beats had an rS configuration in lead V1. The last beat of the six-beat VT run had a different subendocardial origin (marked by the asterisk in section 3). Most of the left posterior septum was activated within 20 ms before activation spread in both left and right directions. The total ventricular activation time of this beat was shorter (64 ms), and the QRS configuration in lead V1 was a low-amplitude R wave. Thus, the polymorphic QRS configuration during the VT could be explained by the changing site of origin of the focal activity, resulting in varying activation patterns.
Fig 12 shows electrograms at selected sites during ventricular beats V1 through V3 of the six-beat VT. The figure shows the two simultaneous early subendocardial sites of origin of beat V1 in sections 5 and 2, shown in the left panel (electrograms A and D, marked by asterisks). Note the presence of conduction block between electrograms B and C, with site C showing an electrotonic potential followed by a late activation potential 60 ms later. Electrogram F shows one of the two simultaneous early subendocardial sites of origin of beat V2 (marked by an asterisk). Electrograms G through M of the V2 beat illustrate the sequential posterior-anterior activation pattern of the right ventricular free wall because of the development of conduction block between the anterior septum and the right ventricle.
Fig 13 illustrates tridimensional isochronal activation maps of the sinus beat (S in the figure) and the first four ventricular beats (V1 to V4) of the tachyarrhythmia shown in Fig 9D. The activation pattern of the sinus beat was roughly similar to the one shown in Fig 11. The V1 map shows the earliest activation site at an apical subendocardial site, only 2 mm distant from that of V1 in Fig 11, top. However, functional conduction block occurred around this site of origin, forcing activation to proceed in a basal direction. A complex reentrant pathway could be mapped, mostly in the septal region in sections 3 to 5 (indicated by the interrupted arrow), with reexcitation occurring at the anterior septal region of section 4. The reentrant circuit activation time was 240 ms. During V2, the activation wave front continued in the form of a clockwise circular wave front in the septum and left ventricular wall around the left ventricular cavity. The tridimensional representation of the circuit resembled a clockwise rotating scroll wave around the left ventricular cavity. The total reentrant circuit conduction time was shorter (200 ms). During V3, a clockwise circular wave front could be mapped in sections 2 to 4, similar to V2, but blocked at different sites in the left ventricular wall. Another clockwise circuit around the right ventricular cavity was simultaneously mapped in sections 2 and 3. During V4, the clockwise circuit around the right ventricular cavity in section 2 continued as two simultaneous clockwise and counterclockwise circuits around the right and left ventricular cavities, respectively. Incomplete clockwise circuits were mapped in sections 3 and 4. Although the activation patterns of V1 to V4 during this tachyarrhythmia were more complex compared with those during the nonsustained VT in Fig 11, some correlation could be made between the tridimensional activation patterns and the QRS configuration in surface leads, especially lead V1. During the V1 beat, a good portion of the septum and left ventricle was activated later than the right ventricle, which may explain the QS configuration in lead V1. Similarly, V2 had a QS configuration in lead V1 that correlated with the circular clockwise activation pattern of the septum and left ventricular wall. The V3 beat showed a transitional RS configuration in lead V1 that approximately correlated with the activation pattern, especially that of sections 2 and 3. It is interesting to note that the change in the QRS configuration of beat V4 into an R wave in lead V1 could be explained by the sudden shift of activation of the left ventricular wall in sections 1 and 2 to a clockwise circulating pattern with predominant left-to-right activation of the ventricular septum. Although it was difficult to accurately map the three-dimensional activation pattern during the characteristic torsade de pointes configuration seen later in the course of this tachyarrhythmia (see Fig 9E), some conclusions could be inferred from the activation patterns of the first four cycles of the tachyarrhythmia. Thus, the twisting QRS pattern seems to correspond to varying orientations of circulating reentrant wave fronts.
Fig 14 shows selected electrograms along the reentrant pathway during the first beat, V1, of the tachyarrhythmia shown in Fig 13. Note that activation started almost 100 ms before the onset of the QRS complex in the surface ECG lead. Electrogram B and both electrograms L and M were recorded on opposite sides of the arc of functional conduction block. An electrotonic deflection (marked by the X) was recorded in electrograms L and M, synchronous in timing with the activation potential in electrogram B. Electrogram L was also the site of reexcitation initiating the second reentrant beat, V2.
