Inhibition of myeloperoxidase to treat left ventricular dysfunction in non-ischaemic cardiomyopathy.

Endothelial dysfunction HFrEF Heart failure Myeloperoxidase Non‐ischaemic cardiomyopathy Prognosis

Journal

European journal of heart failure
ISSN: 1879-0844
Titre abrégé: Eur J Heart Fail
Pays: England
ID NLM: 100887595

Informations de publication

Date de publication:
30 Aug 2024
Historique:
revised: 22 07 2024
received: 10 02 2024
accepted: 05 08 2024
medline: 31 8 2024
pubmed: 31 8 2024
entrez: 30 8 2024
Statut: aheadofprint

Résumé

Non-ischaemic cardiomyopathy (NICMP), an incurable disease terminating in systolic heart failure (heart failure with reduced ejection fraction [HFrEF]), causes immune activation, however anti-inflammatory treatment strategies so far have failed to alter the course of this disease. Myeloperoxidase (MPO), the principal enzyme in neutrophils, has cytotoxic, pro-fibrotic and nitric oxide oxidizing effects. Whether MPO inhibition ameliorates the phenotype in NICMP remains elusive. Prognostic information from MPO was derived from proteomic data of a large human cardiovascular health cohort (n = 3289). In a murine model of NICMP, we studied the mechanisms of MPO in this disease. In a case series, the MPO inhibitor was also evaluated in NICMP patients. Individuals with increased MPO revealed higher long-term mortality and worsening of heart failure, with impaired prognosis when MPO increased during follow-up. MPO infusion attenuated left ventricular ejection fraction (LVEF) in mice with NICMP, whereas genetic ablation or inhibition of MPO decreased systemic vascular resistance (SVR, 9.4 ± 0.7 mmHg*min/ml in NICMP vs. 6.7 ± 0.8 mmHg*min/ml in NICMP/Mpo Myeloperoxidase predicts long-term outcome in HFrEF and its inhibition elicits systemic anti-inflammatory and vasodilating effects which translate into improved left ventricular function. MPO inhibition deserves further evaluation as a novel, complementary treatment strategy for HFrEF.

Identifiants

DOI: 10.1002/ejhf.3435 PMID: 39212229
pubmed: 39212229
doi: 10.1002/ejhf.3435
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Deutsche Forschungsgemeinschaft
ID : 360043781
Organisme : Deutsche Forschungsgemeinschaft
ID : 397484323
Organisme : Deutsche Forschungsgemeinschaft
ID : 236177352
Organisme : Deutsche Forschungsgemeinschaft
ID : RU1678/3-3
Organisme : Deusche Forschungsgemeinschaft
ID : MO 3438/2-1
Organisme : Center for Molecular Medicine Cologne, University of Cologne
ID : 344/2019
Organisme : Center for Molecular Medicine Cologne, University of Cologne
ID : 363/2020
Organisme : Center for Molecular Medicine Cologne, University of Cologne
ID : 358/2021
Organisme : AstraZeneca (Wedel, Germany)

