Genotype-phenotype correlations in patients with pathogenic/likely pathogenic titin variants from the Swiss Arrhythmogenic Cardiomyopathy Registry

Background: Truncating variants in the titin gene () are associated with cardiomyopathy, mainly dilated cardiomyopathy (DCM). The clinical presentation and outcomes of arrhythmogenic phenotypes in these patients are scarcely studied. Methods and results: This was a retrospective Swiss national study including 46 cardiomyopathy patients with pathogenic/likely pathogenic (P/LP) . 63% were male and median age at diagnosis was 47 years. At baseline, 89% patients formally fulfilled current DCM criteria and 17% the 2024 revised Padua criteria for diagnosis of ACM, of which all were of the left-dominant phenotype (arrhythmogenic left ventricular cardiomyopathy). No patient fulfilled arrhythmogenic right ventricular cardiomyopathy (ARVC) criteria. Most were located on the A-band (74%). Median time to last follow-up (FU) was 63 months. Ventricular arrhythmia (VA) events in the primary prevention group significantly increased over time; although, under optimal guideline-directed medical therapy, mean left ventricular ejection fraction and right ventricular function significantly improved during time to last FU. At the time to last FU, 50% fulfilled DCM criteria, whereas 27% fulfilled the criteria for left-dominant ACM. Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) was most commonly in the basal septum, but no patient had higher degree atrioventricular block (AVB). LGE on CMR was not associated with higher rates of VAs. Conclusions: Patients with P/LP most frequently present as DCM or left-dominant ACM, whereas is not a classical ARVC-causing gene. The risk of VA remains high despite favourable remodelling. Left ventricular LGE is frequent and often involves the septum. In contrast to sarcoidosis, high degree AVB seems not to be a typical feature of cardiomyopathy.