Incidence of Atrial and Ventricular Arrhythmias in Patients With Titin Truncating Variants Across the Ventricular Morphofunctional Phenotypic Spectrum.

BACKGROUND: Titin truncating variants (TTNtvs), the most common genetic cause of dilated cardiomyopathy (DCM), are over-represented in early-onset atrial fibrillation (AF) and unexplained sudden cardiac arrest/death (SCA/SCD), suggesting they can cause arrhythmias before development of overt ventricular cardiomyopathy. OBJECTIVES: This study sought to compare the incidence of atrial and ventricular arrhythmias (VAs) between TTNtv-positive patients with genotype-positive but phenotype-negative (G+/P-) disease, nondilated left ventricular cardiomyopathy (NDLVC), and DCM. METHODS: A retrospective review of 1,229 patients in our Arrhythmogenic/Dilated Cardiomyopathy Registry was used to identify those with pathogenic/likely pathogenic TTNtvs. Patients were classified as having G+/P- disease, NDLVC, or DCM using the 2023 European Society of Cardiology guideline for cardiomyopathies. The incidence of AF, sustained VA, appropriate defibrillator therapies, SCA, and SCD was ascertained from medical records. RESULTS: Among 253 TTNtv-positive patients (mean age of 45 ± 16 years; 59% male), 54 (21%) were G+/P-, 49 (20%) were NDLVC, and 150 (59%) were DCM. During a median follow-up of 3.8 years at our institution, new-onset AF was seen in 67 patients (26% of those at risk). There was no significant difference in survival from new-onset AF in patients with NDLVC (HR: 3.29; 95% CI: 0.71-15.3; P = 0.13), although DCM was associated with worse AF-free survival (HR: 4.86; 95% CI: 1.17-20.1; P = 0.03). New-onset VAs were seen in 44 (17%) patients during follow-up, including SCA in 12 (5%) patients. There was no association between NDLVC (HR: 0.71; 95% CI: 0.19-2.69; P = 0.62) and DCM (HR: 0.97; 95% CI: 0.37-2.54; P = 0.95) phenotypes compared with G+/P- patients. Cardiac transplantation was done in 14 (6%) patients, and 6 (2%) died of cardiac causes, including 2 cases of SCD. CONCLUSIONS: When stratified by morphofunctional phenotype, there was no difference in VAs across morphofunctional phenotypes in patients with TTNtvs. This highlights that patients with TTNtvs may be at risk of SCA/SCD even without overt ventricular cardiomyopathy. The risk of new-onset AF was highest in patients with DCM but was seen at all phenotypic stages during follow-up.