Mechanisms of Resetting Reentrant Circuits in Canine Ventricular Tachycardia
Background—Resetting has been used to characterize reentrant circuits causing clinical tachycardias.
Methods and Results—To determine the mechanisms of resetting, sustained ventricular tachycardia was induced in dogs with 4-day-old myocardial infarctions by programmed stimulation. Premature stimulation was accomplished from multiple regions within reentrant circuits; resetting curves were constructed and compared with activation maps. Monotonically increasing responses, or a “mixed” response (increasing portion preceded by a flat portion), occurred. All reentrant circuits had a fully excitable gap. Interval-dependent conduction delay and concealed retrograde penetration led to increased resetting response curves.
Conclusions—Multiple mechanisms revealed by mapping cause resetting of reentrant circuits.
Premature stimulation has been used in clinical studies to characterize reentrant circuits causing ventricular tachycardia.1 2 3 4 5 6 Almendral et al1 noted 3 resetting responses—flat, increasing, and mixed—based on changes in return cycles after progressively premature impulses. They postulated that a flat response indicated a fully excitable gap in the circuit; an increasing response, a partially excitable gap; and a mixed response, a combination of the two. These conclusions are limited by stimulation from outside the reentrant circuit and the inability to map activation to study conduction of the stimulated impulse in the circuit. These limitations do not exist in the canine model of reentrant ventricular tachycardia in which we characterized resetting responses, providing insights for interpreting the resetting response in humans.
Mapping a Canine Model of Myocardial Infarction
We mapped activation in reentrant circuits in the epicardial border zone of 4-day-old canine infarcts during sustained ventricular tachycardias (>30-second duration, monomorphic QRS) induced by programmed stimulation. All methods have been described.7 8
The resetting response was investigated with single premature stimuli delivered during tachycardia at coupling intervals (CIs)10 ms less than the tachycardia cycle length and decreased by 10 ms until failure to capture or tachycardia termination. A complete resetting response was calculated from 5 to 15 premature impulses. Premature stimuli were triggered from the electrogram near the pacing site or from the ECG. When possible, resetting protocols were carried out from different stimulation sites. This involved reinitiation of tachycardias with the same circuits and QRS morphologies. Cycle lengths were sometimes slightly different.
Definitions and Statistical Analyses
CIs of electrograms nearest sites of stimulation (Vnative tach−Vpace) were plotted against return cycles (RCs), the time from local capture of this same electrogram to the next beat of the native tachycardia (Vpace−Vnative tach; Figure 1⇓). Resetting resulted in advancement of tachycardia at both the pacing site and the surface ECG with less than a compensatory pause: CI+RC<2×cycle length of the native ventricular tachycardia (VTCL).
Simple linear regression was performed on resetting response relationships with CI as the independent variable and RC as the dependent variable using the least-squares-fit method.9 The slope (m) and intercept (b) of resetting responses were determined, where RC=m(CI)+b. A resetting response was flat if RC increased <10 ms over a range of CI of ≥30 ms and slope (m) of the CI-RC relationship was ≤0.33. Increasing responses showed progressive lengthening of RCs with decreasing CIs with m>0.33; mixed responses exhibited flat portions at long coupling and increasing responses at shorter CIs.1 Whether the slope significantly differed from 0 was assessed by a 2-tailed t test. The goodness of fit for each line was evaluated by calculating the coefficient of determination (r2).
To evaluate for full recovery of excitability in reentrant circuits, resetting was done with minimally premature stimuli, stimulated impulses whose CIs were within 35 ms of the tachycardia cycle length. Because this was not always possible, residual analysis was also used to extrapolate the resetting response to a CI equal to the VTCL (CIvtcl=VTCL). The appropriate CIvtcl, slope, and intercept of each tachycardia were entered into the formula, RCvtcl=m(CIvtcl)+b, graphically equivalent to extending the regression line to the point where it crosses the CI intercept (abscissa), ie, the RC in response to a minimally premature CI (ie, CI=VTCL). The residual (d) was calculated as the difference between the VTCL and RCvtcl: d=VTCL−RCvtcl. A positive or 0 residual indicates full recovery of excitability; negative residuals are associated with lengthened RCs (increasing response).