Informations de copyright

© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

Références

Lam CSP, Gamble GD, Ling LH, Sim D, Leong KTG, Yeo PSD, et al. Mortality associated with heart failure with preserved vs. reduced ejection fraction in a prospective international multi‐ethnic cohort study. Eur Heart J 2018;39:1770–1780. https://doi.org/10.1093/eurheartj/ehy005
Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 2012;60:1455–1469. https://doi.org/10.1016/j.jacc.2011.11.082
Murphy SP, Kakkar R, McCarthy CP, Januzzi JL. Inflammation in heart failure: JACC state‐of‐the‐art review. J Am Coll Cardiol 2020;75:1324–1340. https://doi.org/10.1016/j.jacc.2020.01.014
Ali M, Pulli B, Courties G, Tricot B, Sebas M, Iwamoto Y, et al. Myeloperoxidase inhibition improves ventricular function and remodeling after experimental myocardial infarction. JACC Basic Transl Sci 2016;1:633–643. https://doi.org/10.1016/j.jacbts.2016.09.004
Askari AT, Brennan ML, Zhou X, Drinko J, Morehead A, Thomas JD, et al. Myeloperoxidase and plasminogen activator inhibitor 1 play a central role in ventricular remodeling after myocardial infarction. J Exp Med 2003;197:615–624. https://doi.org/10.1084/jem.20021426
Maiocchi SL, Ku J, Thai T, Chan E, Rees MD, Thomas SR. Myeloperoxidase: A versatile mediator of endothelial dysfunction and therapeutic target during cardiovascular disease. Pharmacol Ther 2021;221:107711. https://doi.org/10.1016/j.pharmthera.2020.107711
Abu‐Soud HM, Hazen SL. Nitric oxide modulates the catalytic activity of myeloperoxidase. J Biol Chem 2000;275:5425–5430. https://doi.org/10.1074/jbc.275.8.5425
Vita JA, Brennan M‐L, Gokce N, Mann SA, Goormastic M, Shishehbor MH, et al. Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation 2004;110:1134–1139. https://doi.org/10.1161/01.CIR.0000140262.20831.8F
Cheng D, Talib J, Stanley CP, Rashid I, Michaëlsson E, Lindstedt E‐L, et al. Inhibition of MPO (myeloperoxidase) attenuates endothelial dysfunction in mouse models of vascular inflammation and atherosclerosis. Arterioscler Thromb Vasc Biol 2019;39:1448–1457. https://doi.org/10.1161/ATVBAHA.119.312725
Michaëlsson E, Lund LH, Hage C, Shah SJ, Voors AA, Saraste A, et al. Myeloperoxidase inhibition reverses biomarker profiles associated with clinical outcomes in HFpEF. JACC Heart Fail 2023;11:775–787. https://doi.org/10.1016/j.jchf.2023.03.002
Hoonhorst SJM, Timens W, Koenderman L, Lo Tam Loi AT, Lammers JWJ, Boezen HM, et al. Increased activation of blood neutrophils after cigarette smoking in young individuals susceptible to COPD. Respir Res 2014;15:121. https://doi.org/10.1186/s12931‐014‐0121‐2
Zhang R, Brennan ML, Fu X, Aviles RJ, Pearce GL, Penn MS, et al. Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001;286:2136–2142. https://doi.org/10.1001/jama.286.17.2136
Siedlinski M, Jozefczuk E, Xu X, Teumer A, Evangelou E, Schnabel RB, et al. White blood cells and blood pressure: A Mendelian randomization study. Circulation 2020;141:1307–1317. https://doi.org/10.1161/CIRCULATIONAHA.119.045102
Piek A, Koonen DPY, Schouten EM, Lindtstedt EL, Michaëlsson E, de Boer RA, et al. Pharmacological myeloperoxidase (MPO) inhibition in an obese/hypertensive mouse model attenuates obesity and liver damage, but not cardiac remodeling. Sci Rep 2019;9:18765. https://doi.org/10.1038/s41598‐019‐55263‐y
Göbel S, Prochaska JH, Tröbs SO, Panova‐Noeva M, Espinola‐Klein C, Michal M, et al. Rationale, design and baseline characteristics of the MyoVasc study: A prospective cohort study investigating development and progression of heart failure. Eur J Prev Cardiol 2021;28:1009–1018. https://doi.org/10.1177/2047487320926438
Bozkurt B, Coats AJS, Tsutsui H, Abdelhamid CM, Adamopoulos S, Albert N, et al. Universal definition and classification of heart failure: A report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur J Heart Fail 2021;23:352–380. https://doi.org/10.1002/ejhf.2115
Arber S, Hunter JJ, Ross J, Hongo M, Sansig G, Borg J, et al. MLP‐deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 1997;88:393–403. https://doi.org/10.1016/s0092‐8674(00)81878‐4
Brennan ML, Anderson MM, Shih DM, Qu XD, Wang X, Mehta AC, et al. Increased atherosclerosis in myeloperoxidase‐deficient mice. J Clin Invest 2001;107:419–430. https://doi.org/10.1172/JCI8797
Knöll R, Kostin S, Klede S, Savvatis K, Klinge L, Stehle I, et al. A common MLP (muscle LIM protein) variant is associated with cardiomyopathy. Circ Res 2010;106:695–704. https://doi.org/10.1161/CIRCRESAHA.109.206243
Ramachandra CJA, Kp MMJ, Chua J, Hernandez‐Resendiz S, Liehn EA, Knöll R, et al. Inhibiting cardiac myeloperoxidase alleviates the relaxation defect in hypertrophic cardiomyocytes. Cardiovasc Res 2022;118:517–530. https://doi.org/10.1093/cvr/cvab077
Chrysanthopoulou A, Gkaliagkousi E, Lazaridis A, Arelaki S, Pateinakis P, Ntinopoulou M, et al. Angiotensin II triggers release of neutrophil extracellular traps, linking thromboinflammation with essential hypertension. JCI Insight 2021;6:e148668. https://doi.org/10.1172/jci.insight.148668
Baldus S, Rudolph V, Roiss M, Ito WD, Rudolph TK, Eiserich JP, et al. Heparins increase endothelial nitric oxide bioavailability by liberating vessel‐immobilized myeloperoxidase. Circulation 2006;113:1871–1878. https://doi.org/10.1161/CIRCULATIONAHA.105.590083
Mann DL, McMurray JJV, Packer M, Swedberg K, Borer JS, Colucci WS, et al. Targeted anticytokine therapy in patients with chronic heart failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594–1602. https://doi.org/10.1161/01.CIR.0000124490.27666.B2
Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double‐blind, placebo‐controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor‐alpha, in patients with moderate‐to‐severe heart failure: Results of the anti‐TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 2003;107:3133–3140. https://doi.org/10.1161/01.CIR.0000077913.60364.D2
Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, et al. Anti‐inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 2019;139:1289–1299. https://doi.org/10.1161/CIRCULATIONAHA.118.038010
Abbate A, Wohlford GF, Del Buono MG, Chiabrando JG, Markley R, Turlington J, et al. Interleukin‐1 blockade with anakinra and heart failure following ST‐segment elevation myocardial infarction: Results from a pooled analysis of the VCUART clinical trials. Eur Heart J Cardiovasc Pharmacother 2022;8:503–510. https://doi.org/10.1093/ehjcvp/pvab075
van Tassell BW, Canada J, Carbone S, Trankle C, Buckley L, Oddi Erdle C, et al. Interleukin‐1 blockade in recently decompensated systolic heart failure: Results from REDHART (Recently Decompensated Heart Failure Anakinra Response Trial). Circ Heart Fail 2017;10:e004373. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004373
Nakayama T, Sugano Y, Yokokawa T, Nagai T, Matsuyama TA, Ohta‐Ogo K, et al. Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy. Eur J Heart Fail 2017;19:490–498. https://doi.org/10.1002/ejhf.767
Zhang H, Xu A, Sun X, Yang Y, Zhang L, Bai H, et al. Self‐maintenance of cardiac resident reparative macrophages attenuates doxorubicin‐induced cardiomyopathy through the SR‐A1‐c‐Myc axis. Circ Res 2020;127:610–627. https://doi.org/10.1161/CIRCRESAHA.119.316428
Rudolph V, Andrié RP, Rudolph TK, Friedrichs K, Klinke A, Hirsch‐Hoffmann B, et al. Myeloperoxidase acts as a profibrotic mediator of atrial fibrillation. Nat Med 2010;16:470–474. https://doi.org/10.1038/nm.2124
Schrier RW, Abraham WT. Hormones and hemodynamics in heart failure. N Engl J Med 1999;341:577–585. https://doi.org/10.1056/NEJM199908193410806
Rudolph TK, Wipper S, Reiter B, Rudolph V, Coym A, Detter C, et al. Myeloperoxidase deficiency preserves vasomotor function in humans. Eur Heart J 2012;33:1625–1634. https://doi.org/10.1093/eurheartj/ehr193
Lund LH, Lam CSP, Pizzato PE, Gabrielsen A, Michaëlsson E, Nelander K, et al. Rationale and design of ENDEAVOR: A sequential phase 2b‐3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction. Eur J Heart Fail 2023;25:1696–1707. https://doi.org/10.1002/ejhf.2977
Kitahara M, Eyre HJ, Simonian Y, Atkin CL, Hasstedt SJ. Hereditary myeloperoxidase deficiency. Blood 1981;57:888–893. https://doi.org/10.1182/blood.V57.5.888.888

