This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by El-Sherif, N. Articles by Restivo, M. Search for Related Content PubMed PubMed Citation Articles by El-Sherif, N. Articles by Restivo, M.

(Circulation. 1997;96:4392-4399.)
© 1997 American Heart Association, Inc.

Articles

Electrophysiological Mechanism of the Characteristic Electrocardiographic Morphology of Torsade de Pointes Tachyarrhythmias in the Long-QT Syndrome

Detailed Analysis of Ventricular Tridimensional Activation Patterns

Nabil El-Sherif, MD; Masaomi Chinushi, MD; Edward B. Caref, PhD; ; Mark Restivo, PhD

From the Cardiology Division, Department of Medicine, State University of New York Health Science Center and Veterans Affairs Medical Center, Brooklyn, NY.

Correspondence to Nabil El-Sherif, MD, SUNY Health Science Center, Cardiology Division, Box 1199, 450 Clarkson Ave, Brooklyn, NY 11203. E-mail el-sherif.nabil{at}brooklyn.va.gov

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The long-QT syndrome (LQTS) is an electrophysiological (EP) entity characterized by prolongation of cardiac repolarization and the occurrence of polymorphic ventricular tachyarrhythmias (VTs), sometimes with a twisting QRS morphology, better known as torsade de pointes (TdP). In the present study, detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT was performed to provide an EP mechanism of the periodic transition in QRS axis.

Methods and Results The studies were conducted with the anthopleurin-A canine model of LQTS. Tridimensional isochronal maps of ventricular activation were constructed from 256 bipolar electrograms obtained from the use of 64 plunge needle electrodes. In 26 episodes of nonsustained TdP VT, detailed activation maps could be accurately constructed during QRS-axis transitions in surface ECGs. The initial beat of all VTs consistently arose as a subendocardial focal activity, whereas subsequent beats were due to reentrant excitation in the form of rotating scrolls. The VT ended when reentrant excitation was terminated. In 22 of 26 episodes, the transition in QRS axis coincided with the transient bifurcation of a predominantly single rotating scroll into two simultaneous scrolls involving both the right ventricle and left ventricle separately. The common mechanism for initiation or termination of bifurcation was the development of functional conduction block between the anterior or posterior right ventricle free wall and the ventricular septum. In 4 of 26 episodes, a fast polymorphic VT, with an apparent shift in QRS axis, was due to a predominantly single localized circuit that varied its location and orientation from beat to beat, with the majority of ventricular myocardium being activated in a centrifugal pattern.

Conclusions The study provides for the first time an EP mechanism for the characteristic periodic transition of the QRS axis during TdP VT in the LQTS.

Key Words: electrophysiology • torsade de pointes • tachyarrhythmias • electrocardiography

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
The LQTS is an EP 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 TdP.^1,2 Since the initial description of TdP by Dessertenne¹ >30 years ago, many electrophysiologists have been intrigued by the QRS morphological characteristics of the arrhythmia, whereas little progress has been made toward developing a cohesive EP mechanism for the characteristic morphology.

We developed a surrogate canine model of the LQT3 syndrome by using the neurotoxin AP-A.³ In a recent report using this model, we 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.⁴

In the previous report,⁴ only a few examples of self-terminating TdP VT were shown, and the EP mechanism or mechanisms of the twisting QRS pattern were not analyzed in detail. In the present study, we conducted new experiments to provide detailed analysis of ventricular tridimensional activation patterns during nonsustained TdP VT and provide an EP mechanism of the periodic transition in QRS axis in surface ECG leads.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
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 eight purpose-bred mongrel puppies 10 to 12 weeks old and 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 into the femoral artery to monitor blood pressure. ECG leads I, aVF, and V₁ and blood pressure (Statham transducer; Gould) were continuously monitored with a physiological recorder (VR12; PPG Industries). The heart was exposed through a midsternotomy. Core temperature was maintained constant at 37°C by the use of a thermostatically controlled thermal blanket and heat lamp. AP-A was administered as an intravenous bolus of 25 µg/kg followed by a maintenance dose of 1.0 µg/kg per minute. Wild-type AP-A produced through a bacterial expression system was used in this study.⁵

In five experiments, vagal stimulation⁴ was applied to slow the heart rate. In the remaining three experiments, complete AV block was achieved by radiofrequency electrode catheter ablation, resulting in a slow ventricular escape rhythm. On completion of the experiment, the animal was euthanized by electrical induction of ventricular fibrillation, and extirpation of the heart under general anesthesia was performed.

