TY - JOUR
T1 - Titin-related familial dilated cardiomyopathy
T2 - factors associated with disease onset
AU - Johnson, Renee
AU - Fletcher, Robert A
AU - Peters, Stacey
AU - Ohanian, Monique
AU - Soka, Magdalena
AU - Smolnikov, Andrei
AU - Abihider, Katherine E
AU - Ackerman, Michael J
AU - Ader, Flavie
AU - Akhtar, Mohammed M
AU - Amin, Ahmad S
AU - Ashley, Euan A
AU - Atherton, John J
AU - Austin, Rachel
AU - Baas, Annette F
AU - Bagnall, Richard D
AU - Ross, Samantha Barratt
AU - Blouin, Jean-Louis
AU - Brown, Emily E
AU - Bundgaard, Henning
AU - Cannie, Douglas
AU - Chmielewski, Przemyslaw
AU - Correnti, Gemma
AU - Crespo-Leiro, Maria Generosa
AU - Dal Ferro, Matteo
AU - Dellefave-Castillo, Lisa M
AU - Dominguez, Fernando
AU - Dooijes, Dennis
AU - Dybro, Anne M
AU - Ed Demri, Youssef
AU - El Hachmi, Mohamed
AU - Escobar-Lopez, Luis
AU - Foye, Sarah Jajesnica
AU - Franaszczyk, Maria
AU - Gigli, Marta
AU - Lopez, Esther Gonzalez
AU - Goudal, Adeline
AU - Graw, Sharon
AU - Guipponi, Michel
AU - Haan, Eric
AU - Haas, Jan
AU - Hammersley, Daniel J
AU - Hansen, Frederikke G
AU - Hayward, Christopher S
AU - Hey, Thomas Morris
AU - Heymans, Stephane
AU - Ho, Carolyn Y
AU - Houweling, Arjan C
AU - Ingles, Jodie
AU - Ingrey, Angela
AU - Australian Genomics Cardiac Flagship
PY - 2025/12/22
Y1 - 2025/12/22
N2 - 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.
AB - 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.
KW - Dilated cardiomyopathy
KW - Genetics
KW - Prevention
KW - Risk factors
KW - Titin
U2 - 10.1093/eurheartj/ehaf380
DO - 10.1093/eurheartj/ehaf380
M3 - Article
SN - 0195-668X
VL - 46
SP - 5240
EP - 5257
JO - European Heart Journal
JF - European Heart Journal
IS - 48
ER -