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Cardiovascular Research 1998 38(3):617-630; doi:10.1016/S0008-6363(98)00036-4
© 1998 by European Society of Cardiology
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Copyright © 1998, European Society of Cardiology

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

Katayoun Derakhchana,c, René Cardinala,c,*, Sylvain Brunetb, Didier Klugc, Chantal Pharandc, Teresa Kusa,c and Betty I. Sasyniukb

aDepartment of Pharmacology, Université de Montréal, Montréal, Québec, Canada
bDepartment of Pharmacology, McGill University, Montréal, Québec, Canada
cCentre de Recherche, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada

* Corresponding author. Centre de Recherche, Hôpital du Sacré-Coeur de Montréal, 5400 boul. Gouin Ouest, Montréal, Québec, H4J 1C5 Canada. Tel.: +1 (514) 338-2222, ext. 3180; Fax: +1 (514) 338-2694; E-mail: cardinal@crhsc.umontreal.ca

Received 9 July 1997; accepted 19 January 1998


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 
Objective: Polymorphic ventricular tachycardias (PVT) occur spontaneously in canine hearts under the combination of D-sotalol (S), bradycardia and phenylephrine (PE). We investigated the hypotheses that: (1) the activation patterns of the initial PVT beats would be consistent with an origin in the ventricular conduction system; and (2) the inhomogeneous prolongation of repolarisation intervals can provide refractory barriers for re-entrant activity. Methods: Unipolar electrograms were recorded from 127 epicardial (EPI) sites with a sock electrode array as well as from intramural and endocardial sites during PVTs. Electrograms were analysed to generate isochronal maps and measure the spatial distribution of activation–recovery intervals (ARI). Results: Under S (9.9–14.5 mg·l–1), spontaneously terminating PVTs (cycle length of 270±43 ms, n=45) (mean±s.d.) occurred when a PE bolus (10–50 µg·kg–1) was injected. The first beat of the PVTs occurred with a coupling interval of several hundred ms to the preceding idioventricular beat (IDV) without any bridging activity and its earliest EPI breakthrough occurred in areas overlying the terminations of the right or left bundle branch. ARI values measured in IDV (295±47 ms) were significantly prolonged prior to PVT (462±92 ms). Prolongation was greater in apical than in basal epicardial areas, and at endocardial than epicardial sites (to >500 ms). Maximum delays >200 ms developed in the regions of marked ARI prolongation and, in later beats, circus movement re-entry occurred around refractory barriers, shifting between various regions of the ventricles. Conclusion: Thus, PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

KEYWORDS Polymorphic ventricular tachycardia; Torsades de pointes; D-Sotalol; Epicardial mapping; Repolarisation intervals; Canine


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 
Two main hypotheses have been proposed to explain polymorphic ventricular tachycardias (PVTs) related to excessive prolongation of the action potential duration in the presence of class III antiarrhythmic drugs: early afterdepolarisations (EAD) and dispersion of repolarisation intervals providing refractory barriers for re-entry [1, 2]. In previous studies in isolated ventricular preparations from the rabbit heart, we found that D-sotalol induces a greater increase in action potential duration in Purkinje fibres than in muscle, an effect associated with generation of EAD-dependent triggered activity in transitional Purkinje fibres and their propagation into muscle as extra beats [3]. Studies in the whole heart [4]suggested that the initiating beat of PVTs have a subendocardial origin whereas later beats could be generated by re-entry in muscle with disparate monophasic action potential durations. However, the evidence presented in these studies was inconclusive because of the limited number of recording sites. To clarify further the relative contributions of impulse formation in the conduction system and re-entry in muscle, we determined the spatial distribution of repolarisation intervals and activation sequences in the canine heart, the standard model for mapping studies.

Bradycardia-dependent PVTs can occur following infusion of D-sotalol in canine preparations with chronic atrioventricular (AV) block studied in the conscious state [5]but their spontaneous occurrence is lower under anaesthesia, and pacing protocols are needed to achieve reasonable arrhythmia incidence [6, 7]. Likewise, we have found in preliminary experiments that the spontaneous occurrence of D-sotalol-induced PVTs was infrequent when studied in the anaesthetized and open-chest state, conditions necessary to conduct epicardial mapping studies. Carlsson et al. [8, 9]reported that, in the anaesthetized rabbit, the incidence of PVTs induced by class III agents can be significantly increased when, in addition, an {alpha}-adrenergic agonist is infused. Accordingly, we studied PVTs induced by high D-sotalol plasma concentrations and {alpha}-adrenergic stimulation with phenylephrine in anaesthetized canines with AV block. Epicardial mapping and unipolar electrogram recordings from selected endocardial and intramural sites were used to measure activation times as well as activation–recovery intervals (ARI), a measure of local repolarisation intervals [10]. A similar approach was used by El-Sherif et al. [11]in their investigation of anthopleurin A-induced PVTs. One methodological difference, however, is that El-Sherif et al. [11]relied on the systematic use of multiple, regularly spaced needle electrodes (in small puppy hearts) to achieve a high degree of resolution on local events, whereas we put greater emphasis on the global patterns of both the epicardial activation sequences and the epicardial distribution of repolarisation intervals (in larger adult canines). More information is available from an epicardial map than localization of the site of earliest epicardial activation [12–15]. Previous studies [16]have shown that rhythms generated in the His–Purkinje system show typical patterns of epicardial activation (signatures) which can be used as an indirect indication of their origin in the ventricular conduction system. In the present study, the first beat of the PVTs (and a variable number of early beats) displayed activation patterns consistent with an origin in the ventricular conduction system, whereas in later beats of protracted episodes, the activation patterns were consistent with circus movement re-entry around refractory barriers. A preliminary report stating this conclusion has been published in abstract form [17].