When resetting was carried out from ≥2 sites, slopes of regression lines from each site were compared by use of a modified t test.9 When resetting was carried out from 3 sites, slopes of the resetting response underwent ANCOVA. If significant, slopes were then compared pair-wise post hoc with Tukey’s method.9
Pattern of Resetting Response Curves
The resetting response depicted in Figure 1A⇑ is plotted in Figure 1B⇑. A short flat portion occurs (E and F in Figure 1B⇑) where RCs are equal to VTCLs (216 ms). The overall response is “increasing.”1 The high coefficient of determination (r2=0.971) indicates a good linear fit.
Data from all experiments are given in Table 1⇓. Five of the 14 tachycardias revealed a flat response with late coupled resetting impulses over a range of CIs from 20 to 40 ms (see response 11 in Figure 1C⇑). These tachycardias demonstrated an increasing response with earlier premature impulses, an overall mixed response. Nine of 14 tachycardias demonstrated a monotonically increasing response over all CIs. No tachycardias had a strictly flat response. All resetting response slopes were negative and highly significant (Table 1⇓).
A flat portion in the curve has been interpreted as indicating a fully excitable gap in the reentrant circuit.1 We assessed other proposed indicators of a fully excitable gap. Four responses (2, 3, 4, and 11 in Table 1⇑) approach unity in their RCs before reaching unity in their CIs, suggesting full recovery of excitability (Figure 1C⇑). All 7 tachycardias in which resetting was carried out with minimally premature stimuli were reset, with RCs equal to tachycardia cycle lengths suggesting full recovery. The remaining tachycardias could not be assessed this way. We characterized the effects of minimally premature resetting stimuli in these and the previously analyzed 7 tachycardias by residual analysis (Table 2⇓). All tachycardias with flat portions in their resetting response or that reset with RCs equal to the tachycardia cycles have a strongly positive or nearly positive residual (8 tachycardias; residual range, −2 to 45 ms), suggesting full recovery of excitability. Of the remaining 6 tachycardias, the residual was also positive or nearly positive in 4 (responses 7, 8, 10, and 14) and negative to strongly negative in 2 (responses 6 and 13). Damped cycle length oscillations after resetting with late coupled premature stimuli did not occur in any tachycardias, also suggesting full recovery of excitability.10
Table 3⇓ shows results of resetting from ≥2 sites. In 2 experiments (experiments 4 and 5), increasing curves occurred at all stimulation sites; in 1 experiment (experiment 2), a mixed curve occurred from both sites. The slopes of the curves from each site were not significantly different. In 2 experiments (experiments 3 and 6), the types of curves and their slopes varied with stimulation site; a flat portion of the curve occurred only at 1 stimulation site and not the other(s). Slopes of curves from different stimulation sites were significantly different. In Figure 1D⇑ (experiment 6; 3 sites), the lateral resetting site yields a flat response and has the steepest slope with earlier premature stimuli. All regression slopes were significantly different from each other (Table 3⇓).
Mechanisms of Increasing Resetting Response
Interval-Dependent Conduction Delay
An interval-dependent conduction delay occurs when a premature impulse encounters tissue only partially recovered in the reentrant circuit and conducts more slowly. Figure 2A⇓ shows increasing resetting response curves in 1 experiment. A map of the reentrant circuit during tachycardia (CL, 230 ms) is shown in Figure 2B⇓. Activation occurs around 2 lines of functional block parallel to the longitudinal fiber axis. A central common pathway is between the block lines.7 8
Figure 2C⇑ shows activation of a premature impulse delivered at the pulse symbol (arrow in Figure 2A⇑; CI, 187 ms, 43 ms premature). The position of the native tachycardia wavefront at this time is at the dashed line, where it collides with the antidromic reset wavefront. Isochrones crowd as activation of the stimulated (reset) wavefront sweeps around the apical ends of the block lines, arriving at the entrance of the central pathway 30 ms earlier than during native tachycardia. The reset wavefront begins activation of the central pathway at 166 ms, 40 ms late. Activation of this pathway is initially rapid, probably because of the presence of pseudoblock (small arrows)7 or contribution from deeper layers. Conduction through the remainder of the central pathway is the same as during native tachycardia because of recovery distally resulting from slower propagation in the proximal pathway. Similarly, conduction delay increased further with increased prematurity. The block lines are lengthened, but these changes were not responsible for the increased conduction delay. The increasing response reflects interval-dependent conduction delay at discrete points of transverse conduction; at the entrance to the central pathway, the conduction pathway is unchanged. This mechanism, noted in all experiments with an increasing resetting response, was the predominant mechanism in most of them.
