Abstract 4143995: Association of left ventricular summit arrhythmias with pathogenic gene variants

Background: Genetic cardiomyopathies (CM) are increasingly diagnosed among patients with ventricular arrhythmias (VA). There is increasing recognition of the regional nature of potential arrhythmic substrate in genetic CM, including involvement of the basal left ventricular (LV) septum and LV summit. Whether anatomically constrained ventricular arrhythmias predict genetic CM is not known. Research question: Are LV summit arrhythmias associated with pathogenic/likely pathogenic (P/LP) gene variants? Aims: To examine whether LV summit VA is associated with P/LP gene variants in patients referred for ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation. Methods: The cohort included patients with arrhythmia and cardiomyopathy panel genetic testing (Invitae) between 2018 and 2024 who also underwent VT/PVC ablation at the University of Washington. VA location (summit vs. non-summit) was defined using electroanatomic voltage and activation mapping. The prevalence of P/LP gene variants in those with and without LV summit VA were compared using Fisher’s exact testing. Logistic regression was used to examine the association of LV summit VA with P/LP gene variants with multivariable adjustment for anti-rhythm drugs and standard risk factors including age, sex, and LV ejection fraction (LVEF). Results: The study included 57 patients (mean age 55±16 years, 82% male, LVEF 44±13%, n=22/35 PVC/VT ablation). LV summit VA was identified in 10 patients and P/LP gene variants were found in 22 patients. The prevalence of P/LP genetic variants was significantly higher in LV summit vs. non-summit patients (70% vs. 32%, p=0.04). Those with LV summit arrhythmias had a 7-fold higher odds of P/LP genetic variants compared to non-LV summit arrhythmias (adj OR [95% CI]: 6.6 [1.1-39.6]. P/LP variants in LV summit VA individuals were either TTN (n=3 [2 truncating variant, 1 splice site]) or LMNA (n=4 [3 missense, 1 deletion]). Conclusion: LV summit VA are associated with P/LP genetic variants with known tropism for basal septal pathology. This preliminary work supports efforts to expand the paradigm that anatomically-specific VA may represent the electrical manifestation of genetic CM.