Mapping of ventricular tachycardia in patients with ischemic cardiomyopathy: Current approaches and future perspectives

Abstract Despite the technical improvements made in recent years, the overall long‐term success rate of ventricular tachycardia (VT) ablation in patients with ischemic cardiomyopathy remains disappointing. This unsatisfactory situation has persisted even though several approaches to VT substrate ablation allow mapping and ablation of noninducible/nontolerated arrhythmias. The current substrate mapping methods present some shortcomings regarding the accurate definition of the true scar, the modality of detection in sinus rhythm of abnormal electrograms that identify sites of critical channels during VT and the possibility to determine the boundaries of functional re‐entrant circuits during sinus or paced rhythms. In this review, we focus on current and proposed ablation strategies for VT to provide an overview of the potential/real application (and results) of several ablation approaches and future perspectives.


| INTRODUCTION
Radiofrequency catheter ablation is an effective treatment for drugrefractory ventricular tachycardias (VTs) in patients with ischemic cardiomyopathy. 1 However, although the use of three-dimensional (3D) mapping systems and open irrigated catheters and the advent of percutaneous epicardial ablation have improved the overall success rates of these procedures, the recurrence rate of the arrhythmia remains high. 2 In structural heart disease, VT is usually due to scarrelated re-entry. The two commonly adopted treatment strategies are ablation during VT and substrate-based ablation. If a re-entrant VT is reproducible and hemodynamically tolerated, activation and/or entrainment mapping can be used to identify a critical re-entry isthmus and ablate the VT. If VTs are not inducible or not hemodynamically tolerated, ablation can be guided by identifying the VT substrate during sinus rhythm or a paced rhythm. 3 Substratebased approaches involve identifying low-voltage areas and abnormal electrograms that represent surviving myocytes capable of supporting re-entrant VT circuits. 4 Comparing if substrate-based ablation strategy to one guided predominantly by activation/entrainment mapping of inducible and hemodynamically tolerated VTs the results have been variable. 5 However, recent studies seem to suggest that substratebased ablation is superior to the ablation of clinical hemodynamically stable VT, even in patients with only tolerated (clinical and/or induced) VTs. [6][7][8] Mainly because of the unsuitability of a prespecified single approach in all patients and the specificity of each individual case, the problem of identifying the best approach a priori remains unsolved and a combination of the two approaches is commonly employed during VT ablation.
The aims of the present review are the following: 1. to focus on the currently proposed substrate ablation strategies for scar-related VT in ischemic heart disease.
2. to discuss the limitation of the current substrate mapping techniques in scar definition, in abnormal electrograms recording and in the identification, in sinus rhythm, of the sites where functional circuits develops during VT: 3. to propose new strategies to curtail the limitation of current substrate mapping and ablation procedures.

