Abstract Body (Do not enter title and authors here): Background: The effects of sacubitril/valsartan (ARNI) on myocardial tissue characterization in heart failure (HF) with left ventricular ejection fraction (LVEF) <50% are still unclear. Objective: The present study investigated the effects of 9 months of ARNI treatment on LV structure and myocardial tissue characteristics in HF with LVEF <50% using cardiac magnetic resonance (CMR). Methods: This study was a prospective, 2-arm, randomized, open-label clinical trial (SAVE-HF). Sixty-four HF outpatients with LVEF<50% were randomized 1:1 from ACE inhibitor/ARB to ARNI (ARNI group) or control group (continued ACE inhibitor/ARB). CMR was performed to evaluate LV structure and tissue characteristics, including changes in LV extracellular volume fraction (delta ECV) before and after the 9-month period. The primary endpoint was difference in ECV between the two groups. Secondary endpoints included changes in LV volumes and mass, LVEF, extracellular mass (ECM) calculated as LV mass times ECV/100, and intracellular mass (ICM) calculated as LV mass minus ECM. Results: A total of 59 of 64 stable patients (68±12 years; 52 men) completed the 9-month intervention followed by repeated CMR. ARNI decreased systolic BP levels from the first month by approximately 10 mmHg. ARNI group exhibited significant reductions in LV end-diastolic and end-systolic volumes and LV mass. While LVEF and ECV remained unchanged (31.6±5.0 vs. 31.9±5.0%, p=0.26), both ECM and ICM significantly decreased after ARNI. In the control group, systolic BP, LV volumes and LV mass, ECV, ECM and ICM were unchanged. Comparing the two groups, while delta ECV was not significantly different, delta ECM was greater in ARNI group than control group (-3.6±7.3 vs. 0.2±5.3 g, p=0.025), indicating improved LV tissue characteristics. Conclusions: ARNI reduced LV volume and LV mass, accompanied with reduction of both ECM and ICM, and consequently unchanged ECV. These findings may suggest that ARNI may improve LV tissue characteristics and protect from LV remodeling in HF patients with their LVEF<50%.