Dilated cardiomyopathy (DCM), an incurable disease of the cardiomyocyte terminating in systolic heart failure (HFrEF), is prevalent, causes hospitalization and is associated with increased mortality. Despite evidence of immune activation in DCM, anti-inflammatory interventions so far did not prove to alter the course of this disease. Here we show that myeloperoxidase (MPO), the principal heme peroxidase expressed by polymorphonuclear neutrophils (PMN) and monocytes, critically contributes to HFrEF in DCM. Muscle LIM protein (MLP) deficient mice, which spontaneously develop DCM, display increased circulating PMN counts and augmented levels of vessel-immobilized MPO. Genetic ablation and pharmacological inhibition of MPO resulted in enhanced nitric oxide (NO) bioavailability of systemic conductance and resistance vessels, and subsequently restoration of systolic left ventricular (LV) function, whereas infusion of MPO worsened systolic LV function. When patients diagnosed for DCM were treated with an orally available MPO inhibitor, systolic LV function increased, natriuretic peptides declined, and functional status improved. Impairment of endothelial NO bioavailability by release of leukocyte-derived MPO evolves as a disease-aggravating mechanism in DCM. MPO inhibition profoundly improved ventricular function by lowering systemic vascular resistance and thus holds promise as a novel and complementary treatment strategy for patients with DCM.

The authors have declared no competing interest.

EudraCT-No. 2020-002788-80

This work was supported by the Deutsche Forschungsgemeinschaft [GRK 2407 (360043781) to S.G. and D.M., SFB TRR259 (397484323; project A04 to H.W. and S.B.; project A05 to N.G.; project B05 to M.A.; project B06 to S.R.) Grant No. 236177352 CRC1116 (236177352 projects B06, B09) to M.K. and N.G., RU1678/3 3 to V.R., MO 3438/2 1 to M.M.]; the Center for Molecular Medicine Cologne [Baldus B02]; and the Cologne Fortune Program [344/2019 to S.B. (Simon Braumann), 363/2020 to F.S.N., 358/2021 to A.H.]. The clinical phase 2 pilot study was an investigator initiated trial, funded by AstraZeneca (Wedel, Germany).

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The local Ethics Committee of the Medical Faculty of the University of Cologne gave ethical approval for this work (No. 19-1612-AMG-ff). The study is registered as EudraCT-No. 2020-002788-80

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