Language

English

Publication Date

12-22-2025

Journal

European Heart Journal

DOI

10.1093/eurheartj/ehaf380

PMID

40796136

PMCID

PMC12718689

PubMedCentral® Posted Date

8-11-2025

PubMedCentral® Full Text Version

Post-print

Abstract

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.

Keywords

Humans, Male, Cardiomyopathy, Dilated, Female, CDilated cardiomyopathy, Titin, Genetics, Risk factors, Preventiononnectin, Retrospective Studies, Middle Aged, Adult, Risk Factors, Age of Onset, Aged, Atrial Fibrillation, Young Adult

Published Open-Access

yes

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