Impact of functional gene groups on outcomes after ablation of ventricular tachycardia in patients with inherited left ventricular cardiomyopathy: an international multicentre study
Authors: Kimura Y , Wijnmaalen A , Ebert M , Shimizu Y , Rafaj A , Peichl P , Landes R , Gandjbakhch E , Maury P , Muser D , Marchilinski F , Liang J , Bogun F , Zeppenfeld K 
Published: May 2024

Abstract

Background
Advances in genetic testing has enabled identification of pathogenic variants of different functional gene groups associated with non-dilated left ventricular cardiomyopathy (NDLCM)/dilated cardiomyopathy (DCM) and ventricular tachycardia (VT). However, there is limited data on the impact of functional groups on VT ablation outcome.

Aim
We aimed to assess the impact of likely pathogenic/pathogenic variants (LP/Pv) of different functional gene groups on heart failure (HF) outcomes and VT recurrence in patients with NDLCM/DCM after VT ablation.

Methods
Patients with NDLCM/DCM who underwent genetic testing (next-generation sequencing) and were referred for VT ablation were enrolled at 6 participating centers. Patients were followed for VT recurrence, HF-related adverse outcomes (death, left ventricular assist device [LVAD], or heart transplantation due to HF), and all-cause mortality.

Results
A total of 239 patients (age 55±14yrs; male n=193; LVEF 40±12%; amiodarone at admission n=103; ICD n=180) were included. LP/Pv were identified in 128 patients (54%), predominantly found in genes encoding sarcomeric (n=36/128, [28%]; titin n=20, myosin binding protein C n=12), followed by nuclear membrane (n=27/128, [22%]; lamin A/C; n=26), desmosomal (n=23/128, [18%]; desmoplakin n=11, plakophilin n=9), cytoskeleton (n=12/128, [9%]; filamin C n=8), and sarcoplasmic reticulum proteins (n=12/128, [9%]; phospholamban n=10). Variants of unknown significance (n=32) were grouped with patients who tested negative. Acute complete ablation success, defined as non-VT inducibility of any sustained monomorphic VT, was achieved in 113 patients (47%), 63 (56%) with LP/Pv. During a median follow-up of 32 months, 108 patients (45%) had VT recurrence, 41 (17%) had HF-related adverse outcomes (death with/without LVAD in 34, LVAD in 2, heart transplantation in 5) and 47 (20%) died. Patients with LP/Pv were more likely to have VT recurrence, HF-related adverse outcomes and had a higher mortality compared to those without (VT, 68 [53%] vs. 40 [36%]; HF-related adverse outcomes, 30 [23%] vs. 11 [10%]; mortality, 30 [23%] vs. 17 [15%]; log-rank, P&lt;0.01 for all). As compared to patients without LP/Pv, those with LP/Pv in genes encoding nuclear membrane or sarcomeric proteins had significantly worse (P&lt;0.01 for both) and those with LP/Pv in genes encoding desmosomal proteins had similar HF and VT recurrence outcomes (Figure). Of interest, patients with LP/Pv in genes encoding cytoskeleton proteins had favorable HF-related adverse outcomes, but worse VT recurrence (P=0.02) compared to those without LP/Pv (Figure).

Conclusion
In patients with NDLCM/DCM and VT, the impact of LP/Pv on HF and VT-recurrence outcomes after ablation differs across functional groups. Integrating genetic testing in the comprehensive evaluation of patients with NDLCM/DCM undergoing VT ablation may facilitate personalized ablation strategies and early consideration of alternative HF treatments.