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Safety and Tolerability of Neurohormonal Antagonism in Cardiac Amyloidosis

      Highlights

      • ACEi/ARB and MRA can be safely used in cardiac amyloidosis
      • Treatment must be started at a low dose and slowly up-titrated
      • Patients must be monitored quite closely
      • Beta-blockers are less tolerated in AL amyloidosis and/or worse haemodynamic function

      Abstract

      Background

      Drugs for neurohormonal antagonism are usually denied to patients with cardiac amyloidosis (CA) because of safety concerns.

      Methods

      Patients diagnosed with CA at a tertiary referral centre from 2009 to 2019 were enrolled. In the absence of contraindications, beta-blockers, angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB), and mineralocorticoid receptor antagonists (MRA) were started or up-titrated.

      Results

      99 patients were evaluated (72% men, age 80 years [72,83], 33% light-chain and 67% transthyretin amyloidosis); 56% were started on or underwent up-titration of a beta-blocker, 25% of ACEi/ARB, and 39% of MRA; beta-blockers were then prescribed to 87% of patients, ACEi/ARB to 75%, and MRA to 63%, with median bisoprolol, ramipril, valsartan, and spironolactone daily equivalent doses of 2.5 mg, 5 mg, 80 mg, and 25 mg, respectively. Patients starting or starting/up-titrating a beta-blocker did not show a higher frequency of hypotension, fatigue, syncope, symptomatic bradycardia, need for pacemaker implantation, or HF hospitalization. Lower stroke volume and cardiac output (CO) predicted HF hospitalization regardless of amyloidosis type; lower left ventricular ejection fraction predicted hypotension, and lower CO and diastolic blood pressure predicted syncope. Patients who had an ACEi/ARB or MRA being started or up-titrated did not experience more adverse events than other patients.

      Conclusions

      ACEi/ARB and MRA can be safely used in CA, provided that no contraindications are present, treatment is started at a low dose and slowly up-titrated, and patients are monitored quite closely. Beta-blocker therapy is less tolerated in patients with AL amyloidosis and/or worse haemodynamic function.