Antidromic Invasion With Concealed Conduction Delay
Figure 3⇓ shows an example of this mechanism (Figure 3A⇓; resetting response). During the native tachycardia (Figure 3B⇓), 2 reentrant wavefronts rotate around 2 lines of functional block. Figure 3C⇓ maps the activation of the premature impulse C in Figure 3A⇓ delivered at the pulse symbol near site F (CI, 147 ms, 69 ms premature). At the time of the premature stimulus, the native wavefront is at the dashed line. Compared with the native tachycardia (Figure 3B⇓), the block line on the right is shortened by the stimulated orthodromic impulse, and the central pathway is broader. Activation also proceeds antidromically, penetrating into the central pathway between the block lines. The antidromic impulse collides with the native tachycardia impulse at the solid thin line and thin arrows. Figure 3D⇓ shows activation during the native tachycardia proceeding from A to H (long arrows). The resetting impulse (pulse sign) captures near site F (time 0 ms) and propagates orthodromically (F to A) and antidromically (F to C). Collision of the antidromic wavefront occurs between B and C: electrograms between F and C are captured with an antidromic morphology different than during native tachycardia, whereas morphology at B, distal to the collision site, is orthodromic. Meanwhile, the orthodromic stimulated wavefront conducts with interval-dependent conduction delay requiring 100 ms to propagate around the right line of block (F to A); the native tachycardia wavefront required only 78 ms. By the time the orthodromically stimulated wavefront reaches site C, conduction time is 218 ms, equal to the VTCL, and it is no longer premature. Therefore, the change in the right line of block did not influence conduction of the premature impulse. However, the premature impulse continues to exhibit conduction slowing in the region between sites B and F. Conduction through the lower portion of the central common pathway is affected by antidromic invasion with concealed conduction. Figure 3E⇓ shows activation of the central pathway by the orthodromically propagating stimulated wavefront. The wavefront enters the pathway at 120 ms, 20 ms later than during the native tachycardia (≈92 to 101 ms); therefore, interval-dependent conduction slowing through the central pathway is not a factor. Nonetheless, conduction slows in the region where previously there was antidromic premature wavefront–native wavefront collision, evidenced by bunched isochrones between sites B and D. Conduction through the upper end of the pathway is faster (sites D through F), similar to that of the native tachycardia (compare with Figure 3B⇓).
Mechanisms of a Flat Resetting Response
Figure 4A⇓ is a map of the native reentrant circuit, and Figure 4B⇓ depicts the map of a resetting impulse (CI, 242 ms, 30 ms premature) stimulated at the lateral margin (pulse) during the flat part of the curve in Figure 1D⇑ (triangles). A dashed line represents the position of the native reentrant wavefront when the resetting stimulus is delivered. This wavefront collides with the antidromic stimulated wavefront (solid line, small arrows). A similar collision with the second native wavefront occurs at the bottom left (solid line, small arrows). Meanwhile, the stimulated wavefront penetrates the zone of slow conduction orthodromically at the entrance of the central pathway. Activation through this region (isochrones 10 through 90) is no slower than during the native tachycardia (no interval-dependent conduction delay). The stimulated wavefront also proceeds throughout the rest of the circuit without delay, including the region originally activated by the native tachycardia at the time the premature was delivered, shown in the inset above Figure 4B⇓; isochrones do not crowd as the reset wavefront encounters the region of antidromic collision, despite the wavefront arriving at this region 30 ms earlier than the native wavefront. Thus, there is no evidence of interval-dependent conduction delay or antidromic concealment. The conduction time of the reset wavefront is equal to that of the native tachycardia. In the electrograms (Figure 4D⇓), the premature impulse (pulse sign) conducts without delay; the slope of the arrow is parallel to the slope of the arrows of the native tachycardia. There is no evidence of antidromic invasion at site C.
