Background Truncating variants in titin (TTNtv) are the commonest genetic cause of dilated cardiomyopathy (DCM). They are notable for variable penetrance and expressivity, suggestive of environmental or genetic modifiers.Purpose Undertake deep phenotyping by cardiac MRI (CMR) to evaluate alcohol and hypertension as phenotypic modifiers of TTNtv cardiomyopathy.Methods Prospectively recruited DCM patients underwent comprehensive clinical evaluation, CMR with late-gadolinium enhancement and TTN sequencing.Results Overall, 733 subjects, mean age 53.4±14.4 years, 476 men (65.0%) were recruited. TTNtv were found in 82 (11.2%) patients.View this table:Abstract 003 Table 1 Regression analysis evaluating TTNtv and alcohol excess as predictors of LVEFPatients with a history of alcohol excess (n=114, 15.6%) were more likely to be male (n=107 (93.9%) vs n=369 (59.6%), p<0.0001), have lower biventricular function (left/right ventricular ejection fraction; LVEF 36.3% vs 39.5%, p=0.01; RVEF 47.4% vs 52.5%, p<0.0001) and showed a trend to increased mid wall fibrosis (n=49 (43.0%) vs n=207 (33.4%), p=0.05) compared to patients without alcohol excess. There was no difference between groups in age at recruitment.Patients with TTNtv and a history of alcohol excess (n=13) had a lower mean LVEF compared to patients with TTNtv without a history of alcohol excess (n=69) (27.7%±12.7 vs 39.5%±13.1, p=0.005) (Figure 1). There was no difference in LVEF between TTNtv patients with a history of hypertension (n=10) and TTNv patients without (n=72) (37.7% vs 37.6%, p=0.94).Abstract 003 Figure 1 Boxplot showing the change in left ventricular ejection fraction by TTNtv and alcohol status. LVEF= left ventricular ejection fraction. TTN+/- = presence or absence of truncating variants in TTN. EtOH+/- = presence or absence of history of excess alcohol consumption.While TTNtv, a history of alcohol excess or hypertension in isolation did not predict LVEF, the combination of TTNtv and a history of alcohol excess was associated with a 15.4% reduction in LVEF (95% CI −21.9 to −8.8%) compared to a patient without either risk factor (p<0.0001), independently of other predictors of LVEF (gender, NYHA class, mid-wall fibrosis, atrial fibrillation and a family history of DCM) (Table 1). There was no significant interaction between TTNtv and hypertension (Table 2).Conclusions These data demonstrate the potential of using CMR to study cardiovascular endophenotypes of genetic DCM. We identify a novel gene-environmental interaction between TTNtv and alcohol that prompts genetic studies in DCM in the context of high alcohol intake.View this table:Abstract 003 Table 2 Regression analysis evaluating TTNtv and hypertension as predictors of LVEF%U http://heart.bmj.com/content/heartjnl/103/Suppl_1/A2.2.full.pdf