      Keywords

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      References

        • Falk RH
        • Alexander KM
        • Liao R
        • Dorbala S
        AL (light-chain) cardiac amyloidosis: a review of diagnosis and therapy.
        J Am Coll Cardiol. 2016; 68: 1323-1341
        • Ruberg FL
        • Grogan M
        • Hanna M
        • Kelly JW
        • Maurer MS
        Transthyretin amyloid cardiomyopathy: JACC State-of-the-Art review.
        J Am Coll Cardiol. 2019; 73: 2872-2891
        • Manolis AS
        • Manolis AA
        • Manolis TA
        • Melita H
        Cardiac amyloidosis: an underdiagnosed/underappreciated disease.
        Eur J Intern Med. 2019; 67: 1-13
        • Emdin M
        • Aimo A
        • Rapezzi C
        • Fontana M
        • Perfetto F
        • Seferović PM
        • Barison A
        • Castiglione V
        • Vergaro G
        • Giannoni A
        • Passino C
        • Merlini G
        Treatment of cardiac transthyretin amyloidosis: an update.
        Eur Heart J. 2019; 40: 3699-3706
        • Zhang KW
        • Stockerl-Goldstein KE
        • Lenihan DJ
        Emerging therapeutics for the treatment of light chain and transthyretin amyloidosis.
        JACC Basic Transl Sci. 2019; 4: 438-448
        • Aimo A
        • Buda G
        • Fontana M
        • Barison A
        • Vergaro G
        • Emdin M
        • Merlini G
        Therapies for cardiac light chain amyloidosis: An update.
        Int J Cardiol. 2018; 271: 152-160
        • Gillmore JD
        • Maurer MS
        • Falk RH
        • Merlini G
        • Damy T
        • Dispenzieri A
        • Wechalekar AD
        • Berk JL
        • Quarta CC
        • Grogan M
        • Lachmann HJ
        • Bokhari S
        • Castano A
        • Dorbala S
        • Johnson GB
        • Glaudemans AW
        • Rezk T
        • Fontana M
        • Palladini G
        • Milani P
        • Guidalotti PL
        • Flatman K
        • Lane T
        • Vonberg FW
        • Whelan CJ
        • Moon JC
        • Ruberg FL
        • Miller EJ
        • Hutt DF
        • Hazenberg BP
        • Rapezzi C
        • Hawkins PN
        Nonbiopsy diagnosis of cardiac transthyretin amyloidosis.
        Circulation. 2016; 133: 2404-2412
        • Baggiano A
        • Boldrini M
        • Martinez-Naharro A
        • Kotecha T
        • Petrie A
        • Rezk T
        • Gritti M
        • Quarta C
        • Knight DS
        • Wechalekar AD
        • Lachmann HJ
        • Perlini S
        • Pontone G
        • Moon JC
        • Kellman P
        • Gillmore JD
        • Hawkins PN
        • Fontana M
        Noncontrast magnetic resonance for the diagnosis of cardiac amyloidosis.
        JACC Cardiovasc Imaging. 2020; 13: 69-80
        • Lecadet A
        • Bachmeyer C
        • Buob D
        • Cez A
        • Georgin-Lavialle S
        Minor salivary gland biopsy is more effective than normal appearing skin biopsy for amyloid detection in systemic amyloidosis: A prospective monocentric study.
        Eur J Intern Med. 2018; 57: e20-e21
        • González-Calle V
        • Mateos MV.
        Monoclonal gammopathies of unknown significance and smoldering myeloma: Assessment and management of the elderly patients.
        Eur J Intern Med. 2018; 58: 57-63
        • Shephard DA.
        The 1975 Declaration of Helsinki and consent.
        Can Med Assoc J. 1976; 115: 1191-1192
        • Brignole M
        • Auricchio A
        • Baron-Esquivias G
        • Bordachar P
        • Boriani G
        • Breithardt OA
        • Cleland J
        • Deharo JC
        • Delgado V
        • Elliott PM
        • Gorenek B
        • Israel CW
        • Leclercq C
        • Linde C
        • Mont L
        • Padeletti L
        • Sutton R
        • Vardas PE
        • Zamorano JL
        • Achenbach S
        • Baumgartner H
        • Bax JJ
        • Bueno H
        • Dean V
        • Deaton C
        • Erol C
        • Fagard R
        • Ferrari R
        • Hasdai D
        • Hoes AW
        • Kirchhof P
        • Knuuti J
        • Kolh P
        • Lancellotti P
        • Linhart A
        • Nihoyannopoulos P
        • Piepoli MF
        • Ponikowski P
        • Sirnes PA
        • Tamargo JL
        • Tendera M
        • Torbicki A
        • Wijns W
        • Windecker S
        • Kirchhof P
        • Blomstrom-Lundqvist C
        • Badano LP
        • Aliyev F
        • Bänsch D
        • Baumgartner H
        • Bsata W
        • Buser P
        • Charron P
        • Daubert JC
        • Dobreanu D
        • Faerestrand S
