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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095828-03
Application #
8238372
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Sopko, George
Project Start
2010-04-19
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$330,598
Indirect Cost
$83,098
Name
George Washington University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Kuzmiak-Glancy, Sarah; Covian, Raúl; Femnou, Armel N et al. (2018) Cardiac performance is limited by oxygen delivery to the mitochondria in the crystalloid-perfused working heart. Am J Physiol Heart Circ Physiol 314:H704-H715
Garrott, Kara; Dyavanapalli, Jhansi; Cauley, Edmund et al. (2017) Chronic activation of hypothalamic oxytocin neurons improves cardiac function during left ventricular hypertrophy-induced heart failure. Cardiovasc Res 113:1318-1328
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Moreno, Angel; Kuzmiak-Glancy, Sarah; Jaimes Rd, Rafael et al. (2017) Enzyme-dependent fluorescence recovery of NADH after photobleaching to assess dehydrogenase activity of isolated perfused hearts. Sci Rep 7:45744
Garrott, Kara; Kuzmiak-Glancy, Sarah; Wengrowski, Anastasia et al. (2017) KATP channel inhibition blunts electromechanical decline during hypoxia in left ventricular working rabbit hearts. J Physiol 595:3799-3813
Kang, C; Brennan, J A; Kuzmiak-Glancy, S et al. (2016) Technical advances in studying cardiac electrophysiology - Role of rabbit models. Prog Biophys Mol Biol 121:97-109
Kay, Matthew W; Efimov, Igor R (2016) Optical Mapping of Cardiac Electromechanics. Biophys J 111:269-270
Jaimes 3rd, Rafael; Walton, Richard D; Pasdois, Philippe et al. (2016) A technical review of optical mapping of intracellular calcium within myocardial tissue. Am J Physiol Heart Circ Physiol 310:H1388-401
Jaimes 3rd, Rafael; Kuzmiak-Glancy, Sarah; Brooks, Daina M et al. (2016) Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate. Pflugers Arch 468:131-42
Azam, Mohammed Ali; Wagg, Cory S; Massé, Stéphane et al. (2015) Feeding the fibrillating heart: Dichloroacetate improves cardiac contractile dysfunction following VF. Am J Physiol Heart Circ Physiol 309:H1543-53

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