Recording Electrodes and Electrode Localization
Sixty-four plunge needle electrodes were used for tridimensional mapping of the whole ventricle. Details of plunge needle electrode construction and electrode localization were previously reported.⁴ After insertion of plunge needle electrodes, the chest wall was approximated. After termination of the experiment, each plunge needle was removed and carefully replaced by a labeled maptack pin in the exact electrode site. The heart was removed, fixed in formalin, and the location was noted 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 thick. 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
Bipolar electrograms were acquired using two variable-gain 128-channel multiplexed data acquisition systems (DSC 2000; INET Corp), allowing simultaneous recording of 256 channels. Details of the mapping system were previously reported.⁴ Activation times were determined according to previously published criteria.^6,7 Briefly, in uniphasic and triphasic signals, the peak voltage is a reliable predictor of activation time.⁷ In biphasic signals, the activation time was selected at the maximum slope. Computer-generated isochrones of activation were derived from the activation time data and delineated by closed contours at 20-ms intervals beginning with the earliest detected site of activation. For the whole ventricle activation maps, zones of functional unidirectional conduction block were identified using previously defined criteria.^6,7 A continuous line or surface was drawn through these regions and was defined as a zone of functional conduction block.

	Results

Top Abstract Introduction Methods Results Discussion References

 
In eight experiments, there were a total of 36 episodes of nonsustained VT available for analysis that varied in length from 4 to 39 beats (12±6 beats, mean±SD). The CL of VT ranged from 205 to 295 ms (244±28 ms, mean±SD). Fig 1 illustrates four runs of nonsustained VT from four different experiments. There was no statistical difference in the mean CL of VT in dogs subjected to vagally induced bradycardia (241±26 ms) versus complete AV block (246±31 ms, unpaired Student's t test). Fig 1A illustrates a 12-beat run of nonsustained VT at an average CL of 273 ms. In this experiment, complete AV block was present, and the first and last beats in the recording represent slow ventricular escape impulses. The VT had a polymorphic configuration with the distinct undulating pattern especially evident in the second half of the episode in leads I and aVF. Fig 1B illustrates a 15-beat run of nonsustained VT at an average CL of 235 ms with a characteristic change of the QRS axis as if the complex rotated around the baseline. This is especially evident in lead aVF. Fig 1C and 1D illustrate longer runs of nonsustained VT at an average CL of 206 and 213 ms, respectively.

View larger version (44K): [in this window] [in a new window]   Figure 1. ECG recordings of leads I, aVF, and V1 of nonsustained TdP VT from four different experiments. All VTs have a polymorphic configuration with a characteristic undulating pattern, which could be more evident in one or more of the body surface ECG leads. Tridimensional ventricular activation (see following figures) showed that the initiating beat of each episode arose as focal subendocardial activity (marked by stars). Subsequent beats of TdP were always due to intramural reentrant excitation. In some episodes of TdP VT, after termination of reentrant excitation, one or more beats of varying subendocardial focal origin (marked by asterisks) could occur at irregular and consistently longer CLs compared with CLs of reentrant excitation.

The tridimensional ventricular activation maps showed that the initiating beat of each episode of nonsustained VT (marked by star in Fig 1) arose as focal activity from anywhere in the subendocardium and with no preference to a particular site. This beat was always coupled to the prolonged QT interval of the preceding basic impulse. In the present study, subsequent beats in a run of nonsustained VT were always due to intramural reentrant excitation. Each episode terminated when reentrant excitation failed to continue. After termination of reentrant excitation, one or more beats of varying subendocardial focal origin could occur at irregular and consistently longer CLs compared with preceding reentrant tachyarrhythmia (these are marked by asterisks in Fig 1).

Fig 2A through 2C illustrate the tridimensional ventricular activation patterns of the 12-beat VT shown in Fig 1A. The isochrones are drawn as closed contours at 20-ms intervals. (Successive isochrones are labeled as 1, 2, 3, and so on rather than 20 ms, 40 ms, 60 ms, and so on to make it easier to follow the activation patterns of subsequent beats of the VT.) Conduction block between electrode sites is represented in the maps by heavy solid lines. The initiating beat of the VT had a focal subendocardial origin (marked by a star in section 1). Multiple sites showed functional conduction block. The activation wave front advanced from section 1 to section 4, where it proceeded in a very slow counterclockwise circular pathway around the LV cavity before reactivating sites in sections 3 and 4 at isochrone 20, initiating the first reentrant cycle. During V₂, the activation wave front advanced in a clockwise circular pathway in sections 4 and 5 around the LV cavity with reactivation occurring at isochrone 37 in section 4. During V₃ through V₆, reentrant excitation continued in clockwise circular pathways in sections 3 and 4 around the LV cavity. However, the reentrant pathway was different from beat to beat. In the tridimensional maps, the circulating wave fronts are more accurately described as rotating scrolls of activation. During V₇, the rotating scroll continued in sections 4 and 5. However, the development of functional conduction block in the midseptum in sections 2 and 3 forced the occurrence of a rotating scroll around the RV free wall simultaneous with the scroll in sections 4 and 5. This circulating wave front was extinguished by collision in the septum with a counterclockwise wave front around the LV cavity. During V₈, a similar activation pattern continued. During isochrone 97, the activation wave front bifurcated into two distinct simultaneous rotating wave fronts: a clockwise wave front around the LV cavity in section 4, and a clockwise wave front around the RV cavity in section 2. The two wave fronts continued in V₉ with reactivation at isochrone 106 in section 5 and reactivation at isochrone 104 in section 2, respectively. The clockwise wave front in section 5 blocked at isochrone 109 while the circular wave front around the RV cavity continued for one more complete cycle in sections 2 and 3. During V₁₀, this activation wave front proceeded quickly from section 2 to section 4 in a basal-to-apical direction. The circular activation around the RV terminated due to the development of functional conduction block between the RV free wall and anterior septum (section 2 in V₁₁), whereas a very slow clockwise circular wave front redeveloped in section 4 and continued during V₁₂. During V₁₂, the clockwise circular wave front blocked in the anterolateral wall of the LV (in sections 2 through 5) and in the anterior wall of the RV (in section 1), ending the reentrant activity and the episode of VT.

