Although prompt reperfusion treatment restores normal epicardial flow, microvascular dysfunction may persist in some patients with ACS [20, 21]. The presence of microvascular dysfunction is considered a poor prognostic factor in patients with ACS [22–24].
Impaired myocardial perfusion is caused by intraluminal platelets, fibrin thrombi, neutrophil plugging, vasoconstriction, myocyte contracture, local interstitial edema and intramural hemorrhage [6–8]. There have been a number of studies in patients with ACS in which the use of antiplatelet agents and vasodilators attenuated myocardial damage [9, 10, 25–28]. Such findings strongly support the contribution of thrombotic and vasoconstrictor mechanisms leading to the development of impaired microcirculation. Antiplatelet agents play a relevant role in protecting against thrombus microembolization.
Recently the novel antiplatelet agents, ticagrelor and prasugrel, have exhibited greater, more rapid and more consistent platelet inhibition than clopidogrel. Ticagrelor is a non-thienopyridine, direct P2Y12 blocker that is more potent than clopidogrel and is associated with less inter-individual variability. In the PLATO trial, ticagrelor was found to be superior to clopidogrel with respect to cardiovascular outcomes and total mortality without increasing the risk of bleeding .
The dual antiplatelet regimen including aspirin and clopidogrel has been used as the standard antiplatelet modality in patients with ACS; however, clopidogrel has several negative features. For example, the phenomenon of the variability of response to clopidogrel, causing elevated platelet reactivity, is seen in approximately 15 to 30% of patients, and it has been linked to ischemic events including stent thrombosis after PCI. Another issue is the delayed onset of action [29–31] that may be observed with clopidogrel treatment. These drawbacks have led to the development of more potent and rapid-acting antiplatelet agents. Compared with clopidogrel, ticagrelor causes greater, faster and more consistent platelet inhibition .
Beside the potent effect of inhibition of platelet function, ticagrelor has been demonstrated previously to increase adenosine levels by inhibiting adenosine re-uptake at the tissue level and inducing ATP release from human red blood cells, which stimulate vasodilation . In addition, a recent in vivo study in patients with ACS showed a significant increase in adenosine plasma concentration in patients treated with ticagrelor. In previous studies, adenosine has shown multiple mechanisms affecting platelet function, vessel tone and microcirculation. Adenosine inhibits platelet aggregation through the activation of adenosine 2A receptors and also dilates coronary microvessels through the activation of adenosine 2A receptors, which are strongly implicated in the regulation of coronary blood flow [32, 33]. However, the role of adenosine in protecting the ischemic heart remains controversial and the long-term impact of high plasma adenosine concentration on coronary artery disease remains to be determined . These properties of adenosine may be particularly important in the context of diseased vessels and the ischemia associated with ACS.
Consequently, based on the potent antiplatelet effect and pleiotropic properties mediated by the increased adenosine, we postulate that ticagrelor will reduce the microvascular dysfunction in patients with ACS compared with clopidogrel. Therefore, we designed a clinical study that will evaluate the protective effect on microvascular dysfunction of ticagrelor compared with clopidogrel in patients with STEMI and NSTEMI.