Fig 15 shows the two electrograms recorded at the earliest subendocardial site of origin of the V1 beat during both the six-beat VT in Fig 9C and the tachyarrhythmia in Fig 9D. Also shown is the corresponding activation pattern of section 5 of both beats. The earliest sites of origin are marked by asterisks. The most obvious difference between the two V1 beats was that the onset of activation of the V1 beat that initiated the fast tachyarrhythmia in electrogram B was more closely coupled to the preceding local sinus activation (445 ms) compared with the onset of activation of V1 of the six-beat VT run in electrogram A (495 ms). The close coupling interval in the former case infringed on the refractoriness of the surrounding myocardium, resulting in extensive functional conduction block, which was a prerequisite for the occurrence of circus movement reentry. This will be shown in more detail in Fig 16. An additional contributing factor for the difference between the activation patterns of the two V1 beats was that refractoriness (ie, ARIs) at most sites in the apical section was 10 to 30 ms longer in the sinus beat preceding the V1 beat initiating the fast tachyarrhythmia. This could be partly related to the slightly longer RR interval preceding the fast tachyarrhythmia (1000 ms) compared with the RR interval preceding the nonsustained VT (900 ms).
Fig 16 illustrates the isochronal activation and recovery maps of section 5 of the penultimate sinus beat that preceded the V1 beat, which initiated the fast tachyarrhythmia previously shown in Figs 9D, 13, and 14. The map shows that the ARIs were shortest at subepicardial sites (401 to 460 ms) as well as at subendocardial sites around the left ventricular cavity (441 to 460 ms). In the right half of the apical section, there was a uniform increase of ARIs from epicardial to endocardial direction of 45 ms. On the left side of the section, however, there was a steep increase of ARIs from both epicardial and endocardial regions to a midmyocardial zone. The activation potential at the focal site of origin of V1 at site A occurred at a coupling interval of 445 ms, which was 14 ms earlier than the ARI of the preceding sinus beat. This may reflect either some limitations of the accurate measurement of ERP from ARI or slight variation of ARI between the penultimate and last sinus beats. On the other hand, the overall activation pattern of the V1 beat in the apical section correlates, to a great extent, with the pattern of dispersion of refractoriness as shown in the recovery map. Specifically, the lines of functional conduction block corresponded to the sites with a steep gradient of ARIs.
In contrast to the six-beat polymorphic VT shown in Figs 9C and 11 (where all beats were of subendocardial focal origin), in other runs of fast nonsustained VT, the first or second subendocardial focal beat could initiate one or more reentrant cycles, followed by focal activity for the remaining beats. This is illustrated in Fig 17, which shows selected activation patterns of the 12-beat polymorphic VT from experiment 2 shown in Fig 8D. The V1 and V2 beats arose from different subendocardial sites. During the V1 beat at a coupling interval of 700 ms, functional conduction block occurred at several regions in the left ventricle. However, the total ventricular activation time was relatively short at 85 ms. On the other hand, V2, which arose 420 ms after the onset of V1, initiated a complex circus movement reentry, giving rise to V3, which was then followed by an incomplete reentrant cycle. Beats V4 to V12 all had a focal subendocardial site of origin, even though these showed varying degrees of conduction block and conduction delay. The figure also shows that the earliest subendocardial sites of origin were similar in V5 to V7, in V8 to V10, and in V11 and V12. The three different sites of origins of beats V5 to V12 were clustered within a 5- to 7-mm distance.
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Marked dispersion of ARIs was seen not only between midmyocardial and both subepicardial and subendocardial zones of the left ventricular free wall but also between midseptal regions and midmyocardial zones of the left ventricular wall. This is illustrated in Fig 18, which shows four unipolar electrograms during the sinus beat and the first two beats of the 12-beat VT run shown in Fig 17. The figure illustrates the presence of a large dispersion of ARIs between noncontiguous sites in midmyocardial zones. The ARIs at sites 1 and 2 obtained from a midseptal region in section 3 were 479 and 488 ms compared with ARIs at sites 3 and 4 of 769 and 772 ms obtained from the midmyocardial zone of the left ventricular free wall of the same section (a difference of 293 ms). Although the first ectopic beat, V1, had a relatively long coupling interval of 700 ms, activation was blocked at sites 3 and 4 and conducted at sites 1 and 2. Both Figs 17 and 18 show that 11 beats of the 12-beat VT run were focal in origin (F in Fig 18), whereas only the third beat was due to reentrant excitation (R in Fig 18).
