In vivo MRI of mouse heart at 11.7 T: Monitoring of stem-cell therapy for myocardial infarction and evaluation of cardiac hypertrophy.

摘要

Cardiovascular disease (CVD) is one of the major causes of morbidity and mortality in the western world. It accounts for more than a third of the deaths in the United States and is a serious cause of concern. Early detection of the abnormal cardiovascular conditions may help in their diagnosis and treatment, thus, reducing the mortality associated with them. Visualization of the heart and the blood vessels may help in the detection and diagnosis of these diseases in their early stage of development.;Many techniques such as X-ray computed tomography (CT), angiography, magnetic resonance imaging (MRI), echocardiography and nuclear imaging are used for cardiac imaging in the clinic. Among these, MRI stands out due to its advantages such as noninvasiveness, high spatial and temporal resolution, and repeatability and reproducibility of the measurements. It can also be used to obtain functional data from the structural information of the heart, making it a valuable diagnostic tool for various cardiac pathologies.;This dissertation reports the development of cardiac MR imaging methods and its application to cardiac disease models at high magnetic field (11.7 T). Mouse was chosen as the animal model for studying cardiac disease due to several reasons including anatomical similarity of mouse and human hearts, similarity of murine cardiovascular disorders to human, and ease of genetic manipulation in mouse. The development of a cardiac MRI (CMRI) method for mouse at high magnetic field (11.7 T) was the main objective of this dissertation. Optimization of hardware and software parameters was performed to obtain images of the mouse heart, which is characterized by its small size and very fast motion. Methods for data analysis were developed to obtain functional data (ejection fraction, stroke volume, cardiac output etc) from the anatomical and cine-images of the mouse heart.;M-mode echocardiography (ECHO) is one of the most widely used methods for functional analysis of the heart. Therefore, CMRI was compared to ECHO for functional analysis of healthy and infarcted mouse heart. Although the absolute values of functional parameters obtained from the ECHO and CMRI were different, they showed similar trends over time. In general, there was agreement in the ejection fraction measurements made obtained from the two methods.;After development and validation of the method, CMRI was employed for structural and functional evaluation of mouse heart after myocardial infarction (MI). MI was induced in the mice by permanent ligation of the left coronary artery. CMRI was able to detect the structural changes in the MI heart. It also showed a significant decrease in the function of mouse heart after MI.;Another application of CMRI was to assess the cardiac hypertrophy in a transgenic mouse model of chronic hypertension. The hypothesis was that chronic hypertension, created by the transgenic model, leads to cardiac hypertrophy. Previous studies using ECHO were not able to substantially support this hypothesis. However, CMRI of these transgenic mice detected the decrease in the cardiac function and increase in the wall of the left ventricle, thus validating the model itself. Thus, CMRI proved to be a valuable and unique diagnostic tool for assessing cardiac hypertrophy.;Cardiomyoplasty, or implantation of stem cells into the infarcted heart muscle, is emerging as a promising approach for cardiac therapy. Different types of stem cells have been extensively studied for cardiac tissue regeneration, but very few studies have investigated the fate of transplanted stem cells. In this study, CMRI was used to monitor labeled stem cells that were transplanted in the mouse heart after MI. Mouse mesenchymal stem cells were labeled with superparamagnetic iron oxide particles (SPIO), before transplantation in the mouse heart. An optimized CMRI method was developed and tested in vitro, as well as, ex vivo. CMRI enabled the detection of the cells in vivo and their visualization for up to 4 weeks.;In conclusion, in this dissertation the development and validation of cardiac MRI methods for imaging mouse heart at high magnetic field (11.7 T) have been performed successfully. These methods were applied to the evaluation of myocardial infarction and cardiac hypertrophy in mouse and the monitoring of labeled stem cells after their transplantation in the infarcted heart.