Abstract 13192: Local Delivery of Thrombin Inhibiting Nanoparticles Preserves Cardiac Function and Modulates NLRP3 Inflammasome Processes in Acute Myocardial Infarction

Introduction:The role of thrombin in acute myocardial infarction (AMI) has been well described, with recent attention having turned to its effect on NLRP3 inflammasome activation and the role that plays in the pathogenesis of AMI. Perfluorocarbon nanoparticles conjugated to phenylalanine-proline-arginine-chloromethylketone (PPACK NPs) are extremely potent local inhibitors of thrombin, but their role in therapy for AMI remains unclear. We hypothesize that pre-treatment with sustained locally acting PPACK NPs preserves cardiac function by attenuating thrombin-induced inflammatory processes, including those driven by the NLRP3 inflammasome.Methods:Nine mice underwent left anterior descending (LAD) occlusion for 45 minutes. At 30 minutes before LAD occlusion, mice were injected with PPACK (n=5) or control NPs (n=4). 24 hours post-reperfusion, hearts were excised and perfused. LAD was re-occluded and Lectin-488 perfused through the excised heart. Echo was performed pre- and post-reperfusion to assess cardiac function. Hearts were sectioned for follow up histological and protein analysis.Results:PPACK NP treated mice exhibited evidence of preserved cardiac function 24 hours post-reperfusion (Figure 1, A-B), reduced nuclear translocation of p65 in infarcted myocardium (Figure 1, C-D), and reduced inflammatory markers with better vessel preservation in the area adjacent to uninjured myocardium (Figure 1, E-F). The PPACK NP group also demonstrated suppression of NLRP3 inflammasome activation (Figure 2).Conclusion:Local inhibition of thrombin with anti-inflammatory PPACK NPs preserves cardiac function when administered systemically as pre-treatment.