Myocardial Flow Enhancement with Drag Reducing Polymers: Microvascular Mechanisms

使用减阻聚合物增强心肌血流：微血管机制

• 批准号: 8055490
• 负责人: John J Pacella
• 金额: $ 12.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055490
• 关键词: Acute; Address; Adhesions; Area; Attenuated; Automobile Driving; Behavior; Biological Preservation; Blood; Blood Vessels; Blood Volume; Blood capillaries; Blood flow; Canis familiaris; Capillary Resistance; Cardiology; Cause of Death; Cell Communication; Cell Cycle Kinetics; Cells; Clinical; Complex; Contrast echocardiography procedure; Coronary; Coronary Stenosis; Coronary artery; Coronary heart disease; Data; Development; Disease; Endothelial Cells; Erythrocytes; Experimental Animal Model; Experimental Designs; Failure; Fellowship; Funding; Goals; Health; Health Benefit; Hematocrit procedure; Hemorrhagic Shock; Hospitalization; Imaging Techniques; In Vitro; Individual; Intervention; Investigation; Kinetics; Knowledge; Lead; Learning; Leukocytes; Liquid substance; Measurement; Measures; Mechanics; Mediating; Methodology; Microbubbles; Microcirculation; Microscopic; Microspheres; Modeling; Molecular Weight; Morphology; Myocardial; Myocardial Ischemia; Myocardial perfusion; Organ; Oxygen; Perfusion; Physics; Physiological; Physiology; Plasma; Polymers; Principal Investigator; Process; Property; Radiolabeled; Rattus; Research; Research Personnel; Resistance; Rest; Rheology; Simulate; Stenosis; Techniques; Testing; Therapeutic; Tissues; Tracer; Training; Translations; Ultrasonography; Vascular System; Vascular resistance; Vasodilation; Vasomotor; Width; Work; abstracting; acute coronary syndrome; animal data; arteriole; capillary; clinical application; cost; density; design; falls; fluid flow; hemodynamics; improved; in vivo; insight; intravital microscopy; macromolecule; novel strategies; novel therapeutics; pressure; programs; radiotracer; resistance mechanism; skills; tissue oxygenation; tool; treatment strategy

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)

描述（由申请人提供）： 冠心病是全世界死亡的主要原因。 2001 年，有 200 万人因先心病住院，每年费用达 1,330 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）并不能始终如一地恢复微血管灌注，从而产生不良的临床后果。减阻聚合物（DRP）可能会填补这一空白。 DRP 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，首席研究员研究了在分级犬冠状动脉狭窄的情况下 DRP 对心肌灌注的影响。他发现DRPs的微小血管内浓度可以使心肌灌注正常化，并通过降低毛细血管阻力来改善冠脉血流储备，这可能为冠心病的治疗提供一种新的方法。传统上，DRP 可以通过减少流体阻力来增加管道流量。在血管系统中，类似的机制已被理论化，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，作为治疗策略的进一步临床开发将需要对其微血管机制有更深入的了解。因此，该研究计划以 Pi 的完整动物数据为基础，研究 DRP 在微循环水平上的影响。首席研究员将学习用于活体微循环研究的复杂工具，包括微血管压力、微血管血细胞比容以及红细胞和白细胞动力学的测量。这些技术将用于确定 DRP 是否通过以下方式增强灌注：(1) 通过增加毛细血管前驱动压力来改变流体动力学； (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。首席研究员的短期目标是获得微循环领域的大量知识，并学习回答本提案提出的问题的技术。然后，他将运用他的新技能来解决他的临床专业领域——介入心脏病学领域的问题。他的最终目标是通过深入研究冠状动脉微血管机制来改善针对冠状动脉微循环的治疗，包括治疗冠状动脉“无复流”。通过探究 DRP 的微血管机制，该提案提供了学习这些方法的工具。 （摘要完）

项目成果

Modulation of pre-capillary arteriolar pressure with drag-reducing polymers: a novel method for enhancing microvascular perfusion.

用减阻聚合物调节毛细血管前小动脉压力：一种增强微血管灌注的新方法。

• 发表时间: 2012-10
• 作者: Pacella, John J;Kameneva, Marina V;Brands, Judith;Lipowsky, Herbert H;Vink, Hans;Lavery, Linda L;Villanueva, Flordeliza S
• 通讯作者: Villanueva, Flordeliza S

New insights into the microvascular mechanisms of drag reducing polymers: effect on the cell-free layer.

对减阻聚合物微血管机制的新见解：对无细胞层的影响。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Brands, Judith;Kliner, Dustin;Lipowsky, Herbert H;Kameneva, Marina V;Villanueva, Flordeliza S;Pacella, John J
• 通讯作者: Pacella, John J