View larger version (64K): [in this window] [in a new window]   Figure 2. A through C, Tridimensional ventricular activation patterns of the 12-beat nonsustained TdP VT shown in Fig 1 A. The isochrones were drawn as closed contour at 20-ms intervals and labeled as 1, 2, 3, and so on to make it easier to follow the activation patterns of successive beats of the VT. Functional conduction block is represented in the maps by heavy solid lines. The thick bars under the surface ECG lead mark the time intervals covered by each of the tridimensional maps. The V1 beat arose as a focal subendocardial activity (marked by a star in section 1). All subsequent beats were due to reentrant excitation. The twisting QRS pattern was more evident in lead aVF during the second half of the VT episode. The transition in QRS axis (between V7 and V10) correlated with the bifurcation of a predominantly single rotating wave front (scroll) into two separate simultaneous wave fronts rotating around the LV and RV cavities. The final transition in QRS axis (between V10 and V11) correlated with the termination of the RV circuit and the reestablishment of a single LV circulating wave front (see text for more details). P indicates P waves.

Fig 3 shows selected electrograms along the reentrant pathway during the ectopic beat (V₁) that initiated the VT shown in Fig 2. The V₁ impulse had a long coupling interval compared with the proceeding basic beat (700 ms). The first reentrant cycle was relatively long (20 isochrones, 400 ms). Bipolar electrograms recorded from the slowly conducting pathway in section 4 had a wide multicomponent configuration. The first of the double potentials of electrogram J represents activation (A) during isochrone 10, and the second deflection (E) represents an electrotonic potential synchronous with activation of isochrone 13 in section 5, immediately caudal to electrode site J. On the other hand, the first of the double potentials of electrogram K represents an electrotonic potential (E) synchronous with activation at isochrone 9 across the arc of functional conduction block in section 4, whereas the second potential (A) represents activation during isochrone 13. A similar interpretation applies to the double potentials of electrogram Q.

View larger version (51K): [in this window] [in a new window]   Figure 3. Selected local electrograms recorded along the reentrant pathway during the V1 beat of the TdP VT shown in Figs 1A and 2 illustrate complete diastolic bridging during the first reentrant cycle of 400-ms duration. Bipolar electrograms recorded from the very slow conducting component of the circuit in section 4 had a wide multicomponent configuration. Electrograms recorded in close proximity to arcs of functional conduction block had double potentials representing an electrotonic potential (E) and an activation potential (A), respectively. Note that the electrotonic potentials were synchronous with activation at the opposite side of arcs of functional block (electrograms J, K, and Q).

Fig 4 shows selected electrograms of the two simultaneous reentrant circuits during the interval that coincided with the initial "gradual" transition of the QRS axis in lead aVF. Electrograms A through G were recorded along the clockwise circuit around the RV cavity in section 2, and electrograms H through N illustrate the activation of the simultaneous clockwise circuit around the LV cavity in section 4.

View larger version (50K): [in this window] [in a new window]   Figure 4. Selected local electrograms recorded along the two simultaneous reentrant wave fronts during the interval that coincided with the initial "gradual" transition of the QRS axis in lead aVF. Electrograms A through G were recorded along the clockwise circuit around the RV cavity in section 2, whereas electrograms H through N illustrate the activation of the simultaneous clockwise circuit around the LV cavity in section 4.