A map of a more premature stimulus appears in Figure 4C⇑ (CI, 162 ms, 111 ms premature). At this point, the resetting response is increasing; RC is 357 ms. The native reentrant wavefront is at the broken line. The stimulated wavefront propagates further in the antidromic direction than in Figure 4B⇑ before colliding with the native wavefront (solid line, small arrows). Collision also occurs near the apical margin (lower left corner). The stimulated wavefront penetrates the central pathway and slows because of the interval-dependent conduction delay (bunched isochrones). All of the additional conduction time occurs within the central pathway. Again, changes in the block line (at the right) play no major role in the resetting response. Figure 4E⇑ shows that the premature impulse from site D (pulse) penetrates antidromically to site C, which captures early and with a different morphology than during native tachycardia. Collision with the native impulse occurs between sites B and C. The orthodromic reset wavefront propagates more slowly than during unperturbed tachycardia; conduction time from D to A increases to 311 ms from 223 ms, accounting for all of the time difference between the RC and the native tachycardia cycle.
Site-Specific Resetting Responses
Resetting responses from different stimulation sites were sometimes different (Tables 2⇑ and 3⇑). Figure 4⇑ described resetting responses from the lateral margin in experiment 6 (Figure 1D⇑). Figure 5A⇓ shows a map of resetting from the left anterior descending coronary artery (LAD) margin (pulse) in this experiment (CI, 188 ms; RC, 318 ms). The native tachycardia wavefront is at the dashed line. The stimulated wavefront collides with the native wavefront at the solid thin line (small arrows). Activation proceeds at the right (sites A to D) with interval-dependent conduction delay, also shown in Figure 5B⇓. Conduction time from A to D lengthens from 49 to 73 ms. Further interval-dependent conduction delay occurs in the central pathway; conduction time from D to E increases from 75 to 91 ms. Activation time from site E to A changes little, increasing from 147 to 154 ms. There is no evidence of changes in activation pathway or concealed conduction delay in the area of antidromic invasion (sites F to A); the increasing resetting response is due to interval-dependent conduction delay between sites A and E. As in Figure 4C⇑ and E, the portion of the circuit activated first by the orthodromic resetting wavefront exhibits the maximal degree of interval-dependent conduction delay, whereas downstream segments of the circuit are less affected because of the progressive loss of prematurity.
In Figure 5C⇑, activation of the circuit by the stimulated impulse near site F (pulse) (CI, 163 ms; RC, 317 ms) proceeds in the orthodromic and antidromic directions from within the central pathway. The native wavefront is at the dashed line; the collision between the antidromic and native wavefronts is at the solid line and small arrows. Compared with the native tachycardia (Figure 4A⇑), there are no major changes in the circuit pathway. Conduction changes accompanying resetting are shown in Figure 5D⇑. Activation proceeds in the orthodromic and antidromic directions from site F, with the former showing interval-dependent conduction delay, particularly in the region closest to the pacing site (F to A) where the activation time increases from 112 to 133 ms. Activation times distal to this region do not change. Concealed conduction delay is not a factor in the increasing resetting response in this case. Therefore, the center (Figure 5C⇑) resetting response is increasing because of interval-dependent conduction delay in the orthodromic region just proximal to the pacing site.
Taken together, the maps in Figures 4A⇑ through 5D indicate that the presence of proximal interval-dependent conduction delay is the major factor in the site-specific resetting response. The lack of such a delay is evident in a flat response. The differences in slopes of the responses and the intervals over which resetting occurs appear to arise from inhomogeneities in conduction and refractoriness at different points in the circuit and the effects of these inhomogeneities on restitution.
Resetting Response Curves of Canine Ventricular Tachycardia
The resetting response in this canine model resembles that of clinical ventricular tachycardia associated with previous infarction; flat and increasing responses occurred.1 2 3 4 5 6 Flat portions were short, unlike in clinical responses where flat portions occur over as much as 50% of the cycle.1 This difference may be related to different substrates forming reentrant circuits (discussed below). Although resetting responses in our experiments were predominantly increasing, every experiment revealed evidence of a fully excitable gap8 indicated by (1) convergence of the curves at or before the identity point where the normalized CI equaled the normalized RC, (2) resetting with minimally premature stimuli with an RC equal to the reentrant cycle length, or (3) residual analysis. Damped cycle length oscillations during resetting with late-coupled premature stimuli characteristic of circuits with only a partially excitable gap10 were not observed.
