The use and interpretation of entrainment mapping, or

Advances in Arrhythmia and Electrophysiology Challenges and Pitfalls of Entrainment Mapping of Ventricular Tachycardia Ten Illustrative Concepts Roderick Tung, MD The use and interpretation of entrainment mapping, or continuous resetting, of a reentrant tachycardia has been regarded as the gold standard for delineation of the components of a reentrant circuit. 1,2 The response during and after overdrive pacing, whereby 2 wavefronts enter the circuit antidromically (with fusion) and orthodromically, is used to confirm reentry as the arrhythmia mechanism and determine the relationship of the pacing site to the circuit. The fulfillment of classical criteria outlined by Waldo and colleagues 3,4 were synthesized into an anatomic concept for scar-related ventricular tachycardia (VT) by Stevenson et al 5 to portray the structural and architectural basis of circuit conduction meandering between regions of fibrosis. In this construct, a central corridor, or protected isthmus, is bordered between 2 regions of dense scar with a single entrance that is distinct from a single exit, which yields the QRS morphology. 6 This reentrant model has been central to our current mechanistic understanding of scar-mediated VT and is critically important for differentiating critical sites from bystander sites and regions that are unlikely to interrupt or eliminate reentry. 7 However, the nature of reentrant VT in man is more complex than our idealized working construct for many reasons. In clinical practice, the majority of VT is hemodynamically unstable, which precludes the ability to perform entrainment mapping and activation mapping of the entire circuit. 8 Differences in the circuit between patients with untolerated and tolerated VT are not well understood. VT circuits are 3 dimensionally complex with transmural conduction and circuit conduction is unlikely to be planar, as depicted by electroanatomic mapping of the myocardial surface. Exits may be multiple 9,10 and patterns other than loop reentry around scar are likely. Channels of preserved myocardium are frequently not normal in voltage (>1.5 mv) as described in the anatomic isthmuses in Tetralogy of Fallot, 11,12 but rather recorded as dense scar (<0.5 mv). Entrainment mapping is influenced by the current strength and size of the virtual electrode that both paces and records the local response to continuous resetting. In fact, Heisenberg s uncertainty principle is a requisite characteristic to all VT entrainment, where the measurement of the system behavior (circuit) necessitates an alteration (reset) of the system studied. The postentrainment response that is analyzed is not the actual intrinsic VT circuit conduction, but rather a reset of a previously reset pacing wavefront. The proximity of how close and far away near-field and far-field signals, respectively, are detected is unknown for a given electrode pair. Multiple near-field components may be recorded at a given site and pacing typically interacts and captures only one component of the local activation. 13 In this regard, activation mapping may be the purest method to studying the true unperturbed nature of the reentrant circuit. Compared with activation mapping, entrainment mapping has the potential to overestimate or underestimate the true size of the reentrant circuit. 14 If the reentrant circuit is sufficiently small, an irrigated radiofrequency application may eliminate more than one component of the circuit delineated by entrainment. Important insights into the limitations of classical entrainment mapping can be gained by analyzing reentrant circuits and sites exhibiting atypical responses that were not abandoned. There are both inherent limitations and interpretative pitfalls to entrainment mapping; the following case illustrations highlight challenges and pitfalls that should be recognized and overcome during clinical interpretation. Concept 1: Assuming Reentry as Mechanism Overdrive pacing, which is necessary but insufficient to demonstrate entrainment, is frequently assumed to diagnose reentry as the mechanism. Usurping the tachycardia by pacing at a shorter cycle may represent mere overdrive suppression of a focal tachycardia. During entrainment, recognition of constant fusion except the last orthodromically captured beat and progressive fusion are sufficient proof of a reentrant mechanism. Scar-related VT is aptly termed in clinical practice because these pacing criteria are infrequently fulfilled in real-world practice. Furthermore, 20% of VTs in the setting of structural heart disease may be nonreentrant in mechanism. 15,16 Concept 2: Ensure Consistent Capture One of the most common pitfalls of entrainment mapping is the assumption of circuit capture during pacing. Before performing any measurements, consistent local capture should be confirmed. Oscillations or acceleration of tachycardia may result in pseudo-capture if pacing is performed only 10 Received December 23, 2016; accepted February 28, 2017. From the Center for Arrhythmia Care and Heart and Vascular Center, Pritzker School of Medicine, University of Chicago Medicine, IL. Correspondence to Roderick Tung, MD, Center for Arrhythmia Care, The University of Chicago Medicine, 5841 S Maryland Ave, MC 6080, Chicago, IL 60637. E-mail rodericktung@uchicago.edu (Circ Arrhythm Electrophysiol. 2017;10:e004560. DOI: 10.1161/CIRCEP.116.004560.) 2017 American Heart Association, Inc. Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.116.004560 1

