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

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Cardiomyopathy with pathogenic/likely pathogenic titin variants (n=46). Intervention: Pathogenic/likely pathogenic titin variants (TTNtv) vs. Baseline (longitudinal follow-up). Primary outcome: Ventricular arrhythmia (VA) events in the primary prevention group (p=0.012).

Nina Alissa Schätti; Siv Fokstuen; Argelia Medeiros-domingo; U. Maccio; Matthias P. Nägele; Fran Mikulicic; Andreas J. Flammer; Lorraine Sazgary; R. Manka; Verena Wilzeck; F Tanner; Christian Grebmer; Annina S. Vischer; Katja E Odening; Marina Rieder; Frank Ruschitzka; Corinna Brunckhorst; F. Duru; Ardan M Saguner; N R Bonetti

doi:10.1136/openhrt-2025-003750

Key result

Titin cardiomyopathy linked to rising ventricular arrhythmias despite cardiac function recovery on guideline-directed therapy.

P=0.012
n=46

Figures

Key Points

To characterize the clinical presentation, arrhythmogenic phenotypes, and long-term outcomes in patients harboring pathogenic or likely pathogenic truncating titin variants.
Retrospective Swiss national multicenter registry study evaluating N=46 cardiomyopathy patients with pathogenic or likely pathogenic titin truncating variants (63% male, median age at diagnosis 47.5 years).
Assessed cardiomyopathy diagnostic criteria, cardiac magnetic resonance late gadolinium enhancement, and arrhythmic endpoints over a median follow-up of 63 months.
At baseline, 89.1% (n=41) met dilated cardiomyopathy criteria and 17.4% (n=8) met arrhythmogenic cardiomyopathy criteria (all left-dominant phenotype), whereas 0% met arrhythmogenic right ventricular cardiomyopathy criteria.
In the primary prevention cohort (n=41), total ventricular arrhythmia events increased significantly from 19.5% (n=8) at baseline to 65.0% (n=26) at follow-up (p=0.012), driven primarily by non-sustained ventricular tachycardia (19.5% to 47.5%, p=0.012).
Sustained ventricular arrhythmias developed in 17.5% (n=7, p=0.025) of primary prevention patients, although variant location and late gadolinium enhancement were not significantly predictive of arrhythmic events.

Study Design

Type

Observational (n=46)

Multicenter

Yes

Structured PICO

P

Population

46 patients with cardiomyopathy and pathogenic or likely pathogenic titin variants, followed for a median of 63 months.

O

Outcome

Ventricular arrhythmia (VA) events, changes in left ventricular ejection fraction (LVEF) and right ventricular function, and fulfillment of cardiomyopathy criteria at follow-uphard clinical

Main Result

Absolute Event Rate: 65% vs 19.5%

p-value: p=0.012

Limitations

Small sample size limiting statistical power
Retrospective study design
Exploratory nature of the study with no statistical adjustments

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Implication

Patients with pathogenic/likely pathogenic titin variants frequently present with DCM or left-dominant ACM and remain at high risk for ventricular arrhythmias despite favorable reverse remodeling on guideline-directed medical therapy.

Abstract

Background Truncating variants in the titin gene ( TTNtv ) 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) TTNtv . 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 TTNtv 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 TTNtv most frequently present as DCM or left-dominant ACM, whereas TTN 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 TTN cardiomyopathy.

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Cite This Study

Schätti et al. (2026) conducted an observational in Cardiomyopathy with pathogenic/likely pathogenic titin variants (n=46). Pathogenic/likely pathogenic titin variants (TTNtv) vs. Baseline (longitudinal follow-up) was evaluated on Ventricular arrhythmia (VA) events in the primary prevention group (p=0.012). In patients with pathogenic or likely pathogenic titin variants, ventricular arrhythmia events significantly increased over time despite improvements in cardiac function under guideline-directed therapy.

synapsesocial.com/papers/69cf5e3d5a333a821460c675 https://doi.org/10.1136/openhrt-2025-003750

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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Figures

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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