title: The selective NLRP3-inflammasome inhibitor MCC950 reduces infarct size and preserves cardiac function in a pig model of myocardial infarction.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Gerardus P J
authors.initials: GP
authors.lastname: van Hout
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Lena
authors.initials: L
authors.lastname: Bosch
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Guilielmus H J M
authors.initials: GH
authors.lastname: Ellenbroek
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Judith J
authors.initials: JJ
authors.lastname: de Haan
authors.affiliation: Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Wouter W
authors.initials: WW
authors.lastname: van Solinge
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Cooper
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Fatih
authors.initials: F
authors.lastname: Arslan
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
authors.forename: Avril A B
authors.initials: AA
authors.lastname: Robertson
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.|Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Experimental Cardiology Laboratory (Room G02.523), University Medical Center Utrecht, Heidelberglaan 100, PO Box 85500, Utrecht 3508 GA, The Netherlands.|Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
mesh_terms: D000818:Animals; D021721:Balloon Occlusion; D015415:Biomarkers / Q000378:metabolism; D004452:Echocardiography / Q000379:methods; D005260:Female; D005663:Furans; D006439:Hemodynamics / Q000502:physiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007192:Indenes; D058847:Inflammasomes / Q000037:antagonists & inhibitors; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000037:antagonists & inhibitors*; D011897:Random Allocation; D013449:Sulfonamides; D013450:Sulfones / Q000494:pharmacology*; D013552:Swine
chemical_list: D015415:Biomarkers; D005663:Furans; D006576:Heterocyclic Compounds, 4 or More Rings; D007192:Indenes; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013449:Sulfonamides; D013450:Sulfones; C000597426:N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide
keywords: Cardiac function; Infarct size; Inflammasome; Inflammation; Inhibitor; Myocardial infarction