Environmental Risk Factors Are Associated With the Natural History of Familial Dilated Cardiomyopathy
- Author(s)
- Peters, SA; Wright, L; Yao, J; McCall, L; Thompson, T; Thompson, B; Johnson, R; Huynh, Q; Santiago, CF; Trainer, A; Perrin, M; James, P; Zentner, D; Kalman, J; Marwick, TH; Fatkin, D;
- Details
- Publication Year 2025-05-06,Volume 14,Issue #9,Page e037311
- Journal Title
- Journal of the American Heart Association
- Publication Type
- Research article
- Abstract
- BACKGROUND: Familial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this is determined by patient-specific environmental factors is unknown. METHODS AND RESULTS: A retrospective longitudinal cohort study was performed in families with DCM-causing genetic variants. Environmental factors were classified into 2 subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM-promoting factors and (2) heart failure comorbidities. These factors were correlated with DCM diagnosis and disease trajectory after accounting for relevant confounders and familial relatedness. A total of 105 probands and family members were recruited: 51 genotype positive, phenotype positive, 24 genotype positive, phenotype negative, and 30 genotype negative, phenotype negative. Demographic characteristics were similar between the 3 genotype groups. DCM-promoting environmental factors (eg, alcohol excess) were enriched in genotype-positive, phenotype-positive individuals compared with genotype-positive, phenotype-negative (P<0.001) and genotype-negative, phenotype-negative (P=0.003) individuals and were significantly associated with age at DCM onset (hazard ratio, 2.01; P=0.014). Heart failure comorbidities (eg, diabetes) had a similar prevalence in genotype-positive, phenotype-positive and genotype-negative, phenotype-negative individuals but were significantly reduced in the genotype-positive, phenotype-negative group. Fluctuations in left ventricular ejection fraction during follow-up were linked to changes in environmental factors in 35 of 45 (78%) of instances: 32 (91%) of these were DCM-promoting factors. CONCLUSIONS: We identified distinct subsets of environmental factors that affect DCM penetrance and trajectory. Our data highlight DCM-promoting environmental factors as key determinants of penetrance and natural history. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.
- Publisher
- Wiley
- Keywords
- Humans; *Cardiomyopathy, Dilated/genetics/epidemiology/physiopathology/diagnosis; Male; Female; Retrospective Studies; Middle Aged; Adult; Phenotype; Risk Factors; Longitudinal Studies; *Gene-Environment Interaction; Heart Failure/epidemiology; Genetic Predisposition to Disease; Genotype; Pedigree; Age of Onset; Alcohol Drinking/adverse effects/epidemiology; Risk Assessment; Disease Progression; genetic; heart failure; natural history; penetrance; risk modifiers; trajectory
- Department(s)
- Familial Cancer Centre
- Publisher's Version
- https://doi.org/10.1161/jaha.124.037311
- Open Access at Publisher's Site
https://doi.org/10.1161/jaha.124.037311- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-06-03 03:44:12
Last Modified: 2025-06-03 03:44:24