Despite timely reperfusion of an occluded coronary artery by primary percutaneous coronary intervention (PCI), many patients with myocardial infarction (MI) continue to develop myocardial injury and progress to heart failure. This damage is increasingly attributed to impaired perfusion at the level of the coronary microcirculation. Using real-time intravital imaging of the mouse beating heart in vivo, we have previously described multiple microcirculatory disturbances following myocardial ischaemia-reperfusion (IR) injury, with platelet-rich microthrombi emerging as key contributors to reduced functional capillary density [1].  This presentation will outline the intravital and laser speckle contrast imaging (LSCI) methodologies used to enable high-resolution imaging of the anaesthetised mouse beating heart (anaesthesia: ketamine hydrochloride and medetomidine hydrochloride) and describe the spectrum of thromboinflammatory and perfusion related microvascular perturbations observed during myocardial IR injury [2].  All procedures described received local approval from the Animal Welfare and Ethical Review Body (AWERB) and were conducted in accordance with the Animals (Scientific Procedures) Act of 1986 (HO Project licence P552D4447).  The presentation will then address whether contemporary dual antiplatelet therapy (DAPT), widely prescribed post-MI to prevent recurrent ischaemic events and prevent stent thrombosis, confers benefit at the level of the coronary microcirculation. Comparative data following pre-treatment with aspirin in combination with the P2Y12 receptor inhibitors clopidogrel, ticagrelor, or prasugrel will be presented [3].  The findings indicate that, despite partial reductions in capillary microthrombus formation (with variable efficacy between agents), DAPT does not restore ventricular perfusion to pre-injury levels, as assessed by novel application of LSCI to the beating heart. Notably, all DAPT regimens are associated with increased coronary neutrophil recruitment, above that noted with IR injury alone, a response that may exacerbate tissue injury in sterile inflammatory settings and limit salvage of viable myocardium.  To address this, data will be presented exploring inhibition of the pro-inflammatory cytokine interleukin-36 (IL-36), a new member of the IL-1 cytokine family, as a strategy to limit neutrophil infiltration and mitigate microvascular damage [4].  Finally, given the clinical relevance of comorbidities, the presentation will highlight marked differences in basal and post-IR microvascular dysfunction between normoglycaemic and chronically hyperglycaemic mice, and evaluate how DAPT and IL-36R antagonism as monotherapies differentially impact these groups [3,5].