Fig 5 shows selected electrograms during V₁₀ that coincided with the last "abrupt" transition of the QRS axis in lead aVF. As described previously in Fig 3, several bipolar electrograms recorded along the very slow conducting wave front in section 4 had broad multicomponent configurations that reflect electrotonic interaction across zones of functional conduction block^6,7 and/or very slow anisotropic conduction transverse to the long axis of myocardial fibers⁸ (see electrogram D).

View larger version (31K): [in this window] [in a new window]   Figure 5. Selected local electrograms during the interval that coincided with the last "abrupt" transition of the QRS axis in lead aVF. The transition correlated with the termination of the RV circuit and the establishment of a single, very slow, circulating wave front around the LV cavity in section 4. Bipolar electrograms recorded from the very slow wave front had a broad multicomponent configuration.

Correlation of Transition in QRS Axis and Tridimensional Isochronal Activation Pattern
The twisting of the QRS axis in the second half of the VT episode shown in Fig 1A and Figs 2 through 5 was more evident in leads I and aVF but not in lead V₁. In particular, lead aVF showed a "gradual" twisting from a sharp negative complex in V₇ to a sharp positive complex in V₁₀ with two low-amplitude intermediate deflections labeled V₈ and V₉. On the other hand, the transition from the sharp positive V₁₀ complex to the sharp negative V₁₁ complex was rather "abrupt." The changes in the QRS configuration in lead aVF correlated with the changes in tridimensional ventricular activation pattern. The sharp negative QRS configuration of V₇ correlated with the fast apical-to-basal activation pattern. The gradual transition between V₇ and V₁₀ coincided with the change from a single reentrant wave front to two simultaneous circulating wave fronts around the RV and LV cavities. The opposing direction of the activation wave front running predominantly from apex to base in the free RV wall and septum and the activation front running predominantly from base to apex in the free LV wall explains the relatively small-amplitude QRS complex in lead aVF labeled V₈. The block of the apical LV circuit in V₉ allowed a basal-to-apical activation of the ventricles during V₁₀ that correlates with the positive component of the V₁₀ QRS complex in lead aVF. The sharp negative component of the V₁₀ QRS complex, followed by a largely isoelectric segment preceding the inscription of the sharp negative QRS complex of V₁₁- coincided with the termination of the RV circuit and the development of a very slow circulating wave front in apical section 4. Finally, the negative QRS configuration of V₁₁ and V₁₂ in lead aVF correlated with the predominantly apical-to-basal activation pattern of both beats. Although the twisting of the QRS axis was also quite evident in lead I, the correlation between the QRS configuration in lead I, and the tridimensional activation pattern was more difficult to interpret. This is probably because of the difficulty in correlating the frontal plane activation pattern in each of the five sections with the axial projection of lead I on the body surface compared with lead aVF.

Transient Bifurcation of a Single Rotating Scroll During QRS-Axis Transitions
It was not always possible to analyze in detail the tridimensional ventricular activation pattern during the transition in QRS axis in all of the 36 episodes of nonsustained VT because of limitations of the resolution of the recordings. This limitation applied in particular to longer VT episodes at shorter CLs and with multiple undulations of the QRS axis. However, in 22 of 26 examples in which detailed activation maps could be accurately constructed during transitions in QRS axis, the EP mechanism was similar to that shown in Figs 2 through 5. The occurrence of a gradual shift in the QRS axis was associated with the bifurcation of a single circulating wave front into two simultaneous wave fronts. The termination of one of the two circuits and the reestablishment of one predominant circuit would also usher a transition in the QRS axis. A longer transition covering several cycles was usually associated with the gradual dominance of one of the circulating wave fronts.

Wherever two wave fronts occurred, they consistently involved the RV and LV separately. The RV circuit always rotated around the RV cavity, whereas the LV circuit could develop either around the LV cavity or within the LV free wall. This is shown in Fig 6. The figure illustrates the tridimensional activation maps of beats V₆ through V₉ of the VT shown in Fig 1B. During these four cycles, the QRS axis in lead aVF shifted from a predominantly negative QRS complex to a predominantly positive QRS complex, with the QRS of V₇ through V₉ showing a transitional configuration. On the other hand, there was a "sudden" shift of the QRS axis in lead V₁ from a predominantly negative QRS complex in V₆ and V₇ to a predominantly positive QRS complex in V₈ and V₉. The activation maps show that during V₆, there was continuation of a predominantly single clockwise circulating wave front around both the RV and LV due to the presence of functional conduction block in the interventricular septum. During V₇, a predominantly single clockwise wave front around the LV cavity continued while the RV wall was activated passively. During V₈, two distinct circulating wave fronts developed: a counterclockwise wave front in the LV free wall in sections 2 and 3, and a counterclockwise wave front around the RV cavity in sections 1 through 3. The establishment of the two wave fronts was initiated by the development of functional conduction block between the RV free wall and the posterior septum in section 1 through 3. Both the RV and LV circuits continued in V₉. The RV circuit blocked during V₁₀ (not shown), whereas a single intramural circuit in the LV free wall continued. The transitional QRS complexes of V₈ and V₉ in lead aVF could be explained by the presence of two opposing activation wave fronts. Similarly, the sudden transition of QRS axis in lead V₁ could be explained by the sudden shift from a predominantly RV-to-LV activation pattern in V₇ to one with predominantly late activation of the RV free wall in V₈. Reentrant activation terminated by beat V₁₄. The last impulse (V₁₅) was due to a subendocardial focal activity.

