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

Abstract

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.

Impact of angiotensin receptor–neprilysin inhibition on vascular function in heart failure with reduced ejection fraction: A pilot study

“…This improvement is despite patients in our study being on goal-directed medical therapy, including maximal vasodilators at baseline. Our findings complement a recent study where 11 HFrEF patients were longitudinally followed and brachial artery FMD was assessed at baseline (before starting ARNi) and at 1, 2, and 3 months after ARNi initiation (Bunsawat et al, 2020). Importantly, our data are consistent with this prior study in showing a ~3% increase in FMD with ARNi therapy, thereby demonstrating strong reproducibility of the effects of ARNi on FMD in HFrEF.…”

“…Other possible mechanisms for improvement in arterial stiffness may be through anti‐inflammatory properties and sympatho‐inhibitory effects of ARNi. ARNi has been reported to reduce pro‐inflammatory biomarkers, tumor necrosis factor‐alpha (TNF‐α), and interleukin‐18 (IL‐18) in HFrEF (Bunsawat et al, 2020). This, in turn, may reduce elevated oxidative stress seen in HFrEF, reducing vascular inflammation.…”

“…In addition to FMD, the aforementioned study (Bunsawat et al, 2020) also assessed functional capacity with a 6‐min walk test and proinflammatory biomarkers, TNF‐α and IL‐18, were measured. After one month of ARNi therapy, FMD improved, which persisted over the second and third months.…”

“…Recently, a study evaluated brachial artery FMD in eleven HFrEF patients at baseline and 1, 2, and 3 months after ARNi initiation. ARNi improved FMD after one month of treatment, which persisted at two and three months (Bunsawat et al, 2020). These preliminary findings are intriguing and open a new paradigm of a possible mechanism for clinical benefits seen with ARNi in HFrEF.…”

When it’s time for the sex talk, words matter

“…As our colleagues noted, the use of "men" and "women" as nouns to describe biological sex has been a frequent and common practice throughout recent decades (4-8). However, it is also common practice for authors in the field to use the terms "male" and "female" (19)(20)(21)(22)(23)(24). We acknowledge the fact that both approaches have been used in the past does not make one approach, versus the other, right or wrong per se.…”