| Autor: |
Silvis MJM; Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.; Department of Cardiology, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands., Demkes EJ; Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.; Circulatory Health Laboratory, UMC Utrecht Regenerative Medicine Center, University Utrecht, 3508 GA Utrecht, The Netherlands., Timmers L; Department of Cardiology, St. Antonius Hospital, 3430 EM Nieuwegein, The Netherlands., Arslan F; Department of Cardiology, St. Antonius Hospital, 3430 EM Nieuwegein, The Netherlands., de Jager SCA; Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., Sluijter JPG; Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.; Circulatory Health Laboratory, UMC Utrecht Regenerative Medicine Center, University Utrecht, 3508 GA Utrecht, The Netherlands., Mosterd A; Meander Medical Center, Department of Cardiology, 3818 ES Amersfoort, The Netherlands., de Kleijn DPV; Department of Vascular Surgery, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands., Bosch L; Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.; Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands., van Hout GPJ; Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.; Laboratory of Experimental Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands. |
| Abstrakt: |
NLRP3-inflammasome-mediated signaling is thought to significantly contribute to the extent of myocardial damage after myocardial infarction (MI). The purpose of this study was to investigate the effects of the NLRP3-inflammasome inhibitor IZD334 on cardiac damage in a pig model of myocardial infarction. Prior to in vivo testing, in vitro, porcine peripheral blood mononuclear cells and whole blood were treated with increasing dosages of IZD334, a novel NLRP3-inflammasome inhibitor, and were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). After determination of the pharmacological profile in healthy pigs, thirty female Landrace pigs were subjected to 75 min of transluminal balloon occlusion of the LAD coronary artery and treated with placebo or IZD334 (1 mg/kg, 3 mg/kg, or 10 mg/kg once daily) in a blinded randomized fashion. In vitro, NLRP3-inflammasome stimulation showed the pronounced release of interleukin (IL)-1β that was attenuated by IZD334 (p < 0.001). In vivo, no differences were observed between groups in serological markers of inflammation nor myocardial IL-1β expression. After 7 days, the ejection fraction did not differ between groups, as assessed with MRI (placebo: 45.1 ± 8.7%, 1 mg/kg: 49.9 ± 6.1%, 3 mg/kg: 42.7 ± 3.8%, 10 mg/kg: 44.9 ± 6.4%, p = 0.26). Infarct size as a percentage of the area at risk was not reduced (placebo: 73.1 ± 3.0%, 1 mg/kg: 75.5 ± 7.3%, 3 mg/kg: 80.3 ± 3.9%, 10 mg/kg: 78.2 ± 8.0%, p = 0.21). In this pig MI model, we did not observe attenuation of the inflammatory response after NLRP3-inflammasome inhibition in vivo. Consecutively, no difference was observed in IS and cardiac function, while in vitro inhibition successfully reduced IL-1β release from stimulated porcine blood cells. |
