Studies in multi-modal cardiovascular imaging: cardiovascular MRI in humans and targeted fluorescence in an animal model of atherosclerosis

Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality and morbidity in the United States. It encompasses a variety of conditions that involve the heart and/or the vascular system, including coronary heart disease, ischemic heart disease, cardiomyopathy, atherosclerosis and stroke. Understanding the risk factors and mechanisms underlying CVD as well as developing early diagnostic methods has great clinical importance. In this thesis work, we used Magnetic Resonance Imaging (MRI) and studied two aspects of CVD. Firstly, we explored the regional influence of pericardial/periaortic fat on the underlying organs in human subjects. Pericardial fat volume did not correlate with BMI in either obese or control subjects. Left ventricular (LV) function, including stroke volume (r=-0.29, p=0.04) and cardiac output (r=-0.33, p=0.02), was inversely related to LV fat but not right ventricular (RV) fat. LV diastolic function, including early filling rate (E-rate), early/late filling ratio (E/A), showed a stronger correlation to LV fat (E-rate, r=-0.41, p=0.005; E/A, r=-0.31, p=0.04) than RV fat. This evidence suggests local toxic effects of pericardia! fat on cardiac structure/function. Periaortic fat was also found positively linked to plaque volume, which suggests a paracrine role of periaortic fat in atherogenesis. Secondly, we combined in vivo MRI and ex vivo targeted fluorescence imaging to detect vulnerable plaques (VPs) in a rabbit model. The fluorescence signal from enzyme-activated targeted probes (PLGLAG-cy5 and DPRSFL-cy5) co-localized most strongly with vulnerable aortic plaques as detected by MRI. Statistically, fluorescence signal was enhanced (by 40-60%) in VPs as compared to stable ones. In addition, the fluorescence signal was related to the MRI plaque vulnerability measurements, such as outward remodeling and enhanced gadolinium uptake. The combination of MRI and targeted molecular imaging can help us to understand both plaque morphology and functionality, which in turn can increase the diagnostic accuracy of the vulnerable plaques. In conclusion, we identified local toxic effect of regional fat depots on cardiovascular function using MRI. We also demonstrated MRI is a powerful technique in studying CVD. Combination of MRI and molecular imaging can help us understand the morphology and function of the atherosclerotic plaques, which might help early detection of VPs.