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Analysis of the shorter six-beat VT run from the same experiment shown in Fig 8C also revealed that beats 1, 2, 4, 5, and 6 were focal in origin, whereas beat 3 was due to reentrant excitation. In the polymorphic VT that degenerated into ventricular fibrillation shown in Fig 8E, beats 1 and 2 were also focal in origin. However, the reentrant excitation pattern initiated by beat 2 continued and became more complex in subsequent beats.
The Table summarizes the data from the nine experiments. In each experiment, AP-A consistently induced a ventricular bigeminal rhythm, followed by the occurrence of couplets, triplets, and runs of nonsustained polymorphic VT (defined as three or more beats). The nonsustained VT runs could be separated into two groups according to whether all beats in the run were focal in origin (group A) or a combination of focal activity and reentrant excitation (group B). Of the 55 episodes of nonsustained VT that were analyzed, 36 belonged to group A and 19 to group B. The CLs of nonsustained VT in group A ranged from 270 to 400 ms (335±26 ms, mean±SD). The CLs of nonsustained VT in group B were significantly shorter (215 to 285 ms [242±9 ms, mean±SD], P<.001). In this group, the first or second focal beats initiated one or more reentrant cycles before resumption of focal activity. Varying degrees of conduction delay and conduction block were present during focal activity. There was no significant difference in the number of beats in the nonsustained VT runs in the two groups (3 to 12 beats [8±4 beats, mean±SD] in group A compared with 5 to 16 beats [10±4 beats, mean±SD] in group B).
In seven of the nine experiments, there were 10 examples of sustained polymorphic VT. In each one of these episodes, the first or second focal beat initiated reentrant excitation, which continued in subsequent beats with progressive fractionation of activation wave fronts and the development of multiple complete and incomplete circuits (see Fig 14). None of these episodes terminated spontaneously, and direct-current cardioversion had to be applied to restore sinus rhythm. The episodes were characterized by gradual shortening of successive CLs, even though the average CL of the first four beats of these episodes (220±5 ms, mean±SD) was not significantly different from the average CL of the first four beats of group B of self-terminating nonsustained VT (230±8 ms). The two experiments in which sustained VT did not develop were the only ones in which group B nonsustained VT was not observed (see Table).
Of 115 beats, which included both isolated single beats and the first beat in a couplet or a run of VT, 112 clearly arose from a subendocardial site. There were three examples in which the earliest site of origin seemed to be located at a midmyocardial zone. However, proximity to the right or left ventricular cavity and the resolution of the recordings made it difficult to exclude a subendocardial origin.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The LQTS
The LQTS can be either congenital, idiopathic, or acquired.1 2 Recently, genetic mutations have been identified in familial forms of LQTS. Using linkage analysis, defects in genes encoding for putative cardiac potassium channels38 39 and sodium channels19 have been identified. The effects of both mutations are predicted to delay repolarization and result in prolonged APD and long QT interval.
The acquired form of LQTS develops in a limited number of patients exposed to agents that can prolong cardiac repolarization. A plausible hypothesis for the acquired LQTS is that it occurs in individuals who have a subclinical (forme fruste) genetic abnormality of a sarcolemmal ion channel involved in cardiac repolarization that increases their susceptibility to pharmacological agents that further prolong cardiac repolarization. However, no such genetic abnormality has, so far, been identified. On the other hand, it is also plausible to suggest that those individuals may have an exaggerated pattern of the normal tridimensional dispersion of repolarization. The latter could be due to slightly different patterns of expression of normal (ie, nonmutated) sarcolemmal ion channels that contribute to repolarization. This is consistent with the bradycardia dependence of the acquired LQTS, which can further exaggerate the inhomogeneity of repolarization, especially in the presence of pharmacological agents known to prolong the APD.