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Conclusion
 References
 
All procedures for animal experimentation followed the guidelines of the Canadian Council for Animal Care, as monitored by an institutional committee. A hypokalaemic state (K+ <3.0 mmol·l–1) was induced in 10 mongrel dogs by oral administration of furosemide (10–20 mg·kg–1·day–1) and chlorothiazide (500 mg·day–1) or hydrochlorothiazide (40 mg·day–1) while monitoring plasma K levels 2–3 times weekly. Plasma creatinine was not affected by treatment (prediuretic, 103±19 µM; post-treatment, 108±19 µM); however, body weight was reduced by 2–4 kg (without loss of appetite). The 10 hypokalaemic canines (23±5 kg) and 10 other normokalaemic canines (27±3 kg) were studied under anaesthesia induced with Na thiopental (30 mg·kg–1, i.v.) followed by {alpha}-chloralose (60 mg·kg–1, i.v., and 100 mg·h–1). The dogs were intubated endotracheally and ventilated with room air to maintain arterial pH at 7.35–7.45 and pO2 >80 mmHg (10 breaths·min–1 with an adequate tidal volume to achieve a maximum inspiratory pressure of 20 cm H2O). The heart was exposed via sternotomy and pericardiotomy. The AV node was destroyed by direct injection of the smallest amount of formaldehyde (37%, 0.1–1.0 ml) needed to produce complete AV dissociation,[18]after which a slow idioventricular rhythm (IDV; cycle length >1000 ms) arose spontaneously via normal His–Purkinje system automaticity [19, 20]. Bipolar electrodes were attached to epicardial tissue via superficial sutures, avoiding damage to the underlying muscle, to pace the ventricles (120 beats·min–1) and sustain cardiac output, if necessary, while setting up. A bipolar electrogram was recorded from the right atrial appendage for the diagnosis of AV block. A femoral artery was cannulated for blood pressure recording. These signals and a surface ECG were monitored on chart paper and stored on a 16-channel PCM data recorder. The right femoral and external jugular veins were cannulated to infuse drugs and collect blood samples.

A sock electrode array comprising 127 unipolar recording contacts uniformly distributed with an interelectrode distance of 5–10 mm was positioned over the entire ventricular surface for epicardial mapping [16]. In addition, 20 plunge wire electrodes were used to record endocardial unipolar electrograms and 12 needle electrodes were used for intramural recordings in 6 preparations (in 3 of which PVTs occurred and were analysed). The endocardial plunge electrodes were made from Teflon-coated stainless steel wires (0.005-in. diameter) introduced in 25-gauge needles and bent at their tips in the shape of small hooks [18]. Needle electrodes (0.003-in. Teflon-coated stainless steel wires in a 21-gauge needle) allowed us to record 3 pairs of unipolar electrograms at depths of either 1, 4 and 7 mm (short needle electrode), 2, 7 and 12 mm (medium) or 3, 10 and 17 mm (long) into the wall, depending on the thickness of the ventricular wall [21]. In each pair, recording contacts were 1 mm apart and the activation times or repolarisation intervals measured at both were averaged.

The unipolar electrograms (referenced to Wilson's central terminal measured with 4 limb leads) and an ECG lead were recorded using a computerized system. The signals were amplified by programmable-gain analog amplifiers (bandwidth of 0.05 to 225–450 Hz) and converted to digital format at a rate of 500–1000 samples·channel–1·s–1. Data were stored on a hard disk. After the experiment, selected 1-s files of data were retrieved from disk and analysed using custom-made software. For each beat, the negative deflection with maximum slope (–dV/dtmax) was detected automatically on each electrogram and its value was determined according to the three point Lagrange derivative by computing the potential drop between the sampling points preceding and just following the activation point divided by the time interval (i.e. twice the sampling period: 2–4 ms). Activation times were detected at the point of maximum slope of deflections with –dV/dtmax in excess of –0.5 mV·ms–1. All computer-selected events were verified by the operator on a videoscreen with an interactive program. Activation times were measured with reference to the earliest epicardial activation (zero time reference). Isochronal maps were computed automatically by linear interpolation and drawn at 20-ms intervals for selected idioventricular beats and each individual beat of the ventricular tachycardias. For the epicardial activation maps, zones of functional conduction block were identified using previously defined criteria [22–24]. A continuous line was drawn through these regions and defined as a zone of functional dissociation.

