Advertisement

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

  • Kanokwan Bunsawat
    Correspondence
    Corresponding author at: George E. Wahlen Department of Veterans Affairs Medical Center, GRECC 182, Building 2 Room 1D22, 500 Foothill Drive, Salt Lake City, UT 84148, United States of America.
    Affiliations
    Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author
  • Stephen M. Ratchford
    Affiliations
    Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, United States of America

    Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America

    Department of Health and Exercise Science, Appalachian State University, Boone, NC, United States of America
    Search for articles by this author
  • Jeremy K. Alpenglow
    Affiliations
    Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author
  • Josef Stehlik
    Affiliations
    Department of Internal Medicine, Division of Cardiovascular Medicine, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author
  • Adam S. Smith
    Affiliations
    Department of Pharmacy Services, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author
  • Russell S. Richardson
    Affiliations
    Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, United States of America

    Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America

    Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author
  • D. Walter Wray
    Affiliations
    Department of Internal Medicine, Division of Geriatrics, University of Utah, Salt Lake City, UT, United States of America

    Geriatric Research, Education, and Clinical Center, George E. Wahlen Department of Veterans Affairs Medical Center, Salt Lake City, UT, United States of America

    Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, United States of America
    Search for articles by this author

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Autonomic Neuroscience: Basic and Clinical
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Abramson B.L.
        • Ando S.
        • Notarius C.F.
        • Rongen G.A.
        • Floras J.S.
        Effect of atrial natriuretic peptide on muscle sympathetic activity and its reflex control in human heart failure.
        Circulation. 1999; 99: 1810-1815
        • Ando S.
        • Rahman M.A.
        • Butler G.C.
        • Senn B.L.
        • Floras J.S.
        Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin.
        Hypertension. 1995; 26: 1160-1166
        • Azevedo E.R.
        • Kubo T.
        • Mak S.
        • Al-Hesayen A.
        • Schofield A.
        • Allan R.
        • Kelly S.
        • Newton G.E.
        • Floras J.S.
        • Parker J.D.
        Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity.
        Circulation. 2001; 104: 2194-2199
        • Barretto A.C.
        • Santos A.C.
        • Munhoz R.
        • Rondon M.U.
        • Franco F.G.
        • Trombetta I.C.
        • Roveda F.
        • de Matos L.N.
        • Braga A.M.
        • Middlekauff H.R.
        • Negrao C.E.
        Increased muscle sympathetic nerve activity predicts mortality in heart failure patients.
        Int. J. Cardiol. 2009; 135: 302-307
        • Brunner-La Rocca H.P.
        • Kaye D.M.
        • Woods R.L.
        • Hastings J.
        • Esler M.D.
        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; 37: 1221-1227
        • Bunsawat K.
        • Ratchford S.M.
        • Alpenglow J.K.
        • Park S.H.
        • Jarrett C.L.
        • Stehlik J.
        • Smith A.S.
        • Richardson R.S.
        • Wray D.W.
        Sacubitril-valsartan improves conduit vessel function and functional capacity, and reduces inflammation in heart failure with reduced ejection fraction.
        J. Appl. Physiol. (1985). 2021; 130: 256-268
        • Cleland J.G.
        • Swedberg K.
        Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. The International Ecadotril Multi-centre Dose-ranging Study Investigators.
        Lancet. 1998; 351: 1657-1658
        • Cody R.J.
        The sympathetic nervous system and the renin-angiotensin-aldosterone system in cardiovascular disease.
        Am. J. Cardiol. 1997; 80: 9J-14J
        • Cohen-Solal A.
        • Rouzet F.
        • Berdeaux A.
        • Le Guludec D.
        • Abergel E.
        • Syrota A.
        • Merlet P.