Tridimensional Mapping of Recovery Patterns
A significant strength of the present study was the ability to measure the tridimensional distribution of recovery patterns in vivo. There is no practical technique to measure the tridimensional distribution of refractoriness in vivo with a sufficient spatial and temporal resolution. The most common approach to map repolarization is indirect, by measurements of local refractory periods.40 41 Intracellular microelectrode and the surrogate in vivo technique of monophasic action potential recording can provide accurate measurements of APD.42 However, measurements can only be obtained from limited sites and mostly from endocardial or epicardial surfaces. Two major techniques have been used to measure recovery times at multiple sites simultaneously. One is signal processing of extracellular electrograms,21 and the second is an imaging technique using potentiometric fluorescent dyes to optically image action potential patterns using a photodiode array.43 44 45 Both techniques have certain limitations. The primary limitation of optical action potential mapping is that recordings can only be obtained from a bidimensional surface, most commonly the epicardium. The ARI derived from unipolar electrograms has been proposed as a useful measure of the duration of repolarization.21 The validity of the measurement has been demonstrated with respect to refractory periods,21 and evidence for the correlation between ARIs and in vivo transmembrane APDs under a variety of conditions has been reported previously.28 On the other hand, stimulation studies by Steinhaus,29 have identified potential errors of the technique in the presence of nonuniform coupling resistance, nonuniform membrane properties, and alterations in recording site relative to activation sequence.
A limitation of measurements of recovery from both extracellular electrograms and optical action potentials is that these measurements may correlate with APD but not with the refractory period. This situation exists in the presence of postrepolarization refractoriness (eg, in the setting of ischemia).28 It is also possible when there are significant electrotonic interactions that distort the smooth repolarization phase of the action potential,46 a situation that is more likely to occur in LQTS.5 Indeed, it may be argued that local refractoriness, rather than a measurement of APD or a derivative thereof, is more relevant to the development of functional conduction block in a milieu of spatially disperse refractoriness. This argument, in addition to our findings that marked dispersion of ARI could occur across the left ventricular wall in vivo, made it imperative to correlate ARI measurements with ERPs as measured by the extrastimulus technique. We have demonstrated in the present study that both measurements correlated significantly. However, our measurement of ERP is not without limitations. The measurement still depends on the chosen amplitude, duration, and polarity of the stimulating current.41 Furthermore, because the ERP of the surrounding sites was defined as the longest S1-S2 interval that failed to provoke a locally propagated response, it is possible that some local responses may be difficult to measure. Our analysis of simultaneous electrograms from closely spaced (1 mm apart) recording sites would tend to minimize errors in this regard.
The Electrophysiological Mechanism of Ventricular Arrhythmias in LQTS
The present study demonstrates that single ectopic beats, couplets, and the initial beat of polymorphic VT consistently arose as focal activity from a subendocardial site, whereas subsequent beats could be due to either successive subendocardial focal activity or reentrant excitation. The latter was found to be related to infringement of a focal impulse on the spatial dispersion of ARIs, resulting in the development of functional conduction block and circulating wave fronts. Based on our in vitro study of the same animal model, it is reasonable to suggest that the focal activity represents the extracellular manifestation of a conducted EAD arising from a subendocardial Purkinje fiber. Although M cells have been recently identified in the deep subendocardial tissues of endocardial structures formed by invaginations of the free wall (papillary muscles, trabeculae, and septum),5 there are several pieces of evidence against the origin of focal activity from M cells. First, in in vitro studies, M cells failed to develop EADs at concentrations that easily induced EADs in Purkinje fibers. In fact, it was difficult to induce EADs in M cells superfused with AP-A even in the presence of hypokalemia (authors' unpublished data, 1996). Second, in vivo mapping of tridimensional activation almost consistently showed that the focal activity started near the site of the most subendocardial electrode. Third, focal activity, especially those that initiated reentrant excitation, consistently arose at subendocardial sites with "shorter" refractoriness and conducted to surrounding deeper myocardial regions with "longer" refractoriness. This is most consistent with the traditional prerequisites for initiation of circus movement reentry, ie, for activity to start at sites with shorter refractoriness and conduct to sites with longer refractoriness.47 Such a requirement will be difficult to achieve if initial focal activity arises from M cell layers with relatively long APDs.
