Environmental Risk Factors Influence the Natural History of Familial Dilated Cardiomyopathy

BackgroundFamilial 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.