Attenuating reperfusion injury with combined hypothermia and gradual reperfusion.

描述（由申请人提供）：心脏病发作期间的主要护理目标是快速恢复血液灌注。然而，再灌注是矛盾的，虽然它使器官存活；它也使破坏性的生化过程成为可能。虽然已经研究了许多急性心肌梗死（AMI）的辅助治疗方法，但仍需要创新的联合治疗方法。在缺血-再灌注后，低温和逐渐再灌注都对保存心脏组织有好处。这项工作的总体目标是将这两种技术结合起来，以提高AMI的预后，并可能产生协同效益。具体目标：1)研制一种精确控制再灌注流量和组织冷却再加热的联合治疗装置。2)在大型动物平移性缺血-再灌注模型中，证明所提出的联合治疗技术能够谨慎、安全地控制再灌注和组织温度，并提供组织挽救效益。为了实现目标#1，将开发一套固定的设计输入要求和可行性点，将创建五个完全表征和健壮的设备原型，准备进行体内测试，并根据组织冷却能力和体内测试的潜在功效选择最佳操作方案。对于目标2，将在大型动物缺血再灌注模型中测试最佳操作方案。这些结果将表明该方案在减少组织损伤方面是安全有效的，表明存在临床相关组织挽救的潜力。相关性：美国每年约有110,000人进行紧急血管成形术。根据美国心脏协会2010年的统计数据，20%的首次心脏病患者在发病后一年内死亡。FocalCool， LLC的目标是通过安全有效地使用可控制的再灌注低温来减少再灌注损伤，从而改善急诊血管成形术患者的预后。如果第一阶段的目标是证明联合技术的安全性、冷却能力和组织挽救可行性，那么第二阶段的工作将冻结GLP动物试验和IDE应用的设计，并在转化的临床前模型中证明组织挽救的有效性。

DESCRIPTION (provided by applicant): The primary care goal during a heart attack is to quickly restore blood perfusion. Reperfusion, however, is paradoxical, while it enables organ survival; it also enables destructive biochemical processes. While numerous adjunctive therapies for acute myocardial infarctions (AMI) have been studied, innovative combination therapies are needed. Both hypothermia and gradual reperfusion have shown benefit in terms of saving heart tissue following ischemia-reperfusion. The overall goal of this work is to combine these two techniques for additive and perhaps synergistic benefits for improving AMI outcomes. Specific Aims: 1) Develop a combination therapy device that precisely controls reperfusion flow as well as tissue cooling and re-warming. 2) Demonstrate that the proposed combination therapy technology has the ability to carefully and safely control both reperfusion and tissue temperature and provides tissue salvage benefit in a large animal translational ischemia-reperfusion model. To achieve aim #1, a fixed set of design input requirements and feasibility points will be developed, five fully characterized and robust device prototypes will be created ready for in vivo testing, and an optimal operational protocol based on tissue cooling ability and potential efficacy for in vivo testing will be selected. For aim #2, the optimal operational protocl will be tested in a large animal ischemia-reperfusion model. These results will show that the protocol is safe and effective at reducing tissue damage, demonstrating that there is a potential for clinically relevant tissue salvage. Relevance: Approximately 110,000 people each year in the U.S. have an emergency angioplasty procedure. According to the AHA 2010 Statistics, 20% of first time heart attack victims die within one year of the event. FocalCool, LLC's goal is to improve emergency angioplasty patient outcomes by reducing reperfusion injury through safe and effective use of controlled reperfusion hypothermia. If Phase I goals to demonstrate safety, cooling ability, and tissue salvage feasibility of the joint technology are successful, Phase II wok will freeze the design for GLP animal testing and an IDE application and demonstrate efficacy of tissue salvage in a translational preclinical model.