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

Abstract

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 (n = 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 months 2 and 3 (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 months 2 and 3 (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 month 3 (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.NEW & NOTEWORTHY 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.

Keywords: Entresto; flow-mediated dilation; heart failure; reactive hyperemia.

Figure 1.

Brachial artery flow-mediated dilation (FMD) (A, B, and D) and shear rate area under the curve (AUC) from cuff release until peak dilation (C) at baseline and after 1, 2, and 3 mo of treatment with sacubitril-valsartan in patients with heart failure with reduced ejection fraction (n = 11). The FMD data are expressed as percentage change (A), absolute change (B), and %FMD/shear rate AUC (D). Data are presented as mean and individual data (white dots). *Significantly different from baseline, P < 0.05. #Significantly different from 1 mo, P < 0.05.

Figure 2.

Reactive hyperemia following 5-min cuff occlusion in patients with heart failure with reduced ejection fraction at baseline and after 1, 2, and 3 mo of treatment with sacubitril-valsartan (n = 11). Data are presented as means ± SD.

Figure 3.

Six-minute walk test distance in patients with heart failure with reduced ejection fraction at baseline and after 1, 2, and 3 mo of treatment with sacubitril-valsartan (n = 11). Data are presented as mean and individual data (white dots). *Significantly different from baseline, P < 0.05.

Figure 4.

Plasma tumor necrosis factor-α (TNF-α) (A) and interleukin-18 (IL-18) (B) in patients with heart failure with reduced ejection fraction at baseline and after 1, 2, and 3 mo of treatment with sacubitril-valsartan (n = 9 and n = 10, respectively). Data are presented as mean and individual data (white dots). *Significantly different from baseline, P < 0.05.