Titin-related familial dilated cardiomyopathy: factors associated with disease onset

European Heart Journal

11 August 2025
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ESC Journals HEART FAILURE Chronic Heart Failure PREVENTIVE CARDIOLOGY Risk Factors and Prevention VALVULAR, MYOCARDIAL, PERICARDIAL, PULMONARY, CONGENITAL HEART DISEASE Myocardial Disease

Abstract

AbstractBackground 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.

Contributors

Alex Hoerby Christensen
Alex Hoerby Christensen

Author

Copenhagen University Hospital Copenhagen , Denmark

Torsten B Rasmussen
Torsten B Rasmussen

Author

Aarhus University Hospital Aarhus N , Denmark

Christine E Seidman
Christine E Seidman

Author

Brigham and Women's Hospital, Harvard Medical School Boston , United States of America

Anneline S J M te Riele
Anneline S J M te Riele

Author

University Medical Center Utrecht Utrecht , Netherlands (The)

Ahmad S Amin
Ahmad S Amin

Author

Amsterdam University Medical Centre (AUMC) Amsterdam , Netherlands (The)

Maria Generosa Crespo-Leiro
Maria Generosa Crespo-Leiro

Author

CHUAC A Coruna , Spain

Matteo Dal Ferro
Matteo Dal Ferro

Author

Integrated University Health Authority of Trieste Trieste , Italy

Fernando Dominguez
Fernando Dominguez

Author

Hospital Universitario Puerta De Hierro Majadahonda Madrid , Spain

Luis Escobar-Lopez
Luis Escobar-Lopez

Author

Donostia University Hospital San Sebastian , Spain

Jan Haas
Jan Haas

Author

Daniel J Hammersley
Daniel J Hammersley

Author

King's College Hospital London , United Kingdom of Great Britain & Northern Ireland

Thomas Morris Hey
Thomas Morris Hey

Author

Odense University Hospital Odense , Denmark

Steven A Muller
Steven A Muller

Author

University Medical Center Utrecht Utrecht , Netherlands (The)

Farbod Sedaghat-Hamedani
Farbod Sedaghat-Hamedani

Author

University Hospital Heidelberg Heidelberg , Germany

Christoffer Rasmus Vissing
Christoffer Rasmus Vissing

Author

Rigshospitalet - Copenhagen University Hospital Copenhagen , Denmark

Kathy Wu
Kathy Wu

Author

John R Giudicessi
John R Giudicessi

Author

Mayo Clinic Rochester , United States of America

Neal K Lakdawala
Neal K Lakdawala

Author

Brigham and Women's Hospital Boston , United States of America

Luisa Mestroni
Luisa Mestroni

Author

University of Colorado Anschutz Medical Campus Aurora , United States of America

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