Auteurs

Simon Geissen (S)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Simon Braumann (S)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Joana Adler (J)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.

Felix Sebastian Nettersheim (FS)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Dennis Mehrkens (D)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Alexander Hof (A)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Henning Guthoff (H)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Philipp von Stein (P)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.

Sven Witkowski (S)

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Norbert Gerdes (N)

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Frederik Tellkamp (F)

Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, Germany.
University of Cologne, Department of Biology, Institute for Genetics, Cologne, Germany.

Marcus Krüger (M)

Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, Germany.
University of Cologne, Department of Biology, Institute for Genetics, Cologne, Germany.

Lea Isermann (L)

Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, Germany.

Aleksandra Trifunovic (A)

Cologne Excellence Cluster on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Institute for Mitochondrial Diseases and Ageing, Medical Faculty, University of Cologne, Cologne, Germany.

Alexander C Bunck (AC)

Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Martin Mollenhauer (M)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Holger Winkels (H)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Matti Adam (M)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Anna Klinke (A)

Agnes Wittenborg Institute for Translational Cardiovascular Research, Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, University Hospital of the Ruhr-Universität Bochum, Bad Oeynhausen, Germany.

Gregor Buch (G)

Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Vincent Ten Cate (V)

Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Martin Hellmich (M)

Institute of Medical Statistics and Computational Biology (IMSB), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

Malte Kelm (M)

Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.

Volker Rudolph (V)

Agnes Wittenborg Institute for Translational Cardiovascular Research, Clinic for General and Interventional Cardiology/Angiology, Herz- und Diabeteszentrum NRW, University Hospital of the Ruhr-Universität Bochum, Bad Oeynhausen, Germany.

Philipp S Wild (PS)

Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Stephan Rosenkranz (S)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Stephan Baldus (S)

Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.

Classifications MeSH