Sympathoinhibitory effect of sacubitril-valsartan in heart failure with reduced ejection fraction: A pilot study

Abstract

Chronic sympathetic nervous system (SNS) overactivity, characteristic of heart failure (HF) with reduced ejection fraction (HFrEF), is associated with poor prognosis and contributes to increased mortality risk. Sacubitril-valsartan is a recently approved, first-in-class, angiotensin receptor neprilysin inhibitor (ARNI) drug that markedly reduces the risks of death from cardiovascular causes and hospitalization for HF in patients with HFrEF, but the physiological mechanisms underlying these benefits are not fully understood. This single-arm, open-label, prospective study sought to test the hypothesis that short-term treatment with sacubitril-valsartan reduces SNS activity, measured directly via muscle sympathetic nerve activity (MSNA), in patients with HFrEF. MSNA, heart rate (HR), and arterial blood pressure (BP) were assessed in stable Class II and III patients with HFrEF (n = 9, 69 ± 8 yrs.; 28.6 ± 3.6 kg/m²) on contemporary, guideline-directed medical treatment who were subsequently started on sacubitril-valsartan. These measurements were repeated after two months of treatment with sacubitril-valsartan. Sacubitril-valsartan reduced MSNA burst frequency (baseline: 43 ± 10 bursts/min; 2-month: 36 ± 10 bursts/min, p = 0.05) and burst incidence (baseline: 68 ± 16 bursts/100 heartbeats; 2-month: 55 ± 16 bursts/100 heartbeats, p = 0.02), while HR and BP were unchanged following the treatment (p > 0.05). These preliminary findings provide new evidence regarding the ability of sacubitril-valsartan to rapidly reduce SNS activity in patients with HFrEF, suggesting the presence of a novel sympathoinhibitory effect of this new drug class.

Introduction

Chronic elevation of sympathetic nervous system (SNS) activity is a hallmark feature of patients with heart failure (HF) with reduced ejection fraction (HFrEF) (Grassi et al., 2019; Seravalle et al., 2019). The initial reflex increase in SNS activity supports the failing myocardium, serving as a compensatory response to help maintain perfusion pressure and cardiac output. However, sustained SNS overactivity represents a maladaptive process, resulting in end-organ damage (Lambert et al., 2019) and increased risk of fatal arrhythmias (Franciosi et al., 2017), ultimately contributing to the progression and severity of HF (Grassi et al., 2020). Importantly, despite being optimized on current pharmacotherapy, including beta (β)-adrenergic receptor blockade and inhibition of the renin-angiotensin-aldosterone system (RAAS) (De Matos et al., 2004; Kawamura et al., 2009; Mancia et al., 1997; Ruzicka et al., 2013), patients with HFrEF still exhibit elevations in muscle sympathetic nerve activity (MSNA) (Grassi et al., 2019). Given that sympathetic overdrive independently predicts the mortality risk in patients with HFrEF (Barretto et al., 2009), targeting the SNS may represent one of the potential treatment options, as a reduction in MSNA may confer an improvement in clinical prognosis for these patients (Grassi et al., 2020; van Bilsen et al., 2017).

Recently, guidelines for the management of HFrEF have recommended the use of sacubitril-valsartan, a first-in-class combined angiotensin receptor and neprilysin inhibitor (ARNI), in place of an angiotensin-II receptor blocker (ARB) or an angiotensin-converting enzyme inhibitor (ACEi) (Yancy et al., 2017). This change in HF pharmacotherapy guidance stems from results of the PARADIGM-HF (Prospective Comparison of ARNI with an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) trial, which demonstrated the superiority of sacubitril-valsartan to enalapril (an ACEi) in reducing the risks of death from cardiovascular causes and hospitalization for HF in patients with HFrEF (McMurray et al., 2014). The physiological mechanisms underpinning these clear benefits of sacubitril-valsartan are currently not well understood. While it has been speculated that sacubitril-valsartan may possess sympathomodulatory properties (Fabris et al., 2019; Liu, 2018), to our knowledge, no studies have directly examined the short-term effect of treatment with sacubitril-valsartan on SNS activity in patients with HFrEF. Thus, in this single-arm, open-label, prospective study, we sought to test the hypothesis that short-term treatment with sacubitril-valsartan reduces SNS activity, measured directly via MSNA, in patients with HFrEF.