{
  "abstract": "Introduction Muscle damage and heart failure still occurs in a significant proportion of MI patients despite successful primary percutaneous coronary intervention (PCI), with poorer outcomes observed in patients with type-2 diabetes (T2D). This may be due to unresolved problems and inadequate perfusion in the coronary microcirculation. We have previously used intravital microscopy and laser speckle contrast imaging (LSCI) to identify multiple microvascular perturbations in the anaesthetised mouse beating heart in vivo. Platelet-rich microthrombi were amongst the main contributors to reduced functional capillary density (FCD) in the immediate aftermath of reperfusion. Therefore, this study tested whether clinically relevant dual anti-platelet therapies (DAPTs) had any beneficial effects at the level of the coronary microcirculation and whether they remained effective in the setting of chronic hyperglycaemia. Alternative approaches were also tested including platelet GPIbα receptor inhibition and the thrombin inhibitor dabigatran.Methods Mice were pre-treated with aspirin combined with ticagrelor, clopidogrel or prasugrel, an anti-GPIb receptor antibody or dabigatran. Myocardial ischaemia-reperfusion (IR) injury was performed in anaesthetised mice (ketamine hydrochloride and medetomidine hydrochloride) after temporary ligation of the LAD coronary artery. Intravital imaging of the stabilised beating heart assessed FCD and platelet, neutrophil and fibrin events in vivo. LSCI assessed overall left ventricular perfusion in the beating heart. Some mice were fed a high fat diet for 16 weeks to induce an obesity-related chronic hyperglycaemia. Infarct size was measured using Evans blue stain and triphenyl tetrazolium chloride staining.Results Both platelet microthrombus formation, neutrophil adhesion and fibrin deposition rapidly and significantly increased post-reperfusion, primarily within coronary capillaries. Only DAPT with prasugrel, anti-GPIb antibody and dabigatran reduced, but not abolished, microthrombus formation. Surprisingly, most therapies increased neutrophil recruitment above that observed in vehicle treated IR injured hearts, especially DAPT with clopidogrel and ticagrelor. IR injury reduced ventricular perfusion and FCD neither of which were restored to baseline levels with any therapy tested. Remarkable increases in microthrombus formation and neutrophil infiltration were observed in HFD-fed mice. Despite this, DAPT with prasugrel, which was selected for further assessment in these chronically hyperglycaemic mice, demonstrated a remarkable ability to decrease both. Interestingly, ventricular perfusion and FCD was also restored in HFD-fed mice receiving DAPT with prasugrel. However, whilst this therapy reduced infarct size in normal diet-fed mice, it failed to modify the larger infarcts in HFD-fed mice.Conclusion DAPTs failed to fully abolish microthrombus formation at the level of the coronary microcirculation and did not improve ventricular perfusion in IR injured hearts. Worryingly, they also enhanced neutrophil infiltration. Nevertheless, they were able to reduce infarct size in normoglycaemic mice suggesting their cardioprotective benefit may be conferred through a mechanism independent of vasculoprotective effects in the microcirculation. In contrast, whilst reducing the remarkable platelet and neutrophil presence in chronically hyperglycaemic mice, DAPTs did not impact the larger infarcts in these mice suggesting alternative therapies are needed to cardioprotect in the setting of a diabetic co-morbidity.",
  "authors": [
    {
      "affiliations": [
        "Department of Cardiovascular Sciences, University of Birmingham"
      ],
      "name": "Neena Kalia"
    }
  ],
  "title": "BS25 Testing whether DAPTS offer any vasculoprotective benefit at the level of the coronary microcirculation in vivo",
  "uid": "bf210c79-8d15-51ae-848a-15271eb1b448"
}