Activation–recovery intervals (ARI), an index of the local repolarisation interval which is highly correlated to refractory period measurements, were measured from dV/dtmax in the activation complex (RS) to the maximum positive slope in the T-wave [10]of each of the 127 unipolar electrograms. ARI measurements were made during idioventricular beats showing a constant bundle branch morphology [16]under baseline (control) and conditions in which repolarisation intervals were prolonged (sotalol infusion, phenylephrine bolus). ARI values are reported at maximum effect of sotalol alone or in combination with phenylephrine on repolarisation intervals. When PVTs occurred, the ARI was measured, in each case, in the idioventricular beats occurring prior to or following a PVT (to avoid interference of the first tachycardia beat with the T-wave of the idioventricular beat). The ARI was also measured in the last beat of the PVT (in which there was no interference from a subsequent closely coupled depolarisation). Isocontour lines were generated by computer and drawn at 20-ms intervals beginning with the shortest ARI value.

2.1 Drug administration
D-Sotalol was administered as a bolus of 8 mg·kg–1 over 10 min followed immediately by infusion of 4 mg·kg–1·h–1 to achieve high plasma levels. Infusion was continued for at least 30 min before making any measurement. Beginning 75–120 min after the onset of sotalol infusion, phenylephrine (10–50 µg·kg–1) was injected as an i.v. bolus at progressively increasing doses (in 10 µg·kg–1 increments at 15- to 20-min intervals) until PVT occurred. Blood samples were collected when PVTs occurred and the plasma was frozen at –80°C. Plasma levels of D-sotalol were measured later using high-pressure liquid chromatography and UV absorbance detection [25, 26].

Whenever PVT degenerated into ventricular fibrillation, conversion back to idioventricular rhythm was achieved by application of a DC countershock.

2.2 Statistical analysis
The data are expressed as mean±s.d. Statistical analyses were performed using Student's t-test and two-way analysis of variance (ANOVA) to analyze the data presented in Table 1. Comparisons were considered to be statistically significant when P<0.05.


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  		Table 1 Effects of D-sotalol and a combination of D-sotalol and phenylephrine on epicardial activation–recovery intervals in relation to PVT occurrence

 

   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Conclusion
 References
 
All preparations showed an IDV rhythm which, under control conditions, was stable and uninterrupted by any arrhythmia. During D-sotalol infusion, single, double or triple ventricular premature depolarisations occurred in all preparations. IDV cycle lengths (CL) were slowed under sotalol (normokalaemia, from 1290±380 to 1685±310 ms, P<0.05; hypokalaemia, from 1241±399 to 1587±472 ms, P<0.05). When, in addition to D-sotalol infusion, phenylephrine was injected, PVT occurred, as illustrated in Fig. 1 (upper tracing), in 7/10 normokalaemic preparations and in 4/10 hypokalaemic preparations. Phenylephrine (required dose of 30 µg·kg–1, on the average; minimum dose of 20 µg·kg–1) induced a marked increase in blood pressure from 106±25/58±17 mmHg (systolic/diastolic) to 196±44/123±32 mmHg), which lasted for about 15 min. The relatively greater PVT incidence in normokalaemia might have been related to a slightly slower IDV rate in this group. Since there was no qualitative difference in the arrhythmias observed between the normokalaemic and hypokalaemic groups, no distinction was made between the 2 groups. PVTs, which lasted for at least 5 consecutive beats and displayed varying beat-to-beat QRS morphologies in the surface ECG and unipolar epicardial electrograms, occurred at D-sotalol plasma concentrations ranging between 9.9 and 14.5 mg·l–1 (12.2±2 mg·l–1). Forty-five PVTs terminated spontaneously (lasting for 18±14 beats; range of 5–59 beats) and displayed a mean CL of 270±43 ms (178–383 ms), CL being calculated in each case by dividing the total duration by the number of beats. In addition, 10 PVTs degenerated into ventricular fibrillation, an event occurring more frequently in preparations in which needle electrodes were used (7 episodes in 3/6 preparations) than in preparations in which only epicardial recordings were made (3 episodes in 3/14 preparations).


Figure 1
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  		Fig. 1 Focal mechanism underlying IDV beats and PVT. Upper trace: ECG lead II. A: polar representation of the epicardial surface (top) and diagrammatic representation of an imaginary horizontal tissue slice (bottom) made at the level indicated by shading on the epicardial surface. The epicardial areas overlying the terminations of the right bundle branch (RB) and anterior (A) and posterior (P) divisions of the left bundle branch (LB) and its septal ramifications are also indicated, as expected on the basis of anatomical data [27–29]. The position of two transmural needle electrodes (1, 2) and plunge wire electrode contacts on the endocardium (dots) are indicated. a and b (epicardium) and c–g (slice) are sites where unipolar electrograms shown in Fig. 2 were obtained. B,C: isochronal maps of two IDV beats displaying distinct QRS polarity on the ECG. D–F: isochronal maps and transmural activations for the first (D), ninth (E) and twenty-fifth (F) beats of the 27-beat PVT. In this and subsequent figures, the numbers in the upper right-hand corner of each map indicate the cycle length (CL) with reference to the next beat. RV, right ventricle; LV, left ventricle. In the isochronal maps, lines were drawn at 20-ms intervals and the shading indicates the area of the earliest 10-ms activation.

