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

描述(申请人提供)：在美国，近650万人患有冠心病。在不稳定性心绞痛发作期间，受影响的心肌组织会经历短暂的急性缺血发作，然后再灌流，通常是以较低的流速。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性心律失常的机制：将冠脉血流扰动引起的组织代谢局部变化与由此导致的电活动障碍联系起来。尽管心肌新陈代谢和其电活动之间存在明显的因果联系，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同时研究它们。拟议的研究旨在填补这一空白。具体目标1是通过采用1)用于快速成像NADH荧光的高分辨率相机、2)通向心电的脉冲紫外光照射以及3)用于第三个荧光成像相机的硬件和软件来增加我们现有的双重成像系统的能力。具体目标2是实施技术，使代谢紊乱引起的心律失常能够在生理温度(37摄氏度)下使用工作心脏制剂进行研究。具体目的3是利用多模式荧光成像技术研究急性缺血损伤和随后再灌注时工作心脏准备的特殊病理情况。这些情况包括：快速起搏、纤颤、低流量再灌注和缺血预适应。有了这些目标，我们将在方法学方面取得重大进展，以便在冠状动脉血流、心脏代谢和心脏电生理学的研究领域进行交叉研究，同时也有可能更好地理解在冠状动脉血流不稳定时导致致命性心律失常的生理学。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。 公共卫生相关性：不稳定心绞痛环境中的急性缺血和再灌注引起的快速性心律失常可能是致命的，因为它们是心源性猝死的常见罪魁祸首。我们研究的主要目标是进一步了解不稳定心绞痛引起的组织代谢的动态异质性如何导致心律失常。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. 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.