View larger version (66K): [in this window] [in a new window]   Figure 6. Tridimensional ventricular activation patterns of V6 through V9, which coincided with the transition of QRS axis of the nonsustained TdP VT as shown in Fig 1B. The initial transition of the axis coincided with the bifurcation of a single circulating wave front in V6 and V7 into two simultaneous wave fronts around the RV cavity and intramurally in the LV free wall, respectively, during V8 and V9. (See text for more details.)

Apparent QRS-Axis Transitions During Single Circulating Wave Fronts
In four episodes of nonsustained VT, the transition in QRS axis was not associated with the transient development of two competing LV and RV circulating wave fronts but rather a localized single reentrant circuit that varied in location from beat to beat, with most of the ventricle being activated in a centrifugal fashion. In these examples, the transition in QRS axis did not resemble the "torsade de pointes" pattern, but instead was described as a polymorphic configuration. One example is shown in Fig 7. The surface ECG leads show a seven-beat run of nonsustained VT with a polymorphic QRS configuration. A transition in QRS axis is seen in all three leads. Fig 8A and 8B illustrate the tridimensional activation maps of the sinus beat and V₁ through V₇. As was always the case, the V₁ beat that initiated the VT episode arose as a focal subendocardial activity (marked by the star in section 2) and initiated a localized intramural reentrant circuit in the apical region of the LV wall in sections 4 and 5. Reentrant activation continued during V₂ through V₆ with continuous shifting of the location and orientation of a single reentrant wave front within a relatively small region in the apical portion of the LV in sections 4 and 5. During V₂ through V₆, the majority of ventricular myocardium (sections 1 through 3) were activated in a centrifugal pattern from the localized reentrant wave front in the apical region. The beat-to-beat variation in the activation pattern of sections 1 through 3 could explain the changes in QRS configuration in the surface ECG leads. For example, in lead aVF, the positive QRS configuration of V₁ correlated with the predominantly basal-to-apical activation pattern. On the other hand, the largely negative QRS configuration of V₂ through V₄ correlated with a predominantly apical-to-basal activation patterns. The negative small-amplitude (almost isoelectric) QRS configuration of V₅ could be explained by the fact that although the major direction of activation of both RV and LV tended to run from apex to base, the majority of ventricular myocardium was activated simultaneously within only 40 ms (isochrones 40 through 42). Reentrant activation terminated in V₆ and V₇ was due to a subendocardial focal discharge (marked by a star in section 5).

View larger version (14K): [in this window] [in a new window]   Figure 7. ECG leads I, aVF, and V1 of a seven-beat run of nonsustained polymorphic VT from another experiment. The transition in QRS axis in all leads did not resemble the "torsade de pointes" pattern. S indicates sinus beat.

View larger version (59K): [in this window] [in a new window]   Figure 8. A and B, Tridimensional ventricular activation patterns of the sinus beat (s) and V1 through V7 of the nonsustained polymorphic VT shown in Fig 7. V1 arose as a focal subendocardial activity (marked by the star in section 2) and initiated a localized intramural reentrant circuit in sections 4 and 5. Reentrant activation continued during V2 through V6 with continuous shifting of the location and orientation of a single reentrant wave front within a relatively small region in sections 4 and 5. During V2 through V6, the majority of ventricular myocardium (sections 1 through 3) was activated in a centrifugal pattern from the localized reentrant wave front. Reentrant activation terminated in V6 and V7 occurred 400 ms later due to a subendocardial focal activity (marked by a star in section 5).

Fig 9 illustrates selected electrograms during V₁ and V₂ in the seven-beat VT episode shown in Figs 7 and 8. Electrograms A through H illustrate the continuous activation during the first reentrant cycle. As was shown in Fig 3, bipolar electrograms recorded in close proximity to arcs of functional conduction block frequently exhibited double potentials that represented electrotonic (E) and activation (A) potentials (see electrograms E, H, and I). The V₂ map and electrograms I through L illustrate an important observation. The first reentrant wave front reactivated a subendocardial site in the LV wall in section 4 at isochrone 11 (electrogram H) and isochrone 12 (electrogram I). This was followed by a rapid activation (within 5 ms) of localized corresponding subendocardial sites in sections 3, 2, and 1 (represented by electrograms J, K, and L, respectively). This fast, localized subendocardial activation strongly suggests retrograde conduction along branches of the left bundle. This observation emphasizes the potential contribution of conduction through the His-Purkinje system to the varying activation pattern during polymorphic VT. Fig 9 also shows that during the focal beat, V₇, the electrode sites recorded relatively synchronous electrograms compared with those recorded during reentrant excitation, especially at apical sites (E through H). The onset of V₇ focal activity occurred 400 ms after termination of reentrant activation.