The marked dispersion of repolarization across the left ventricular wall in vivo demonstrated in the present study was due to the differential response of midmyocardial cell layers to a pharmacological agent that prolongs APD (ie, AP-A) and to CL changes (ie, bradycardia). In the presence of AP-A, the midmyocardial cell layer showed a steep APD-CL relationship with marked prolongation of APD at longer CLs compared with subepicardial and subendocardial cell layers (Fig 7). This finding represents the in vivo correlate to the original in vitro observations of the Antzelevitch group,13 14 33 who showed differences in ion channel constituents, rate dependence, and pharmacological sensitivity of midmyocardial M cells compared with subepicardial and subendocardial cells. In the present study, we did not analyze in a systematic fashion the distribution of myocardial cell layers with M cells electrophysiological characteristics. In vitro studies in human48 and dog5 hearts suggest that M cells may constitute 30% to 40% of the left ventricular free wall. We also have not examined in detail the kinetics of ARI and CL. Previous studies have shown that APD decay after a step decrease to a new steady CL consisted of a two-exponential (fast and slow) time course, with most of the APD decay occurring within the first one or few shorter cycles.49 50 A similar relationship could be inferred, for example, from analysis of Fig 2, where prolonged ARIs resulting in local conduction block of the V1 beat with a longer coupling interval shortened significantly after this beat. This resulted in successful local conduction of the V2 beat at a much shorter coupling interval.
Our demonstration in vivo of a steep, and almost abrupt, difference in ARIs across the left ventricular wall, similar to what has been shown in in vitro slice preparations,33 came as a surprise to us. We expected that in the in vivo heart, cell-to-cell coupling would permit electrotonic interaction that would minimize the differences in APD and refractoriness. Our findings suggest the presence of increased intercellular resistance in vivo, resulting in different degrees of uncoupling between epicardial and midmyocardial cell layers as well as between the latter and subendocardial cell layers. The exact mechanism of this uncoupling is unclear at present. It has been suggested that in the human heart the spatial geometric orientation of epicardial layers perpendicular to subepicardial layers, with action potential characteristics of M cells, may explain the poor intercellular coupling between the two cell layers.48 Further studies are required to examine the gap junction distribution and the space constant across the left ventricular wall and to correlate the findings with the transition between cell types.
Several studies have suggested circus movement reentry as a mechanism of the polymorphic VT in LQTS.4 5 51 52 The present study showed that at least two factors are critical for the development of reentrant excitation: one, the coupling interval of the initiating beat to the preceding complex, and two, the site of origin of the initiating focal activity in relation to regions with steep dispersion of repolarization. Focal activity that initiated reentrant excitation had a shorter coupling interval compared with those that failed to induce reentry and arose in proximity to regions with marked dispersion of repolarization (see Figs 15 and 16). This resulted in the development of long arcs of functional conduction block, forcing the activation wave front to propagate in a circuitous pathway. However, because of the varying site of origin of the initial focal activity and the dynamic nature of local dispersion of refractoriness in relation to the preceding CL, a quantitative comparison of mean coupling intervals and local refractoriness variation for beats that initiated reentry versus those that did not could not be accomplished. The electrophysiological relevance of the short-long sequence that frequently precedes polymorphic VT also relates to the above two factors. The compensatory long cycle following a ventricular premature beat results in both prolongation and increased dispersion of local refractoriness. Nevertheless, the first focal beat of the polymorphic VT has to arise close to the site of marked dispersion of refractoriness to initiate block and reentrant excitation. The perpetuation or termination of reentrant excitation after the first reentrant cycle may depend on the pattern of adaptation of refractoriness to the abrupt shortening of the CL caused by the first reentrant cycle. The kinetics of ARI adaptation to abrupt shortening of CL at different sites and its relationship to perpetuation or interruption of reentrant activation are complex and, as mentioned above, were not systematically investigated in the present study.
