521The impact of genetic mutations on ventricular tachycardia substrate types and ablation outcome in patients with non ischemic cardiomyopathy

Abstract

Background: There are limited data on the prevalence of genetic mutations associated with malignant ventricular tachycardia (VT) in patients with non-ischemic cardiomyopathy (NICM) referred for VT ablation. In addition, the impact of pathogenic mutations on the arrhythmogenic substrate localization and ablation outcome has not yet been investigated. Methods: Eighty-nine patients (56615years 84% male, LV ejection fraction 38613%) with NICM referred for ablation of recurrent sustained VT and a predominantly left sided arrhythmogenic substrate between 2008-2017 were included. All patients underwent electroanatomical voltage mapping (EAVM) and testing of 55 NICM-related genes using next generation sequencing. EAVM data were analyzed with regard to uni (<7.95mV)-and bipolar (<1.5mV) low-voltage areas with fragmented, double and late potentials in order to determine the scar-related substrate for VT. Patients were followed for VT recurrence and mortality. Patients with (likely) pathogenic mutations were compared to patients with either no mutations or with variants of unknown significance (VOUS). Results: The prevalence of class 4/5 (likely pathogenic/pathogenic) mutations was 36% (N=32/89). The most frequent mutations were found in LMNA-[N=10, 11%], TTN-[N=4, 5%], PLN-[N=4, 5%], DSP-, ABCC9-, MYPH-and RBM20-[N=2 respectively, 2% each] genes. VOUS were identified in 19 patients (22%). Analysis of EAVM revealed two dominant scar patterns: anteroseptal in 50 patients (56%) and inferolateral in 39 patients (44%). Patients with a class 4/5 mutation had more often an anteroseptal scar pattern, N=25/32 (78%) vs. N=25/57 (44%) of patients without mutation/VOUS P=0.002. After a median follow-up of 2.0 years (IQR 1.9-3.0), 51 (57%) patients experienced VT recurrence: 26/32 (81%) with a class 4/5 mutation vs. 25/57 (44%) without mutation/VOUS P<0.001. Mortality was 27% (N=24) and was significantly higher in patients with a (likely) pathogenic mutation (N=16/32, 50%) vs. patients without mutation/VOUS (N=8/57, 14%) P<0.001. Multivariate analysis showed that presence of a (likely) pathogenic genetic mutation was associated with a decreased 2-year VT-free-survival (hazard ratio 1.7, CI 1.1-2.5, P=0.008). Conclusions: In patients with NICM and recurrent VT a genetic cause is frequently identified and associated with a poor VT-free survival. Patients with a pathogenic mutation often show an anteroseptal scar pattern which, in combination with potential disease progression, may significantly impact ablation outcome.