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Genetic Penetrance in Dilated Cardiomyopathy
Quick Takes
- Approximately 11% of genotype-positive relatives developed dilated cardiomyopathy (DCM) during a median follow-up of 3 years.
- Age, ECG abnormalities, presence of variants in motor sarcomeric genes, and certain cardiac imaging parameters (LVEF, LVEDD, and LGE) were associated with a higher risk of developing DCM in this population.
- These findings may be particularly relevant for future clinical trials, since data on penetrance and the factors associated with disease onset are critical for the design of early intervention/prevention studies in the field of genetic cardiomyopathies.
Study Questions:
What is the penetrance of new dilated cardiomyopathy (DCM) diagnosis in genotype positive (G+) relatives and the factors associated with DCM development?
Methods:
The investigators evaluated 779 G+ subjects (35.8 ± 17.3 years, 459 [59%] females, 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers. Time to DCM development was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Hazard ratios (HRs) of variables associated with DCM development were obtained by univariable and multivariable analyses using Cox proportional hazards regression models. The proportional hazards assumption was investigated using Schoenfeld residuals.
Results:
After a median follow-up of 37.1 months (interquartile range, 16.3-63.8), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 [95% CI, 2.3-3.5] per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank 0.016 and p < 0.001, respectively). In a multivariable model excluding cardiac magnetic resonance (CMR) parameters, independent predictors of DCM development were: older age (HR per 1-year increase, 1.02; 95% CI, 1.0-1.04), an abnormal electrocardiogram (ECG) (HR, 2.13; 95% CI,1.38-3.29), presence of variants in motor sarcomeric genes (HR, 1.92; 95% CI,1.05-3.50), lower left ventricular ejection fraction (LVEF) (HR per 1% increase, 0.86; 95% CI, 0.82-0.90), and larger LV end-diastolic diameter (LVEDD) (HR per 1 mm increase, 1.10; 95% CI, 1.06 1.13). Multivariable analysis in individuals with CMR and late gadolinium enhancement (LGE) assessment (n = 360, 45%) identified LGE as an additional independent predictor of DCM development (HR, 2.52; 95% CI,1.43-4.45).
Conclusions:
The authors report that following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years.
Perspective:
This study reports that ~11% of G+ carriers developed DCM following a first negative screening, over a median follow-up of 3 years. Furthermore, age, ECG abnormalities, presence of variants in motor sarcomeric genes and certain cardiac imaging parameters (LVEF, LVEDD, and LGE) were associated with a higher risk of developing DCM in this population. These findings may be particularly relevant for future clinical trials with specific disease-modifying therapies, since data on penetrance and the factors associated with disease onset are crucial for the design of early intervention and prevention studies in the field of genetic cardiomyopathies. In addition, studies are needed to identify therapies that prevent DCM onset in apparently healthy carriers of genetic variants associated with DCM.
Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Genetic Arrhythmic Conditions
Keywords: Cardiomyopathy, Dilated, Genetics
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