Author + information
- Received May 26, 2006
- Revision received October 30, 2006
- Accepted November 16, 2006
- Published online March 27, 2007.
- Oliver R. Segal, MRCP,
- Anthony W.C. Chow, MD, FRCP,
- Vias Markides, MD, MRCP,
- D. Wyn Davies, MD, FRCP, FHRS and
- Nicholas S. Peters, MD, FRCP, FHRS⁎ ()
- ↵⁎Reprint requests and correspondence:
Prof. Nicholas S. Peters, Waller Cardiac Department, St. Mary’s Hospital, Praed Street, London W2 1NY, United Kingdom.
Objectives The purpose of this study was to examine the resetting response in human ventricular tachycardia (VT) circuits with 3-dimensional mapping.
Background In characterizing re-entry with the resetting response, inferences are made about interaction of single ventricular extrastimuli (SVE) with VT.
Methods Non-contact mapping was used to examine the effects of SVE from 25 sites on 10 infarct-related VT circuits.
Results The local temporal excitable gap (EGap) was 113.8 ± 64.3 ms, 25.8 ± 11.2% of VT cycle length. In 7 VT circuits there was a clear difference in the EGap at different points in the circuit. All circuits could be pre-excited over a range of SVEs, resulting in either: 1) premature activation throughout the circuit resulting in reset; 2) premature activation at entry, but subsequent interval dependent conduction slowing (IDCS) resulting in a fully compensatory return cycle; or 3) change to functional lines of block and return cycle QRS morphology. The principal determinant of whether SVE resulted in reset was the degree of IDCS within the diastolic pathway (DP) of the circuit. Resetting occurred from 9 sites (7 VT) but was absent from 15 sites despite pre-excitation of a sizeable EGap in the circuit in all cases.
Conclusions In infarct-related VT, all circuits can be pre-excited over a range of SVEs, the effect of which is dependent on the degree of IDCS within the DP or modification of functional block defining the circuit. Failure to reset does not therefore indicate the absence of an EGap or failure of entry to the circuit. The temporal and spatial properties of the EGap vary at different sites of entry to the circuit.
The resetting response, the use of premature stimuli to advance a re-entrant tachycardia, has been used to examine the properties of the excitable gap (EGap) in circuits causing ventricular tachycardia (VT) in both animal models and human studies (1–6). Almendral et al. (7) identified 3 patterns of resetting response in re-entrant human VT circuits: flat (due to full excitability of the EGap), increasing (partial excitability), and mixed (initially fully excitable then partially excitable with shorter coupling intervals [CIs]). However, these inferences were based only on the surface electrocardiogram (ECG) and electrograms at the site of pacing and 1 other site and on the premise of fixed, anatomically constrained re-entrant circuits. We and others have shown that lines of block that define human infarct-related VT circuits have functional characteristics (8–11) and what is not known is the mechanism by which extrastimulated wavefronts interact with native VT circuits, what effects this has on lines of block, and how these manifest in response to extrastimuli and the surface ECG. Understanding these interactions will help characterize and classify circuits causing VT in the quest to develop more specific strategies for ablation, anti-tachycardia pacing, and drug therapies.
We have previously examined the interaction between extrastimuli and functional components of VT circuits and properties of the EGap in the well characterized canine infarct model with epicardial isochronal mapping (3,12). We demonstrated that temporal and spatial qualities of the EGap vary at different points within the circuit (12). In the present study, we have used non-contact mapping to characterize the interaction of premature extrastimuli in human, infarct-related VT circuits in order to address the hypotheses that because lines of block defining such circuits have significant functional components, temporal properties of the EGap vary at different sites of entry within these circuits and changes to lines of block and conduction properties within re-entrant circuits underlie the different effects seen with extrastimuli.
