Recent discoveries showing that primitive, pluripotential stem cells may differentiate into functional myocardial or vascular tissue have ignited great interest and sparked studies utilizing these cells as a treatment strategy for acute myocardial infarction, chronic ischemic heart disease and left ventricular dysfunction. Current efforts have focused on two main sources of replacement cells: bone marrow derived progenitor cells (BMCs) and skeletal myoblasts. Transplantation of skeletal myoblasts has been associated with the development of fatal arrhythmias and the engrafted cells do not appear to establish functional electrical connection with the surrounding healthy cardiac muscle. Consequently, autologous bone marrow has become a promising and practical alternative, as pre-clinical data suggest that these cells result in functional improvement. However, the mechanism by which donor BMCs impact myocardial recovery and function remain unknown. One unique patient population that would clearly benefit from cellular cardiomyoplasty are patients with severe ventricular dysfunction requiring mechanical ventricular assist devices (VADs). The increasing reliability and utilization of VADs, coupled with the excitement surrounding stem cell myocardial therapy, suggests a potentially synergistic partnership in the treatment of advanced heart failure. We propose to define the efficiency of BMC survival and the mechanisms of myocardial remodeling and repair in patients during VAD support.
Specific Aim 1 : Determine the safety and efficacy of introducing autologous CD 34+ progenitor BMCs into the myocardium of patients with end-stage cardiomyopathy undergoing insertion of VAD as a bridge to cardiac transplantation.
Specific Aim 2 : Define the mechanisms through which intramyocardial delivery of autologous BMCs enhances myocardial structure and function myocardial tissue will be assessed at the time of VAD implantation and cell administration and again at the time of VAD removal.
Specific Aim 3 : Define the role of the systemic and myocardial inflammatory milieu that exists prior to and following intramyocardial BMC stem cell administration in patients undergoing VAD insertion and to explore the impact of the milieu effects on the myocardial response to stem cell administration. ? ? ?