The Mechanism of Twisting and/or Polymorphic QRS Morphology of Torsade de Pointes
Since the initial description of torsade de pointes tachyarrhythmia by Dessertenne,1 many electrophysiologists have been intrigued by the QRS morphological characteristics of the arrhythmia, sometimes at the expense of proposing a cohesive electrophysiological mechanism. The original hypothesis proposed by Dessertenne was that the change of the QRS axis was due to two competing foci. Several investigators proposed explanations based on shifting circus movement reentry. In a study of reentrant activity in isolated cardiac muscle, Pertsov et al51 suggested that a spiral wave of reentrant excitation migrating along the epicardial surface could explain the twisting QRS morphology of torsade de pointes. Abildskov and Lux52 used a computer model consisting of a pathway with short refractory periods bisecting regions with longer refractory periods. Premature stimulation from the region with shorter refractoriness initiated figure-8 circus movement reentry with progressive migration of the site of the reentrant circuit. A contrasting hypothetical model by Antzelevitch and Sicouri5 proposed a midmyocardial column of a functional barrier created by the population of M cells with longer refractory periods. A premature activation wave front arising outside the barrier would propagate along the edge of the column, enter the M region after expiration of its refractoriness, and then reenter at the border to initiate circus movement. Repetition of this type of circus movement with progressively shifting sites of reentry could yield the electrical migration characteristic of torsade de pointes.
In the present study, analysis of tridimensional activation patterns illustrated two different mechanisms for the polymorphic QRS morphology of VTs in the LQTS. When the arrhythmia was due to repetitive focal activity, the change in QRS morphology was due to shifting of the site of origin of the ectopic activity, resulting in varying activation patterns and QRS configuration. When the arrhythmia was due to repetitive reentrant excitation, the twisting QRS morphology was due to varying orientations of the circulating wave fronts or, more accurately, of the circulating scrolls. Frequently, two or more simultaneous circulating scrolls were present, sometimes rotating in opposite directions in a figure-8 pattern. It is important to emphasize that the circulating scrolls were not in the form of spirals (ie, circulating activity around a small central core53 ) but rather in the form of large wave fronts circulating around either an anatomic obstacle (ie, the right or left ventricular cavities) or long central arcs of functional block. The location and configuration of successive circulating scrolls were more complex compared with the simple schema proposed by other investigators.5 52 This should not be surprising considering the complex pattern of adaptation of refractoriness following the first reentrant cycle.
Limitations of the Experimental Model
The experimental model has many characteristics of the clinical syndrome. However, the classic torsade de pointes morphology was uncommonly observed, and long episodes of fast tachyarrhythmia rarely terminated spontaneously. This is different from the clinical counterpart, where it is not unusual for fast torsade de pointes VT to terminate spontaneously.1 34 35 Thus, the conclusions regarding the mechanism of the ECG morphology of torsade de pointes VT are not definitive.
The accuracy of tridimensional mapping of activation is directly proportional to the resolution of the recordings. A higher resolution would require the insertion of a larger number of plunge needle electrodes. This would be limited primarily by the potential of negative electrophysiological and/or hemodynamic sequelae from needle insertion. In the present study, the use of small-sized puppies and 64 plunge needle electrodes resulted in a resolution of 4 to 9 mm between needles but a 1- to 2-mm resolution along the needles. This may sometimes not be adequate to resolve small functional reentrant circuits, which could be misinterpreted as a focal pattern. This limitation would not affect the primary conclusions of the present study, namely, that single ectopic beats, couplets, as well as the initial beat of polymorphic VT represented focal activity and that the first or second focal activity could initiate reentrant excitation. However, it is possible, for example, that in a fast nonsustained VT, as shown in Fig 17, some of the later beats that were interpreted as focal in origin may have been the result of a small reentrant circuit.
In summary, tridimensional mapping of activation and recovery patterns in a relevant animal model has provided a cohesive electrophysiological mechanism of VTs in LQTS. The technique for measurement of tridimensional recovery patterns in the ventricle can be used to obtain valuable insight into the arrhythmogenic role of spatial inhomogeneity of recovery in this and in other animal models of VT.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by Veterans Administration medical research funds. We wish to thank Shu Zhang and Mohammad Piracha for their contribution to needle fabrication and surgical preparation and Antoinette Wells and Joyce Ince for surgical assistance and care of the animals.
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Footnotes |
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Reprint requests to Nabil El-Sherif, MD, SUNY Health Science Center, Cardiology Division, Box 1199, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail el-sherif.nabil@brooklyn.va.gov.
Previously published as preliminary results in abstract form (Circulation. 1995:92[suppl I]:I-641; Biophys J. 1996;70:A277).