 
3.1 Epicardial activation mapping during IDV rhythms and PVTS: focal patterns
IDV beats showed distinctive epicardial activation patterns (signatures) depending on their focal origin in the His–Purkinje system in relation to the anatomy of the conduction system, as reported previously [16, 27–29]. Fig. 1 shows the mapping characteristics of two IDV beats with distinct ECG morphologies, one (IDV1) preceding and the other (IDV2) following the spontaneous termination of a 27-beat PVT. In IDV1 (Fig. 1B), the earliest epicardial breakthrough occurred in the anterior paraseptal region of the right ventricular wall (0) indicating the involvement of the right bundle branch (RBB), but the earliest 10-ms breakthrough area (shading) also extended to the anteroapical regions of the left ventricle in the territory overlying the anterior division of the left BB (LBB). In IDV2 (Fig. 1C), the earliest 10-ms epicardial breakthrough area extended over the posteroapical regions of the ventricles (0), suggesting the involvement of the posterior division of the LBB, and a secondary breakthrough (8 ms) occurred in the anterior paraseptal region of the right ventricle, suggesting that the impulse was also conducted from the RBB. This interpretation of the epicardial patterns was supported by recordings at right and left ventricular endocardial sites (as indicated in the slice diagrams: panels B and C, and Fig. 2) showing that the earliest activation occurred at endocardial sites either in the right or left ventricle. The total epicardial activation times were short, another feature typical of IDV beats (54±13 ms) [16].


Figure 2
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  		Fig. 2 Subendocardial origin of IDV beats and the PVT illustrated in Fig. 1. Upper trace: ECG lead II. Selected unipolar electrograms recorded from sites indicated in Fig. 1. Activation times are indicated (ms), using the earliest epicardial activation as the 0 time reference. Note that, in all beats, the earliest endocardial activations preceded the epicardial activations, and that the endocardial electrograms displayed double deflections, the first presumably associated with Purkinje fiber activation and the second, with muscle fibre activation.

 
In the first PVT beat (Fig. 1D), the early area extended over the anterior paraseptal and apical regions, and endocardial activation (Fig. 2: sites c and d) preceded the epicardial activation (sites a and b), as in the IDV beats. In the ninth beat of the tachycardia (panel E), the early epicardial breakthrough as well as the earliest subendocardial activation occurred in the posterior left ventricular free wall (sites e and f), thereby suggesting a more peripheral origin of the impulse in the posterior division of the LBB. In the last PVT beats (panel F), the earliest epicardial breakthrough again occurred in the anterior paraseptal region of the right ventricle and a secondary breakthrough occurred in the posterior wall of the left ventricle, and epicardial breakthroughs were preceded by activations at corresponding subendocardial sites (g and f). Thus, the polymorphic character of the PVT illustrated in Fig. 1 may have been caused by shifting sites of origin in the ventricular conduction system or changing conduction patterns from a constant focus. Patterns which were consistent with a focal mechanism occurred in all beats in some PVTs, especially short ones. In longer PVTs, such patterns occurred more frequently in the early beats (vide infra).

The first beat of all PVTs was always consistent with a focal mechanism. This first beat occurred with a coupling interval of several hundred ms to the preceding IDV beat (531±97 ms) without any bridging activity being detected between the latest activation in the IDV beat and the earliest activation in the first PVT beat. We attributed failure to detect bridging activity to the focal nature of the arrhythmia rather than to a limitation of the epicardial and, when available, intramural electrode arrays. The epicardial activation patterns in the first beat of PVTs were consistent with a RBB origin in 12 of the 55 PVTs and with a LBB origin in 21 others. In the remaining 22, the early epicardial breakthrough in the first beat did not occur in accordance with the usual BB signatures because of the effect of prolonged repolarisation intervals on impulse conduction, as is illustrated in Figs. 3–5GoGo.


Figure 3
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  		Fig. 3 Epicardial distribution of ARI in IDV beats recorded under baseline conditions (A, control) and during infusion of D-sotalol alone (B) or in combination with phenylephrine (C). Polar representation of the ventricular epicardial surface in which the base is along the circumference and the centre is at the apex. For clarity, ARI values are indicated at only half of the 127 recording sites. The large numbers indicate the minimum and maximum values, and the value at a basal site where the first of the two unipolar electrograms shown in lower part of each panel was recorded (the other electrogram is the one with the longest ARI). Isocontour lines were drawn at 20-ms intervals. Shading indicates regions where ARIs were >500 ms. Dark lines indicate locations where the difference between ARIs at neighbouring recording sites was ≥100 ms. C shows the distribution of ARIs in an IDV beat preceding the PVT shown in Fig. 4 (IDV beat indicated by an asterisk in the upper trace of Fig. 4). Low amplitude atrial (A) deflections are indicated on the top electrogram in control panel.