View larger version (45K): [in this window] [in a new window]   Figure 9. Selected local electrograms during V1 and V2 of the seven-beat VT episode shown in Figs 7 and 8. Electrograms A through H illustrate the continuous diastolic activation during the first reentrant cycle. Bipolar electrograms recorded in close proximity to an arc of functional conduction block had double potentials that represent electrotonic (E) and activation (A) potentials, respectively. During V2, very fast activation of corresponding localized subendocardial sites in section 4, 3, 2, and 1 (represented by electrograms I through L, respectively) suggest retrograde conduction along branches of the left bundle.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
EP Mechanism of TdP VT in the LQTS
The present study confirms, in more detail, the basic tenets of the EP mechanism of polymorphic VT in the LQTS as previously reported.⁴ However, an important modification is necessary. In the previous report, we stated that "the initial beat of polymorphic VT consistently arose as a subendocardial focal activity, whereas subsequent beats were due to successive subendocardial focal activity, reentrant excitation, or a combination of both mechanisms." Nonsustained polymorphic VT in LQTS were 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). The CL of group A VT was significantly longer (335±26 ms, mean±SD) compared with group B VT (242±9 ms, mean±SD, P<.001).⁴ Group A VT never resembled the TdP pattern. In the present study, all fast polymorphic VTs (with or without the classic TdP configuration) were due to successive reentrant excitation initiated by a subendocardial focal activity. As already described here, in some instances, termination of fast reentrant VT was followed by one or more focal beats occurring at a much longer CL. However, during the fast VT, there never was a combination of focal and reentrant excitation. Thus, our previous report of such a combination of the two mechanisms (eg, Figs 17 and 18 in ⁴ is not confirmed by the present observations. It is fair, however, to mention that the previous conclusion was qualified as follows: "Because of the limitations of the recordings resolution ... beats that were interpreted as focal in origin may have been the result of a small reentrant circuit."⁴

Mechanisms of Twisting QRS Axis of TdP VT
We have clearly demonstrated in the present report that when tridimensional activation patterns could be accurately constructed during the transition in QRS axis of a TdP VT, the mechanism was consistently due to the transient bifurcation of a predominantly single rotating scroll into two simultaneously rotating scrolls involving both the RV and LV. The RV scroll always rotated around the RV cavity. On the other hand, the LV scroll could develop either around the LV cavity (Fig 2) or in the LV free wall (Fig 6). The initiating mechanism for the bifurcation of the single wave front frequently was the development of functional conduction block between the anterior or posterior RV free wall and the interventricular septum. The termination of the RV wave front was also frequently associated with the development of functional conduction block ahead of the circulating wave front between the RV free wall and the anterior or posterior border of the septum (see V₉ map in Fig 6). In other instances, the RV circulating wave front was extinguished through collision with an opposing wave front in the interventricular septum (see V₇ map in Fig 2B). The RV circulating wave front usually did not exhibit a localized zone of slow conduction. This may suggest that the conduction block that develops at the border between the thin RV free wall and the much thicker interventricular septum may be, at least in part, secondary to an impedance-mismatch mechanism.⁹ On the other hand, LV circuits frequently encompassed a varying zone of slow conduction, and conduction block usually developed in this slow zone probably secondary to decremental conduction. Although it was more difficult to correlate accurately, there was evidence that a period of transitional complexes covering more than one cycle was associated with gradual dominance of one of the two circulating wave fronts before termination of the other wave front (see the transitional QRS complexes labeled V₈ and V₉ in Fig 2B and 2C).

A tachyarrhythmia with TdP-like morphology in a transmural ECG could be induced by erythromycin, an I_Kr blocker, in an arterially perfused canine LV wedge preparation.¹⁰ Simultaneous transmembrane recordings were highly suggestive of reentry as the underlying mechanism. It is possible that the transient bifurcation of a single impulse into two scroll waves as the basis of QRS transitions of TdP can occur anywhere in the ventricle. The characteristic mechanism involving the RV and LV described here may be partly related to the longer pathway required to accommodate the longer wavelength of reentrant circuits in the AP-A model (average CL, 244 ms).

