Author:
Geissen Simon,Braumann Simon,Adler Joana,Nettersheim Felix Sebastian,Mehrkens Dennis,Hof Alexander,Guthoff Henning,Stein Philipp von,Witkowski Sven,Gerdes Norbert,Isermann Lea,Trifunovic Aleksandra,Bunck Alexander C.,Mollenhauer Martin,Winkels Holger,Adam Matti,Klinke Anna,Hellmich Martin,Kelm Malte,Rudolph Volker,Rosenkranz Stephan,Baldus Stephan
Abstract
AbstractDilated 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.
Publisher
Cold Spring Harbor Laboratory