The most important late complication of myocardial infarction is congestive heart failure, which often results from pathologic left ventricular remodeling. Currently no therapy directly addresses repair or replacement of damaged myocardium. Cellular cardiomyoplasty, the technique of transplanting progenitor cells into the heart, represents a highly promising new treatment strategy. Among the different potential cellular sources, mesenchymal stem cells (MSCs) derived from bone marrow are emerging as a leading candidate. We have shown in a swine model of infarction that MSCs can be transplanted by intramyocardial (IM) injection (via surgical or percutaneous approaches) with robust engraftment and differentiation into a myocyte-like phenotype, resulting in improved LV function and attenuated remodeling. Yet many challenges remain before translating this treatment strategy into clinical use. Accordingly, we propose studies to further simplify MSC delivery and develop noninvasive means of assessing their engraftment and effect. Using swine chronically instrumented to measure cardiac mechanical efficiency and randomized to a particular mode of MSC delivery following infarction, we will first test two hypotheses: 1) intracoronary delivery of stem cells is equivalent or superior to IM administration, with respect to engraftment, cardiac energetics and function, and 2) there is an optimum time frame during which MSC transplantation yields maximum engraftment. Subsequently, in noninstrumented animals similarly randomized we will test the additional hypotheses that: 3) MSCs can be magnetically labeled, located and quantified by MRI following transplantation, and 4) MRI can reliably determine the impact of transplanted MSCs on cardiac function and infarct size. The results of these studies will provide novel insights into the optimum mode and timing of MSC delivery and will show that both their fate and impact on ventricular remodeling can be noninvasively assessed by MRI. Furthermore, these noninvasive techniques will be immediately transferable to human clinical trials.