A total of 9 patients (62.7 ± 5.1 years, 1 female), all undergoing ablation of VT, were studied with the non-contact mapping system (EnSite 3000, Endocardial Solutions Inc., St. Paul, Minnesota). All had poor left ventricular (LV) function (ejection fraction 32.9 ± 6.3%) and previous, remote (>6 months) myocardial infarction (4 anterior, 3 inferior, and 2 both anterior and inferior). Five patients were taking amiodarone, 2 patients amiodarone and mexilitene, 1 patient sotalol, and 1 patient was intolerant of antiarrhythmic medication. Local ethics committee approval was obtained, and patients had given written informed consent.
Non-contact mapping of VT has been described in detail before (13). In brief, a 9-F 64-wire balloon mounted multi-electrode array was deployed in the LV retrogradely, a 3-dimensional LV geometry created, and high resolution isopotential maps recorded. A standard quadripolar catheter was positioned at the right ventricular apex, and 2 7-F mapping/ablation catheters were deployed into the LV, with a retrograde and trans-septal approach. The ECG and contact catheter data were recorded on a conventional electrophysiological system. Ventricular tachycardia induction was attempted by programmed stimulation with the Wellens protocol (14).
Pacing was attempted from both LV catheters and the right ventricular apex (RVA) catheter. The single ventricular extrastimuli (SVE) were delivered during VT starting at the VT cycle length (CL) and then 10-ms decrements until loss of local capture (refractoriness), change in VT morphology, or termination of VT occurred. If local capture was not obtained at any interval when pacing in the LV, resetting was attempted from an alternative site. Resetting was attempted from at least 3 sites (right ventricular and 2 LV positions) if the tachycardia remained hemodynamically stable. Data analysis was performed off-line after the procedure.
Calculation of the EGap
For the purposes of calculating the properties of the EGap, reconstructed electrograms were selected from the outer (systolic) portion of the circuit, parallel and adjacent to the line of block defining the diastolic pathway (Fig. 1A).Activation times were defined as the maximum negative slope (dV/dt) of unipolar electrograms, and local CLs of the native cycle, the paced cycle, and the return cycle were measured at each site. An example is shown in Figure 2.Accuracy of this measurement was confirmed by examining the morphology and intervals of reconstructed bipolar electrograms at the same sites (with a function of the Endocardial Solutions Inc. software) and by analysis of activation patterns. Measurements were not performed during periods of marked CL variability.
The “local excitable gap” was defined as the difference between the native VTCL and the shortest CI at which any SVE captured the circuit at that site. Unless the shortest CI of this range either terminated the tachycardia or failed to enter the circuit (despite capture and propagation to the circuit from the stimulus site), the difference between VTCL and this shortest CI represents a minimum duration of the EGap, which might be an underestimate but not an overestimate of the true extent of the EGap.
“VT exit site” (Fig. 1) was defined as the point from which rapidly expanding systolic activation on the isopotential map was seen synchronous with or just before QRS onset.
“Diastolic activity” was defined as depolarization on the isopotential map that could be continuously tracked back in time from a VT exit site.
Lines of “functional block” divided activation between adjacent endocardial areas by >50 ms during VT, were not fixed, and were not present during sinus rhythm or pacing. When present, they produced dissociated activation in adjacent regions and local electrograms with double potentials.
Areas of endocardium with small, fractionated, or absent electrograms (<0.5 mV) during sinus rhythm, pacing, or VT were colored gray in the figures.
The “native cycle” was defined as a complete cycle of the unperturbed circuit in sustained monomorphic VT.
The “extrastimulated wavefront” was defined as the wavefront of activation arising and then propagating from the site of stimulation. The extrastimulated cycle was the cycle in which systolic fusion occurred between native VT and the extrastimulated wavefront.
“Return cycle” was defined as the cycle of VT that followed the extrastimulated cycle.
The “zone of pre-excitation” was defined as the length of the region throughout which the extrastimulated wavefront entered the circuit (modifying local electrograms). The greatest degree of pre-excitation occurred at the most orthodromic end of this zone, with subsequent orthodromic propagation as the extrastimulated cycle.
