Abstract Body (Do not enter title and authors here): Background: Genetic risk and myocardial strain have emerged as early indicators of susceptibility to dilated cardiomyopathy (DCM). However, it remains unclear whether these markers are associated with one another and enhance the prediction of incident disease.

Aim: We evaluated the interplay between measures of myocardial strain by cardiac magnetic resonance imaging (CMR) and genetic (monogenic and polygenic) risk for DCM, and their capabilities for predicting incident disease.

Methods: We performed a retrospective analysis of 39,217 participants in the UK Biobank without cardiomyopathy, heart failure, or valvular heart disease at enrollment. Genetic risk was determined by the presence of a high confidence rare variant across 12 ClinGen-prioritized DCM genes and/or a high DCM polygenic risk score (PRS). CMR-derived measures of left ventricular (LV) myocardial strain, size, and function were obtained. Myocardial strain assessments included LV global longitudinal (GLS), global circumferential (GCS) and global radial strain (GRS).

Results: Both monogenic and polygenic risk for DCM were most strongly correlated with LV GCS as compared to LVGLS or LVGRS. Specifically, compared to non-carriers of DCM-rare variants, TTN rare variant carriers (n=139) demonstrated worse LVGCS (-19.79 vs. -22.40, p=1.51e-21). Participants with high DCM polygenic risk also had worse mean LVGCS (top 10% vs. middle 50% of the DCM PRS, -21.43 vs. -22.39, p = 8.06e-53) (Figure 1). In addition, those with a significant relative interval decline in LVGCS (≥ 12%, n=45) had a higher median PRS (0.43 vs. -0.05, p=0.0097) compared to those without (n=177); this relationship was not evident for LV GLS or GRS. Multivariable Cox regression models adjusted for baseline LVEF, age, sex and body mass index showed that both LVGCS (HR=1.56 [1.13–2.14] per standard deviation (SD) of LVGCS, p=0.0065) and DCM PRS (HR=1.52 per SD of PRS [1.19–1.95], p=0.00072) were associated with an increased risk of incident non-ischemic cardiomyopathy (n=67).

Conclusion: High genetic risk for DCM is strongly associated with worse LVGCS, and both genetic risk and LVGCS may have value for incident disease prediction.