Mouse Model of Heart Attack and Stroke Shows Improved Survival with MPO Inhibition

Thromboembolic events, including myocardial infarction (MI) or stroke, caused by the rupture or erosion of unstable atherosclerotic plaques are the leading cause of death worldwide[1][1]. Unfortunately, the lack of a mouse model that develops advanced coronary atherosclerosis and that exhibits a high incidence of spontaneous plaque rupture with MI or stroke has greatly stymied development of more effective therapeutic approaches for reducing these events beyond what has been achieved with aggressive lipid lowering. Herein, we describe a novel mouse model that develops widespread advanced atherosclerosis including in coronary, brachiocephalic, and carotid arteries. These mice show high mortality following Western Diet feeding with clear evidence of plaque rupture, MI, and stroke. To validate the utility of this model, mice were treated with the drug candidate AZM198, which inhibits myeloperoxidase, an enzyme primarily produced by activated neutrophils and predictive of rupture of human atherosclerotic lesions[2][2]–[7][3]. AZM198 treatment resulted in marked improvements in survival with a greater than 60% decrease in the incidence of plaque rupture, MI, and stroke. In summary, our work describes a novel mouse model that closely replicates late-stage clinical events of advanced human atherosclerotic disease and evidence that this model can be used to identify and test potential new therapeutic agents to prevent major adverse cardiac events. ### Competing Interest Statement The authors declare the following competing interests: SH, NB, BK and MP are current or former employees of AstraZeneca (and own AZ shares). The MPO inhibitor used in this study (AZM198) was developed by AstraZeneca. AZ has an MPO inhibitor program in clinical development. GKO received partial funding for this project through a research alliance between AstraZeneca and the University of Virginia Robert M. Berne Cardiovascular Research Center. All other authors declare no competing interests. [1]: #ref-1 [2]: #ref-2 [3]: #ref-7