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的主要死亡原因。2001年，有200万冠心病住院治疗，每年的费用为1330亿美元。目前用于治疗急性冠状动脉综合征的策略，包括恢复心外膜冠状动脉通畅性，不能持续恢复微血管灌注，这具有不良临床后果。减阻聚合物（DRP）可以填补这一空白。DRP可能通过靶向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，主要研究者研究了在分级犬冠状动脉狭窄情况下DRP对心肌灌注的影响。他发现，微量的血管内浓度的DRP使心肌灌注正常化，并通过降低毛细血管阻力改善冠状动脉血流储备，这可能为冠心病的治疗提供一种新的方法。传统上，已知DRP通过降低流体阻力来增加管流。在血管系统中，类似的机制被理论化，但精确的微血管作用机制尚不清楚。在实验动物模型中确定了DRP的潜在健康益处后，进一步的临床开发作为治疗策略将需要对其微血管机制有更深入的了解。因此，本研究计划建立在Pi的完整动物数据的基础上，通过研究DRPs在微循环水平的影响。主要研究者将学习活体微循环研究的复杂工具，包括微血管压力，微血管血细胞比容，红细胞和白细胞动力学的测量。这些技术将用于确定DRP是否通过（1）通过增加毛细血管前驱动压力改变流体动力学;（2）改变微血管红细胞分布;（3）改变白细胞-内皮相互作用;或其组合来增强灌注。主要研究者的短期目标是获得微循环领域的知识，并学习回答本提案提出的问题的技术。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其微血管机制来改善针对冠状动脉微循环的治疗，包括冠状动脉“无复流”的治疗。通过询问DRPs的微血管机制，本建议提供了一个工具来学习这些方法。 (End摘要）

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)