Marta Gigli

BACKGROUND: Titin truncating variants ( TTN tv) represent the most common genotype underlying dilated cardiomyopathy but are also detected in the general population, exhibiting incomplete penetrance and marked phenotypic variability. This heterogeneity complicates clinical interpretation and risk stratification. Emerging molecular evidence suggests that truncating location within the gene may influence disease mechanisms. We aimed to investigate whether TTNt v location also affects clinical phenotype and prognosis. METHODS: We established an international multicenter registry of phenotypically affected carriers of pathogenic or likely pathogenic TTN tv. Patients were classified into 3 groups: A-band, Z/I-band, and M-band. A case-control study assessed the enrichment of TTN tv across regions. The primary outcome was a composite of all-cause mortality and heart transplantation. Secondary outcomes included: (1) sudden cardiac death or major ventricular arrhythmias and (2) heart failure-related death/heart transplantation/left ventricular assist device implantation. RESULTS: The study included 467 patients (81% probands, 73% men, median age 47 years, 81% dilated cardiomyopathy phenotype). Most carried TTN tv in the A-band (80% versus 15% Z/I-band and 5% M-band). All groups showed enrichment compared with GnomAD, with greater Bayesian-estimated penetrance for A-band variants. Over a median follow-up of 83 months, the primary end point was similar across groups. However, the risk of sudden cardiac death/major ventricular arrhythmias was significantly higher in M-band carriers (45% M-band versus 23% Z/I-band versus 12% A-band; P =0.001), especially as the first disease manifestation. Band location independently predicted sudden cardiac death/major ventricular arrhythmias risk, whereas left ventricular ejection fraction was predictive only in A- and Z/I-band groups. CONCLUSIONS: TTN tv are differently enriched across the gene in patients with dilated cardiomyopathy/non-dilated left ventricular cardiomyopathy. Penetrance and risk of sudden cardiac death/major ventricular arrhythmias differ according to variant location, supporting the TTN truncation site as a parameter that should be considered for personalized risk stratification in TTN cardiomyopathy.

Background and Aims: Truncating variants in the TTN gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) but also occur as incidental findings in the general population. This study investigated factors associated with the clinical manifestation of TTNtv. Methods: An international multicentre retrospective observational study was performed in families with TTNtv-related DCM. Shared frailty models were used to estimate associations of variant characteristics with lifetime risk of DCM, and logistic regression to estimate odds ratios (ORs) for individual-level clinical risk factor profiles (cardiac conditions, cardiovascular comorbidities, lifestyle) and DCM. Results: A total of 3158 subjects in 1043 families with TTNtv-related DCM were studied. TTNtv-positive subjects were 21-fold more likely to develop DCM [OR, 21.21; 95% confidence interval (CI), 14.80–30.39]. Disease onset was earlier in males, but was similar for TTNtv of different types and locations. The presence of clinical risk factors was associated with earlier DCM onset (OR, 3.41; 95% CI, 2.06–5.64), with a prior history of atrial fibrillation having a two-fold increased odds of DCM (OR, 2.05; 95% CI, 1.27–3.32). The prevalence of clinical risk factors increased with age; however, the strength of the DCM association was greatest for young-onset (<30 years) disease (OR, 4.75; 95% CI, 2.35–9.60). Administration of beta-adrenergic receptor or renin-angiotensin system-blocking drugs prior to overt DCM was associated with 87% reduced odds of DCM (OR, .13; 95% CI, .08–.23). Conclusions: Disease onset in TTNtv-associated familial DCM is dependent on individual patient context and is potentially modifiable by risk factor management and prophylactic therapeutic intervention.

Importance: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.Objective: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.Design, Setting, and Participants: This was an international, multicenter, retrospective cohort study conducted from February 2023 to June 2024. The Filamin C Registry Consortium included 19 referral centers for genetic cardiomyopathies worldwide. Participants included carriers of pathogenic or likely pathogenic FLNCtv. Phenotype negative was defined as the absence of any pathological findings detected by 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance.Exposures: Composite of SCD and MVA in carriers of FLNCtv.Main Outcomes and Measures: The primary outcome was a composite of SCD and MVA, the last including aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions.Results: Among 308 individuals (median [IQR] age, 45 [33-56] years; 160 male [52%]) with FLNCtv, 112 (36%) were probands, and 72 (23%) were phenotype negative. Median (IQR) left ventricular ejection fraction (LVEF) was 51% (38%-59%); 89 participants (34%) had LVEF less than 45%, and 50 (20%) had right ventricular dysfunction. During a median (IQR) follow-up of 34 (8-63) months, 57 individuals (19%) experienced SCD/MVA, with an annual incidence rate of 4 cases per 100 person-years (95% CI, 3-6). Incidence rates were higher in probands vs nonprobands and in phenotype-positive vs phenotype-negative individuals. A predictive model estimating SCD/MVA risk was derived from multivariable analysis, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF with a time-dependent area under the curve (AUC) ranging between 0.76 (95% CI, 0.67-0.86) at 12 months and 0.78 (95% CI, 0.70-0.86) at 72 months. Notably, the association of LVEF with the SCD/MVA risk was not linear, showing significant lower risk for values of LVEF greater than 58%, and no increase for values less than 58%. Internal validation with bootstrapping confirmed good accuracy and calibration of the model. Results were consistent in subgroups analysis (ie, phenotype-positive carriers and phenotype-positive carriers without MVA at onset).Conclusions and Relevance: Results suggest that the risk of SCD/MVA in phenotype-positive carriers of FLNCtv was high. A 5-variable predictive model derived from this cohort allows risk estimation and could support clinicians in the shared decision for prophylactic ICD implantation. External cohort validation is warranted.

Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine–Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4–7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events. Graphical summary reporting the main findings of the study. Features associated with risk of events include predictors from multivariable models as well as analysis of implications of myocardial injury episodes. aHR, adjusted hazard ratio; ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NDLVC, non-dilated left ventricular cardiomyopathy; (N)SVT, (non)sustained ventricular tachycardia; PVC, premature ventricular contraction; TFC, 2010 Task Force Criteria; TWI, T-wave inversion; VA, ventricular arrhythmia. Created with BioRender.com.

Background: Hereditary cardiovascular diseases comprise several different entities. In this study, we focused on cardiomyopathies (i.e., hypertrophic, dilated, arrhythmogenic, and left ventricular non‐compaction), channelopathies (i.e., Brugada syndrome and long QT syndrome), and aortopathies and pulmonary arterial hypertension (i.e., thoracic/abdominal aortic aneurysm and pulmonary arterial hypertension), and genetically characterized 200 Italian patients affected by these diseases.Methods: We employed whole‐exome sequencing (WES), focused on four in silico gene panels, and the MLPA method for hypertrophic and arrhythmogenic right ventricular cardiomyopathy cases.Results: Cardiomyopathies affected 87.5% of analyzed patients, channelopathies 7%, and aortopathies and pulmonary arterial hypertension 5.5%. The molecular diagnosis was confirmed for 21.5% of cases with a higher detection rate in familial forms (34%) than sporadic ones (14%). We highlighted the importance of family segregation to better understand the pathogenic role of the identified variants and their involvement in the clinical phenotype. Negative results could be ascribed to the high genetic and clinical heterogeneity of hereditary cardiovascular diseases; clinical follow‐up and revaluation of WES data will be essential.Conclusion: This study highlights the importance of a multi‐step approach (WES and MLPA) to characterize hereditary cardiovascular diseases, provides crucial information for clinical management and recurrence risk estimation, and lays the foundation for future personalized therapies.