Received February 5, 1996; accepted May 24, 1996.
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References |
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P. C. Viswanathan, R. M. Shaw, and Y. Rudy Effects of IKr and IKs Heterogeneity on Action Potential Duration and Its Rate Dependence : A Simulation Study Circulation, May 11, 1999; 99(18): 2466 - 2474. [Abstract] [Full Text] [PDF]
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P. C Viswanathan and Y. Rudy Pause induced early afterdepolarizations in the long QT syndrome: a simulation study Cardiovasc Res, May 1, 1999; 42(2): 530 - 542. [Abstract] [Full Text] [PDF]
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N. El-Sherif, E. B. Caref, M. Chinushi, and M. Restivo Mechanism of arrhythmogenicity of the short-long cardiac sequence that precedes ventricular tachyarrhythmias in the long QT syndrome J. Am. Coll. Cardiol., April 1, 1999; 33(5): 1415 - 1423. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Cellular and Ionic Basis for T-Wave Alternans Under Long-QT Conditions Circulation, March 23, 1999; 99(11): 1499 - 1507. [Abstract] [Full Text] [PDF]
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D. Lacroix, F. Extramiana, P. Delfaut, M. Adamantidis, D. Grandmougin, D. Klug, S. Kacet, and B. Dupuis Factors affecting epicardial dispersion of repolarization: a mapping study in the isolated porcine heart Cardiovasc Res, March 1, 1999; 41(3): 563 - 574. [Abstract] [Full Text] [PDF]
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E. Robert, A. G. M. Aya, J. E. de la Coussaye, P. Peray, J.-M. Juan, J. Brugada, J.-M. Davy, and J.-J. Eledjam Dispersion-based reentry: mechanism of initiation of ventricular tachycardia in isolated rabbit hearts Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H413 - H423. [Abstract] [Full Text] [PDF]
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S. M. Pogwizd, J. P. McKenzie, and M. E. Cain Mechanisms Underlying Spontaneous and Induced Ventricular Arrhythmias in Patients With Idiopathic Dilated Cardiomyopathy Circulation, December 1, 1998; 98(22): 2404 - 2414. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Cellular Basis for the ECG Features of the LQT1 Form of the Long-QT Syndrome : Effects of ß-Adrenergic Agonists and Antagonists and Sodium Channel Blockers on Transmural Dispersion of Repolarization and Torsade de Pointes Circulation, November 24, 1998; 98(21): 2314 - 2322. [Abstract] [Full Text] [PDF]
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G.-X. Yan, W. Shimizu, and C. Antzelevitch Characteristics and Distribution of M Cells in Arterially Perfused Canine Left Ventricular Wedge Preparations Circulation, November 3, 1998; 98(18): 1921 - 1927. [Abstract] [Full Text] [PDF]
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G.-X. Yan and C. Antzelevitch Cellular Basis for the Normal T Wave and the Electrocardiographic Manifestations of the Long-QT Syndrome Circulation, November 3, 1998; 98(18): 1928 - 1936. [Abstract] [Full Text] [PDF]
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E. Drouin, G. Lande, and F. Charpentier Amiodarone reduces transmural heterogeneity of repolarization in the human heart J. Am. Coll. Cardiol., October 1, 1998; 32(4): 1063 - 1067. [Abstract] [Full Text] [PDF]
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W. Zareba, A. J. Moss, P. J. Schwartz, G. M. Vincent, J. L. Robinson, S. G. Priori, J. Benhorin, E. H. Locati, J. A. Towbin, M. T. Keating, et al. Influence of the Genotype on the Clinical Course of the Long-QT Syndrome N. Engl. J. Med., October 1, 1998; 339(14): 960 - 965. [Abstract] [Full Text] [PDF]
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M. Chinushi, M. Restivo, E. B. Caref, and N. El-Sherif Electrophysiological Basis of Arrhythmogenicity of QT/T Alternans in the Long-QT Syndrome : Tridimensional Analysis of the Kinetics of Cardiac Repolarization Circ. Res., September 21, 1998; 83(6): 614 - 628. [Abstract] [Full Text] [PDF]
