Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

Myeloperoxidase is a central mediator of Anthracycline-induced Cardiomyopathy
W. Kreuzberg1, F. Nettersheim1, D. Schlüter1, S. Geißen1, D. Mehrkens1, S. Braumann1, A. Hof2, H. Nemade3, M. Torun3, J. Kargapolova1, R. J. Nies4, M. Adam1, H. Winkels1, S. Baldus5, M. Mollenhauer1
1Klinik III für Innere Medizin, Herzzentrum der Universität zu Köln, Köln; 2Herzzentrum - Kardiologie, Universitätsklinikum Köln, Köln; 3Klinik III für Innere Medizin - Experimentelle Kardiologie, Universitätsklinikum Köln, Köln; 4Klinik III für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin, Universitätsklinikum Köln, Köln; 5Klinik für Kardiologie, Angiologie, Pneumologie und Internistische Intensivmedizin, Herzzentrum der Universität zu Köln, Köln;
Background: Cardiotoxicity is a major complication of anthracycline therapy, which affects up to 10% of patients exposed to current chemotherapeutic regimens and negatively impacts prognosis. Despite the increasing number of cancer survivors, effective pharmacotherapies for prevention of anthracycline-induced cardiomyopathy (AICM) are currently lacking. Increased plasma levels of myeloperoxidase (MPO), a heme enzyme released by activated polymorphonuclear neutrophils, predict occurrence of cardiac dysfunction in patients treated with anthracyclines. Accordingly, prolonged cardiac neutrophil-infiltration was identified as a central contributor to AICM in a murine disease model. Yet, the specific mechanisms by which neutrophils mediate AICM have not yet been clarified. We hypothesized that the observed contribution of infiltrating neutrophils to AICM might be primarily driven by release of MPO.

Methods and Results: Doxorubicin (DOX; 20 mg/kg bodyweight), a prototype anthracycline, or sodium chloride (NaCl) were administered intravenously to eight- to twelve-week-old myeloperoxidase-deficient (Mpo-/-) mice on C57BL/6J background and wildtype littermates through a jugular vein catheter. Seven days after treatment, cardiac function was determined by echocardiography and organs were collected for further analysis. In line with previous data, DOX-treated animals exhibited higher frequencies of blood and cardiac neutrophils compared to NaCl-treated controls. Additionally, plasma and cardiac MPO levels were increased upon DOX-administration. Neutrophil-like HL-60 cells exhibited increased MPO release and expression of the activation marker CD11b upon exposition to DOX in vitro as compared to control treatment, indicating that DOX directly activates neutrophils. DOX induced extensive oxidative and nitrosative stress in cardiac tissue and, more specifically, carbonylation of sarcomeric proteins, which has been implicated in impairment of cardiac contractility. Mpo-/- mice were protected from DOX-induced nitrosative stress and carbonylation of sarcomeric proteins. Additionally, co-treatment of human induced pluripotent stem cell-derived cardiomyocytes (CM) with DOX and MPO in vitro led to a significantly higher reduction of CM-contractility than DOX-treatment alone, indicating that MPO is a critical mediator of DOX-induced oxidative damage and cardiac dysfunction. Furthermore, cardiac tissues from DOX-treated animals exhibited pronounced apoptosis and signs of an inflammatory response, which was characterized by increased macrophage infiltration, NF-κB activation, and expression of several pro-inflammatory cytokines. Mpo-/- mice exhibited significantly reduced cardiac apoptosis and signs of inflammation. Finally, echocardiography revealed that Mpo-/- mice and mice treated with the MPO-inhibitor 4-Aminobenzoic acid hydrazide were protected from the development of DOX-induced cardiac dysfunction.

Conclusions: Herein we identified MPO as a critical mediator of AICM. In line with previous data, we demonstrate that DOX triggers cardiac neutrophil infiltration and induces MPO release. Moreover, we show that MPO directly impairs cardiac contractility trough oxidation of sarcomeric proteins, triggers cardiac inflammation and thus enhances cardiomyocyte apoptosis. Considering that an orally administrable MPO inhibitor has been developed and proved to be safe in early clinical trials, MPO emerges as a promising pharmacological target for prevention of AICM.

https://dgk.org/kongress_programme/jt2022/aP1255.html