The PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial identified a marked reduction in the risk of death from cardiovascular causes or hospitalization for heart failure (HF) in patients with HF with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan. The mechanisms responsible for this improvement have not been fully identified, but may be related, in part, to improvements in vascular function and functional capacity, two important predictors of mortality and morbidity in this patient group. PURPOSE: We sought to test the hypothesis that short-term treatment with sacubitril-valsartan would improve vascular function and functional capacity in patients with HFrEF. METHODS: Eleven stable, class II/III patients with HFrEF (10M/1F, age: 69±3 yrs; BMI: 29.0±1.0 kg/m²; ejection fraction: 27±3%) were studied prior to initiation of treatment and at months 1, 2 and 3 of sacubitril-valsartan therapy. Vascular function was evaluated by brachial artery flow-mediated dilation (FMD) and reactive hyperemia (RH), while functional capacity was determined using the six-minute walk test (6MWT). RESULTS: Treatment with sacubitril-valsartan improved brachial artery %FMD after 1 month of treatment, and this favorable response persisted during months 2 and 3 (baseline: 3.25±0.53%; 1-month: 5.23±0.71%; 2-month: 5.81±0.54%; 3-month: 6.35±0.84%, p<0.05). Likewise, %FMD normalized for the shear stimulus improved significantly at months 2 and 3 (baseline: 0.08±0.01%; 1-month: 0.13±0.01%; 2-month: 0.17±0.02%; 3-month: 0.20±0.03%). There was no change in RH, an index of microvascular function, at any time point (p>0.05). The 6MWT distance also increased significantly at months 2 and 3 (baseline: 420±28m; 1-month: 436±30m; 2-month: 465±35m; 3-month: 460±33m), but the changes in 6MWT distance were not correlated to the changes in %FMD or %FMD normalized for the shear stimulus (r=0.13, p=0.39 and r=0.01, p=0.97, respectively). CONCLUSIONS: These preliminary findings provide new evidence for the efficacy of short-term treatment with sacubitril-valsartan to improve vascular function and functional capacity, two possible mechanisms underlying this treatment’s benefits, in patients with HFrEF.