| ACTIVATION/ENTRAINMENT MAPPING AND SUBSTRATE MAPPING
Conventional mapping techniques (activation mapping and entrainment mapping) have been used to define the mechanism of tolerated arrhythmias and to identify a critical re-entry isthmus and the potential ablation sites. 9 Entrainment mapping is a technique that uses pacing to confirm the re-entrant mechanism of VT and identify critical and noncritical areas of a VT circuit helping classify pacing sites as isthmus, bystander, and inner or outer loop sites of the VT circuit. 10 Alternative ablation methods involving mapping and ablation in sinus or paced rhythm have been developed for patients with unmappable VT although they are also commonly used also in patients with tolerated VTs. Substrate-based ablation strategies include linear lesions along the infarct border, ablation of late potentials (LPs) and local abnormal ventricular activity (LAVA), scar homogenization, scar de-channeling, pace mapping, and scar/core isolation ( Figure 1).
Linear ablation ( Figure 1B) was developed in order to replicate the surgical experience of subendocardial resection. 11 Marchlinski et al. 4 first described the use of linear ablation lesions crossing the border zone and intersecting the best pace-map site to target multiple unmappable VTs.
Ablation of LPs ( Figure 1C) relates to elimination of any abnormal, fractionated electrogram with a duration that extended beyond the end of the surface QRS ( Figure S1), according to the definition of Cassidy et al. 12 modified with subsequent experiences 8 (Figure 2A).
Ablation of local abnormal ventricular activities ( Figure 1C) refers to elimination of LAVA. LAVA is a global term that incorporates all abnormal ventricular signals that represent near-field signals of slowly conducting tissue and hence potential VT isthmuses. 13 and occurring anytime during or after the far-field ventricular electrogram in sinus rhythm 7 ( Figure 2B).
In the scar homogenization approach ( Figure 1D), ablation lesions are empirically extended throughout the entire scar based on the substrate map defined by 3D mapping and targeting any abnormal potentials (delayed and fragmented) in normal sinus rhythm. 6 More recently, Tung et al. 14 and Berruezo et al. 15 proposed a "scar de-channeling" approach in which conductive channels are identified by means of high-density voltage mapping or electrogram analysis.
Radiofrequency applications at the entrance to these conductive channels can block conduction inside (a part of) the scar without extensive ablation. 15 ( Figure 1E).
F I G U R E 1 The most common strategies of ventricular tachycardia (VT) ablation. A, Schematic representation of a VT substrate. Areas of dense scar containing channels of surviving fibers forming possible VT isthmuses of re-entrant VT circuits. B, Linear ablation lesions extended perpendicular from the border zone to the area of dense scar. C, Scar de-channeling. D, Scar homogenization. E, Ablation of local abnormal ventricular activity (LAVA) and late potentials (LPs). F, Core isolation Pace mapping consists in pacing from areas of abnormal electrogram (EGMs) in and around the scar, in an attempt to match the clinical VT morphology, and can help to approximate the anatomic location of VT. 9 Pacing from within the scar can also identify slowconduction channels, which are marked by a prolonged stimulus to QRS interval (S-QRS), 16 while pacing at the VT exit site will yield a "matched" QRS with a short S-QRS. Recently, it has been recognized that an abrupt transition between a paced-QRS that matches the clinical VT (exit site) and a nonmatched paced-QRS (entrance site) can identify an isthmus. 17 Lately, techniques involving electrical isolation of the scar (scar isolation and core isolation, Figure 1F) have been developed. 9 Tilz et al. 18 hypothesized that, in selected post-myocardial infarction (MI) patients with a circumscribed scar, encircling the arrhythmogenic area would be feasible and cause electrical dissociation of the isolated area from the remainder of the left ventricle, while Tzou et al. 19 proposed the "core isolation" approach. This is a stepwise approach that starts identifying critical or core VT circuit elements based on careful electrophysiological characterization and ablating these areas circumferentially with the goal of achieving electric isolation.
Scar homogenization seems to have a higher success rate in terms of both acute success (inducibility at the end of the procedure) and VT free survival compared with the other ablation strategies (Table 1).
However, the fact that more ablation is more effective probably means that selective mapping and ablation methods have a low specificity.
The above-described strategies of substrate ablation can be implemented not only in the endocardium, but also in the epicardium when an epicardial approach is adopted. In patients with ischemic cardiomyopathy, epicardial ablation is most commonly undertaken after failed endocardial ablation, although in some studies greater freedom from recurrence has been reported when a combined endocardial-epicardial approach is performed from the beginning. 20 However, in common practice, not uniform approach is utilized in VT ablation and at least 2 to 3 methods should be combined to identify critical circuit areas. For example, in the same patient, activation, and entrainment mapping can be used for inducible/tolerated VT, while 1 or 2 of the substrate mapping strategies is utilized for not inducible/not tolerated VT. Again, voltage mapping and LPs mapping an ablation are commonly used during the same procedure in patients with not tolerated VTs.