 

Figure 4
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  		Fig. 4 Shifting location of circus movement re-entry circuits associated with ARI dispersion. Upper trace: ECG lead II. ARI map of IDV (same as in Fig. 3C) and isochronal maps depicting the activation sequences in the first beat and in selected PVT beats. The earliest breakthrough in beat 1, occurred in the posterior wall of the left ventricle at the site of shortest ARI in an area of marked ARI dispersion. In the early PVT beats (1st, 2nd), the configuration of the circus movement activation sequence appeared to be determined by the initial dispersion of ARIs in the posterior wall. In the subsequent beats (beginning with beat 4), the position of the earliest epicardial activation at the beginning of each activation cycle (0), the position of the most delayed activation and the line of functional dissociation (thick line) shifted between various regions of the ventricles. Note that the maximum delay accounted for a large proportion of the CL. Isochronal lines are drawn at 20 ms intervals and the thick lines indicate bunching of isochronal lines >100 ms between functionally dissociated sites.

 

Figure 5
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  		Fig. 5 Selected unipolar electrograms recorded during the IDV beat and the first three beats of the PVT illustrated in Fig. 4. The position of selected unipolar electrograms, A–M, are indicated on the polar representation of the epicardial surface. Arrows indicate timing of activation in ms. The electrogram recorded from site A is shown both at the top and bottom of the figure to illustrate that it is the one where activation occurred at the beginning of each beat (top) and also neighbouring the site of most delayed activation (site M).

 
3.2 Epicardial distribution of repolarisation intervals and epicardial activation patterns during PVTS: circus movement
In contrast to the PVT illustrated in Fig. 1, marked activation delay occurred in the first or early beats in other PVTs (especially the more protracted ones) in relation to excessive prolongation of the repolarisation intervals. In a representative preparation illustrated in Fig. 3, ARIs measured under baseline conditions (panel A) were generally longer in the apical areas than in the more basal areas, in accordance with previously published data from refractory period measurements [30]and isopotential mapping [31], thereby creating a dispersion of ARIs measured as the difference between the minimum and maximum values on the epicardial surface (dispersion of 70 ms in Fig. 3A). ARIs increased during D-sotalol infusion (Fig. 3B) and even more when, in addition, a phenylephrine bolus was injected (Fig. 3C), but prolongation was inhomogeneous. ARIs in excess of 500 ms extended typically over the apical and paraseptal areas, occasionally extending to the anterior and lateral basal regions of the left ventricle (Fig. 3B and C: shading) and creating a border along which there was considerable ARI dispersion (≥100 ms between neighbouring recording sites) as seen in the posterior wall of the left ventricle (Fig. 3B,C, dark lines) and in the anterior paraseptal region (see below, Fig. 6).


Figure 6
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  		Fig. 6 Transmural distribution of ARIs and activation delay development in the early beats of a PVT. Left-hand panel: upper diagram, polar representation of the epicardial surface with anatomical landmarks; lower diagrams, ventricular slice diagrams at the basal, mid-ventricular and apical levels indicating the position of needle electrodes (lines) and plunge wire electrode contacts (dots). Twelve needle electrodes were positioned at selected loci consisting of the right ventricular outflow tract (RVOT, sites 1, 2) and the posterior wall (3–6) at the basal level, the anterolateral (7) and posterolateral wall (8) at mid-ventricular level, and the anterolateral (9) and posterior wall (10–12) at the apical level. In addition, 20 plunge wire electrodes were positioned at the endocardial surface of the right and left ventricles to detect the early activations caused by impulses from the right and left bundle branches (as indicated by dots in the mid-level and apical slice diagrams). At each needle electrode site, intramural values indicated in the slice diagram are averages of the measurements made with the two recording contacts (1 mm spacing) at each of 3 intramural levels, and the epicardial value (italic) is from the sock electrode array (for a total of 4 values). Second panel: distribution of ARIs at the epicardium (upper map) and transmurally (lower diagrams). In the epicardial map, the shading indicates regions where ARIs were >500 ms, and thick lines indicate local dispersion ≥100 ms. Third and fourth panels: epicardial isochronal maps of the first two PVT beats. Isochronal lines are drawn at 20-ms intervals, shading indicates the earliest 5-ms breakthrough area. All activation times are expressed with reference to the earliest epicardial activation. The early beats were attributed to a focal mechanism of subendocardial origin but markedly delayed activation and conduction block (-||) developed during the 2nd beat.

