Genetic Variants in the Titin Gene and Their Association with Arrhythmogenic Cardiomyopathy Phenotypes, Sudden Cardiac Death Risk Stratification, and Response to Implantable Cardioverter-Defibrillator Therapy: A Deep Phenotyping Cohort Study

✅ Abstract Background: Variants in the titin (TTN) gene represent one of the most common genetic substrates underlying cardiomyopathies, including arrhythmogenic cardiomyopathy (ACM). TTN truncating and missense variants have been associated with variable phenotypic expression, arrhythmic burden, and risk of sudden cardiac death (SCD). However, the relationship between TTN variant profiles, detailed phenotypic manifestations, and response to implantable cardioverter-defibrillator (ICD) therapy remains incompletely understood. Objectives: To evaluate the association between TTN genetic variants and ACM phenotypes, assess their predictive value for SCD risk stratification, and analyze outcomes following ICD implantation in a deeply phenotyped cohort. Methods: This multicenter prospective cohort study enrolled 312 patients with genetically confirmed TTN variants and clinical or imaging features consistent with ACM. Comprehensive deep phenotyping included advanced cardiac imaging with cardiac magnetic resonance (CMR), electrocardiographic and electrophysiological evaluation, exercise testing, and circulating biomarker profiling. TTN variants were classified according to American College of Medical Genetics and Genomics (ACMG) criteria. The primary endpoint was a composite of SCD, aborted SCD, or sustained ventricular arrhythmias. Secondary endpoints included appropriate ICD therapies, heart failure progression, and all-cause mortality. Median follow-up was 48 months. Results: TTN truncating variants were identified in 58% of patients, while missense variants accounted for 42%. Patients with truncating variants demonstrated greater ventricular dilatation, reduced biventricular systolic function, and higher prevalence of myocardial fibrosis on CMR compared with those harboring missense variants (p < 0.01 for all comparisons). The primary arrhythmic endpoint occurred in 27% of patients with truncating variants versus 14% with missense variants (hazard ratio [HR] 2.03; 95% confidence interval [CI], 1.22–3.37; p = 0.006). TTN truncating variants remained independently associated with arrhythmic risk after adjustment for left ventricular ejection fraction, fibrosis burden, and clinical risk markers. Among patients receiving ICDs, those with truncating variants exhibited higher rates of appropriate ICD therapies (HR 1.89; 95% CI, 1.10–3.23; p = 0.021), suggesting increased arrhythmic susceptibility but effective device-mediated risk mitigation. Conclusions: TTN genetic variants are strongly associated with phenotypic heterogeneity and arrhythmic risk in patients with ACM. TTN truncating variants identify a high-risk subgroup with increased susceptibility to malignant ventricular arrhythmias and greater reliance on ICD therapy for secondary prevention. Integration of genetic profiling with advanced phenotyping may enhance precision risk stratification and guide personalized management strategies in ACM.