“Reset” was defined as advancement of the tachycardia by at least 20 ms by an SVE (i.e., the interval from the last QRS complex of native VT to the return cycle QRS complex was at least 20 ms <2 VTCLs). Surface QRS morphology of the return cycle had to be identical to QRS morphology of the native cycle. The resetting interval was defined as the proportion of the EGap during which SVEs reset the circuit.
“Interval dependent conduction slowing” (IDCS) was defined as slowing of conduction (compared with conduction velocity in native VT) within the re-entrant circuit, the degree of slowing being inversely related to the degree of prematurity.
“Resetting response patterns,” the shape of the CI-return cycle curves, were defined as increasing, flat, or mixed if the respective return cycle increased, remained constant (within 10 ms), or was initially flat and then increasing in response to progressively shorter CIs (over at least 30 ms). If different response patterns were observed for the same VT at 2 different sites, the pattern over which pacing produced the larger resetting window was chosen as the response pattern for that VT.
Statistical analysis was performed with SPSS 10.0 (SPSS Inc., Chicago, Illinois). Statistical significance was defined as p < 0.05, and linear regression analysis was performed where appropriate. Results are expressed as mean ± SD. Means were compared with ttests for independent samples.
Pacing was achieved from 25 sites in 10 sustained, monomorphic VT (VTCL 433.5 ± 69.8 ms) in 9 patients (Table 1).The local temporal EGap (measured from the outer [systolic] portion of the circuit, parallel and adjacent to the line of block defining the diastolic pathway and demonstrated in Fig. 1) for all pacing episodes was 113.8 ± 64.3 ms (range 32 to 222 ms) which was 25.8 ± 11.2% of CL (range 8.1% to 41.9%). In 7 VT in 6 patients, there was a clear difference in the local temporal EGap at different sites of entry to the circuit (Table 1).
Interaction of the extrastimulated wavefront with the VT circuit
A common finding in all VTs, from sites at which local capture was achieved, was that the extrastimulated wavefront pre-excited the VT circuit. Following entry of the extrastimulated wavefront into the zone of pre-excitation, 3 different types of interaction between the extrastimulated wavefront and the VT circuit were identified.
Pre-excitation resulting in reset
In these examples, the extrastimulated wavefront propagated in an orthodromic direction to preexcite the circuit, with sufficient conduction velocity to result in premature exit from the diastolic pathway (DP) to reset the tachycardia. No significant alterations in lines of functional block bordering the DP were observed.
Figure 3shows a sequence of non-contact data during an example of reset in patient 4. The flat isopotential maps represent the entire LV endocardium cut along 1 border and laid open, with anatomical markers labeled. Purple represents resting (non-depolarized) endocardium that changes to white on full depolarization. The other colors represent the spectrum of partial depolarization. The pale blue line represents a line of block bordering the DP of the VT circuit, and the gray area represents presumed infarct scar forming the other border. The white circles in panel 1 show the positions of the reconstructed electrograms shown beneath the maps. The arrows next to the electrograms show progression of activation corresponding with the isopotential maps.
Panels 1 to 4 show activation in the native VT cycle (CL 320 ms). Panel 1 shows activation within the DP. Activation then spreads apically across the inferior wall (panel 2) before proceeding towards the septum and anterior walls (panels 3) and finally to the base of the heart before re-entering the diastolic pathway (panel 4).
Panels 5 to 8 show activation during the extrastimulated cycle. Panel 5 shows activation at the paced extrastimulus in the posterior wall. Activation spreads from this region inferiorly and apically in panels 6 and 7. An additional line of block has formed in the antero-apical region (left middle area and bottom right corner panels 6 to 8) preventing activation spreading across the anterior wall toward the diastolic pathway. Electrogram A (corresponding with panel 6) shows the extrastimulated wavefront has pre-excited the VT circuit after 230 ms (i.e., 90 ms early). The pre-excited electrogram in channel A has a different morphology to native VT, owing to the different direction of activation from the pacing site to the VT circuit. Activation then proceeds in an orthodromic direction septally and basally (panel 7) with minimal conduction slowing before approaching the entry point to the DP (panel 8) after 237 ms (83 ms early).
