Comparing anti-platelet and anti-thrombin therapies in the ischaemia-reperfusion injured coronary microcirculation of healthy and diabetic mice.

Patients with type 2 diabetes mellitus (T2DM) face increased risk of heart failure after myocardial infarction (MI), despite successful PCI and dual anti-platelet therapy (DAPT), due to coronary microvascular obstruction. This study examined whether DAPTs provide vasculoprotective benefits in injured coronary microvessels, including in the setting of chronic hyperglycaemia. Mice were fed a normal (ND) or high-fat diet (HFD) for 16 weeks and treated with vehicle, aspirin plus ticagrelor, clopidogrel, prasugrel or cangrelor, anti-GPIbα antibody, or dabigatran. Intravital imaging assessed platelet, neutrophil, and fibrin presence in the beating heart subjected to ischaemia-reperfusion injury (IRI). Laser speckle contrast imaging evaluated overall ventricular perfusion, and infarct size was determined histologically. IRI increased platelet and neutrophil accumulation in coronary capillaries and reduced perfusion. DAPTs, particularly using prasugrel, and anti-GPIbα reduced platelet numbers but increased neutrophil infiltration. Despite limited perfusion improvement, infarct size decreased. Fibrin deposition was also extensive and contributed to platelet recruitment, as shown using dabigatran. HFD-fed mice demonstrated markedly elevated thromboinflammatory cell accumulation. DAPT with prasugrel reduced platelet and neutrophil presence, but left a significant residual presence of both. Despite perfusion improvements, infarcts remained larger. Our data do not support a simple linear relationship between reduced platelet microthrombi, improved perfusion, and infarct limitation. Whilst early platelet inhibition confers cardioprotection independently of flow recovery in healthy mice, metabolic compromise uncouples microvascular flow from myocardial tissue survival. This may explain the diminished cardioprotective efficacy of DAPTs in patients with T2DM and supports exploring combination vasculoprotective therapies targeting multiple microvascular perturbations.