2 Tung VT Entrainment Challenges Figure 1. A, A duodecapolar records signals within dense scar at standard gain in our laboratory (1000 ). Split and late potentials with local delay (red box) with an amplitude of 0.01 mv (blue arrow) are revealed at a maximum gain (10 000 ). B, Postpacing response to overdrive pacing (15 ma) during ventricular tachycardia from the site (duodecapolar catheter [DD] 11,12) with amplitude of 0.01 mv recorded during sinus rhythm. Three classical criteria for isthmus site are fulfilled from DD 11,12 site with postpacing interval=tachycardia cycle length (PPI=TCL; 560 ms), EGM QRS=S-QRS (210 ms), and concealed fusion in both intracardiac and surface recordings.

3 Tung VT Entrainment Challenges to 20 ms faster. Although a longer duration of pacing and faster drive cycles are more likely to demonstrate continuous resetting, this is counterbalanced by a greater chance to terminate or disrupt tachycardia. Termination during pacing with reinitiation is difficult to prove and disprove although local electrograms may be useful. As a general rule, if concealed fusion is seen on the surface leads, the first assumption should be that the pacing train was insufficient to entrain the tachycardia. Concept 3: Cannot See: Critical Sites May Be Below Standard Visual Detection Entrainment mapping requires the ability to capture an electrogram component of interest during overdrive pacing. The term dense scar is misleading as there is no conduction that occurs within fibrotic cells, but rather within interspersed viable myocardium that is registered as extremely low voltage. The concept that channels can be macroscopically identified with voltage threshold titration has been recently questioned. 17 In Figure 1A, the isthmus electrogram that was characterized by entrainment was not visible with a 1-mm electrode with 2-mm spacing on the recording system at a standard gain of 1000. With a voltage of 0.01 mv, the critical site during sinus rhythm was only apparent at 10 standard gain. In Figure 1B, this site was proven to be critical with fulfillment of 3 classical criteria for an isthmus during and after entrainment. Automated mapping systems set a lowvoltage threshold (typically 0.03 0.05 mv) to differentiate Figure 2. A, A low-voltage split potential recorded on the distal ablation electrode pair cannot be captured at maximum pacing output (25 ma) during sinus rhythm. Ventricular tachycardia (VT) is induced with the catheter stabilized at this site, and early far-field diastolic activity is seen. Rapid termination of VT occurs on radiofrequency delivery at this inexcitable site. B, Entrainment of VT from Abl d fails to capture the local electrogram activated during mid-diastole and instead captures the larger amplitude component activated within the QRS. A bystander with slight surface fusion is demonstrated based on the postpacing interval tachycardia cycle length (PPI TCL) difference of 35 ms, which is the same as the S-QRS to EGM QRS difference. (Continued )

4 Tung VT Entrainment Challenges Figure 2 Continued. C, Despite failure to entrain the isthmus, the isthmus was demonstrated by prompt termination within 5 s of radiofrequency delivery. true signal from nonphysiological low-amplitude noise. It is important to note that in such cases, the isthmus site will be concealed from visual detection, giving no reason to attempt entrainment. Concept 4: Cannot Capture: Unexcitable Tissue Can Be Critical Although the achievement of loss of capture, or electrically unexcitable scar, is a desirable postablation end point within Figure 3. Marked saturation artifact in the pacing channel on distal ablation electrode pair obscures ability to determine whether the fractionated near-field component or larger amplitude far-field component is captured. Examination of the proximal electrode recording (blue solid arrows) confirms that the similarly timed component was captured, just downstream from the stimulus as it is no longer seen at the expected S-QRS interval during ventricular tachycardia (dashed arrows indicate absent EGM). Overall, this demonstrates a bystander response to entrainment, where the postpacing interval tachycardia cycle length (PPI TCL; 150 ms) difference is the same as the S-QRS EGM QRS interval difference (150 ms). Abl d indicates distal ablation electrode pair; and RV, right ventricle.

