Stem Cell Therapy and Postinfarction LV Remodeling

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DESCRIPTION (provided by applicant): After a period of stable postinfarction left ventricular (LV) remodeling, progressive myocardial dysfunction can develop that ultimately leads to overt congestive heart failure (CHF). The present therapeutic options for post infarction LV remodeling and heart failure are limited. Although cardiomyocytes lose the capability to proliferate after birth, several exciting recently published studies have shown that tissue specific stem cells may have the ability to generate cells of tissues from unrelated organs. The primary focus of the current proposal is to examine whether a small population of multipotent stem cells persists in post-natal tissues, and whether these stem cells can be used to treat myocardial infarct. These studies will use a swine model of postinfarction LV remodeling in which about 30 percent of the animals develop CHF within 8 weeks after coronary artery occlusion. Studies will determine whether stem cell transplantation can prevent infarct expansion and aneurysm formation or prevent the transition to heart failure. The effect of stem cell transplant on energy metabolism will also be examined. Following myocardial infarction longitudinal closed chest studies will measure LV mass and volume, ejection fraction and wall stress with magnetic resonance (MR) imaging, while myocardial ATP, creatine phosphate (CP), inorganic phosphate (Pi), and the regulation of oxidative phosphorylation will be examined with 31P-MR spectroscopy. To examine the potential for stem cell proliferation and differentiation in an ischemic environment, stem cells will be transferred into the coronary bed distal to a left anterior descending coronary artery (or a left circumflex coronary artery) occlusion. To test whether the beneficial effects are greater when the cells are transplanted as differentiated myocytes, stem cells will be predifferentiated to myocytes in culture and then transferred into the infarct. To determine whether cell transplantation is more beneficial in the presence of an open infarct-related coronary artery, cells will be transplanted into the infarcted myocardium when the coronary is opened after infarct has been produced by 24 hours of occlusion. By providing insight into the feasibility of stem cell transplantation, the results may lead to new treatments for LV ischemic injury or failure.