        Effects of carvedilol on myocardial sympathetic innervation in patients with chronic heart failure.
        J. Nucl. Med. 2005; 46: 1796-1803
        • De Matos L.D.
        • Gardenghi G.
        • Rondon M.U.
        • Soufen H.N.
        • Tirone A.P.
        • Barretto A.C.
        • Brum P.C.
        • Middlekauff H.R.
        • Negrao C.E.
        Impact of 6 months of therapy with carvedilol on muscle sympathetic nerve activity in heart failure patients.
        J. Card. Fail. 2004; 10: 496-502
        • de Souza S.B.
        • Rocha J.A.
        • Cuoco M.A.
        • Guerra G.M.
        • Ferreira-Filho J.C.
        • Borile S.
        • Krieger E.M.
        • Bortolotto L.A.
        • Consolim-Colombo F.M.
        High muscle sympathetic nerve activity is associated with left ventricular dysfunction in treated hypertensive patients.
        Am. J. Hypertens. 2013; 26: 912-917
        • Delehanty J.M.
        • Himura Y.
        • Elam H.
        • Hood Jr., W.B.
        • Liang C.S.
        Beta-adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content.
        Am. J. Phys. 1994; 266: H930-H935
        • Delius W.
        • Hagbarth K.E.
        • Hongell A.
        • Wallin B.G.
        General characteristics of sympathetic activity in human muscle nerves.
        Acta Physiol. Scand. 1972; 84: 65-81
        • Dell’Oro R.
        • Gronda E.
        • Seravalle G.
        • Costantino G.
        • Alberti L.
        • Baronio B.
        • Staine T.
        • Vanoli E.
        • Mancia G.
        • Grassi G.
        Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report.
        J. Hypertens. 2017; 35: 2532-2536
        • Deo S.H.
        • Fisher J.P.
        • Vianna L.C.
        • Kim A.
        • Chockalingam A.
        • Zimmerman M.C.
        • Zucker I.H.
        • Fadel P.J.
        Statin therapy lowers muscle sympathetic nerve activity and oxidative stress in patients with heart failure.
        Am. J. Physiol. Heart Circ. Physiol. 2012; 303: H377-H385
        • Evans S.R.
        Clinical trial structures.
        J. Exp. Stroke Transl. Med. 2010; 3: 8-18
        • Fabris E.
        • Merlo M.
        • Rapezzi C.
        • Ferrari R.
        • Metra M.
        • Frigerio M.
        • Sinagra G.
        Sacubitril/valsartan: updates and clinical evidence for a disease-modifying approach.
        Drugs. 2019; 79: 1543-1556
        • Franciosi S.
        • Perry F.K.G.
        • Roston T.M.
        • Armstrong K.R.
        • Claydon V.E.
        • Sanatani S.
        The role of the autonomic nervous system in arrhythmias and sudden cardiac death.
        Auton. Neurosci. 2017; 205: 1-11
        • Ge Q.
        • Zhao L.
        • Ren X.M.
        • Ye P.
        • Hu Z.Y.
        LCZ696, an angiotensin receptor-neprilysin inhibitor, ameliorates diabetic cardiomyopathy by inhibiting inflammation, oxidative stress and apoptosis.
        Exp. Biol. Med. (Maywood). 2019; 244: 1028-1039
        • Grassi G.
        • Seravalle G.
        • Cattaneo B.M.
        • Lanfranchi A.
        • Vailati S.
        • Giannattasio C.
        • Del Bo A.
        • Sala C.
        • Bolla G.B.
        • Pozzi M.
        Sympathetic activation and loss of reflex sympathetic control in mild congestive heart failure.
        Circulation. 1995; 92: 3206-3211
        • Grassi G.
        • D’Arrigo G.
        • Pisano A.
        • Bolignano D.
        • Mallamaci F.
        • Dell’Oro R.
        • Quarti-Trevano F.
        • Seravalle G.
        • Mancia G.
        • Zoccali C.
        Sympathetic neural overdrive in congestive heart failure and its correlates: systematic reviews and meta-analysis.
        J. Hypertens. 2019; 37: 1746-1756
        • Grassi G.
        • Seravalle G.
        • Esler M.
        Sympathomodulation in congestive heart failure: from drugs to devices.
        Int. J. Cardiol. 2020; 321: 118-125
        • Hsiao F.C.
        • Wang C.L.
        • Chang P.C.
        • Lu Y.Y.
        • Huang C.Y.
        • Chu P.H.
        Angiotensin receptor neprilysin inhibitor for patients with heart failure and reduced ejection fraction: real-world experience from Taiwan.
        J. Cardiovasc. Pharmacol. Ther. 2020; 25: 152-157
        • Janig W.
        Sympathetic nervous system and inflammation: a conceptual view.