5 Tung VT Entrainment Challenges scar, 18,19 the sensitivity and specificity of this phenomenon is incompletely understood. Because contact can impact tissue excitability, the classification of unexcitable tissue with criteria from contact force sensing technology warrants further study. In Figure 2A, a split late potential is seen, and the local electrogram cannot be captured with high-output pacing at 25 ma at 2 ms during baseline rhythm. However, VT is induced with the catheter stabilized at this site, where early diastolic activation is present and rapid termination of VT is achieved. Because of the inability to capture, this critical site could not be characterized by entrainment mapping. For this reason, we have shifted our definition of critical sites with retrospective data analyses to include those that exhibit diastolic activation and are promptly terminated with ablation, which is one of the clinical end goals of entrainment mapping. 20 In Figure 2B, a multicomponent local electrogram signal is recorded during VT. One component is mid-diastolic and highly fractionated (A), with a lower amplitude than the component activated during the QRS (B). Pacing performed at 10 ma resulted in acceleration of the tachycardia with nearconcealed fusion. However, examination of the pacing train Figure 4. A, Oscillatory tachycardia cycle length before, during, and after entrainment (distal ablation electrode pair, Abl d) impairs the ability to make a conclusive postpacing interval tachycardia cycle length (PPI TCL) measurement. There are variable S-QRS intervals that are consistent with the EGM QRS oscillations during tachycardia. Decremental and variable conduction is most likely, although multiple exit sites is also possible. B, Despite an interdeterminate long PPI entrainment response, rapid termination occurred during ablation.

6 Tung VT Entrainment Challenges reveals a long S-QRS without local capture of component A. Instead, only component B is captured, which yields a bystander response. Subtle surface fusion may be the result of high-output antidromic capture just after QRS onset, where the last paced orthodromic wavefront is not fused. In this case, capture of the most likely candidate for isthmus conduction could not be achieved, as selective recruitment of the higher amplitude B occurred. It is possible that altering the timing of pacing into circuit may have increased the probability of capturing component A. Because of the promising diastolic component recorded from this site, ablation was performed, and termination of VT occurred in <5 seconds (Figure 2C). Accurate interpretation of this failure to entrain the critical isthmus component with capture of a simultaneously recorded bystander was necessary to prevent abandonment of this perfect site. Concept 5: Determining Local Electrogram Capture: Use of Neighbors Careful examination of the local electrogram of interest during overdrive pacing is critical to determine direct capture (absent because of recruitment by pacing stimulus) versus orthodromic capture (downstream component accelerated to paced cycle length). Additionally, the use of neighboring electrodes can be particularly useful when interpreting entrainment. Orthodromic capture with intracardiac concealed fusion provides additional clues when interpreting entrainment responses. In Figure 3, a low-frequency, high-amplitude (far-field) component is seen on the distal ablation recording channel and a high-frequency, low-amplitude (near-field) component. Saturation artifact on the pacing channel makes it difficult to assess if the high-frequency component was captured directly or orthodromically, which confounds accurate measurement of the PPI. Examination of the proximal electrode recording (blue solid arrows) confirms that the similarly timed near-field component was captured during pacing (blue dashed arrows), demonstrating a bystander response to entrainment, where the PPI TCL difference is the same as the S-QRS to EGM QRS interval difference. Simultaneous capture of both near- and farfield components is also possible with high current strength, although it seems that the far-field component on the proximal electrode is not altered by pacing, with the near-field superimposed within the far-field component because of orthodromic downstream capture from distal electrode pacing. Concept 6: Good Long Postpacing Intervals The observation of baseline tachycardia characteristics is necessary to determine the stability of the circuit. When oscillations in tachycardia cycle length are present, assessing the postpacing interval is inconclusive and uninterpretable. Therefore, attempts at overdrive pacing should be avoided, although subtle oscillations may be missed in real time. Overdrive pacing has the potential to destabilize, accelerate, transition, or terminate a tachycardia. For this reason, it is important to examine the morphology and rate of tachycardia before and after the pacing train. Termination with a nonpropagated stimulus can be missed without careful analysis of the pacing train. Furthermore, decremental conduction may result from rapid pacing and pacing should be performed <30 ms faster than tachycardia to minimize this effect. 3 Figure 4A illustrates decremental and variable isthmus circuit conduction that occurs before, during, and after pacing, which obscures an accurate measurement of PPI. Similar phenomena have been shown in typical cavotricuspid isthmus flutter. 21 There is oscillation in the EGM QRS interval during tachycardia (TCL 390 460 ms), and these changes in isthmus conduction are observed during pacing with similar variations in S-QRS Figure 5. A postpacing interval shorter than tachycardia cycle length is more likely explained by remote capture deeper into the circuit from high-output pacing (distal ablation electrode pair, Abl d), effectively shortening the reset circuit length. Only the terminal component of the continuous fractionated electrogram is directly captured during pacing. Concealed fusion is present, and the S-QRS is consistent with a proximal site >70% of tachycardia cycle length. Termination was achieved at this site with longer application of radiofrequency (20 s). PPI indicates postpacing interval.

