Quantitative cardiac imaging to evaluate stem cell therapy of myocardial infarction

Cellular cardiomyoplasty has emerged as a promising therapy for myocardial infarction. The ultimate goal of cardiomyoplasty is to restore the contractile function of the heart through regeneration of myocardium which is lost due to the ischemic insult or through promotion of growth and angiogenesis of host myocardium in the infarct border zone. Recent studies suggest that embryonic stem cell (ESC)-derived cardiomyocytes are able to regenerate myocardium by forming grafts in the infarcted heart. In contrast, endothelial stem cells are not able to transdifferentiate into cardiomyocytes but secrete growth factors and cytokines, which promote angiogenesis and/or prevent apoptosis of the host cardiomyocytes. While angiogenesis and graft formation have been confirmed by postmortem immunostaining, it is not known whether regional perfusion and contractile function has been improved as the results of generation of new blood vessels and myocardium, respectively. The primary goal of this thesis is the development of in vivo imaging methods to quantify regional contractile and perfusion function on a rodent model of myocardial infarction. The graft formed by ESC-CMs was demonstrated in improving the regional contractile function and such improvement was detected by the displacement-encoding with stimulated echo (DENSE) MRI which allows pixel-wise tissue tracking. The myocardium regional contractile function (orthogonal strains) was obtained from DENSE image analysis. Grafting Human Umbilical Vascular Endothelial Cells (HUVECs) leads to an increase of regional myocardial blood flow compared to vehicle treated hearts and such improvement was detected by spin-labeling MRI based non-invasive technique for blood flow quantification. The spin-labeling MRI technique was also validated with standard but invasive microsphere method in measuring myocardial blood flow. The thesis work also includes imaging-based non-invasive tracking of stem cell survival and localization over time after engraftment. A positive contrast technique - SWeep Imaging with Fourier Transformation (SWIFT) was implemented which demonstrated unique strengths to detect superparamagnetic iron oxide (SPIO)-labeled stem cells grafted in myocardium in vivo . Dual-labeling strategy using SPIO and reporter gene was shown to gain complementary information of cell delivery, survival and graft morphology