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

Simon Geissen; Simon Braumann; Joana Adler; Felix Sebastian Nettersheim; Dennis Mehrkens; Alexander Hof; Henning Guthoff; Philipp von Stein; Sven Witkowski; Norbert Gerdes; Frederik Tellkamp; Marcus Krüger; Lea Isermann; Aleksandra Trifunovic; Alexander C Bunck; Martin Mollenhauer; Holger Winkels; Matti Adam; Anna Klinke; Gregor Buch; Vincent Ten Cate; Martin Hellmich; Malte Kelm; Volker Rudolph; Philipp S Wild; Stephan Rosenkranz; Stephan Baldus

doi:10.1002/ejhf.3435

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

Eur J Heart Fail. 2024 Aug 30. doi: 10.1002/ejhf.3435. Online ahead of print.

Authors

Simon Geissen^#^{1

2

3}, Simon Braumann^#^{1

2

3}, Joana Adler¹, Felix Sebastian Nettersheim^{1

3}, Dennis Mehrkens^{1

2

3}, Alexander Hof^{1

3}, Henning Guthoff^{1

3}, Philipp von Stein¹, Sven Witkowski⁴, Norbert Gerdes⁴, Frederik Tellkamp^{5

6}, Marcus Krüger^{5

6}, Lea Isermann^{2

5}, Aleksandra Trifunovic⁵, Alexander C Bunck⁷, Martin Mollenhauer^{1

2

3}, Holger Winkels^{1

2

3}, Matti Adam^{1

2

3}, Anna Klinke⁸, Gregor Buch⁹, Vincent Ten Cate⁹, Martin Hellmich¹⁰, Malte Kelm⁴, Volker Rudolph⁸, Philipp S Wild⁹, Stephan Rosenkranz^{1

2

3}, Stephan Baldus^{1

2

3}

Affiliations

¹ Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany.
² Cologne Cardiovascular Research Center (CCRC), University of Cologne, Cologne, Germany.
³ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
⁴ Division of Cardiology, Pulmonology, and Vascular Medicine, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
⁵ 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.
⁶ University of Cologne, Department of Biology, Institute for Genetics, Cologne, Germany.
⁷ Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸ 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.
⁹ Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
¹⁰ Institute of Medical Statistics and Computational Biology (IMSB), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.

^# Contributed equally.

PMID: 39212229
DOI: 10.1002/ejhf.3435

Abstract

Aims: 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.

Methods and results: 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^-/-mice, n = 8, p = 0.006, data expressed as mean ± standard error of the mean) and improved left ventricular function (LVEF 30.3 ± 2.2% in NICMP vs. 40.7 ± 1.1% in NICMP/Mpo^-/- mice, n = 16, p < 0.0001). Four patients diagnosed with NICMP and treated with an MPO inhibitor over 12 weeks showed increase in LVEF, decline in natriuretic peptides and improved 6-min walking distance. MPO inhibitor-related changes in the proteome of NICMP patients predicted reduced mortality when related to the changes in the proteome of the above referenced cardiovascular health cohort.

Conclusions: 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.

Keywords: Endothelial dysfunction; HFrEF; Heart failure; Myeloperoxidase; Non‐ischaemic cardiomyopathy; Prognosis.

Abstract

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