Sympathoinhibitory effect of sacubitril-valsartan in heart failure with reduced ejection fraction: A pilot study
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.
Section snippets
Study population
We recruited nine male patients with NYHA Class II-III HFrEF from the HF clinic at the University of Utah. The inclusion criteria were a diagnosis of chronic HFrEF with left ventricular ejection fraction ≤40%, ongoing guideline-directed medical treatment for HF for at least 6 months, and a clinical decision to initiate treatment with sacubitril-valsartan. Exclusion criteria included frequent arrhythmias that would interfere with MSNA signals, uncorrected primary valvular disease, current
Disease characteristics and sacubitril-valsartan tolerance
Six patients were being transitioned to sacubitril-valsartan from ACEi, and three patients from ARB. Patient characteristics and clinical variables at baseline and in response to the treatment are documented in Table 1. No changes were observed for any of these patient characteristics and clinical variables as a consequence of the treatment (p > 0.05). Disease-related characteristics and pharmacologic information for the patients with HFrEF are documented in Table 2. Treatment with
Discussion
Using a single-arm, open-label approach, we sought to determine the impact of sacubitril-valsartan, a first-in-class ARNI drug, on directly measured SNS activity in patients with HFrEF. Following two months of treatment with sacubitril-valsartan, we observed a reduction in resting MSNA burst frequency (≈17%) and burst incidence (≈19%) in patients with HFrEF. To our knowledge, this is the first study to identify the rapid sympathoinhibitory effect of this drug class, thereby providing
Conclusions
The present study demonstrates that sacubitril-valsartan lowered resting sympathetic activity in patients with HFrEF after a brief duration of treatment, providing preliminary, new insight regarding the therapeutic potential for this drug class to target the sympathetic nervous system in HF.
CRediT authorship contribution statement
K.B., S.M.R., R.S.R., and D.W.W. conceived and designed research; J.S. and A.S. supervised patient recruitment and safety, as well as the treatment; K.B., S.M.R., and J.A. performed experiments; K.B. and S.M.R. analyzed data; K.B., R.S.R., and D.W.W. drafted manuscript; all authors edited, revised, and approved final version of manuscript.
Declaration of competing interest
The authors have no other funding, financial relationships, or conflicts of interest to disclose.
Acknowledgments
The authors thank the participants for their time and effort. This work was funded in part by the National Institutes of Health (R01 HL118313, D.W.W.; R56 AG057584, R.S.R; T32 HL139451, K.B.), the U.S. Department of Veterans Affairs (RX001311, D.W.W.; E6910-R, E1697-R, E3207-R, E1572-P, and E9275-L, R.S.R) and the American Heart Association (18POST33960192; K.B.).
References (47)
- et al.
Increased muscle sympathetic nerve activity predicts mortality in heart failure patients
Int. J. Cardiol.
(2009) - et al.
Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects
J. Am. Coll. Cardiol.
(2001) - et al.
Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. The International Ecadotril Multi-centre Dose-ranging Study Investigators
Lancet
(1998) The sympathetic nervous system and the renin-angiotensin-aldosterone system in cardiovascular disease
Am. J. Cardiol.
(1997)- et al.
Impact of 6 months of therapy with carvedilol on muscle sympathetic nerve activity in heart failure patients
J. Card. Fail.
(2004) - et al.
The role of the autonomic nervous system in arrhythmias and sudden cardiac death
Auton. Neurosci.
(2017) - et al.
Sympathomodulation in congestive heart failure: from drugs to devices
Int. J. Cardiol.
(2020) Sympathetic nervous system and inflammation: a conceptual view
Auton. Neurosci.
(2014)- et al.
Augmented sympathoinhibitory effect of valsartan when added to angiotensin-converting enzyme inhibitor in patients with left ventricular dysfunction
J. Cardiol.
(2009) - et al.
Treatment of heart failure with fosinopril: an angiotensin converting enzyme inhibitor with a dual and compensatory route of excretion
Am. J. Hypertens.
(1997)
Evaluation of beta-blocker therapy in patients with dilated cardiomyopathy—clinical meaning of iodine 123-metaiodobenzylguanidine myocardial single-photon emission computed tomography
Am. Heart J.
2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the Management of Heart Failure: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines and the Heart Failure Society of America
J. Am. Coll. Cardiol.
Effect of atrial natriuretic peptide on muscle sympathetic activity and its reflex control in human heart failure
Circulation
Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin
Hypertension
Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity
Circulation
Sacubitril-valsartan improves conduit vessel function and functional capacity, and reduces inflammation in heart failure with reduced ejection fraction
J. Appl. Physiol. (1985)
Effects of carvedilol on myocardial sympathetic innervation in patients with chronic heart failure
J. Nucl. Med.
High muscle sympathetic nerve activity is associated with left ventricular dysfunction in treated hypertensive patients
Am. J. Hypertens.
Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content
Am. J. Phys.
General characteristics of sympathetic activity in human muscle nerves
Acta Physiol. Scand.
Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report
J. Hypertens.
Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure
Am. J. Physiol. Heart Circ. Physiol.
Clinical trial structures
J. Exp. Stroke Transl. Med.
Cited by (6)
A new lead: Sacubitril-valsartan's unique benefit in HFrEF could lie with sympathoinhibition
2022, Autonomic Neuroscience: Basic and ClinicalNeural control of the circulation during exercise in heart failure with reduced and preserved ejection fraction
2023, American Journal of Physiology - Heart and Circulatory PhysiologySympathetic modulation as a goal of antihypertensive treatment: from drugs to devices
2023, Journal of HypertensionExploration of Mechanisms of Sacubitril/Valsartan in the Treatment of Cardiac Arrhythmias Using a Network Pharmacology Approach
2022, Frontiers in Cardiovascular Medicine