Study Limitations
The accuracy of tridimensional mapping of activation is directly proportional to the resolution of the recordings. In the present study, the recording resolution was 4 to 8 mm between needles and 2 mm along the needles. Sometimes, this may not be adequate to resolve small reentrant circuits, which may be misinterpreted as focal activity. This limitation, however, had little bearing on the results in the present study because conclusions regarding the mechanism of transition of QRS axis of TdP VT were obtained from VT runs in which tridimensional activation patterns could be accurately constructed and consistently revealed reentrant excitation. Although in several examples of fast TdP VT with periodic transitions in QRS axis, the resolution of the recordings did not allow accurate analysis of successive transition episodes, there is no reason to believe that a different EP mechanism was operative. The correlation between the isochronal tridimensional activation pattern and the body surface ECG should be considered an approximation. The position of the heart in the thoracic cavity was disturbed by the thoracotomy, even through the chest wall was approximated, and by insertion of multiple plunge needles. Furthermore, there was no way to evaluate with accuracy the relative contribution of the different isochrones of activation to the overall pattern of the surface ECG; the latter represents a vectorial summation of multiple isochrones.

	Selected Abbreviations and Acronyms

 

AP-A = anthopleurin-A AV = atrioventricular CL = cycle length EP = electrophysiological LQTS = long-QT syndrome LV = left ventricular, ventricle RV = right ventricular, ventricle TdP = torsade de pointes VT = ventricular tachyarrhythmia

	Acknowledgments

 
This work was supported in part by funds from the Department of Veterans Affairs Medical Research Service (Drs El-Sherif and Restivo) and a Medtronic Japan Fellowship Award (Dr. Chinushi). We wish to thank Victoria Stoyanovsky, Richard Levin, and Drs Jacqueline Chen, Sabu John, and Monir Chaudhry for their technical support and Antoinette Wells and Joyce Ince for their care of the animals.

Received July 3, 1997; revision received September 4, 1997; accepted September 9, 1997.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Dessertenne F. La tachycardie ventriculaire á deux foyers opposés variables. Arch Mal Coeur. 1966;59:263–272.
   
2. Jackman WM, Clark M, Friday KJ, Aliot EM, Anderson J, Lazzara R. Ventricular tachyarrhythmias in the long QT syndrome. Med Clin North Am. 1984;68:1079:1104.[Medline] [Order article via Infotrieve]
   
3. El-Sherif N, Zeiler RH, Craelius W, Gough WB, Henkin R. QTU prolongation and polymorphic ventricular tachyarrhythmias due to bradycardia-dependent early afterdepolarizations. Circ Res. 1988;63:286–305.[Abstract/Free Full Text]
   
4. El-Sherif, N, Caref EB, Yin H, Restivo M. The electrophysiological mechanism of ventricular tachyarrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res. 1996;79:474–492.[Abstract/Free Full Text]
   
5. Gallagher MJ, Blumenthal KM. Cloning and expression of wild-type and mutant forms of the cardiotonic polypeptide anthopleurin B. J Biol Chem. 1992;267:13958–139636.[Abstract/Free Full Text]
   
6. Restivo M, Gough WB, El-Sherif N. Ventricular arrhythmias in subacute myocardial infarction period: high-resolution activation and refractory patterns of reentrant rhythms. Circ Res. 1990;66:1310–13277.[Abstract/Free Full Text]
   
7. Ndrepepa G, Caref EB, Yin H, El-Sherif N, Restivo M. Activation time determination by high-resolution unipolar and bipolar extracellular electrograms in the canine heart. J Cardiovasc Electrophysiol. 1995;6:174–178.[Medline] [Order article via Infotrieve]
   
8. Nassif G, Dillon SM, Rayhill S, Wit AL. Reentrant circuits and the effects of heptanol in a rabbit model of infarction with a uniform anisotropic border zone. J Cardiovasc Electrophysiol. 1993;4:112–133.
   
9. Fast VG, Kléber AG. Block of impulse propagation at an abrupt tissue expansion: evaluation of the critical strand diameter in a 2- and 3-dimensional computer models. Cardiovasc Res. 1995;30:449–459.[Medline] [Order article via Infotrieve]
   
10. Antzelevitch C, Sun ZQ, Zhang ZQ, Yan GX. Cellular and ionic mechanisms underlying erythromycin-induced long QT and torsade de pointes. J Am Coll Cardiol. 1996;28:1836–1848.[Abstract]
    

This article has been cited by other articles:

				M. Chinushi, D. Izumi, K. Iijima, S. Ahara, S. Komura, H. Furushima, Y. Hosaka, and Y. Aizawa Antiarrhythmic vs. pro-arrhythmic effects depending on the intensity of adrenergic stimulation in a canine anthopleurin-A model of type-3 long QT syndrome Europace, February 1, 2008; 10(2): 249 - 255. [Abstract] [Full Text] [PDF]