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M. A. Vos, S. H. M. de Groot, S. C. Verduyn, J. van der Zande, H. D. M. Leunissen, J. P. M. Cleutjens, M. van Bilsen, M. J. A. P. Daemen, J. J. Schreuder, M. A. Allessie, et al. Enhanced Susceptibility for Acquired Torsade de Pointes Arrhythmias in the Dog With Chronic, Complete AV Block Is Related to Cardiac Hypertrophy and Electrical Remodeling Circulation, September 15, 1998; 98(11): 1125 - 1135. [Abstract] [Full Text] [PDF]
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L. Eckardt, W. Haverkamp, M. Borggrefe, and G. Breithardt Experimental models of torsade de pointes Cardiovasc Res, July 1, 1998; 39(1): 178 - 193. [Abstract] [Full Text] [PDF]
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M. Zabel, T. Klingenheben, M. R. Franz, and S. H. Hohnloser Assessment of QT Dispersion for Prediction of Mortality or Arrhythmic Events After Myocardial Infarction : Results of a Prospective, Long-term Follow-up Study Circulation, June 30, 1998; 97(25): 2543 - 2550. [Abstract] [Full Text] [PDF]
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O. Berenfeld and J. Jalife Purkinje-Muscle Reentry as a Mechanism of Polymorphic Ventricular Arrhythmias in a 3-Dimensional Model of the Ventricles Circ. Res., June 1, 1998; 82(10): 1063 - 1077. [Abstract] [Full Text] [PDF]
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K. Derakhchan, R. Cardinal, S. Brunet, D. Klug, C. Pharand, T. Kus, and B. I. Sasyniuk Polymorphic ventricular tachycardias induced by D-sotalol and phenylephrine in canine preparations of atrioventricular block: initiation in the conduction system followed by spatially unstable re-entry Cardiovasc Res, June 1, 1998; 38(3): 617 - 630. [Abstract] [Full Text] [PDF]
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W. Shimizu, T. Kurita, K. Matsuo, K. Suyama, N. Aihara, S. Kamakura, J. A. Towbin, and K. Shimomura Improvement of Repolarization Abnormalities by a K+ Channel Opener in the LQT1 Form of Congenital Long-QT Syndrome Circulation, April 28, 1998; 97(16): 1581 - 1588. [Abstract] [Full Text] [PDF]
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H. S. Oster, B. Taccardi, R. L. Lux, P. R. Ershler, and Y. Rudy Electrocardiographic Imaging : Noninvasive Characterization of Intramural Myocardial Activation From Inverse-Reconstructed Epicardial Potentials and Electrograms Circulation, April 21, 1998; 97(15): 1496 - 1507. [Abstract] [Full Text] [PDF]
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J. F. Spear and E. N. Moore Modulation of quinidine-induced arrhythmias by temperature in perfused rabbit heart Am J Physiol Heart Circ Physiol, March 1, 1998; 274(3): H817 - H828. [Abstract] [Full Text] [PDF]
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S. Nattel Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs Cardiovasc Res, March 1, 1998; 37(3): 567 - 577. [Abstract] [Full Text] [PDF]
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N. El-Sherif, M. Chinushi, E. B. Caref, and M. Restivo Electrophysiological Mechanism of the Characteristic Electrocardiographic Morphology of Torsade de Pointes Tachyarrhythmias in the Long-QT Syndrome : Detailed Analysis of Ventricular Tridimensional Activation Patterns Circulation, December 16, 1997; 96(12): 4392 - 4399. [Abstract] [Full Text]
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E. P. Anyukhovsky, E. A. Sosunov, S. J. Feinmark, and M. R. Rosen Effects of Quinidine on Repolarization in Canine Epicardium, Midmyocardium, and Endocardium : II. In Vivo Study Circulation, December 2, 1997; 96(11): 4019 - 4026. [Abstract] [Full Text]
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V. A. Maltsev and A. I. Undrovinas Cytoskeleton modulates coupling between availability and activation of cardiac sodium channel Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1832 - H1840. [Abstract] [Full Text] [PDF]
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W. Shimizu and C. Antzelevitch Sodium Channel Block With Mexiletine Is Effective in Reducing Dispersion of Repolarization and Preventing Torsade de Pointes in LQT2 and LQT3 Models of the Long-QT Syndrome Circulation, September 16, 1997; 96(6): 2038 - 2047. [Abstract] [Full Text]
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