Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

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Left ventricular assist device recipients have survival outcomes similar to those of nonbridged recipients after cardiac transplantation, despite their significantly higher immunologic risk. The reduced rate of transplantation and the increased incidence of rejection observed in sensitized left ventricular assist device recipients are prevented by immunomodulatory therapy. Sensitization will remain an important issue with increased use of left ventricular assist devices, and improved understanding of this is essential to achieve better outcomes in the management of patients with end-stage heart failure.

, and S. Itescu. Myocardial neovascularization by bone marrow angioblasts results in cardiomyocyte regeneration. Am J Physiol Heart Circ Physiol 287: H525-H532, 2004; 10.1152/ ajpheart.00058.2004.-The primary cardiac response to ischemic insult is cardiomyocyte hypertrophy, which initiates a genetic program culminating in apoptotic myocyte loss, progressive collagen replacement, and heart failure, a process termed cardiac remodeling. Although a few cardiomyocytes at the peri-infarct region can proliferate and regenerate after injury, no approaches are known to effectively induce endogenous cardiomyocytes to enter the cell cycle. We recently isolated, in human adult bone marrow, endothelial progenitor cells, or angioblasts, that migrate to ischemic myocardium, where they induce neovascularization and prevent myocardial remodeling. Here we show that increasing the number of angioblasts trafficking to the infarct zone results in dose-dependent neovascularization with development of progressively larger-sized capillaries. This results in sustained improvement in cardiac function by mechanisms involving protection against apoptosis and, strikingly, induction of proliferation/ regeneration of endogenous cardiomyocytes. Our results suggest that agents that increase myocardial homing of bone marrow angioblasts could effectively induce endogenous cardiomyocytes to enter the cell cycle and improve functional cardiac recovery. stem cells; myocardial remodeling; myocardial infarction AN INTEGRAL COMPONENT of the healing process after a myocardial infarction is compensatory hypertrophy of viable cardiomyocytes at the peri-infarct rim to increase pump function in response to the loss of infarcted tissue (9, 24). However, cardiomyocyte hypertrophy initiates a genetic program that culminates in apoptotic loss of the cardiomyocytes, expansion of the initial infarct area, progressive collagen replacement, and heart failure (1,5,19,20), a process termed cardiac remodeling. Pharmacological means to prevent cardiomyocyte hypertrophy remain the mainstay of postinfarct therapy to prevent remodeling and heart failure. Recent observations have suggested that a second compensatory response of viable cardiomyocytes at the peri-infarct region is to proliferate and regenerate after injury (3, 7). Although cardiomyocyte regeneration can be accomplished by providing exogenous precursors, for example, from the bone marrow (17), no approaches are known to effectively induce endogenous cardiomyocytes to enter the cell cycle.We recently put forward the hypothesis that hypertrophied cardiomyocytes undergo apoptosis, because the endogenous capillary network cannot provide the compensatory increase in perfusion required for cell survival (12). Vascular network formation is the result of a complex process that begins in the prenatal period with induction of vasculogenesis by hemangioblasts, cells derived from the human ventral aorta that give rise to endothelial and hematopoietic elements (4, 6, 10, 13). Postnatal vasculogenesis occurs via pathways ...