7 Tung VT Entrainment Challenges intervals. Subtle changes in QRS morphology are seen during pacing and tachycardia, which may alternatively indicate slight shifts in exit that account for cycle length oscillation. Despite a seemingly long PPI, the site was proven to be critical with abrupt termination during ablation (Figure 4B). Concept 7: Good Short Postpacing Intervals The finding of a postpacing interval that is shorter than tachycardia cycle length is a curious phenomenon. Short PPI has been described in the setting of misinterpreting the return to a far-field electrogram not captured by the pacing stimulus, which should be more accurately termed a pseudoshort PPI response. 13 Alternatively, transient acceleration of tachycardia may yield a seemingly short PPI. However, when near-field capture is present, a short PPI may result from a high-output stimulus, resulting in capture of downstream far-field tissue beyond the electrogram of interest. In this theory, the larger virtual electrode leapfrogs or captures deeper into the circuit, resulting in a shorter-than-expected return wavefront, which seems to be shorter than the TCL. In Figure 6. A, Outer loop response (distal ablation electrode pair, Abl d) is seen because of the presence of manifest fusion most evidence in V 3 through V 5 surface leads. The site is close to the exit site because of short S-QRS and the postpacing interval=tachycardia cycle length (PPI=TCL). B, This site was not abandoned, and ablation successfully terminated the ventricular tachycardia and rendered it noninducible.