 
Infusion of D-sotalol caused significant prolongation of the ARIs in all preparations (Table 1). The maximum value (but not the minimum value) as well as the dispersion were further increased when phenylephrine was injected in preparations in which PVTs occurred (Table 1A). In preparations in which such arrhythmias did not occur (Table 1B), phenylephrine failed to produce any further prolongation of the maximum value or increase in the dispersion. In fact, the minimum, maximum and average values measured under the combination of D-sotalol and phenylephrine tended to be lower than under D-sotalol alone, an effect which may have been related to a slight acceleration of the IDV rate after phenylephrine injection (from a CL of 2401±1010 to 2085±940 ms). Much smaller ARI dispersion was measured in the last beats of the PVTs (97±34 ms), but it increased again in the IDV beats that followed PVT termination, thereby suggesting that changes in the magnitude of ARI dispersion were rate-dependent effects.

The ARIs measured just prior to the PVT illustrated in Fig. 1 (ARIs not shown) were prolonged in the left ventricular apical regions but their values were <500 ms; therefore, marked activation delay did not develop during the PVT (and a focal mechanism was the only one involved in PVT generation). In contrast, Fig. 4 illustrates a PVT occurring in a situation in which marked ARI prolongation occurred (ARI >500 ms). In the first PVT beat, an impulse presumably originating from the LBB could only emerge in more basal regions of the posterior left ventricular wall and thence be conducted into right ventricular regions (Fig. 4, arrow; Fig. 5, sites B–F), because of the refractory barrier created in the more apical regions. The impulse thereby circumvented the boundary between the areas of high and low ARI values. Note that there was spatial correspondence between the dark line in the ARI map and the dark line in the activation map of the first beat, suggesting that the line of ARI dispersion acted as an arc of functional dissociation during conduction of the first tachycardia impulse. It then turned around a singular point (Figs. 4 and 5Go, site G) located at the end of the arc of dissociation, from which it was conducted into the left ventricle (sites I–M), thereby generating very late activation in the posterior left ventricle (site M: 252 ms). This was followed by re-excitation in the basal area of the posterior left ventricular wall (Fig. 5, site A: 378 ms, which became time 0 for the second beat) and the circular activation pattern was repeated again. During the second beat, 294 ms of the 342 ms CL between the second and third beat could be accounted for by actual activations detected with the epicardial sock electrode array, and during the third beat, 316 ms of the 338 ms CL were accounted for by actual detections. In the following and later beats, circular activation sequences generated delay spanning virtually the entire tachycardia CLs, but the arcs of functional dissociation (thick lines) strayed away from the region where ARI dispersion ≥100 ms had been observed in the IDV beats (as illustrated in Fig. 4 for beats 4, 13, 22, 39 and 56). Thus, shifting of the circus movement configuration between various regions of the ventricles was another cause of change in the ECG morphology. Although virtually complete circular activation sequences could be mapped from the epicardial recordings, the occurrence of double (beat 13) or multiple breakthroughs (beat 39) and apparently dissociated circular activation sequences (beat 22, 2 arrows) suggested that subendocardial and intramural activations might be involved in re-entry.

3.3 Transmural patterns of repolarisation intervals and activation sequences
Endocardial and intramural recordings were analysed in 23 PVTs to investigate the transmural distribution of ARIs and to document the potential involvement of intramural pathways in circus movement re-entry, as illustrated in Fig. 6Fig. 7. ARIs measured at the epicardial surface were typically prolonged over the apical half of the left ventricle and their dispersion was >100 ms in the anterior and posterior paraseptal regions and left lateral wall (dark isocontour lines) (Fig. 6, centre). Similarly, ARIs measured intramurally and endocardially at the mid-ventricular and apical levels were relatively longer than those which were measured at the basal level. Transmurally, ARIs measured at deeper needle electrode contacts were, in general, longer than those which were measured in the mid-wall or closer to the subepicardium (Table 2A). The ARIs measured at endocardial locations were greater than those measured at epicardial sites and their difference was greater in the right than in the left ventricle (Table 2B,C).


Figure 7
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  		Fig. 7 Possible involvement of intramural pathways in re-entry developing in later PVT beats. Epicardial and transmural activation patterns in an early (third) and later beat (eighth) of the PVT illustrated in Fig. 6. The 3rd beat was generated in association with early endocardial activation (presumably via a focal mechanism). In contrast, the 8th beat displayed a re-entrant pattern in the apical regions, generating the next beat (beat 9 beginning at 286 ms). Right-hand diagrams illustrate the possible involvement of intramural activations in re-entry.