Activation Maps and Resetting Mechanisms
Maps of flat responses or minimally premature impulses revealed propagation of the reset wavefront at the same conduction velocity and reentrant cycle as the native tachycardia, confirming interpretation of the curves that this model of anisotropic reentry has a fully excitable gap.8
All resetting responses had an increasing component. The principle mechanism was interval-dependent conduction delay, progressive slowing of conduction with increasing prematurity.8 10 11 Delay was most pronounced at the turning points around lines of functional block. Thus, when resetting was carried out proximal to such areas, interval-dependent conduction slowing was facilitated. The window of reset also reflected the local excitable gap at the pacing site.8 10 A second mechanism for an increasing response was antidromic concealed conduction, previously only suspected clinically.12 Special circumstances are required for its manifestation. The antidromic wavefront must propagate temporally (not just spatially) for a sufficient time to affect (slow) orthodromic conduction.4 In addition, the wavefront must exhibit sufficient spatial capture to be apparent on the activation map. Stimulation near a site of slow conduction may result in little spatial propagation; thus, the presence of the antidromic wavefront may be difficult to detect. Slow propagation of the orthodromic reset wavefront might then be (incorrectly) ascribed to an interval-dependent conduction delay.
A third possible mechanism proposed to explain clinical resetting is changes in the functional barriers.13 Such changes did not contribute to the increasing resetting response in our experiments.
The underlying heterogeneity of circuit conduction and refractory properties was responsible for site-specific resetting responses, not intervening tissue outside the reentrant circuit between the pacing site and the circuit, as might occur in clinical studies,2 5 12 because the pacing sites were close to or in the circuits. If several regions of the reentrant circuit exhibit interval-dependent conduction delay, then the resetting response is determined by the relationship of the pacing site to these different regions and their respective restitution relationships. Thus, a premature stimulus delivered proximal to a site of interval-dependent conduction delay with a steep restitution response may be slowed sufficiently to arrive relatively late at a second site of interval-dependent delay further downstream. The proximal site will therefore “protect” the distal site and will tend to govern the resetting response. In the converse circumstance, a site of interval-dependent conduction delay with a modest restitution relationship may only partially delay the orthodromic reset wavefront, which will then interact with a downstream region of delay with a steeper restitution relationship, albeit less than if it had not encountered the first region. The interaction of the pacing site and the regions of interval-dependent conduction delay, as well as the restitution relationships, gives rise to this site-specific behavior. Different resetting responses may be elicited clinically from different sites of stimulation, and termination of clinical ventricular tachycardia in response to premature simulation is dependent in part on the steepness of the response.5
Boersma et al11 were unable to demonstrate resetting in a rabbit model of anisotropic reentry and concluded that “it seems very unlikely that clinical tachycardia based on functional reentry can be reset.” This disparity with our results reflects differences in the models of reentry that may have important clinical implications for understanding human ventricular tachycardia. In the epicardial border zone of healing infarcts, structural changes influence the properties of the reentrant circuits, particularly the remodeling of gap junctions associated with block lines,8 14 and may be responsible, along with wavefront curvature, for the occurrence of a fully excitable gap.8 Larger anatomical barriers may contribute to the formation of some reentrant circuits causing clinical tachycardia. The variable contribution of anatomic and functional circuit properties may explain different resetting responses among circuits, with the larger fully excitable gaps associated with the more marked structural changes including anatomic reentry.
This work was supported by grants R37 HL-31393 and HL-30557 from the National Heart, Lung and Blood Institute. Dr Hanna is an investigator of the American Heart Association, Southeast Pennsylvania. Dr Peters is an investigator of the British Heart Foundation (RG-2000003).
- Received December 31, 1999.
- Revision received August 31, 2000.
- Accepted September 8, 2000.
- Copyright © 2001 by American Heart Association
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