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

van Hout, Gerardus P. J., Bosch, Lena, Ellenbroek, Guilielmus H. J. M., de Haan, Judith J., van Solinge, Wouter W., Cooper, Matthew A., Arslan, Fatih, de Jager, Saskia C. A., Robertson, Avril A. B., Pasterkamp, Gerard and Hoefer, Imo E. (2016) The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction. European Heart Journal, 38 11: 1-10. doi:10.1093/eurheartj/ehw247


Author van Hout, Gerardus P. J.
Bosch, Lena
Ellenbroek, Guilielmus H. J. M.
de Haan, Judith J.
van Solinge, Wouter W.
Cooper, Matthew A.
Arslan, Fatih
de Jager, Saskia C. A.
Robertson, Avril A. B.
Pasterkamp, Gerard
Hoefer, Imo E.
Title The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction
Journal name European Heart Journal   Check publisher's open access policy
ISSN 0195-668X
1522-9645
Publication date 2016-07-17
Year available 2017
Sub-type Article (original research)
DOI 10.1093/eurheartj/ehw247
Open Access Status Not yet assessed
Volume 38
Issue 11
Start page 1
End page 10
Total pages 10
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 2705 Cardiology and Cardiovascular Medicine
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.
Formatted abstract
Aims Myocardial infarction (MI) triggers an intense inflammatory response that is associated with infarct expansion and is detrimental for cardiac function. Interleukin (IL)-1β 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-1β 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.
Keyword Infarct size
Inflammation
Inhibitor
Myocardial infarction
Inflammasome
Cardiac function
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P5.02
Institutional Status UQ
Additional Notes Published online 17 July 2016

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 09 Sep 2016, 01:31:19 EST by Susan Allen on behalf of Institute for Molecular Bioscience