INCREASED MYOCARDIAL SALVAGE WITH CONTROLLED REPERFUSION

通过控制再灌注增加心肌挽救率

• 批准号: 2222703
• 负责人: Jakob VINTEN-JOHANSEN
• 金额: $ 26.54万
• 依托单位: WAKE FOREST UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-05-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2222703
• 关键词: acidosis; adenosine; coronary occlusion /thrombosis; dogs; electron microscopy; extracorporeal circulation; heart circulation; heart contraction; hydrogen channel; leukocytes; myocardial infarct sizing; myocardial ischemia /hypoxia; nitric oxide; radioactive microsphere technique; reperfusion; tissue /cell culture; vascular endothelium; vasodilators

Coronary occlusion and reperfusion produces a predictable pattern of morphologic injury and contractile dysfunction. Recent studies suggest that the ultimate extent of myocardial damage resulting from reversible coronary occlusion is the sum of ischemic injury and reperfusion injury. Therapy directed specifically at the reperfusion injury component should reduce infarct size and improve contractile function. However, the hydrodynamic (coronary pressure-flow) conditions of reflow is not recognized as a determinant of postischemic injury. The studies in this proposal will test the overall hypothesis that appropriate control exercised over the hydrodynamic conditions during the early moments of reperfusion will reduce the extent of morphologic injury and contractile dysfunction in the area at risk compared to the abruptly reperfused counterpart. Furthermore, we will test the hypotheses that the mechanisms underlying this myocardial salvage by controlled reperfusion hydrodynamics are 1) preservation of endothelial integrity and elaboration of endothelium-derived relaxing factors (EDRF, nitric oxide), or 2) prolonged washout of endogenous adenosine or hydrogen ions from the reperfused area at risk. In acute models of left anterior descending (LAD) coronary artery occlusion, LAD blood flow will be restored either ABRUPTLY (simulating angioplasty and immediate thrombosis) or gradually in a CONTROLLED manner over the early moments of reperfusion. Coronary blood flow will be adjusted using an extracorporeal perfusion system. Parameters of myocardial salvage include segmental contractile function (sonomicrometry), regional myocardial blood flow (radioactive microspheres), infarct size, ultrastructure, and endothelial-dependent and independent responses related to EDRF. SPECIFIC AIM 1 will determine the appropriate management of controlled (gradual) reperfusion and characterize its efficacy and longevity over clinically relevant ranges of ischemia. SPECIFIC AIM 2 will determine the potential mechanisms of myocardial salvage, including 1) preservation of endothelial integrity and the role of endothelial-derived factors, 2) prolonged washout of adenosine from the reperfused segment allowing greater exertion of its myoprotective effects, and 3) gradual rather than abrupt washout of acidosis. The process of controlled reperfusion is clinically feasible and the myocardial salvage attained clinically relevant. The data from these experiments will provide a fundamental understanding of reperfusion injury, and will develop a rationale for clinical avoidance of reperfusion injury, resulting in greater myocardial salvage, and decreased patient morbidity and mortality.

冠状动脉闭塞和再灌注会产生可预测的模式 形态损伤和收缩功能障碍。 最近的研究表明 可逆的心肌损伤的最终损害 冠状动脉闭塞是缺血性损伤和再灌注损伤的总和。 专门针对再灌注损伤部分的治疗应 降低梗塞大小并改善收缩功能。 但是， 反流的流体动力（冠状动脉 - 流）条件不是 被公认为是缺血后损伤的决定因素。 关于这一点的研究 提案将检验适当控制的总体假设 在早期的流体动力条件下进行运动 再灌注将减少形态损伤的程度和收缩的程度 与突然重复的区域相比，该地区的功能障碍 对准。 此外，我们将检验 通过受控再灌注的这种心肌抢救的机制 流体动力学是1）保存内皮完整性和 阐述内皮衍生的放松因子（EDRF，一氧化氮）， 或2）长时间清洗内源性腺苷或氢离子 危险区域的重复区域。 在左前下降的急性模型中 （LAD）冠状动脉阻塞，LAD血液流量也将恢复 突然（模拟血管成形术和立即血栓形成）或逐渐 在再灌注的早期，以受控的方式受控。 冠状动脉 血流将使用体外灌注系统进行调整。 心肌救助的参数包括节段收缩功能 （Sonomictry），区域心肌血流（放射性 微球），超大型，超微结构和内皮依赖性 和与EDRF有关的独立响应。 具体目标1将决定 对受控（逐渐）再灌注的适当管理和 表征其对临床相关范围的功效和寿命 缺血。 特定目标2将确定潜在机制 心肌挽救，包括1）保存内皮完整性 以及内皮衍生因素的作用，2）长时间的冲洗 腺苷的腺苷从重新填充的细分市场中，允许更大的努力 感染效果，以及3）逐渐而不是突然冲洗 酸中毒。 受控再灌注的过程在临床上是可行的 心肌挽救在临床上具有相关性。 来自 这些实验将提供对再灌注的基本理解 受伤，并将为临床避免的基本原理发展 再灌注损伤，导致更多的心肌挽救，并 患者发病率和死亡率降低。