Despite significant IDCS within the DP, return cycle electrogram D is advanced by 36 ms, and the tachycardia has been reset. Return cycle surface QRS morphology has not been altered. Interval dependent conduction slowing within the DP was a universal finding at short CIs, with loss of prematurity from entry to exit point of DP of 44.1 ± 21.1 ms, measured from the most pre-excited intervals compared with native cycle.
Pre-excitation with IDCS resulting in a fully compensatory return cycle
As with instances of reset, in these cases the extrastimulated wavefront pre-excited the circuit orthodromically with premature orthodromic entry into the DP. However, reset did not occur, owing to sufficient IDCS within the DP to result in a fully compensatory return cycle.
Figure 4shows the isopotential maps of an example of an SVE resulting in a fully compensatory return cycle from an alternative pacing site in Patient #4. Panels 1 to 4 show the last native VT cycle (CL 320 ms) before stimulation. Again, activation originates from the DP just before QRS onset in the mid-inferior wall with systolic activation continuing in panels 2 through 4.
The extrastimulated wavefront captures the postero-apical wall (panel 5) before spreading basally (panel 6) to enter the zone of pre-excitation (panel 7). Panel 8 shows the extrastimulated wavefront approaching the DP.
Electrogram A is activated 69 ms early with marked change in morphology compared with native tachycardia. Subsequent orthodromic propagation to areas B, C, and D occurs with only minor change to electrogram morphology and only a minor degree of conduction slowing before re-entering the DP. Despite pre-excitation of the DP, there is sufficient conduction slowing within the DP itself that a fully compensatory return cycle ensues (electrograms Fig. 4).
Pre-excitation with change to return cycle QRS morphology
Similar to the previous mechanisms, the extrastimulated wavefront pre-excited the circuit orthodromically but then interacted with and altered lines of functional block within the circuit thereby altering the pattern of systolic activation of the return cycle wavefront and surface QRS morphology.
An example of this phenomenon in patient 2 is shown in Figure 5(VTCL 370 ms). Panels 1 to 4 of Figure 5show activation during the native cycle before stimulation in a typical figure-8 re-entrant pattern. Panel 1 shows activation exiting the DP in the mid-septal region before spreading basally and inferiorly (panel 2), then anteriorly (panel 3), and then re-entering the DP (panel 4).
The extrastimulated wavefront arises in the basal septum (panel 5) and is prevented from conducting anteriorly, owing to the presence of a new line of block contiguous with the line of block bordering the DP. Activation enters the zone of pre-excitation (panel 6) before spreading inferiorly and laterally. Panel 8 shows the line of block has extended into the septal region such that single loop re-entry now occurs during the return cycle wavefront (panels 9 to 11), accounting for the altered return cycle QRS morphology. The white area at the bottom right corner of panel 8 is a continuance of and adjacent to the area of activation (white) at the bottom left corner of the same panel. Altered return cycle electrograms are shown beneath the maps.
During conduction through the DP, the line of block bordering the DP has returned to normal and activation re-exits the DP in panel 12 in the same area as in panel 1, native VT resumes, and surface QRS morphology returns to the original morphology. Systolic intracardiac electrogram morphology is not altered.
Of the 25 pacing protocols, pre-excitation of the circuit caused reset in 10 pacing protocols in 7 patients, including 2 patients where reset occurred from more than 1 pacing site (Patients #1 and #3). Pre-excitation resulting in a fully compensatory return cycle occurred throughout 14 pacing protocols in 7 VT (Table 1). This phenomenon also occurred after an initial period of reset in 1 patient (Patient #7, protocol 6). The mean, local EGap for VT in which reset occurred was 119.9 ± 73.2 ms and was 106.7 ± 51.5 ms in those in which a fully compensatory return cycle occurred (p = 0.70).
