Protective Effects of Therapeutic Neutrophil Depletion and Myeloperoxidase Inhibition on Left Ventricular Function and Remodeling in Myocardial Infarction

Abstract

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.

Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities

“…250 Inhibition of MPO (myeloperoxidase) released by neutrophils in the infarct improves cardiac remodeling particularly when initiated within the first 24 hours post-MI. 288,289 In contrast, neutrophil NADPH oxidase deficiency did not influence the infarct size. 290 In analogy to the M1/M2 nomenclature in macrophage polarization, a biphasic response of proinflammatory N1 dominating the inflammatory phase followed by anti-inflammatory CD206+ IL-10 producing N2 neutrophils in the proliferative phase has been proposed.…”

“…Neutrophil depletion restricted to the time of experimentally induced MI improves infarct healing by limiting early inflammation. 289,294 However, prolonged neutrophil depletion during the inflammatory and into the proliferative phase post-MI has detrimental effects. 295 Mechanistically, lack of neutrophil-derived LCN2 inhibits the development of reparative macrophages with high efferocytosis capacity in the late infarct.…”

Remodeling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO

“…LAD ligation was performed as previously described. 58 Mice were anesthetized with isoflurane, received low dose buprenorphine subcutaneously (Essex-Pharma, Munich, Germany; 0.05 mg/kg bodyweight) for analgesia and were placed on a heating pad to regulate body temperature. Following endotracheal intubation, animals were ventilated with 150 strokes/min and stroke volume of 7 μl/g bodyweight (Harvard Apparatus, Holliston, MA, USA).…”

Rationale and design of ENDEAVOR: A sequential phase 2b–3 randomized clinical trial to evaluate the effect of myeloperoxidase inhibition on symptoms and exercise capacity in heart failure with preserved or mildly reduced ejection fraction

“…19,20 Contrasting effects of myeloperoxidase inhibition have been observed in different mouse models of left ventricular dysfunction. [21][22][23] Nevertheless, these modes of action may improve microvascular endothelial function and the function of the heart and other organs (e.g. lungs, kidneys, skeletal muscle) and may improve clinical outcomes in patients with HFpEF and HFmrEF.…”

“…In pre‐clinical studies, myeloperoxidase inhibitors reduce free radical production, systemic inflammation and vascular dysfunction ( Figure ) 19,20 . Contrasting effects of myeloperoxidase inhibition have been observed in different mouse models of left ventricular dysfunction 21–23 . Nevertheless, these modes of action may improve microvascular endothelial function and the function of the heart and other organs (e.g.…”