Introduction: Progression to heart failure is a known consequence of longstanding hypertrophic cardiomyopathy (HCM); however, routine function markers such as ejection fraction (EF) are often inadequate to predict dysfunction progression. The objective of this abstract was to create a novel metric, the Hybrid Strain Index (HSI), that can provide better characterization of heart failure progression. We hypothesized that longitudinal changes in a mouse model with known cardiac dysfunction could be more accurately differentiated with HSI than EF. Methods: Longitudinal 4D ultrasound (4DUS) data from mice with hypertrophic cardiomyopathy secondary to cardiac deletion of the carnitine palmitoyltransferase 2 enzyme ( Cpt2 M-/- ; n=12) and littermate controls (n=14) were analyzed using a custom MATLAB toolbox that derived both global volumetric (e.g., EF) and regional kinematic (e.g., circumferential and longitudinal strain) measurements. The circumferential and longitudinal regions most sensitive to disease progression were identified as the base (E θθ ) and posterior-wall (E LL ), respectively. The HSI metric was then calculated as the L2 norm of those peak-strain values. Results: To identify the earliest age of deviation between Cpt2 M-/- and controls, 95% confidence intervals from linear regression through HSI values intersected at 5.7 weeks old, compared to 7.1 weeks old using EF, suggesting HSI provides earlier sensitivity to cardiac dysfunction. Additionally, area-under-curve (AUC) measurements from ROC analysis of each metric, regardless of age, showed greater differentiation between cohorts using HSI (AUC = 0.91) than EF (AUC = 0.84). This further suggests enhanced diagnostic value of HSI compared to EF in the setting of cardiac dysfunction. Conclusions: The proposed HSI metric demonstrated greater sensitivity to detecting cardiac dysfunction and disease progression, compared to EF, in a mouse model of hypertrophic cardiomyopathy ( Cpt2 M-/- ).