Pre-excitation resulting in change to return cycle QRS morphology occurred in 3 pacing protocols in 2 patients (Patients #2 and #4). In 1 of these protocols this phenomenon occurred with all extrastimuli delivered (Patient #2, protocol 2) until failure of capture occurred, and in 2 of these protocols it was seen after an initial period of reset (Patient #4, protocol 2; and Patient #2, protocol 1).
All pacing protocols ended with either failure of local capture (n = 22), termination of tachycardia with pacing (n = 2), or sustained change in VT morphology (n = 1).
The mean resetting interval for all episodes of reset in 7 VT was 100.7 ± 66 ms, which was 90.0 ± 24.2% of the EGap for those VT and 23.7 ± 12.8% of VTCL (range 8.1% to 41.9%). The resetting interval in all but 1 of these VT was longer than 10% of CL. There was no significant correlation between resetting interval and CL of VT (r = 0.63, p = 0.13).
Resetting response patterns
The response pattern was increasing in 3 VT, mixed in 3 VT, and a flat response in 1 VT (Fig. 6).No VT displayed a decreasing response pattern. Patients with a mixed or flat response pattern had significantly larger resetting intervals than patients displaying a solely increasing response pattern (140.5 ± 59.5 ms vs. 47.7 ± 19.1 ms, p = 0.046).
In this first detailed characterization of the effects of SVEs on global endocardial activation patterns in human infarct-related VT, the following findings have been identified for the first time. The temporal properties of the EGap vary at different sites of entry to the circuit; therefore measurement of the gap at a single site does not represent a value applicable to the whole circuit. Furthermore, pre-excitation of at least part of the circuit was a universal finding in this study; therefore failure to reset VT does not indicate the absence of an EGap. In the present study, the site of principal conduction slowing was located within the diastolic pathway portion of the circuit. This factor was the principal determinant of the effects of SVEs, reflecting the degree of excitability of the EGap within the DP itself, and might result in resetting, conduction with a fully compensatory return cycle, or alteration of lines of block leading to a change in systolic activation and altered surface QRS morphology.
Pre-excitation and the properties of the EGap
In the present study, the size of the EGap varied at different entry points to the circuit. In addition, the nature of the EGap varied with pacing from different sites such that resetting occurred from 1 site whilst sufficient IDCS occurred at another so that a fully compensatory return cycle resulted, even when the temporal EGap was large.
Ventricular tachycardia terminations occurred from more than 1 site in the same patient (Patient #6). That the difference between VTCL and the CI of the extrastimulus causing termination is a measure of the full extent of the EGap demonstrates conclusively that the temporal EGap varies at different points within the circuit. Other examples of increasing prematurity showed very substantial differences (16.2% difference between shortest CIs from different pacing sites) likely also denoting significant differences in the extent of the EGap.
The present study has identified flat, mixed, and increasing resetting response patterns in different VT, and as shown previously by Almendral et al. (7), mixed or flat response patterns were seen in VT with longer temporal EGaps. Thus, it seems that the longer the temporal EGap, the more likely a portion of it is fully excitable and therefore that a premature stimulus enters and propagates prematurely throughout the circuit to advance the tachycardia.
Mechanism of conduction slowing within the diastolic pathway
Pre-excitation resulting in a fully compensatory return cycle tended to occur in VT where the temporal EGap was relatively small (as a percentage of VTCL), consistent with premature stimuli encountering only partially excitable myocardium (15). Following orthodromic propagation in the systolic portion, conduction slowing then occurred principally within the DP.
It is likely that this observation results from a combination of properties of the DP, including structural features, such as change in muscle fiber orientation causing conduction anisotropy at entry to and within the DP (demonstrated in the canine infarct model) (1,3,12), and functional factors, including current source/sink relationships and altered gap-junctional organization (16). We have previously demonstrated that the greatest degree of conduction slowing in human infarct-related VT circuits occurs at changes of trajectory within the DP (10).
