Peters Stacey A, Wright Leah, Yao Jess, McCall Lauren, Thompson Tina, Thompson Bryony, Johnson Renee, Huynh Quan, Santiago Celine F, Trainer Alison, Perrin Mark, James Paul, Zentner Dominica, Kalman Jon, Marwick Thomas H, Fatkin Diane
Department of Cardiology Royal Melbourne Hospital Melbourne Victoria Australia.
Department of Genomic Medicine Royal Melbourne Hospital Melbourne Victoria Australia.
J Am Heart Assoc. 2025 May 6;14(9):e037311. doi: 10.1161/JAHA.124.037311. Epub 2025 May 2.
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.
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 (<0.001) and genotype-negative, phenotype-negative (=0.003) individuals and were significantly associated with age at DCM onset (hazard ratio, 2.01; =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.
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.
家族性扩张型心肌病（DCM）的特征是表型外显率存在显著差异。而这在多大程度上由患者特异性环境因素决定尚不清楚。
对携带导致DCM的基因变异的家族进行了一项回顾性纵向队列研究。根据与心肌收缩力降低存在因果关系的证据，将环境因素分为2个亚组，即（1）促DCM因素和（2）心力衰竭合并症。在考虑了相关混杂因素和家族相关性后，将这些因素与DCM诊断及疾病轨迹进行关联分析。共招募了105名先证者及其家庭成员：51名基因型阳性、表型阳性，24名基因型阳性、表型阴性，以及30名基因型阴性、表型阴性。3个基因型组之间的人口统计学特征相似。与基因型阳性、表型阴性个体（<0.001）和基因型阴性、表型阴性个体（=0.003）相比，促DCM环境因素（如过量饮酒）在基因型阳性、表型阳性个体中更为常见，且与DCM发病年龄显著相关（风险比，2.01；=0.014）。心力衰竭合并症（如糖尿病）在基因型阳性、表型阳性个体和基因型阴性、表型阴性个体中的患病率相似，但在基因型阳性、表型阴性组中显著降低。随访期间左心室射血分数的波动在45例中的35例（78%）与环境因素变化有关：其中32例（91%）为促DCM因素。
我们识别出了影响DCM外显率和疾病轨迹的不同环境因素亚组。我们的数据突出了促DCM环境因素是外显率和自然病史的关键决定因素。总体而言，这些发现为家族性DCM的危险因素评估提供了一个新框架，并对临床管理具有重要意义。
