Sacubitril-Valsartan Improves Conduit Vessel Function and Functional Capacity, and Reduces Inflammation in Heart Failure with Reduced Ejection Fraction
The PARADIGM-HF 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, but the physiologic 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, 10M/1F, 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 pro-inflammatory biomarkers, tumor necrosis factor-alpha (TNF-α) and interleukin-18 (IL-18) were obtained at baseline and again at 1, 2, and 3 months of treatment. %FMD improved after 1 month of treatment, and this favorable response persisted for months 2 and 3 (baseline: 3.25±1.75%; 1mo: 5.23±2.36%; 2mo: 5.81±1.79%; 3mo: 6.35±2.77%), while RH remained unchanged. 6MWT distance increased at months 2 and 3 (baseline: 420±92 m; 1mo: 436±98 m; 2mo: 465±115 m; 3mo: 460±110 m), and there was a sustained reduction in TNF-α (baseline: 2.38±1.35 pg/mL; 1mo: 2.06±1.52 pg/mL; 2mo: 1.95±1.34 pg/mL; 3mo: 1.92±1.37 pg/mL) and a reduction in IL-18 at months 3 (baseline: 654±150 pg/mL; 1mo: 595±140 pg/mL; 2mo: 601±176 pg/mL; 3mo: 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.