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

描述（由申请人提供）：在美国，近650万人患有冠心病。在不稳定型心绞痛发作期间，受影响的心肌组织经历短暂的急性缺血发作，随后通常以降低的流速进行再灌注。本申请中提出的工作的总体目标是从一个新的角度研究缺血和再灌注心律失常的机制：将冠状动脉血流扰动引起的组织代谢局部变化与电活动中的干扰联系起来。尽管心肌代谢与其电活动之间存在明确的因果关系，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准备中一起研究它们。拟议的研究旨在填补这一空白。具体目标1是通过结合1）用于NADH荧光快速成像的高分辨率相机，2）门控到ECG的脉冲紫外光照明，和3）用于第三荧光成像相机的硬件和软件来增加我们现有的双成像系统的能力。具体目标2是实施技术，使代谢紊乱引起的心律失常，在生理温度（37 ℃）下使用工作心脏准备进行研究。具体目标3是使用多模式荧光成像来研究急性缺血损伤和随后再灌注的工作心脏准备中的特定病理条件。这些情况包括：快速起搏、纤颤、低流量再灌注和缺血预处理。有了这些目标，我们将提供在冠状动脉血流，心脏代谢和心脏电生理学的研究领域的交叉点进行研究所需的方法学的重大进展，同时也提供了潜在的，以获得更好的了解生理学，导致致命的心律失常在不稳定的冠状动脉血流。最终，这将为预防心脏性猝死的可能治疗干预提供新的见解。

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.