The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction

Abstract

Aims Myocardial infarction (MI) triggers an intense inflammatory response that is associated with infarct expansion and is detrimental for cardiac function. Interleukin (IL)-1b and IL-18 are key players in this response and are controlled by the NLRP3-inflammasome. In the current study, we therefore hypothesized that selective inhibition of the NLRP3-inflammasome reduces infarct size and preserves cardiac function in a porcine MI model. Methods and results Thirty female landrace pigs were subjected to 75 min transluminal balloon occlusion and treated with the NLRP3-inflammasome inhibitor MCC950 (6 or 3 mg/kg) or placebo for 7 days in a randomized, blinded fashion. After 7 days, 3D-echocardiography was performed to assess cardiac function and Evans blue/TTC double staining was executed to assess the area at risk (AAR) and infarct size (IS). The IS/AAR was lower in the 6 mg/kg group (64.6+8.8%, P = 0.004) and 3 mg/kg group (69.7+7.2%, P = 0.038) compared with the control group (77.5+6.3%). MCC950 treatment markedly preserved left ventricular ejection fraction in treated animals (6 mg/kg 47+8%, P = 0.001; 3 mg/kg 45+7%, P = 0.031; control 37+6%). Myocardial neutrophil influx was attenuated in treated compared with non-treated animals (6 mg/kg 132+72 neutrophils/ mm2, P = 0.035; 3 mg/kg 207+210 neutrophils/mm2, P = 0.5; control 266+158 neutrophils/mm2). Myocardial IL-1b levels were dose-dependently reduced in treated animals. Conclusions NLRP3-inflammasome inhibition reduces infarct size and preserves cardiac function in a randomized, blinded translational large animal MI model. Hence, NLRP3-inflammasome inhibition may have therapeutic potential in acute MI patients.