Unraveling the links between genetics and electrophysiological phenotype of sustained monomorphic ventricular tachycardias in left and biventricular arrhythmogenic cardiomyopathy

Abstract

Abstract Background and objective Arrhythmogenic cardiomyopathy (ACM) is an inherited disease with a high arrhythmogenic potential. Despite previous research efforts, a comprehensive electrophysiological characterization of sustained monomorphic ventricular tachycardias (SMVT) by genotype has not yet been achieved. Purpose Establishing a correlation between the electrophysiological SMVT substrate and the causative genotype of left and biventricular ACM. Methods Observational and retrospective multicenter study of a serie of 71 patients from 18 European and American centers with left/biventricular ACM, carriers of pathogenic genetic variants, in whom an electrophysiological study (EPS) was performed for SMVT ablation. Localization of SMVT-circuit in the EPS was performed by activation mapping, pacemapping and substrate characterization by voltage and decremental-conduction functional analysis. Results The cohort had a median age of 49,65 IQR 19,06 years, with the majority being male (54, 76.1%). Significant differences, according to genotype, were found in the anatomical localization of SMVT critical isthmus (p 0.001), figure 1. Patients with mutations in desmoplakin showed biventricular involvement and SMVTs with positive QRS in V1. Substrate could be located in endocardium and epicardium of left ventricle (LV) inferolateral segments. Patients with filamin-C variants had exclusive LV impairment, although the morphology and origin of SMVTs were identical to those observed in desmoplakin. In the case of mutations in lamin-A, the substrate was found mainly in LV septal endocardium. Patients with variants in plakoglobin-2, desmoglein-2 and TMEM43 showed biventricular involvement with negative QRS in V1 SMVTs and right ventricular origin (in the free wall in the case of plakoglobin-2 and in the outflow tract in the case of desmoglein-2 and TMEM43). During clinical follow-up, 26,03 IQR 54,47 months, approximately one third of patients (19, 26,8%) experienced recurrence of clinical SMVT, with significant differences between genotypes (log-rank 0,001), figure 2. Conclusions The analysis of these data provides discriminatory SMVT localization patterns between the different genotypes and evaluates the effectiveness of EPS as a therapeutic tool in this group of patients.