ABSTRACT
Despite recent advances in revascularization interventions (endovascular therapy or surgery), advanced arterial obstructive disease that causes chronic ischemia or acute myocardial infarction is associated with high rates of morbidity and mortality. Cardiac muscle does not have an inherent mechanism for repair and renewal, which according to current paradigms reflects the lack of an organspecific stem cell able to proliferate along a cardiomyogenic lineage. Scar formation with subsequent congestive heart failure and vulnerability to arrhythmia remain major causes of morbidity and mortality. Myocardial infarction causes irreversible cardiomyocyte injury, which initiates myocardial remodeling that may produce ventricular dilatation and loss of cardiac function. By some means that remain unclear, myocardial infarction causes increased release of bone marrow stem cells into the circulation, and these cells home in on areas of injured tissue. These localized stem cells may then set off repair of the myocardium, but in some patients the number of cells in the injured tissue may not be adequate to prevent cardiovascular events. Clinical evidence suggests that the number of circulating endothelial progenitor cells, presumably from bone marrow, is negatively correlated with combined cardiovascular risk, and also positively correlated with vascular function as measured by flow-mediated brachial artery reactivity in healthy men.1 The ability to initiate and augment the repair process starting immediately after acute myocardial infarction by in vivo administration of an adequate number of stem cells would be a significant therapeutic advance, since bone marrow and bone marrow-derived stem cells have been shown to differentiate into various phenotypes, including endothelial cells and cardiomyocytes.2-5
Optimal angiogenesis and arteriogenesis require expression of multiple growth factors in appropriate sequence and concentration. Such complexity would be impossible to achieve therapeutically by administration of arbitrarily
selected individual growth factors. Therefore, it appears unlikely that a single growth factor (either the gene or peptide) given to the patient with myocardial or leg ischemia will optimally increase collateral flow.6-8 Cultured bone marrow
cells or bone marrow-derived stem cells secrete growth factors, including vascular endothelial growth factor (VEGF) and MCP1, and conditioned medium from the cultured cells can cause changes in vitro (endothelial cell proliferation and migration, and tube formation by both endothelial and smooth muscle cells) that, in vivo, would be associated with angiogenesis and arteriogenesis.9,10 These findings lend mechanistic support to the concept that bone marrow stem cells may offer a unique strategy for therapeutic angiogenesis and arteriogenesis.
