PDF(Pubmed)
Abstract：
Myocardial necrosis following the successful reperfusion of a coronary artery occluded by thrombus in a patient presenting with ST-elevation myocardial infarction (STEMI) continues to be a serious problem, despite the multiple attempts to attenuate the necrosis with agents that have shown promise in pre-clinical investigations. Possible reasons include confounding clinical risk factors, the delayed application of protective agents, poorly designed pre-clinical investigations, the possible effects of routinely administered agents that might unknowingly already have protected the myocardium or that might have blocked protection, and the biological differences of the myocardium in humans and experimental animals. A better understanding of the pathobiology of myocardial infarction is needed to stem this reperfusion injury. P2Y12 receptor antagonists minimize platelet aggregation and are currently part of the standard treatment to prevent thrombus formation and propagation in STEMI protocols. Serendipitously, these P2Y12 antagonists also dramatically attenuate reperfusion injury in experimental animals and are presumed to provide a similar protection in STEMI patients. However, additional protective agents are needed to further diminish reperfusion injury. It is possible to achieve additive protection if the added intervention protects by a mechanism different from that of P2Y12 antagonists. Inflammation is now recognized to be a critical factor in the complex intracellular response to ischemia and reperfusion that leads to tissue necrosis. Interference with cardiomyocyte inflammasome assembly and activation has shown great promise in attenuating reperfusion injury in pre-clinical animal models. And the blockade of the executioner protease caspase-1, indeed, supplements the protection already seen after the administration of P2Y12 antagonists. Importantly, protective interventions must be applied in the first minutes of reperfusion, if protection is to be achieved. The promise of such a combination of protective strategies provides hope that the successful attenuation of reperfusion injury is attainable.
摘要：
在ST段抬高型心肌梗死（STEMI）患者中，血栓阻塞的冠状动脉成功再灌注后的心肌坏死仍然是一个严重的问题。尽管在临床前研究中已显示出有望减轻坏死的药物进行了多次尝试。可能的原因包括混杂的临床风险因素，保护剂的延迟使用，设计不当的临床前调查，常规给药的药物可能在不知不觉中已经保护了心肌或可能阻断了保护，以及人类和实验动物心肌的生物学差异。为了阻止这种再灌注损伤，需要更好地了解心肌梗塞的病理生物学。P2Y12受体拮抗剂使血小板聚集最小化,并且目前是STEMI方案中预防血栓形成和传播的标准治疗的一部分。偶然,这些P2Y12拮抗剂还显著减轻了实验动物的再灌注损伤,并推测在STEMI患者中提供了类似的保护作用.然而,需要额外的保护剂来进一步减少再灌注损伤.如果添加的干预通过不同于P2Y12拮抗剂的机制进行保护,则有可能实现附加保护。炎症现在被认为是导致组织坏死的缺血和再灌注的复杂细胞内反应的关键因素。在临床前动物模型中，对心肌细胞炎性体组装和激活的干扰在减轻再灌注损伤方面显示出巨大的希望。事实上，执行者蛋白酶caspase-1的封锁，补充P2Y12拮抗剂给药后已经看到的保护。重要的是,必须在再灌注的第一分钟内采取保护性干预措施，如果要实现保护。这种保护性策略的组合的希望提供了成功减轻再灌注损伤的希望。
