Abstract
AbstractBackgroundFamilial 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.MethodsA retrospective longitudinal cohort study was performed in families with DCM-causing genetic variants. Environmental factors were classified into two subsets based on evidence for a causal link to depressed myocardial contractility, termed (1) DCM-promoting factors and (2) heart failure (HF) comorbidities. These factors were correlated with DCM diagnosis, disease trajectory, and adverse events.Results105 probands and family members were recruited: 51 genotype-positive, phenotype-positive (G+P+), 24 genotype-positive, phenotype-negative (G+P-), and 30 genotype-negative, phenotype-negative (G-P-). Baseline characteristics were similar between the 3 genotype groups. DCM-promoting environmental factors (eg. alcohol excess) were enriched in G+P+ individuals compared to G+P-(P<0.001) and G-P-(P=0.003) and were significantly associated with age at DCM onset (HR 2.01,P=0.014). HF comorbidities (eg. Diabetes) had a similar prevalence in G+P+ and G-P-but were significantly reduced in the G+P-group. Fluctuations in left ventricular ejection fraction during follow-up were linked to changes in environmental factors in 35/45 (78%) of instances: 32 (91%) of these were DCM-promoting factors. HF comorbidities, but not DCM-promoting factors, were associated with adverse events in G+ individuals (OR 4.9,P=0.004).ConclusionWe identified distinct subsets of environmental factors that affect DCM penetrance and adverse outcomes respectively. Our data highlight DCM-promoting environmental factors as key determinants of penetrance and disease trajectory. Collectively, these findings provide a new framework for risk factor assessment in familial DCM and have important implications for clinical management.
Publisher
Cold Spring Harbor Laboratory