| THE LIMITATIONS OF SUBSTRATE MAPPING IN PATIENTS WITH ISCHEMIC VT
Ineffectiveness of VT ablation is probably related both to the inadequacy of current mapping strategies and to the limited depth and extent of myocardial injury created by radio frequency ablation, especially in patients with intramural substrate when significant portions of the re-entry circuit are deep to the endocardium, beyond the limits of catheter ablation using standard irrigated catheters. In the situation of arrhythmogenic substrate remote from the site of radio frequency application, adjunctive ablation techniques can be helpful, including: ablation at high powers for a prolonged duration, ablation from multiple sites surrounding the arrhythmogenic site using simultaneous unipolar or bipolar configuration, the use of an irrigated needle tip catheter in an effort to reach the deep intramural substrate, and the use of noninvasive stereotactic radio-ablation which consists of irradiation of the arrhythmogenic area in a manner similar to tumor radiotherapy. [21][22][23][24] In summary, over the years, many efforts to facilitate catheter ablation of post-myocardial infarction VT have been made. The substrate-based VT ablation techniques, which require specific F I G U R E 2 Morphology and time of onset of electrograms are related to the direction of the propagating impulse. A masked electrogram during sinus rhythm (left) becomes an evident abnormal and late potential during pacing from the right ventricular apex (right) Indeed, all the substrate mapping procedures described are based on one or more of the following strategies, which present some major challenges: 1. definition of low-voltage areas (scar, dense scar, transitional border zone) by unipolar and bipolar voltage mapping.
3. localization in sinus rhythm of channels defined by fixed anatomical barriers.  (Figure 3). In one study, the median bipolar and unipolar scar area was seen to vary by 22% and 14%, respectively, as the activation wavefront varied. 27 As critical sites for VT may be localized in regions that are normal during one wavefront, mapping an alternate activation wavefront is therefore useful in order to increase the sensitivity in detecting the arrhythmogenic substrate. The angle of incidence, that is, the orientation of the catheter relative to the tissue, determines the location of the electrode relative to the tissue, and thus the amplitude of the bipolar recordings. 28 Electrode size and interelectrode spacing also affect the amplitude of the bipolar electrogram, as well as conduction velocity. 28 Finally, the tissue contact and the filtering used affect the amplitude of the electrogram. 28 These findings suggest that the electrogram amplitude may not truly reflect the histological status of the directly recorded myocardium (bipolar electrograms) and even of the underlying myocardium (unipolar recordings). These observations have been confirmed by studies comparing electroanatomic mapping and magnetic resonance imaging, with or without delayed contrast enhancement, 29  where there is a sharp transition from thin-to-thick tissue (from isthmus to lateral boundaries). This occurs because the available current is insufficient to activate the greater volume of tissue in the thin-tothick direction sometimes already in normal conditions but more frequently after a premature beat with a short coupling interval or during a short cycle length rhythm such as that present during VT. 38 Indeed, the wavefront curvature becomes convex as it travels from a lesser to a greater volume, and when the curvature becomes critically convex, functional conduction block will occur, owing to the difficulty in delivering a sufficient electrical charge to the larger volume of tissue distal to the activating wavefront (source-sink mismatch) ( Figure S2). 38 If a difference in thickness is present, but not crucial, a critical convex curvature will not be attained, conduction block will not occur, and only slow conduction through the discontinuities of lateral boundaries (pseudo-block) will ensue. In the light of How can we curtail the limitations of substrate mapping described in the previous paragraphs?

| DEFINITION OF LOW-VOLTAGE AREAS
Regarding the first two points, it is evident that the use of highdensity mapping by means of small electrodes with short center-tocenter inter-electrode spacing may help to reduce some of the misinterpretations of conventional substrate mapping with standard ablation catheters with a 3.5 or 4 mm tip and a larger inter-electrode distance. Although bipolar voltage amplitude in the healthy ventricle is similar between linear (standard) and multielectrode high-density mapping catheters, mapping resolution within areas of low voltage and scar is enhanced with multielectrode catheters that identify areas of preserved myocardial bundles (channels) otherwise considered dense scar by standard linear catheters. 39 Indeed, the use of high-density mapping with small electrodes and short center-to-center inter-electrode spacing enables surviving myocardial fibers, that show a higher voltage signal, to be identified inside heterogeneous low-voltage areas; this approach differs from lowdensity mapping by means of standard ablation catheters, which records activity from a large area and is associated with high interpolation between points. High-density mapping is expected to produce a more reliable ventricular map with a better resolution, on which the scar, border zone and viable myocardium outside and inside the scar are more precisely delineated (Figure 4). In addition, mapping with multi-electrode catheters yields more data points and better variability   43 Regions with this specific structural configuration correspond to segments with the specific electrogram characteristics described by Nayyer et al. 42 Using this method would allow most of the procedural time to be spent ablating arrhythmogenic areas and obviate the need to induce the VT or perform extensive scar mapping.
Another mechanism invoked for the initiation of a functional reentry is dispersion of refractoriness and of total recovery time 44 as shown in canine infarcts models. 36 Therefore, sites with prolonged refractoriness and/or prolongation of total recovery time could be another ablation target during sinus rhythm.