Protective Effects of Therapeutic Neutrophil Depletion and Myeloperoxidase Inhibition on Left Ventricular Function and Remodeling in Myocardial Infarction
Henning Guthoff,
Alexander Hof,
Anna Klinke,
Martina Maaß,
Jürgen Konradi,
Dennis Mehrkens,
Simon Geißen,
Felix S. Nettersheim,
Simon Braumann,
Erik Michaelsson,
Richard J. Nies,
Samuel Lee,
Marie-Christin Redzinski,
Vera B. M. Peters,
Harshal N. Nemade,
Philipp von Stein,
Holger Winkels,
Volker Rudolph,
Stephan Baldus,
Matti Adam,
Martin Mollenhauer
Affiliations
Henning Guthoff
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Alexander Hof
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Anna Klinke
Clinic for General and Interventional Cardiology/Angiology, Agnes Wittenborg Institute for Translational Cardiovascular Research, Herz- und Diabeteszentrum NRW, University Hospital of the Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany
Martina Maaß
Division of Dry-Eye and Ocular GVHD, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany
Jürgen Konradi
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Dennis Mehrkens
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Simon Geißen
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Felix S. Nettersheim
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Simon Braumann
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Erik Michaelsson
Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Z4-46798 Gothenburg, Sweden
Richard J. Nies
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Samuel Lee
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Marie-Christin Redzinski
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Vera B. M. Peters
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Harshal N. Nemade
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Philipp von Stein
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Holger Winkels
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Volker Rudolph
Clinic for General and Interventional Cardiology/Angiology, Agnes Wittenborg Institute for Translational Cardiovascular Research, Herz- und Diabeteszentrum NRW, University Hospital of the Ruhr-Universität Bochum, 32545 Bad Oeynhausen, Germany
Stephan Baldus
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Matti Adam
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Martin Mollenhauer
Department for Experimental Cardiology, Faculty of Medicine, University of Cologne, and Clinic III for Internal Medicine, University Hospital Cologne, 50937 Cologne, Germany
Myocardial infarction (MI) is a leading cause of morbidity and mortality worldwide. Improved survival has led to an increasing incidence of ischemic cardiomyopathy, making it a major reason for hospitalization in the western world. The inflammatory response in the ischemic myocardium determines the extent of structural remodeling and functional deterioration, with neutrophils (PMN) being a key modulator of the propagation and resolution of inflammation. The heme enzyme myeloperoxidase (MPO) is abundantly expressed in PMN and is an important mediator of their inflammatory capacities. Here, we examine the effects of PMN reduction, MPO deficiency and MPO inhibition in two murine models of MI. Reduction in PMN count resulted in less scar formation and improved cardiac function. Similar results were obtained in genetically MPO deficient mice, suggesting that MPO is a critical factor in PMN-mediated cardiac remodeling. To test our findings in a therapeutic approach, we orally administered the MPO inhibitor AZM198 in the context of MI and could demonstrate improved cardiac function and reduced structural remodeling. Therefore, MPO appears to be a favorable pharmacological target for the prevention of long-term morbidity after MI.