 

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  		Table 2 Effects of D-sotalol and a combination of D-sotalol and phenylephrine on transmural activation–recovery intervals

 
The epicardial map of the first PVT beat (Fig. 6, third panel from the left) displayed a RBB focal pattern, in which the earliest epicardial breakthrough (site a, 0) was preceded by activation at underlying subendocardial sites (site b, –26 ms). The CL between the first tachycardia beat and the preceding IDV beat was 664 ms. Right and left ventricular transmural activation sequences occurred in the endocardial to epicardial direction, in agreement with the presumed origin of the first beat in the conduction system. The second PVT beat (Fig. 6, right panel) also displayed a RBB focal pattern but with even earlier endocardial activation (site b, –38 ms) and a secondary breakthrough located in the right ventricular outflow tract, probably because of the shorter CL between the first and second beats (407 ms). Also, the left ventricular epicardial sites were activated with considerable delay and block occurred at several subendocardial sites. In the third PVT beat (Fig. 7, left panel) as well as in the fourth and fifth beats (not shown), the sites of earliest activation shifted to left ventricular endocardial sites (–82 ms), suggesting that emergence of the impulse from the conduction system had shifted to the LBB. This was followed by epicardial breakthroughs in the anterior left ventricular wall (0), anterior paraseptal region (4 ms) and posterior left ventricular wall (14 ms), i.e. in areas located around the more apical regions which were activated with considerable delay.

In contrast, the 6th and following beats may have been generated by re-entry possibly involving intramural pathways, as illustrated for beat 8 (Fig. 7, centre panel, and accompanying right-hand diagrams). The earliest epicardial activation (0) occurred in the posterior left ventricular wall, from which two broad epicardial activation sequences occurred along the more basal regions of: (1) the posterior left and right ventricles (arrow leading to activation of the anterior right ventricular wall at 140 ms); and (2) the lateral left ventricle (arrow leading to activation of the anterior left ventricle at 120 ms). Another, more localized, activation sequence occurred from the earliest epicardial activation to the left lateral wall and into the apical regions, in which activation was markedly delayed (>200 ms). As illustrated in the diagrams, intramural pathways may have been involved in re-entry: in one such pathway, epicardial activation in the left lateral wall (102 ms) was followed by endocardial activation (118 ms) and conduction back to the epicardium in the apical region (188 ms), and in another, delayed activation in the apical region (224 ms) was conducted back to the endocardium (260 and 276 ms) and again to the epicardium (286 ms), marking the beginning of the next tachycardia beat. Thus, propagation in and out of the apical region may have occurred via intramural pathways (although a subepicardial return path cannot be excluded). Involvement of intramural pathways could explain the occurrence of a secondary breakthrough in the anterior paraseptal area (34 ms).

3.4 Summary of epicardial activation patterns during PVTS
Activation patterns of PVT beats were classified as either: (a) circus movement of excitation (with development of delay adjacent to the earliest activation of the next beat); or (b) focal. Fig. 8 shows that beats displaying activation patterns consistent with a focal mechanism occurred more frequently in PVTs of short duration, whereas circus movement re-entrant patterns were more prominent in the later beats of PVTs and in those with a long duration, as illustrated in Fig. 4. Fig. 1 shows an example of a protracted PVT in which all beats were generated via a focal mechanism. This example was chosen because it illustrated a further mechanism for the twisting pattern of the PVT.


Figure 8
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  		Fig. 8 Proportion of beats attributed to a focal mechanism and circus movement re-entry in 43 PVTs. Abscissa: duration of each PVT (number of beats). The shortest PVT lasted for 5 beats and the longest, for 59 beats. In PVTs of short duration, most of the beats corresponded to a focal mechanism, whereas in most protracted episodes a greater proportion corresponded to circus movement re-entry.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Conclusion
 References
 
PVTs occurred spontaneously (i.e. without programmed stimulation) under the combination of a slow heart rate, high D-sotalol plasma concentration and phenylephrine. Similar synergistic effects of {alpha}1-adrenergic stimulation and class III antiarrhythmic agents on the induction of torsades de pointes have been demonstrated in the rabbit heart [8, 9]. The synergistic or additive effects of phenylephrine and D-sotalol on repolarisation intervals reported herein could be related to prolongation of the action potential duration by both agents through inhibition of the delayed rectifier current IK [32, 33]. It is also possible that the marked pressor responses to phenylephrine, perhaps inducing stretch-activated depolarisations, [34, 35]might have played a role in PVT generation. This study supports the notion that the first PVT beat and a variable number of subsequent beats are generated through a focal mechanism probably associated with the conduction system, whereas later beats may be generated by a re-entrant mechanism associated with refractory barriers created by increased dispersion of repolarisation intervals.

4.1 Focal mechanism
When transmural mapping was performed, epicardial and intramural activations were always found to be preceded by endocardial activation and, in many PVTs, the early epicardial breakthrough patterns of the first and early tachycardia beats were similar to those of the IDV beats, which are known to be generated by normal Purkinje fibre automaticity. In support of their origin in the conduction system, electrograms showing double deflections, presumably corresponding to activation of Purkinje fibre and muscle, occurred in the endocardial recordings (but never in intramural and epicardial recordings). In all PVTs, the CL between the first beat and the preceding IDV beat was several hundred ms and no bridging activity was detected. Therefore, the first beat appeared to be generated by activity designated as ‘focal’. Shifting epicardial breakthrough location occurring during PVTs could be caused through change in the location of the focus between the RBB and the various divisions of the LBB [27–29]. Alternatively, conduction times may have varied, while the impulses originated from a fixed focus, because of the relatively refractory state associated with short CL in the face of prolonged ARIs. However, no deliberate effort was made to precisely localize the foci in the conduction system and to assess conduction times along the BB.

