Low flow reperfusion after acute myocardial ischemia: when too little is too much

急性心肌缺血后的低流量再灌注：太少就是太多

• 批准号: 8238372
• 负责人: Matthew W. Kay
• 金额: $ 33.06万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-19 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8238372
• 关键词: Acute; Address; Affect; Area; Arrhythmia; Biomedical Engineering; Breeding; Calcium; Cardiac; Computer software; Coronary; Coronary heart disease; Custom; Development; Disease; Electrocardiogram; Electrophysiology (science); Exposure to; Faculty; Fiber; Fluorescence; Goals; Heart; Heterogeneity; Image; Injury; Investments; Ischemia; Ischemic Preconditioning; Kinetics; Knowledge; Life; Lighting; Link; Measurement; Measures; Mechanics; Membrane Potentials; Metabolic; Metabolism; Methodology; Methods; Modification; Monitor; Morphologic artifacts; Motion; Myocardial Ischemia; Myocardial tissue; Myocardium; NADH; Organ; Pathologic; Perfusion; Photobleaching; Physiologic pulse; Physiological; Physiology; Positioning Attribute; Preparation; Preventive; Protocols documentation; Publishing; Reperfusion Therapy; Research; Resolution; Resources; Signal Transduction; System; Tachyarrhythmias; Techniques; Temperature; Testing; Therapeutic Intervention; Time; Tissues; Ultrasonography; Ultraviolet Rays; United States; Unstable angina; Ventricular; Work; base; charge coupled device camera; clinically relevant; computerized data processing; design; detector; experience; fluorescence imaging; heart electrical activity; heart metabolism; imaging modality; improved; insight; instrument; instrumentation; muscle metabolism; novel; preconditioning; prevent; public health relevance; research study; sudden cardiac death; synergism; tool

DESCRIPTION (provided by applicant): In United States almost 6.5 million people are living with coronary heart disease. During episodes of unstable angina, the affected myocardial tissue experiences transient episodes of acute ischemia followed by reperfusion, often at reduced flow rates. The overall goal of the work proposed in this application is to study mechanisms of ischemia and reperfusion arrhythmias from a new perspective: that of connecting local changes in tissue metabolism caused by perturbations in coronary flow to the resulting disturbances in electrical activity. Despite a clear causative link between cardiac muscle metabolism and its electrical activity, surprisingly few studies have attempted to study them together in working heart preparations using fluorescence imaging. The proposed studies aim to fill this gap. Specific Aim 1 is to increase the capabilities of our existing dual imaging system by incorporating 1) a high resolution camera for fast imaging of NADH fluorescence, 2) pulsed ultraviolet light illumination that is gated to the ECG, and 3) hardware and software for a third fluorescence imaging camera. Specific Aim 2 is to implement techniques that will allow arrhythmias resulting from metabolic disturbances to be studied at physiologic temperatures (37oC) using working heart preparations. Specific Aim 3 is to use multi-mode fluorescence imaging to study specific pathologic conditions in working heart preparations of acute ischemic injury and subsequent reperfusion. These conditions include: rapid pacing, fibrillation, low-flow reperfusion, and ischemic preconditioning. With these Aims, we will provide major advances in the methodology required to conduct studies at the intersection of the research fields of coronary flow, cardiac metabolism, and cardiac electrophysiology while also providing the potential to gain improved understanding of the physiology that causes lethal arrhythmias during unstable coronary flow. Ultimately, this will provide new insights into possible therapeutic interventions to prevent sudden cardiac death. PUBLIC HEALTH RELEVANCE: Tachyarrhythmia resulting from acute ischemia and reperfusion within the settings of unstable angina can be deadly as they are the common culprits of sudden cardiac death. The broad goal of our studies is to further understand how the dynamic heterogeneity of tissue metabolism that results from unstable angina breeds arrhythmias. Ultimately, this will provide new insights into possible therapeutic interventions to prevent sudden cardiac death.

描述（由申请人提供）：在美国，有近650万人患有冠心病。在不稳定的心绞痛的发作中，受影响的心肌组织经历了急性缺血的短暂发作，然后再灌注，通常以降低的流速。在本应用中提出的工作的总体目标是研究缺血和再灌注心律不齐的机制，从新的角度：连接冠状动脉流动引起的组织代谢局部代谢的变化与导致电活动的干扰。尽管心脏肌肉代谢与其电活动之间存在明显的病因联系，但令人惊讶的是，很少有研究试图使用荧光成像在工作心脏制备中一起研究它们。拟议的研究旨在填补这一空白。具体目的1是通过合并1）高分辨率摄像头来提高我们现有的双成像系统的功能，以快速成像NADH荧光，2）将脉冲的紫外线照明粘贴到ECG上，以及3）硬件和软件，用于第三荧光成像相机。具体目的2是实施技术，该技术将允许使用工作心脏制剂在生理温度（37oC）下研究代谢障碍引起的心律不齐。具体目的3是使用多模式荧光成像来研究急性缺血性损伤和随后再灌注的心脏准备中的特定病理条件。这些条件包括：快速起搏，纤颤，低流量再灌注和缺血性预处理。通过这些目标，我们将在冠状动脉流动，心脏代谢和心脏电生理学的研究领域进行研究所需的方法方面取得重大进展，同时还提供了对在不稳定冠状动脉流动期间对生理学产生致命心律失常的生理学理解的潜力。最终，这将为可能采取的治疗干预措施提供新的见解，以防止心脏突然死亡。 公共卫生相关性：在不稳定心绞痛的情况下，由于急性缺血和再灌注引起的心律失常可能是致命的，因为它们是心脏突然死亡的常见罪魁祸首。我们研究的广泛目标是进一步了解组织不稳定的组织代谢的动态异质性如何产生心律不齐。最终，这将为可能采取的治疗干预措施提供新的见解，以防止心脏突然死亡。