Myocardial Flow Enhancement with Drag Reducing Polymers: Microvascular Mechanisms

描述(由申请人提供)： 冠心病是世界范围内主要的死亡原因。2001年，有200万人因冠心病住院，每年的费用为1330亿美元。目前治疗急性冠脉综合征的策略，包括恢复心外膜冠状动脉通畅，不能始终如一地恢复微血管灌注，这会造成不良的临床后果。减阻聚合物(DRP)可以填补这一空白。DRPs可能通过针对血流的流变学和流体动力学来降低血管阻力。在AHA的支持下，首席调查员研究了在分级犬冠状动脉狭窄的背景下，DRPS对心肌灌注的影响。他发现，血管内微小浓度的DRPs通过降低毛细血管阻力来正常化心肌灌注和改善冠脉血流储备，这可能为冠心病的治疗提供一种新的方法。传统上，DRP通过降低流体阻力来增加管道流量。在血管系统中，类似的机制被理论化，但确切的微血管作用机制尚不清楚。在实验动物模型中确定了DRPS的潜在健康益处后，进一步的临床开发作为一种治疗策略将需要对其微血管机制有更多的了解。因此，这项研究计划建立在PI的完整动物数据的基础上，通过在微循环水平上调查DRPS的影响。首席研究员将学习用于体内微循环研究的尖端工具，包括测量微血管压、微血管红细胞压积以及红细胞和白细胞动力学。这些技术将被用来确定DRP是否通过(1)通过增加毛细血管前驱动压改变流体动力学；(2)改变微血管红细胞分布；(3)改变白细胞-内皮相互作用；或其组合来增强血流灌注。首席调查员的短期目标是获得微循环领域的知识基金，并学习回答这一提议提出的问题的技术。然后，他将应用他的新技能来解决他的临床专业领域--介入心脏病学--的问题。他的最终目标是通过深入研究冠脉微循环的微血管机制，改进针对冠脉微循环的治疗方法，包括治疗冠脉“无复流”。通过询问DRP的微血管机制，该建议提供了一个学习这些方法的工具。 (摘要结束)

DESCRIPTION (provided by applicant): Coronary heart disease is the leading cause of death worldwide. In 2001 there were 2 million CHD hospitalizations with an annual cost of $133 billion. Current strategies for the treatment of acute coronary syndromes, which includes restoring epicardial coronary artery patency, do not consistently restore microvascular perfusion, which has adverse clinical consequences. Drag-reducing polymers (DRPs) may fill this void. DRPs reduce vascular resistance, potentially by targeting the rheology and hydrodynamics of blood flow. Under AHA support, the Principal Investigator has studied the effects of DRPs on myocardial perfusion in the setting of graded canine coronary stenoses. He has found that minute intravascular concentrations of DRPs normalize myocardial perfusion and improve coronary flow reserve by decreasing capillary resistance, and this may provide a novel approach for the treatment of coronary heart disease. Traditionally, DRPs are known to augment pipe flow through reductions in fluid resistance. In vascular systems, similar mechanisms are theorized but the precise microvascular mechanism of action is unknown. Having established the potential health benefits of DRPs in experimental animal models, further clinical development as a therapeutic strategy will require a greater understanding of its microvascular mechanisms. Accordingly, this research program builds on the Pi's intact animal data by investigating DRPs effects at the microcirculatory level. The Principal Investigator will learn sophisticated tools for intravital microcirculation research, including measurements of microvascular pressure, microvascular hematocrit, and red cell and leukocyte kinetics. These techniques will be used to determine whether DRPs enhance perfusion through (1) Alterations in hydrodynamics by increasing precapillary driving pressure; (2) Changing microvascular red cell distribution; (3) Altering leukocyte-endothelial interactions; or a combination thereof. The Principal Investigator's short term goal is to gain a fund of knowledge in the field of the microcirculation and to learn the techniques to answer the questions posed by this proposal. He will then apply his new skill set to address questions in his field of clinical expertise, interventional cardiology. His ultimate goal is to improve treatments aimed at the coronary microcirculation, including treatment of coronary 'no-reflow,' by delving into its microvascular mechanisms. By interrogating the microvascular mechanisms of DRPs, this proposal provides a vehicle to learn these methodologies. (End of Abstract)