8 Tung VT Entrainment Challenges Figure 5, a continuous, fractionated, low-amplitude electrogram is recorded, and pacing (10 ma) directly captures the terminal half of the complex signal. The timing of this component is consistent with a proximal location in the diastolic corridor, and concealed fusion is observed. The PPI is 15 ms shorter than the TCL, which is due to the shorter S-QRS compared with EGM QRS because of capture deeper into the circuit, making it closer to the exit. This site was not abandoned, and termination of tachycardia was observed during ablation. Concept 8: Manifest Fusion May Be Good Enough Concealed fusion requires complete match of the 12-lead morphology. In cases where subtle surface fusion is observed, outer loop sites are suggested when the postpacing interval approximates the tachycardia cycle length. It is important to note that many beats of a single morphology are not identical during tachycardia, which may represent fusion of closely approximated exits. However, in the classic figure by Stevenson et al, the outer loop is activated after VT exits from the isthmus. In Figure 6A, there is capture with short S-QRS, suggesting proximity to the exit, but overt fusion is observed when pacing at 10 ma. Rate-related changes may account for the inability to achieve concealed fusion or capture outside the circuit occurs with high-output pacing. We have previously demonstrated a dual response with simultaneous capture of 2 distinct electrogram components as a pseudo-outer loop from within the isthmus. 22 Alternatively, multiple exit sites from a common isthmus may account for manifest fusion during entrainment from a central isthmus. 10 Termination of VT during the first radiofrequency application resulted at this outer loop site (Figure 6B). Concept 9: Adjacent Bystanders Can Be Extremely Close Dead-end pathways or blind loops have a unique and specific response to entrainment. These sites are connected to the circuit with long postpacing and S-QRS characteristics because of the time required to get into the circuit and back to the bystander site. The size and proximity of bystanders relative to the circuit have not been well characterized because of the fact that they are undesirable ablation targets that are unlikely to interrupt reentry. The most fundamental concept to bystander activation during entrainment is that the EGM QRS interval is shorter than S-QRS by the same amount that PPI exceeds TCL. This is due to the fact that the EGM QRS during VT is a pseudo-interval because the wavefront recorded within the bystander is recorded while the circuit propagates closer to the exit. In Figure 7, the use of a multielectrode catheter (2 mm interelectrode spacing) demonstrates how the activation that seemingly proceeds from MP 3,4 to MP 5,6 is a pseudo-interval. During pacing, concealed fusion is seen although the local activation time between capture of MP 3,4 to MP 5,6 increases by 120 ms, which prolongs the PPI. This demonstrates that 3,4 is separately activated away the circuit, where MP 5,6 was proven to be the critical isthmus site, only 2 mm away. This may account for some sites that have bystander characteristics that still interrupt VT during ablation. Concept 10: Uncharacterized Responses: Circuits Do Not Read Textbooks Because of the complex nature of myocardial scar and nonuniform conduction that is perturbed by a pacing stimulus, not all circuit components may be characterized by our idealized construct of reentry around scar. Some entrainment Figure 7. Entrainment of a bystander site (MP 3,4) with recording of the critical isthmus (MP 5,6 and MP 7,8) using a multielectrode catheter. Pacing demonstrates that the activation that appears to propagate from MP 3,4 and MP 5,6 during ventricular tachycardia is a pseudo-interval as the activation between these 2 sites separated by 2 mm is prolonged during pacing.

9 Tung VT Entrainment Challenges Figure 8. An uncharacterized response to entrainment (pacing at Abl d) where the PPI is longer than TCL (115 ms), subtle fusion is seen, and S-QRS is longer than EGM QRS (30 ms). Despite characteristics that suggest adjacent and remote bystander, rapid termination of ventricular tachycardia was achieved at this site. responses do not fit a singular classification of circuit location. In Figure 8, the postpacing interval is long, but the excess over TCL (115 ms) is far greater than the EGM QRS to S-QRS difference (30 ms). Additionally, there is slight fusion of the surface leads. This response has features of remote bystander and adjacent bystander sites. This site was not abandoned because of the nearly concealed fusion present without clear fulfillment of bystander classification. The long PPI may potentially be explained by decremental conduction or capture of a different electrogram component not visualized at the standard gain that precedes the electrogram component measured. Rapid termination of VT occurred at this site, suggesting an atypical entrainment response from a critical isthmus site. It should be noted that ablation was not performed solely on the basis of the entrainment response but rather through the incorporation of electroanatomic mapping, both voltage and functional propagation, fractionated electrogram characteristics, in addition to pacemapping. Summary Although entrainment mapping is a time-honored, powerful electrophysiological technique that provides insight into arrhythmia mechanisms and circuit characterization, many limitations are inherent because of the perturbations that occur when the natural state of arrhythmia is probed (Heisenberg uncertainty principle). These recording variables, such as pacing current strength, electrode size/spacing, filtering, gain, and noise, introduce additional factors that challenge the practice of entrainment mapping. Importantly, an improved understanding of the conceptual factors that are associated with exceptions to the rule may be useful to avoid interpretative errors. Cognitive adjustments during the clinical practice of entrainment mapping are likely to improve our ability to find gold (isthmus), when the gold standard seemingly leads us astray. None. Disclosures References 1. Callans DJ, Hook BG, Josephson ME. Comparison of resetting and entrainment of uniform sustained ventricular tachycardia. Further insights into the characteristics of the excitable gap. Circulation. 1993;87:1229 1238. 2. Stevenson WG, Weiss JN, Wiener I, Nademanee K, Wohlgelernter D, Yeatman L, Josephson M, Klitzner T. Resetting of ventricular tachycardia: implications for localizing the area of slow conduction. 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