Electrophysiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy

BACKGROUND: Among inherited cardiomyopathies involving the left ventricle, whether dilated or not, certain genotypes carry a well-established arrhythmic risk, notably manifested as sustained monomorphic ventricular tachycardia (SMVT). Nonetheless, the precise localization and electrophysiological profile of this substrate remain undisclosed across different genotypes. METHODS: Patients diagnosed with cardiomyopathy and left ventricle involvement due to high-risk genetic variants and SMVT treated by electrophysiological study were recruited from 18 European/US centers. Electrophysiological study, imaging, and outcomes data after ablation were assessed in relation to genotype. RESULTS: Seventy-one patients were included (49.6 Q1-Q3 [40-60] years, 76% men). They were divided into 4 groups according to the affected protein: desmosomal (DSP, PKP2, DSG2, and DSC2), nuclear membrane (LMNA and TMEM43), cytoskeleton (FLNC and DES), and sarcoplasmic reticulum (PLN). Desmosomal genes, TMEM43, and PLN were associated with biventricular disease, while variants in LMNA and cytoskeleton genes had predominant left ventricle involvement (P=0.001). The location of the clinical-SMVT substrate was significantly different based on genotype (P=0.005). DSP and cytoskeleton genes presented SMVTs with right bundle branch block morphology, which origin was identified in the inferolateral segments of the left ventricle. The other desmosomal genes (PKP2 and DSG2), along with TMEM43, showed SMVTs with left bundle branch block morphology and predominantly right ventricular substrate. In contrast, LMNA substrate was mainly observed in the interventricular septum. During a median of 26 Q1-Q3 (10.6-65) months, 27% of patients experienced recurrences of clinical SMVT with differences between genotypes (log-rank 0.016). Nuclear membrane genes demonstrated the highest recurrence rate compared with desmosomal genes (hazard ratio, 4.56 [95% CI, 1.5-13.8]). CONCLUSIONS: The anatomic substrate of SMVTs shows a strong correlation with the underlying genotype, electrocardiographic morphology, and recurrence rate. Particularly, patients with nuclear membrane gene variants have a significantly higher recurrence rate compared with those with desmosomal gene variants.