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，然后再灌注，通常以降低的血流速率。本研究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：将冠状动脉血流紊乱引起的局部组织代谢变化与由此引起的电活动紊乱联系起来。尽管心肌代谢及其电活动之间存在明确的因果关系，但令人惊讶的是，很少有研究试图在工作心脏准备中使用荧光成像来研究它们。拟议的研究旨在填补这一空白。具体目标1是通过整合1)用于NADH荧光快速成像的高分辨率相机，2)对ECG进行门控的脉冲紫外光照明，以及3)用于第三个荧光成像相机的硬件和软件，来提高我们现有双成像系统的能力。具体目标2是实施技术，允许在生理温度（37℃）下使用工作心脏制剂研究由代谢紊乱引起的心律失常。特异性目的3：利用多模式荧光成像技术研究急性缺血性损伤及随后再灌注工作心脏准备过程中的特定病理条件。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，我们将在进行冠状动脉血流、心脏代谢和心脏电生理研究领域交叉研究所需的方法方面取得重大进展，同时也提供了在不稳定冠状动脉血流期间引起致命性心律失常的生理学方面获得更好理解的潜力。最终，这将为预防心源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.