Genotype-phenotype correlations in patients with titin variants and cardiomyopathy from a Swiss cohort

Abstract Background Alterations in titin (TTN) are mostly described with dilated cardiomyopathy (DCM). Few studies identified TTN variants in arrhythmogenic cardiomyopathy (ACM), but the overlap of dilated and arrhythmogenic phenotypes in TTN variants is scarcely studied. Most pathogenic TTN variants are located on the A-band, but there is few knowledge about the phenotypic presentation of I-band and Z-disc (non-A-band) variants. Purpose The aim of this study is to characterize and investigate the outcome of patients with cardiomyopathy and pathogenic (P) or likely pathogenic (LP) TTN variants with a particular focus on the cardiomyopathy phenotype (DCM vs. ACM) at initial presentation and follow-up. Further, we studied the association of the TTN variant (A-band vs. non-A-band regions) and a unique phenotype. Methods This is a retrospective multicenter study from a Swiss cohort including 34 patients with P/LP TTN variants and cardiomyopathy. The variables of the secured anonymized database include patient characteristics, genetic, ECG, echocardiographic, and cardiac magnetic resonance (CMR) data. Ventricular arrhythmia (VA) events were divided into non-sustained ventricular tachycardia (nsVT), sustained ventricular tachycardia (sVT) and sudden cardiac arrest (SCA +/- ventricular fibrillation). Results Of 34 included patients, 68% were male. Median age at presentation was 43.5 years. 29 (85%) patients presented with DCM, 7 (21%) left dominant ACM (2020 Padua criteria) and none ARVC (2010 ARVC Task Force criteria). At median follow-up of 48.5 months, 17 (50%) patients had VA events (15 nsVT, 5 sVT and 3 SCA events). VA events significantly increased over time (p=0.008) and were not associated with gender or left ventricular ejection fraction (LVEF) <35%. Under optimal guideline-directed medical therapy (GDMT) mean LVEF and right ventricular function increased significantly (LVEF: 28.3±14.4% vs. 41.9±9.8% and right ventricular fractional area change (RV FAC): 24.7±7.5% vs. 35.8±4.8%, p<0.05). Late gadolinium enhancement (LGE) on CMR was commonest in the basal septum, but no patient had higher degree atrioventricular block (AVB) at baseline and follow-up. At last follow-up, 8 (24%) patients fulfilled ACM and 13 (38%) DCM criteria (Figure 1). Most TTN variants were located on the A-band (21, 62%), 10 (29%) on the non-A-band regions. Latter had higher rates of sVT (log-rank p=0.041) during follow-up (Figure 2). 20 (59%) had LP and 11 (32%) P variants. P variant carriers were younger at disease presentation compared to LP variant carriers. Conclusion Patients with TTN variants frequently present as DCM, whereas presentation as left dominant ACM is less common. TTN does not seem to be a classical ARVC causing gene. Despite favourable biventricular remodelling under GDMT, ventricular arrhythmic events increase during follow-up. I-band and Z-disk variants are associated with a higher risk of sVT, which may help in the risk stratification process.