Inhibition of Myeloperoxidase to Treat Left Ventricular Dysfunction in Non-Ischaemic Cardiomyopathy
Year: 2024
Type: article
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.
DOI: 10.1002/ejhf.3435
Authors: 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
Institutions: University of Cologne, University Hospital Cologne, Heinrich Heine University Düsseldorf, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, University Hospitals of the Ruhr-University of Bochum, Heart and Diabetes Center North Rhine-Westphalia, Ruhr University Bochum, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,250
OpenAlex ID: W4402054504