These observations in combination are consistent with the theories of anisotropic re-entry (1,3,12,16) and of spiral wave re-entry where slowing of conduction is most marked at sites of greatest curvature (17) and in which the properties of the EGap might vary at different points within the spiral.
Changes to lines of functional block
This study has shown that SVEs can lead to changes to lines of block within the circuit leading to alteration of return cycle systolic activation patterns and QRS morphology. Extension of lines of block with pacing has been observed in the canine post-infarction model by El Sherif et al. (2). Waldecker et al. (18) have also shown that a train of extrastimuli causes progressive change to lines of block on a beat-by-beat basis.
Alteration of systolic activation patterns due to a single extrastimulus delivered close to lines of block defining the DP might also be consistent with anisotropic or spiral wave re-entry in which a curving wavefront might cease to propagate when a critical curvature is reached despite the presence of excitable tissue (19).
Isopotential mapping with the non-contact system cannot discriminate between areas of surviving endocardium with underlying infarction and areas of myocardium where normal conduction is present throughout all tissue layers. Isopotential mapping might not be able to discriminate precisely between areas of partial and completely infarcted tissue within an area of myocardium with low voltage electrograms. However, an inability to discriminate precisely in these respects will not materially affect the conclusions of this study in which non-contact mapping has permitted, for the first time, detailed insight of the interaction of extrastimuli with re-entrant VT. Calculation of the EGap with single extrastimuli is still dependent, at least in part, on conduction characteristics of the intervening tissue between pacing site and circuit, and as such, the true EGap might be larger than the calculated EGap presented in the present study.
Although this study necessitated mapping of only the systolic portion of the circuit, the diastolic portion of the circuits was detectable at least in part in all cases. However, because entry and exit sites were always detectable with the non-contact system, measurements of conduction time within the diastolic pathway were always possible and sufficient for this study.
Evaluation of the EGap in the present study employed paced extrastimuli from a non-controlled, limited number of sites. Although pacing site location was not identified to be a determinant in the subsequent interaction of an SVE with the VT circuit, a systematic approach to pacing site location and number of protocols performed might have yielded an alternative result.
Finally, the numbers in this study were relatively small; there might be other mechanisms of responses to extrastimuli not seen in this study.
This work was supported by British Heart Foundation Grants PG/2001030 and RG/05/009, London, United Kingdom. Drs. Segal, Chow, and Markides were supported by grants from the British Heart Foundation.
- Abbreviations and Acronyms
- coupling interval
- cycle length
- diastolic pathway
- excitable gap
- interval dependent conduction slowing
- left ventricle
- single ventricular extrastimuli
- ventricular tachycardia
- Received May 26, 2006.
- Revision received October 30, 2006.
- Accepted November 16, 2006.
- American College of Cardiology Foundation
- Dillon S.M.,
- Allessie M.A.,
- Ursell P.C.,
- et al.
- El Sherif N.,
- Gough W.B.,
- Restivo M.
- Hanna M.S.,
- Coromilas J.,
- Josephson M.E.,
- et al.
- Almendral J.M.,
- Stamato N.J.,
- Rosenthal M.E.,
- et al.
- Callans D.J.,
- Zardini M.,
- Gottlieb C.D.,
- et al.
- Chow A.W.,
- Schilling R.J.,
- Davies D.W.,
- et al.
- Chow A.W.,
- Segal O.R.,
- Davies D.W.,
- et al.
- Peters N.S.,
- Coromilas J.,
- Hanna M.S.,
- et al.
- Schilling R.J.,
- Peters N.S.,
- Davies D.W.
- Allessie M.A.,
- Bonke F.I.,
- Schopman F.J.
- Peters N.S.,
- Coromilas J.,
- Severs N.J.,
- et al.
- Cabo C.,
- Pertsov A.M.,
- Baxter W.T.,
- et al.
- Waldecker B.,
- Coromilas J.,
- Saltman A.E.,
- et al.
- Allessie M.A.,
- Schalij M.J.,
- Kirchhof C.J.,
- et al.