OC 35.3 - Dual anti-platelet therapies are ineffective at preventing blockage of the coronary microcirculation following ischaemia reperfusion injury in mice.

Background: Ischaemia-reperfusion injury (IRI), caused by inadequate perfusion in cardiac microcirculation due to thrombo-inflammation, leads to larger infarcts and heart failure (HF). Although dual anti-platelet therapies (DAPTs) effectively reduce recurrent myocardial infarctions (MIs), HF persists in many DAPT-treated patients. The effectiveness of DAPTs on unblocking the coronary microcirculation remains unknown.

Aims: Determine the effectiveness of DAPTs in limiting thrombo-inflammation and re-establishing blood flow in the murine coronary microcirculation post IRI.

Methods: Mice were pre-treated with vehicle control (VC), aspirin alone or combined with either ticagrelor, clopidogrel or prasugrel. Myocardial IRI was performed on anaesthetised mice. Intravital imaging of the coronary microcirculation in the beating mouse heart was used to visualise fluorescently labelled platelets and neutrophils during reperfusion. Laser speckle contrast imaging (LSCI) on the surface of the beating heart measured tissue perfusion. Flow cytometry analysed platelet activation and cardiac damage markers.

Results: DAPTs effectively reduced platelet activation in response to CRP and ADP compared to VC. However, intravital imaging revealed no reduction in % coverage by platelet microthrombi in the coronary microcirculation in response to aspirin alone (1.79%), or combined with ticagrelor (1.08%), clopidogrel (1.05%) or prasugrel (0.69%) compared to VC (1.79%). Interestingly, neutrophil recruitment was increased compared to VC (2.08%) upon treatment with aspirin (6.22%; P=0.002) and aspirin and clopidogrel (6.35%; P=0.0001) but was unaffected by aspirin with ticagrelor (2.84%) or prasugrel (3.33%), suggesting certain DAPTs may enhance neutrophil infiltration to the coronary microcirculation causing further blockages. LSCI during reperfusion showed no DAPTs were able to restore left ventricle perfusion back to normal (sham) levels. Assessment of damage markets at the cellular level displayed no differences between VC and DAPTS.

Conclusion(s): DAPTs do not prevent platelet microthrombi from obstructing the coronary microcirculation after IRI and may enhance neutrophil infiltration, emphasizing the need for new MI treatment targets to avert HF.