        Auton. Neurosci. 2014; 182: 4-14
        • Januzzi Jr., J.L.
        • Prescott M.F.
        • Butler J.
        • Felker G.M.
        • Maisel A.S.
        • McCague K.
        • Camacho A.
        • Pina I.L.
        • Rocha R.A.
        • Shah A.M.
        • Williamson K.M.
        • Solomon S.D.
        • Investigators P.-H.
        Association of change in N-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction.
        Jama. 2019; 322: 1085-1095
        • Kawamura A.
        • Yuasa F.
        • Yokoe H.
        • Masue Y.
        • Sugiura T.
        • Iwasaka T.
        Augmented sympathoinhibitory effect of valsartan when added to angiotensin-converting enzyme inhibitor in patients with left ventricular dysfunction.
        J. Cardiol. 2009; 53: 171-178
        • Keir D.A.
        • Badrov M.B.
        • Tomlinson G.
        • Notarius C.F.
        • Kimmerly D.S.
        • Millar P.J.
        • Shoemaker J.K.
        • Floras J.S.
        Influence of sex and age on muscle sympathetic nerve activity of healthy normotensive adults.
        Hypertension. 2020; 76: 997-1005
        • Klein I.H.
        • Ligtenberg G.
        • Neumann J.
        • Oey P.L.
        • Koomans H.A.
        • Blankestijn P.J.
        Sympathetic nerve activity is inappropriately increased in chronic renal disease.
        J. Am. Soc. Nephrol. 2003; 14: 3239-3244
        • Kobalava Z.
        • Kotovskaya Y.
        • Averkov O.
        • Pavlikova E.
        • Moiseev V.
        • Albrecht D.
        • Chandra P.
        • Ayalasomayajula S.
        • Prescott M.F.
        • Pal P.
        • Langenickel T.H.
        • Jordaan P.
        • Rajman I.
        Pharmacodynamic and pharmacokinetic profiles of sacubitril/valsartan (LCZ696) in patients with heart failure and reduced ejection fraction.
        Cardiovasc. Ther. 2016; 34: 191-198
        • Kubo T.
        • Ando S.
        • Picton P.
        • Atchison D.J.
        • Notarius C.F.
        • Pollard M.J.
        • Abramson B.L.
        • Floras J.S.
        Atrial natriuretic peptide augments the variability of sympathetic nerve activity in human heart failure.
        J. Hypertens. 2001; 19: 619-626
        • Kusaka H.
        • Sueta D.
        • Koibuchi N.
        • Hasegawa Y.
        • Nakagawa T.
        • Lin B.
        • Ogawa H.
        • Kim-Mitsuyama S.
        LCZ696, angiotensin II receptor-neprilysin inhibitor, ameliorates high-salt-induced hypertension and cardiovascular injury more than valsartan alone.
        Am. J. Hypertens. 2015; 28: 1409-1417
        • Lambert E.A.
        • Esler M.D.
        • Schlaich M.P.
        • Dixon J.
        • Eikelis N.
        • Lambert G.W.
        Obesity-associated organ damage and sympathetic nervous activity.
        Hypertension. 2019; 73: 1150-1159
        • Liu R.C.
        Focused treatment of heart failure with reduced ejection fraction using sacubitril/valsartan.
        Am. J. Cardiovasc. Drugs. 2018; 18: 473-482
        • Mancia G.
        • Giannattasio C.
        • Grassi G.
        Treatment of heart failure with fosinopril: an angiotensin converting enzyme inhibitor with a dual and compensatory route of excretion.
        Am. J. Hypertens. 1997; 10: 236S-241S
        • Matsukawa T.
        • Gotoh E.
        • Minamisawa K.
        • Kihara M.
        • Ueda S.
        • Shionoiri H.
        • Ishii M.
        Effects of intravenous infusions of angiotensin II on muscle sympathetic nerve activity in humans.
        Am. J. Phys. 1991; 261: R690-R696
        • McMurray J.J.
        • Packer M.
        • Desai A.S.
        • Gong J.
        • Lefkowitz M.P.
        • Rizkala A.R.
        • Rouleau J.L.
        • Shi V.C.
        • Solomon S.D.
        • Swedberg K.
        • Zile M.R.
        • Investigators, P.-H., Committees
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N. Engl. J. Med. 2014; 371: 993-1004
        • Polito M.V.
        • Silverio A.
        • Rispoli A.
        • Vitulano G.
        • Auria F.
        • De Angelis E.
        • Loria F.
        • Gigantino A.
        • Bonadies D.
        • Citro R.
        • Carrizzo A.
        • Galasso G.
        • Iaccarino G.
        • Vecchione C.
        • Ciccarelli M.
        Clinical and echocardiographic benefit of sacubitril/valsartan in a real-world population with HF with reduced ejection fraction.
