Genetics, Comorbidities Associated With Cardiomyopathy and Atrial Fibrillation

The TTN gene is commonly associated with dilated cardiomyopathy (DCM), which can be induced in carriers of the gene by outstanding covariates like age and sex, according to a recent study reported in the European Heart Journal.

DCM is a prevalent myocardial disorder where the left ventricle (LV) becomes enlarged and weakens, reducing its ability to efficiently pump blood. This type of cardiomyopathy is common among individuals younger than 50 years and presents sporadically in 10% to 20% of cases, often of an unknown cause or on a genetic basis.¹ With the increasing number of individuals identified as carriers of the TTN gene (TTNtv) by genetic testing, researchers aimed to assess preexisting comorbidities, the induction influence of the gene, and varying outcomes.

Genetic factors may increase the risk of developing dilated cardiomyopathy in addition to covariates like age and sex. | Image Credit: AdobeStock_jaojormami.jpeg

As the leading cause of heart failure, DCM is most prevalent among individuals aged 20 to 60 years and occurs more often in men than women. To investigate the cause of DCM, researchers identified 3158 participants from 1043 families with TTNtv-related DCM from 12 countries and monitored their heart health over a 30-year period (1993-2023). The primary cohort consisted of 3106 individuals in families with clinically reportable TTNtv. When assessing familial genetic relations, the first person diagnosed (proband) with DCM was considered if there was LV or biventricular systolic dysfunction and dilation. The primary cohort was comprised of 966 individuals established as TTNtv-positive probands (69% males) and 2140 relatives (49% males), of whom 66% were TTNtv-positive. Overall, there were 705 TTNtv gene variants (nonsense variants, frameshift insertions or deletions, and canonical splice sites) identified in the 1043 families, 540 variants of which were unique to a single individual and 165 that recurred in 2 to 20 of the families.

TTNtv-positive individuals were 21 times more likely to develop DCM than TTNtv-negative individuals (OR, 21.21; 95% CI, 14.80-30.39). Also, the onset of DCM appeared earlier in TTNtv-positive probands compared with their family members. There were also strong associations of DCM with male sex, age, and presence of cardiovascular disease before DCM diagnosis. Other risk factors seen in both men and women included heavy alcohol consumption, obesity, pregnancy, and other factors generally associated with broad heart failure, like diabetes and hypertension.² Researchers also found that having a history of atrial fibrillation (AF) multiplied the odds of DCM development by 2 (OR, 2.05; 95% CI, 1.27-3.32).¹

However, the study authors noted an 87% marked reduction in odds of developing DCM (OR, 0.13; 95% CI, 0.08-0.23) in those who were TTNtv-positive and receiving a β-adrenergic receptor or renin-angiotensin system blocker, typically for treatment of hypertension or AF, before their DCM diagnosis. There were also a plethora of comorbidities and risk factors observed as age progressed throughout the study. The most common among young males were heavy alcohol intake, AF, and obesity, while in females, the single most prevalent factor was pregnancy, followed by obesity and thyroid disease. Meanwhile, hypertension and AF were the top 2 risk factors in males and females with DCM who were 60 years or older.

“AF is a common complication of severe DCM due to any cause and is likely related to atrial dilatation,” the study authors explained. “Of note, TTNtv has been associated with early-onset and lone AF in the absence of discernible ventricular cardiomyopathy, raising the possibility of a primary atrial cardiomyopathy and arrhythmogenic substrate.”

Limitations of the study explained that the family-based findings may not be directly applicable to the sporadic nature of nearly half of all DCM cases. Because the study is purely observational, researchers called for further rigorous evaluation of the impact of clinical risk factors on DCM severity and outcomes.

“Here we provide new evidence that the onset of TTNtv-related familial DCM is not determined solely by the TTNtv but is also closely related to the individual patient environment,” the study authors wrote. “We suggest that aggressive intervention to identify and treat, or avoid, disease-exacerbating clinical risk factors is crucial, especially in the young.”

References

1. Johnson R, Fletcher RA, Peters S, et al. Titin-related familial dilated cardiomyopathy: factors associated with disease onset. Eur Heart J. Published online August 11, 2025. doi:10.1093/eurheartj/ehaf380

2. Peters SA, Wright L, Yao J, et al. Environmental risk factors influence the natural history of familial dilated cardiomyopathy. J Am Heart Assoc. 2025;14(9):e037311. doi:10.1161/JAHA.124.037311