Measurements of myocardial blood flow (MBF) and contractile function are essential to the evaluation of coronary heart disease (CHD). While compromised contractile function occurs as CHD advances, a growing concept is that coronary microvascular disease with impaired MBF reserve is an early marker of CHD, is prognostic of adverse events, and is potentially causal of additional coronary vascular disease, such as in the setting of diabetes with hyperglycemia. Due to the ready availability of genetically-manipulated animals, mouse models are widely used to investigate molecular mechanisms underlying CHD. We previously developed cine DENSE MRI to quantify contractile function in mice with high accuracy, resolution, and ease of analysis. We also applied multi-parametric MRI in gene-modified mice to elucidate the roles of various receptors and enzymes in normal cardiac function and in post-infarct left-ventricular remodeling. Next, we propose to focus on imaging to elucidate mechanisms underlying coronary microvascular dysfunction by assessment of MBF in mice. Basic MBF imaging in mice using first-pass MRI and arterial spin labeling (ASL) have previously been demonstrated by us and others, however, through acceleration using compressed sensing (CS) and improved tracer kinetic modeling, we propose to develop substantial improvements to spatial resolution, scan time, and quantitation. Furthermore, we propose comparison studies to determine which method is most accurate and reproducible. Subsequently, we propose to apply MBF imaging in hyperglycemic diabetic mice (Akita mice), where we will test the hypothesis that advanced glycation end products (AGEs) and the receptor for AGE (RAGE) mediate hyperglycemic coronary microvascular dysfunction. To accomplish these goals we have three specific aims. First, we will use novel CS methods to develop (a) a motion-compensated dual-contrast first- pass gadolinium-enhanced MRI technique for MBF imaging in mice and (b) an accelerated ASL MRI technique for high-resolution MBF imaging in less than 10 minutes. In our second aim we will compare and validate first- pass MRI and ASL for MBF imaging in mice, using microspheres as a gold standard.
This aim will include reproducibility studies. In our third aim we will use MBF and other imaging to test the hypothesis that RAGE-/- mice are protected from coronary microvascular disease that develops in akita mice. The successful completion of these aims would lead to improved imaging methods for quantifying MBF in mice. In one particular application, MBF imaging would be used to establish the role of RAGE in coronary microvascular disease secondary to diabetic hyperglycemia.

Public Health Relevance

The diabetes epidemic in the U.S. continues to rise, leading to increased hyperglycemia and associated complications including coronary macrovascular and microvascular disease. We propose to develop improved methods for quantitative imaging of myocardial blood flow reserve for mice, and to use these methods in gene- modified mice to elucidate molecular mechanisms that underlie the link between diabetes, hyperglycemia, and coronary microvascular disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB001763-10
Application #
8683171
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Liu, Guoying
Project Start
2003-09-05
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Naresh, Nivedita K; Butcher, Joshua T; Lye, Robert J et al. (2016) Cardiovascular magnetic resonance detects the progression of impaired myocardial perfusion reserve and increased left-ventricular mass in mice fed a high-fat diet. J Cardiovasc Magn Reson 18:53
Chen, Xiao; Yang, Yang; Cai, Xiaoying et al. (2016) Accelerated two-dimensional cine DENSE cardiovascular magnetic resonance using compressed sensing and parallel imaging. J Cardiovasc Magn Reson 18:38
Naresh, Nivedita K; Chen, Xiao; Moran, Eric et al. (2016) Repeatability and variability of myocardial perfusion imaging techniques in mice: Comparison of arterial spin labeling and first-pass contrast-enhanced MRI. Magn Reson Med 75:2394-405
Epstein, Frederick H; Vandsburger, Moriel (2016) Illuminating the Path Forward in Cardiac Regeneration Using Strain Magnetic Resonance Imaging. Circ Cardiovasc Imaging 9:
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Naresh, Nivedita K; Chen, Xiao; Roy, Rene J et al. (2015) Accelerated dual-contrast first-pass perfusion MRI of the mouse heart: development and application to diet-induced obese mice. Magn Reson Med 73:1237-45
Mehta, Bhairav B; Auger, Daniel A; Gonzalez, Jorge A et al. (2015) Detection of elevated right ventricular extracellular volume in pulmonary hypertension using Accelerated and Navigator-Gated Look-Locker Imaging for Cardiac T1 Estimation (ANGIE) cardiovascular magnetic resonance. J Cardiovasc Magn Reson 17:110
Ramachandran, Raghav; Chen, Xiao; Kramer, Christopher M et al. (2015) Singular Value Decomposition Applied to Cardiac Strain from MR Imaging for Selection of Optimal Cardiac Resynchronization Therapy Candidates. Radiology 275:413-20
Bilchick, Kenneth C; Kuruvilla, Sujith; Hamirani, Yasmin S et al. (2014) Impact of mechanical activation, scar, and electrical timing on cardiac resynchronization therapy response and clinical outcomes. J Am Coll Cardiol 63:1657-66

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