Fat deposition and repolarization: another brick in the wall promoting ventricular tachycardia?

This editorial refers to ‘Lipomatous metaplasia prolongs repolarization and increases repolarization dispersion within post-infarct ventricular tachycardia circuit cites’ by L. Xu et al., https://doi.org/10.1093/europace/euac222. The outcome of ventricular tachycardia (VT) mapping and ablation remains far from optimal. Since the beginning of invasive electrophysiology, mapping has been focusing on depolarization. There remains, however, a lack of consensus on the optimal substrate mapping strategy. To improve clinical outcomes, additional tools have been introduced to characterize the structural substrate with the use of cardiac magnetic resonance (CMR) and/or computed tomography (CT) imaging,1,2 or to assess repolarization with the use of dedicated mapping techniques.3 For long, VT circuits have been described in two dimensions as we did not have access to depth information. The three-dimensional nature of VT circuits was recently clarified. This raised further interest in pre-operative imaging to assess the three-dimensional structure of the substrate. However, the ability of CT or CMR imaging to accurately identify VT circuits/isthmus/corridors remains a debated topic, given the current spatial resolution of imaging systems, the lack of consensus on the definition of imaging markers, and the lack of thorough validation. The current imaging features employed to identify VT isthmus/corridors include wall thickness or late-enhancement (fibrosis) mapping. Both approaches were validated against VT activation maps, but all VTs may not be inducible in patients, and some VTs may remain non-mappable. Additional information given by imaging may be of importance, such as fat deposition within scar. Several groups have studied the prevalence and distribution of fat within post-infarction scar and its relationship with VT circuits.4–7 In patients with post-myocardial infarction VT and undergoing catheter ablation, the reported prevalence of fatty metaplasia on CT is highly variable in the literature. This is explained not only by the influence of infarct age and size but also by the different definitions used to identify fat. Should this become an important feature to define ablation targets, a prior standardization of fat thresholds would be desirable. With respect to patient outcomes, intra-myocardial fat was shown to be associated with higher rates of VT recurrence and all-cause mortality.6 It is yet unclear, though, whether this is due to a confounding effect of infarct age/size, to an altered efficacy of ablation within fat, or to an actual arrhythmogenic role of fat. Nonetheless, there is increasing evidence that fatty metaplasia has an important effect on local electrophysiology, which may promote slow conduction and subsequent re-entry.5,6 Xu et al.7 showed that VT isthmus/corridors preferentially traverse infarcted tissue in areas with intra-myocardial fat. The underlying hypothesis is that fat increases regional resistance, thus reducing current loss as impulses traverse corridors adjacent to fat deposition. The inflammatory secretum of adipocytes may also play a role, as it was shown to promote electrophysiological remodelling in adjacent cardiomyocytes. Apart from imaging, until now, depolarization (timing, voltage, signal characteristics) was the only parameter used for mapping. The use of repolarization parameters such as activation recovery interval (ARI) has been prevented, in clinical practice, by our difficulty to obtain reliable and reproducible measurements. Several parameters may interfere with repolarization evaluation and particularly with ARI measurement, such as the catheter used for recordings, contact force, heart rate, or activation wavefront. An intense debate continues regarding the methodology of measuring repolarization in clinical practice. Technically, there are also some limitations, as automated algorithms often mis-assign key components of the electrogram (EGM), such as the T wave, requiring manual re-annotation. Still, several clinical studies have shown that VT circuits are associated with repolarization heterogeneity.3,8,9 Thus, targeting the regions exhibiting repolarization heterogeneities may represent a potential strategy to eliminate ventricular arrhythmia.10 In this issue of Europace, Xu et al.9 report on the relationship between fat deposition and ARIs in patients presenting with post-infarction VT. They further explore how these two parameters (one structural and one functional) relate to VT circuits, in a series of 33 patients referred for VT ablation with available pre-operative CMR and CT studies. Cardiac magnetic resonance was processed using commercially available software to identify VT corridors, while fat deposition was assessed on CT scan images. The EGMs recorded with the ablation catheter were processed by using dedicated software to automatically measure ARIs. The results indicate that repolarization is prolonged and more heterogeneous in CMR corridors traversing through or near intra-myocardial fat than in those traversing scar without fat. In addition, ARI dispersion exhibited a significantly stronger association with critical VT corridor/isthmus, when compared with ARI duration. Lastly, myocardial fat in scar or the border zone, but not myocardial scar alone, was found to be the primary substrate of increased repolarization dispersion during sinus rhythm, facilitating VT re-entry. These results are of great interest as they suggest a combined role of fat and repolarization disorders in the formation of VT circuits, which might define novel ablation strategies in patients with post-infarction VT. However, several issues may limit the interpretability of the results and prevent direct clinical implications. The first limitation lies in the use of CT to identify myocardial fat. Histopathological series have shown that fatty metaplasia is almost constant after myocardial infarction and that it appears quite early after.11 In contrast, the prevalence of fat on CT appears to be lower and almost exclusively present in old infarcts.12 This discrepancy outlines the spatial resolution limitations of current imaging techniques, and one should keep in mind that in contrast to histology, fat detected on CT only corresponds to macroscopic fat deposition. In that domain, the novel photon-counting CT technology may dramatically improve the sensitivity of imaging to unmask fat deposition within the myocardium, while enabling robust quantification.13 A second limitation pertains to the sensitivity and specificity of CMR to identify VT corridors. In this series, a total of 421 corridors were identified on CMR, i.e. 13/patient. This definition of VT corridors is further blurred by the discrimination between critical and non-critical VT corridors, which appears to be solely based on the ability to map the VT circuit or exit site. Of the 421 VT corridors identified on CMR, 98 (3/patient) were eventually shown to host critical VT circuits on intracardiac mapping. But can all the so-called critical VT circuits be identified by mapping? Every electrophysiologist performing VT ablation has experienced the frustration of not being able to induce VT. Moreover, when inducible, mapping does not always allow for an accurate identification of the so-called critical VT isthmus. Therefore, it is very likely that some of the ‘non-critical’ corridors are actually critical for VTs that are not mapped. Regarding the assessment of repolarization, the authors acknowledge that 39% of all EGMs had to be rejected, because it is deemed inappropriate for the computation of ARIs. Still, a mean of 147 EGMs/patient could be analysed in the scar or in its border zone, including 47/patient in intra-myocardial fat areas. Although methodological questions remain regarding the robustness of ARI measurements, the number of observations reported in this study remains meaningful. Overall, the authors should be congratulated for introducing a novel concept on the pathophysiology of post-infarction VT, which may eventually help us improve patient outcomes after VT ablation. If the results were to be replicated, this could translate into novel therapeutic strategies aiming at limiting fat deposition after myocardial infarction to prevent arrhythmia occurrence and at targeting areas of heterogeneous repolarization for treating VT.