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Genotype-First Approach to Cardiomyopathy Outcomes
Quick Takes
- The presence of cardiomyopathy-associated predicted deleterious variants is associated with an increased risk for all-cause mortality, clinical diagnosis of cardiomyopathy, and composite cardiomyopathy-related outcomes.
- These findings suggest a potential role for genetic screening of cardiomyopathy-associated predicted deleterious variants in informing cardiovascular outcomes.
- Additional studies are indicated to identify high-penetrance variants, cost-effectiveness, phenotype modifiers at the population level, and early measures to ameliorate the genetic risk.
Study Questions:
What is the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes?
Methods:
The investigators assessed variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations and were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure [HF], arrhythmia, stroke, and death). The primary outcome was all-cause mortality. The secondary outcomes were: 1) developing clinical cardiomyopathy later in life; and 2) composite outcome of any one of the following: HF, clinical diagnosis of cardiomyopathy, stroke, cardiac implantable electronic device (CIED) insertion, atrial fibrillation, sustained and nonsustained ventricular tachyarrhythmia, and/or mortality. Time-to-event analysis was performed using Cox proportional hazard regression corrected for sex and using age as timescale.
Results:
Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.01-1.25; p = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR, 5.75; 95% CI, 4.58-7.23; p < 0.0001), and elevated risk for composite outcome (HR, 1.29; 95% CI, 1.20-1.39; p < 0.0001) than CMP-G- individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups.
Perspective:
This study reports that the presence of cardiomyopathy-associated predicted deleterious variants is associated with an increased risk for all-cause mortality, clinical diagnosis of cardiomyopathy, and composite cardiomyopathy-related outcomes. These findings suggest a potential role for genetic screening of cardiomyopathy-associated predicted deleterious variants in informing cardiovascular outcomes. Additional studies are indicated to identify high-penetrance variants, cost-effectiveness, phenotype modifiers at the population level, and early measures to ameliorate the genetic risk. These steps will help realize the premise of precision medicine and gene-first preventive screening for cardiomyopathies.
Clinical Topics: Heart Failure and Cardiomyopathies
Keywords: Cardiomyopathies, Genotype
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