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.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Liu, Guoying
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Biomedical Engineering
Schools of Medicine
United States
Zip Code
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
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
Mina, Yair; Rinkevich-Shop, Shunit; Konen, Eli et al. (2013) Mast cell inhibition attenuates myocardial damage, adverse remodeling, and dysfunction during fulminant myocarditis in the rat. J Cardiovasc Pharmacol Ther 18:152-61
Vandsburger, Moriel H; French, Brent A; Kramer, Christopher M et al. (2012) Displacement-encoded and manganese-enhanced cardiac MRI reveal that nNOS, not eNOS, plays a dominant role in modulating contraction and calcium influx in the mammalian heart. Am J Physiol Heart Circ Physiol 302:H412-9
Fiorentino, Niccolo M; Epstein, Frederick H; Blemker, Silvia S (2012) Activation and aponeurosis morphology affect in vivo muscle tissue strains near the myotendinous junction. J Biomech 45:647-52
Epstein, Frederick H; Meyer, Craig H (2011) Myocardial perfusion using arterial spin labeling CMR: promise and challenges. JACC Cardiovasc Imaging 4:1262-4
Naresh, Nivedita K; Ben-Mordechai, Tamar; Leor, Jonathan et al. (2011) Molecular Imaging of Healing After Myocardial Infarction. Curr Cardiovasc Imaging Rep 4:63-76
Vandsburger, Moriel H; Epstein, Frederick H (2011) Emerging MRI methods in translational cardiovascular research. J Cardiovasc Transl Res 4:477-92
Janiczek, Robert L; Blackman, Brett R; Roy, R Jack et al. (2011) Three-dimensional phase contrast angiography of the mouse aortic arch using spiral MRI. Magn Reson Med 66:1382-90
Vandsburger, Moriel H; Janiczek, Robert L; Xu, Yaqin et al. (2010) Improved arterial spin labeling after myocardial infarction in mice using cardiac and respiratory gated look-locker imaging with fuzzy C-means clustering. Magn Reson Med 63:648-57

Showing the most recent 10 out of 27 publications