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

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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.