Abstract 13478: Does Blockade of Platelet Aggregation after Stenting for STEMI Protect Against Reperfusion Injury?
Blockade of platelet activation after myocardial infarction and stenting is standard clinical care to minimize stent thrombosis. But it is unknown whether it offers any immediate cardioprotective effects. Accordingly we tested whether blocking platelet activation would modify infarct size in a primate model of ischemia-reperfusion. OM2 is an investigational antibody (Otsuka) against human/primate platelet-specific collagen receptor glycoprotein VI (GPVI), and blocks platelet activation in response to collagen. Macaque monkeys underwent 90-min left anterior descending coronary artery occlusion/4-h reperfusion. In untreated monkeys 43% of the ischemic zone infarcted, but only 28% when OM2 was given just prior to reperfusion. To see if other anti-platelet agents protect we tested the ADP receptor blocker Cangrelor (Cng). Cng at reperfusion elicited similar protection. Ischemic postconditioning (IPOC) with six 30-second cycles of reperfusion/ischemia also duplicated the protection. OM2 reacts with only primate/human platelets, but Cng is effective in rabbits. To investigate mechanisms of protection Cng was given at reperfusion to rabbits undergoing 30-min regional ischemia/3-h reperfusion. Cng reduced infarct size from 37% in control hearts to only 18%. That protection could be completely blocked by either of the PI3-kinase inhibitors wortmannin or LY294002, the MEK and therefore ERK inhibitor PD98059, the non-selective adenosine receptor antagonist 8-p-(sulfophenyl) theophylline, or the free radical scavenger N-(2-mercaptopropionyl) glycine. These antagonists block protection from IPOC in this species. When Cng was combined with four 30-second cycles of IPOC, no added protection was seen suggesting that both protected by the same mechanism. Delaying administration of Cng until 10 min after onset of reperfusion abrogated protection. Hence in two species blockers of platelet aggregation protect against infarction by activating IPOC's protective signaling suggesting that patients who receive anti-platelet agents while undergoing primary percutaneous intervention may already be fully postconditioned. The mechanism is unknown but it could explain why most recent trials of cardioprotective agents have shown no benefit.
- © 2011 by American Heart Association, Inc.