        • Hasdai D
        • Hoes AW
        • Le Heuzey JY
        • Mavrakis H
        • McDonagh T
        • Merino JL
        • Nawar MM
        • Nielsen JC
        • Pieske B
        • Poposka L
        • Ruschitzka F
        • Tendera M
        • Van Gelder IC
        • Wilson CM
        • ESC Committee for Practice Guidelines (CPG)
        • Document Reviewers
        ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA).
        Eur Heart J. 2013; 34: 2281-2329
        • Cohn JN
        • Levine TB
        • Olivari MT
        • Garberg V
        • Lura D
        • Francis GS
        • Simon AB
        • Rector T
        Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure.
        N Engl J Med. 1984; 311: 819-823
        • Packer M.
        The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure.
        J Am Coll Cardiol. 1992; 20: 248-254
        • Packer M.
        Evolution of the neurohormonal hypothesis to explain the progression of chronic heart failure.
        Eur Heart J. 1995; 16 (Suppl F): 4-6
        • Senni M
        • Paulus WJ
        • Gavazzi A
        • Fraser AG
        • Díez J
        • Solomon SD
        • Smiseth OA
        • Guazzi M
        • Lam CS
        • Maggioni AP
        • Tschöpe C
        • Metra M
        • Hummel SL
        • Edelmann F
        • Ambrosio G
        • Stewart Coats AJ
        • Filippatos GS
        • Gheorghiade M
        • Anker SD
        • Levy D
        • Pfeffer MA
        • Stough WG
        • Pieske BM
        New strategies for heart failure with preserved ejection fraction: the importance of targeted therapies for heart failure phenotypes.
        Eur Heart J. 2014; 35: 2797-2815
        • Verloop WL
        • Beeftink MM
        • Santema BT
        • Bots ML
        • Blankestijn PJ
        • Cramer MJ
        • Doevendans PA
        • Voskuil M
        A systematic review concerning the relation between the sympathetic nervous system and heart failure with preserved left ventricular ejection fraction.
        PLoS One. 2015; 10e0117332
        • 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
        • Vergaro G
        • Aimo A
        • Prontera C
        • Ghionzoli N
        • Arzilli C
        • Zyw L
        • Taddei C
        • Gabutti A
        • Poletti R
        • Giannoni A
        • Mammini C
        • Spini V
        • Passino C
        • Emdin M
        Sympathetic and renin-angiotensin-aldosterone system activation in heart failure with preserved, mid-range and reduced ejection fraction.
        Int J Cardiol. 2019; 296: 91-97
        • Floras JS.
        Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure.
        J Am Coll Cardiol. 1993; 22: 72a-84a
        • Kawano H
        • Do YS
        • Kawano Y
        • Starnes V
        • Barr M
        • Law RE
        • Hsueh WA
        Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts.
        Circulation. 2000; 101: 1130-1137
        • Delcayre C
        • Swynghedauw B.
        Molecular mechanisms of myocardial remodeling. The role of aldosterone.
        J Mol Cell Cardiol. 2002; 34: 1577-1584
        • Cohn JN.
        Structural basis for heart failure. Ventricular remodeling and its pharmacological inhibition.
        Circulation. 1995; 91: 2504-2507
        • Nuvolone M
        • Milani P
        • Palladini G
        • Merlini G
        Management of the elderly patient with AL amyloidosis.
        Eur J Intern Med. 2018; 58: 48-56
        • Gonzalez-Duarte A.
        Autonomic involvement in hereditary transthyretin amyloidosis (hATTR amyloidosis).
        Clin Auton Res. 2019; 29: 245-251
        • Goldstein DS.
        Cardiac dysautonomia and survival in hereditary transthyretin amyloidosis.
        JACC Cardiovasc Imaging. 2016; 9: 1442-1445
        • Ponikowski P
        • Voors
        • Anker AA
        • Bueno SD
        • Cleland H
        • Coats JGF
        • Falk AJS
        • González-Juanatey V
        • Harjola JR
        • Jankowska VP
        • Jessup EA
        • Linde M
        • Nihoyannopoulos C
        • Parissis P
        • Pieske JT
        • Riley B
        • Rosano JP
        • Ruilope GMC
        • Ruschitzka LM
        • Rutten F
        • van der FH
        • Meer P
        • ESC Scientific Document Group
        ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.
        Eur Heart J. 2016; 37: 2129-2200
        • Baek S
        • Park SH
        • Won E
        • Park YR
        • Kim HJ
        Propensity score matching: a conceptual review for radiology researchers.
        Korean J Radiol. 2015; 16: 286-296