Environmental Risk Factors Are Associated With the Natural History of Familial Dilated Cardiomyopathy

• DOI: 10.1161/jaha.124.037311
• Publication Date: 2025-05-02T11:59:49Z
• Authors: Stacey A. Peters; Leah Wright; Jess Yao; Lauren McCall; Tina Thompson; Bryony Thompson; Renee Johnson; Quan Huynh; Celine F. Santiago; Alison Trainer; Mark Perrin; Paul James; Dominica Zentner; Jon Kalman; Thomas H. Marwick; Diane Fatkin
• Keywords: Penetrance; Dilated Cardiomyopathy; Proband

Background Familial dilated cardiomyopathy (DCM) is characterized by marked variability in phenotypic penetrance. The extent to which this determined patient‐specific environmental factors unknown. Methods and Results A retrospective longitudinal cohort study was performed families with DCM‐causing genetic variants. Environmental were classified into 2 subsets based on evidence for a causal link depressed myocardial contractility, termed (1) DCM‐promoting (2) heart failure comorbidities. These correlated DCM diagnosis disease trajectory after accounting relevant confounders familial relatedness. total of 105 probands family members recruited: 51 genotype positive, phenotype 24 negative, 30 negative. Demographic characteristics similar between the 3 groups. (eg, alcohol excess) enriched genotype‐positive, phenotype‐positive individuals compared phenotype‐negative ( P <0.001) genotype‐negative, =0.003) significantly associated age at onset (hazard ratio, 2.01; =0.014). Heart comorbidities diabetes) had prevalence but reduced group. Fluctuations left ventricular ejection fraction during follow‐up linked changes 35 45 (78%) instances: 32 (91%) these factors. Conclusions We identified distinct that affect penetrance trajectory. Our data highlight as key determinants natural history. Collectively, findings provide new framework risk factor assessment have important implications clinical management.