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 #
5R01HL095828-04
Application #
8454499
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
2013-04-01
Budget End
2014-03-31
Support Year
4
Fiscal Year
2013
Total Cost
$316,680
Indirect Cost
$81,060
Name
George Washington University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
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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
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
Posnack, Nikki Gillum; Idrees, Rabia; Ding, Hao et al. (2015) Exposure to phthalates affects calcium handling and intercellular connectivity of human stem cell-derived cardiomyocytes. PLoS One 10:e0121927
Wengrowski, Anastasia M; Wang, Xin; Tapa, Srinivas et al. (2015) Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function. Cardiovasc Res 105:143-50
Kuzmiak-Glancy, Sarah; Jaimes 3rd, Rafael; Wengrowski, Anastasia M et al. (2015) Oxygen demand of perfused heart preparations: how electromechanical function and inadequate oxygenation affect physiology and optical measurements. Exp Physiol 100:603-16
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
Cauley, Edmund; Wang, Xin; Dyavanapalli, Jhansi et al. (2015) Neurotransmission to parasympathetic cardiac vagal neurons in the brain stem is altered with left ventricular hypertrophy-induced heart failure. Am J Physiol Heart Circ Physiol 309:H1281-7
Posnack, Nikki Gillum; Brooks, Daina; Chandra, Akhil et al. (2015) Physiological response of cardiac tissue to bisphenol A: alterations in ventricular pressure and contractility. Am J Physiol Heart Circ Physiol 309:H267-75
Kay, Matthew; Kuzmiak-Glancy, Sarah; Rogers, Jack (2015) Racing to the flatline: heart rate and β-adrenergic stimulation quicken the pace. Am J Physiol Heart Circ Physiol 308:H977-9

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