        Sci. Rep. 2020; 106665
        • Ruzicka M.
        • Floras J.S.
        • McReynolds A.J.
        • Coletta E.
        • Haddad H.
        • Davies R.
        • Leenen F.H.
        Do high doses of AT(1)-receptor blockers attenuate central sympathetic outflow in humans with chronic heart failure?.
        Clin. Sci. 2013; 124: 589-595
        • Sauer A.J.
        • Cole R.
        • Jensen B.C.
        • Pal J.
        • Sharma N.
        • Yehya A.
        • Vader J.
        Practical guidance on the use of sacubitril/valsartan for heart failure.
        Heart Fail. Rev. 2019; 24: 167-176
        • Sciascia S.
        • Apra F.
        • Baffa A.
        • Baldovino S.
        • Boaro D.
        • Boero R.
        • Bonora S.
        • Calcagno A.
        • Cecchi I.
        • Cinnirella G.
        • Converso M.
        • Cozzi M.
        • Crosasso P.
        • De Iaco F.
        • Di Perri G.
        • Eandi M.
        • Fenoglio R.
        • Giusti M.
        • Imperiale D.
        • Imperiale G.
        • Livigni S.
        • Manno E.
        • Massara C.
        • Milone V.
        • Natale G.
        • Navarra M.
        • Oddone V.
        • Osella S.
        • Piccioni P.
        • Radin M.
        • Roccatello D.
        • Rossi D.
        Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19.
        Clin. Exp. Rheumatol. 2020; 38: 529-532
        • Seravalle G.
        • Lonati L.
        • Buzzi S.
        • Cairo M.
        • Quarti Trevano F.
        • Dell’Oro R.
        • Facchetti R.
        • Mancia G.
        • Grassi G.
        Sympathetic nerve traffic and baroreflex function in optimal, normal, and high-normal blood pressure states.
        J. Hypertens. 2015; 33: 1411-1417
        • Seravalle G.
        • Quarti-Trevano F.
        • Dell’Oro R.
        • Gronda E.
        • Spaziani D.
        • Facchetti R.
        • Cuspidi C.
        • Mancia G.
        • Grassi G.
        Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction.
        J. Hypertens. 2019; 37: 443-448
        • van Bilsen M.
        • Patel H.C.
        • Bauersachs J.
        • Bohm M.
        • Borggrefe M.
        • Brutsaert D.
        • Coats A.J.S.
        • de Boer R.A.
        • de Keulenaer G.W.
        • Filippatos G.S.
        • Floras J.
        • Grassi G.
        • Jankowska E.A.
        • Kornet L.
        • Lunde I.G.
        • Maack C.
        • Mahfoud F.
        • Pollesello P.
        • Ponikowski P.
        • Ruschitzka F.
        • Sabbah H.N.
        • Schultz H.D.
        • Seferovic P.
        • Slart R.
        • Taggart P.
        • Tocchetti C.G.
        • Van Laake L.W.
        • Zannad F.
        • Heymans S.
        • Lyon A.R.
        The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.
        Eur. J. Heart Fail. 2017; 19: 1361-1378
        • Williams B.
        • Cockcroft J.R.
        • Kario K.
        • Zappe D.H.
        • Brunel P.C.
        • Wang Q.
        • Guo W.
        Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: the PARAMETER study.
        Hypertension. 2017; 69: 411-420
        • Yamazaki J.
        • Muto H.
        • Kabano T.
        • Yamashina S.
        • Nanjo S.
        • Inoue A.
        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. 2001; 141: 645-652
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • Butler J.
        • Casey Jr., D.E.
        • Colvin M.M.
        • Drazner M.H.
        • Filippatos G.S.
        • Fonarow G.C.
        • Givertz M.M.
        • Hollenberg S.M.
        • Lindenfeld J.
        • Masoudi F.A.
        • McBride P.E.
        • Peterson P.N.
        • Stevenson L.W.
        • Westlake C.
        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. 2017; 70: 776-803
        • Zeng Y.
        • Moscicki A.B.
        • Sahasrabuddhe V.V.
        • Garcia F.
        • Woo H.
        • Hsu C.H.
        • Szabo E.
        • Dimond E.
        • Vanzzini S.
        • Mondragon A.
        • Butler V.
        • DeRose H.
        • Chow H.S.
        A prospective, single-arm, open-label, non-randomized, phase IIa trial of a nonavalent prophylactic HPV vaccine to assess immunogenicity of a prime and deferred-booster dosing schedule among 9–11 year-old girls and boys - clinical protocol.
        BMC Cancer. 2019; 19290