Sacubitril-valsartan improves conduit vessel function and functional capacity and reduces inflammation in heart failure with reduced ejection fraction.

The Prospective comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and morbidity in Heart Failure trial identified a marked reduction in the risk of death and hospitalization for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) treated with sacubitril-valsartan (trade name Entresto), but the physiological processes underpinning these improvements are unclear. We tested the hypothesis that treatment with sacubitril-valsartan improves peripheral vascular function, functional capacity, and inflammation in patients with HFrEF. We prospectively studied patients with HFrEF ( = 11, 10 M/1 F, left ventricular ejection fraction = 27 ± 8%) on optimal, guideline-directed medical treatment who were subsequently prescribed sacubitril-valsartan (open-label, uncontrolled, and unblinded). Peripheral vascular function [brachial artery flow-mediated dilation (FMD, conduit vessel function) and reactive hyperemia (RH, microvascular function)], functional capacity [six-minute walk test (6MWT) distance], and the proinflammatory biomarkers tumor necrosis factor-α (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and at 1, 2, and 3 mo of treatment. %FMD improved after 1 mo of treatment, and this favorable response persisted for and (baseline: 3.25 ± 1.75%; 1 mo: 5.23 ± 2.36%; 2 mo: 5.81 ± 1.79%; 3 mo: 6.35 ± 2.77%), whereas RH remained unchanged. 6MWT distance increased at and (baseline: 420 ± 92 m; 1 mo: 436 ± 98 m; 2 mo: 465 ± 115 m; 3 mo: 460 ± 110 m), and there was a sustained reduction in TNF-α (baseline: 2.38 ± 1.35 pg/mL; 1 mo: 2.06 ± 1.52 pg/mL; 2 mo: 1.95 ± 1.34 pg/mL; 3 mo: 1.92 ± 1.37 pg/mL) and a reduction in IL-18 at (baseline: 654 ± 150 pg/mL; 1 mo: 595 ± 140 pg/mL; 2 mo: 601 ± 176 pg/mL; 3 mo: 571 ± 127 pg/mL). This study provides new evidence for the potential of this new drug class to improve conduit vessel function, functional capacity, and inflammation in patients with HFrEF. We observed an approximately twofold improvement in conduit vessel function (brachial artery FMD), increased functional capacity (6MWT distance), and a reduction in inflammation (TNF-α and IL-18) following 3 mo of sacubitril-valsartan therapy. These findings provide important new information concerning the physiological mechanisms by which this new drug class provokes favorable changes in HFrEF pathophysiology.