In about 40% of the initial beats of PVTs, the earliest epicardial breakthrough occurred in more basal regions of the left ventricle, in contrast with patterns occurring in IDV beats. In such cases, the marked prolongation of repolarisation intervals in apical and paraseptal regions may have acted as a constraint forcing the impulses generated in the LBB to propagate around these refractory barriers and to break through sideways, in regions where ARIs were shorter (as the posterior wall of the left ventricle in Fig. 4, beat 1).

The data presented herein are consistent with El-Sherif et al.'s findings in canine preparations in which ARIs were prolonged and PVTs were induced following treatment with anthopleurin-A, which produces block of sodium channel inactivation [11]. Their main evidence supporting the notion that focal PVT beats originated from Purkinje fibres, was that the focal activity consistently started near recording contacts of intramural probes closest to the endocardium. Our study offers further evidence in support of this view by showing that focal beats displayed epicardial patterns typical of those generated by impulses originating from the conduction system and that direct recordings from endocardial sites consistently preceded activation at either intramural or epicardial sites.

4.2 Circus movement re-entry
Patterns consistent with circus movement re-entry, in which activity encompassed virtually the entire CL, tended to be more frequent in later beats, although they could occasionally occur as early as the second. The marked dispersion of repolarisation intervals appeared to provide refractory barriers and attendant functional dissociation, setting the stage for re-entry. In the early beats, the lines of functional dissociation corresponded to areas of maximum dispersion of ARIs (as mapped in the preceding IDV beat), but in later beats, they shifted between different regions of the ventricles. This is consistent with the fact that the dispersion of ARIs probably decreased in successive beats of PVTs in an interval-dependent manner, being least in the last. Shifting circulating wavefronts is another mechanism explaining the polymorphic character of PVTs, as noted by El-Sherif et al. in the anthopleurin A model [11].

This study is, to the best of our knowledge, the first to show the spatial distribution of repolarisation intervals over the entire epicardial surface (and selected intramural and endocardial sites) and the inhomogeneous character of their prolongation in response to sotalol alone or in combination with phenylephrine. Such inhomogeneity led to the development of marked dispersion of ARIs between apical and basal regions of the ventricles, as well as endocardial and epicardial recording sites. It is a remarkable fact that, in the left ventricular apical and paraseptal areas, impulses propagating from subendocardial muscle were conducted to the overlying subepicardial muscle with marked delay (>200 ms), since the ARIs measured at subendocardial sites were similar to or even greater than those which were measured at subepicardial sites. One possibility is that the delay developed at intramural sites with even more prolonged ARIs, which would have been missed. Another possibility is that the ARI measurements extracted from the epicardial unipolar electrograms would have underestimated refractoriness, as might occur if prolongation of repolarisation intervals occurring at subepicardial sites were associated with local responses generated by electrotonic interaction with subendocardial muscle displaying prolonged action potential duration [36].

Reports from Antzelevitch's laboratory suggest that certain regions of the ventricles appear to have special properties, such as a greater susceptibility to prolongation of their action potential duration, because of the existence of ‘M’-cells which would be distinct from the usual muscle fibres [37]. It is possible that M-cells may have contributed to the inhomogeneous prolongation of repolarisation intervals observed in our experiments. No clear pattern has yet been determined regarding the spatial distribution of M-cells; however, the available data indicate that it will be a complex one, M-cells having been reported to occur in the deep subepicardial muscle layers of the ventricular free wall and deep subendocardial layers in the septum, papillary muscles and trabeculae. Whether M-cells have contributed or not to their inhomogeneity, it is also possible that the greater prolongation of repolarisation intervals occurring at endocardial sites could be related to prolongation of action potential duration in Purkinje fibres, since repolarisation intervals measured from unipolar electrograms recorded from the endocardium probably represent composites of extracellular potentials generated by both Purkinje fibres and muscle [38].


   5 Conclusion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
References
 
This study suggests that PVTs occurring spontaneously under conditions of delayed repolarisation originate from shifting sites in the ventricular conduction system and that re-entrant activity shifting between various regions of the ventricle may occur in later beats of the more sustained arrhythmias.

Time for primary review 20 days.


   Acknowledgements
 
The authors wish to acknowledge the expert technical assistance of Ms. Caroline Bouchard and Mr. Pierre Fortier, as well as the expert secretarial assistance of Ms. Suzan Senechal. This work was supported by a grant from the Heart and Stroke Foundation of Québec and also grants from the Medical Research Council of Canada to R.C. and B.I.S. K.D. was supported by a Studentship award from the Heart and Stroke Foundation of Canada.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Conclusion
 References
 

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