				S. T. Morita, D. P. Zipes, H. Morita, and J. Wu Analysis of action potentials in the canine ventricular septum: No phenotypic expression of M cells Cardiovasc Res, April 1, 2007; 74(1): 96 - 103. [Abstract] [Full Text] [PDF]

				B. London, L. C. Baker, P. Petkova-Kirova, J. M. Nerbonne, B.-R. Choi, and G. Salama Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT J. Physiol., January 1, 2007; 578(1): 115 - 129. [Abstract] [Full Text] [PDF]

				M. Viitasalo, L. Oikarinen, H. Swan, H. Vaananen, J. Jarvenpaa, H. Hietanen, J. Karjalainen, and L. Toivonen Effects of Beta-Blocker Therapy on Ventricular Repolarization Documented by 24-h Electrocardiography in Patients With Type 1 Long-QT Syndrome J. Am. Coll. Cardiol., August 15, 2006; 48(4): 747 - 753. [Abstract] [Full Text] [PDF]

				N. Ueda, D. P. Zipes, and J. Wu Coronary occlusion and reperfusion promote early afterdepolarizations and ventricular tachycardia in a canine tissue model of type 3 long QT syndrome Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H607 - H612. [Abstract] [Full Text] [PDF]

				C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]

				N. Ueda, D. P. Zipes, and J. Wu Functional and transmural modulation of M cell behavior in canine ventricular wall Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2569 - H2575. [Abstract] [Full Text] [PDF]

				N. Ueda, D. P Zipes, and J. Wu Prior ischemia enhances arrhythmogenicity in isolated canine ventricular wedge model of long QT 3 Cardiovasc Res, July 1, 2004; 63(1): 69 - 76. [Abstract] [Full Text] [PDF]

				M. Pourrier, S. Zicha, J. Ehrlich, W. Han, and S. Nattel Canine Ventricular KCNE2 Expression Resides Predominantly in Purkinje Fibers Circ. Res., August 8, 2003; 93(3): 189 - 191. [Abstract] [Full Text] [PDF]

				G.-X. Yan, R. S. Lankipalli, J. F. Burke, S. Musco, and P. R. Kowey Ventricular repolarization components on the electrocardiogram: Cellular basis and clinical significance J. Am. Coll. Cardiol., August 6, 2003; 42(3): 401 - 409. [Abstract] [Full Text] [PDF]

				B. London, L. C. Baker, J. S. Lee, V. Shusterman, B.-R. Choi, T. Kubota, C. F. McTiernan, A. M. Feldman, and G. Salama Calcium-dependent arrhythmias in transgenic mice with heart failure Am J Physiol Heart Circ Physiol, February 1, 2003; 284(2): H431 - H441. [Abstract] [Full Text] [PDF]

				M. Chinushi, H. Kasai, M. Tagawa, T. Washizuka, Y. Hosaka, Y. Chinushi, and Y. Aizawa Triggers of ventricular tachyarrhythmias and therapeutic effects of nicorandil in canine models of LQT2 and LQT3 syndromes J. Am. Coll. Cardiol., August 7, 2002; 40(3): 555 - 562. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Sympathetic modulation of the long QT syndrome Eur. Heart J., August 2, 2002; 23(16): 1246 - 1252. [PDF]

				D. Lacroix, P. Gluais, C. Marquie, C. D'Hoinne, M. Adamantidis, and M. Bastide Repolarization abnormalities and their arrhythmogenic consequences in porcine tachycardia-induced cardiomyopathy Cardiovasc Res, April 1, 2002; 54(1): 42 - 50. [Abstract] [Full Text] [PDF]

				G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1968 - H1975. [Abstract] [Full Text] [PDF]

				A. Halkin, A. Roth, I. Lurie, R. Fish, B. Belhassen, and S. Viskin Pause-dependent torsade de pointes following acute myocardial infarction: A variant of the acquired long QT syndrome J. Am. Coll. Cardiol., October 1, 2001; 38(4): 1168 - 1174. [Abstract] [Full Text] [PDF]

				C. Antzelevitch Heterogeneity of cellular repolarization in LQTS: the role of M cells Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K2 - K16. [Abstract] [PDF]

				C. Antzelevitch Transmural dispersion of repolarization and the T wave Cardiovasc Res, June 1, 2001; 50(3): 426 - 431. [Full Text] [PDF]

				C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]

				K. Yamamoto, T. Tamura, R. Imai, and M. Yamamoto Acute Canine Model for Drug-Induced Torsades de Pointes in Drug Safety Evaluation--Influences of Anesthesia and Validation with Quinidine and Astemizole Toxicol. Sci., March 1, 2001; 60(1): 165 - 176. [Abstract] [Full Text] [PDF]

<