| Summary: | 博士 === 國立臺灣大學 === 臨床醫學研究所 === 97 === The goal of cell therapy in the ischemic heart disease is to optimize ventricular remodeling and regenerate myocardial structures. However, the treatment effect in humans is modest, in contrast to that in animals, where the effect is marked and significant. Thus, it is necessary to know the mechanism underlying successful cell therapy to resolve the efficacy discrepancy between species. There are two strategies in the current cell therapy: one is stem cell transplantation and the other is stem cell mobilization. It is known stem cell recruitment to heart is determined by a concentration gradient of stromal-derived factor 1 (SDF-1) from bone marrow to peripheral blood and from blood to injured myocardium. However, this gradient is decreased in chronic myocardial infarction (MI). Importantly, bone marrow stromal cells (BMSCs) are cells that can secrete high concentrations of SDF-1. Therefore, in the research of stem cell transplantation, using rabbits as an experimental model of chronic myocardial infarction (MI), we determined whether autologous BMSC transplantation could recruit more stem cells to the heart in order to improve ventricular remodeling, and we explored the changes in SDF-1 levels in the bone marrow, peripheral blood, and myocardium before and after cell therapy. MI was induced in male New Zealand White rabbits (2.5-3kg) by ligation of the left anterior descending coronary artery. Two months later, the rabbits were randomized to either a saline or BMSC group, where the latter received an injection of 2x106 autologous BMSCs into the left ventricular cavity. Four weeks after therapy, the SDF-1 gradients from marrow to blood and that from blood to myocardium increased in the BMSC-treated rabbits compared with saline-treated rabbits. This was accompanied by an increase in cells positive for CD34, CD117, and STRO-1 in myocardium, resulting in more capillary density, better cardiac function, and a decrease in infarct size.We concluded that generation of a SDF-1 gradient toward the heart is a novel effect of BMSC-based cell therapy. This effect facilitates stem cell recruitment to remodeled myocardium and supports improvement in cardiac function.
Regarding stem cell mobilization, we study the role of stem cell mobilization in cardiac rehabilization. Cardiac rehabilitation is believed to increase myocardial perfusion reserve (MPR), but this has not been adequately studied because of poor delineation of infarcted myocardium in the previous studies. We determined the effect of cardiac rehabilitation on MPR in the remote and infarcted myocardium with contrast-enhanced magnetic resonance imaging. We then investigated whether cardiac rehabilitation could influence plasma levels of angiogenic cytokines and their correlation with myocardial blood flow (MBF). Thirty-nine postinfarction patients were recruited for this study and randomly assigned to a training group (n = 20) or a nontraining group (n = 19). Those in the training group participated in a 3-month rehabilitation training program at an exercise intensity of 55% to 70% of peak oxygen uptake (VO2), while those in the nontraining group continued their usual lifestyle. Nineteen age-, weight-, and height-matched subjects without cardiovascular risk factors were selected as healthy controls. In the postinfarction patients, a MPR reduction was seen not only in the infarcted myocardium, but also in the remote myocardium. In the training group, exercise capacity increased by 15% (P<0.01) up to the same level as in healthy controls. The post-training MPR was also increased in both the remote (+30%, P<0.01) and infarcted myocardium (+25%, P<0.05) and reached the same level as in healthy controls. The change in exercise capacity correlated with the change in MPR in the remote myocardium (r=0.55, P<0.001 for peak VO2). In the nontraining group, exercise capacity and MPR were unchanged. In conclusion, cardiac rehabilitation improves MPR in both the infarcted and remote myocardium, with a parallel increase in exercise capacity. In addition, postinfarction patients had a higher plasma levels of vasculoendothelial growth factor (VEGF) and SDF-1. Only SDF-1 was inversely associated with stress MBF in both remote and infarcted myocardium (r=0.62, p,0.001). After 3 months, the training group’s stress MBF had increased by 33% in the remote (p<0.001) and 28% in infarcted myocardium (p=0.02), while VEGF decreased by 9% (p=0.01), and SDF-1decreased by 11% (p=0.02). The change in SDF-1 was inversely correlated with the change in stress MBF in both remote (r=0.40, p=0.01) and infarcted myocardium (r=0.50, p=0.001). In the non-training group, MBF and cytokines were unchanged.
In conclusions, the present doctoral thesis combined basic research and clinical studies to demonstrate how angiogenic cytokines, especially SDF-1, are involved in the mechanism and efficacy of cell therapy. We first showed the generation of a SDF-1 gradient toward the heart is a novel effect of BMSC-based cell therapy. This effect facilitates stem cell recruitment to remodeled myocardium and supports improvement in cardiac function. Then we performed a prospective and randomized clinical trial showing (1) the possibility of functional recovery of resistant vessels in the infarcted myocardium after cardiac rehabilitation and (2) an inverse relation between plasma SDF-1 and myocardial perfusion, suggesting a feedback regulation of SDF-1 due to increased blood supply to the myocardium after cardiac rehabilitation. This result also indicates that a large prospective study is needed to determine whether including serial measurements of SDF-1 during follow-up improves the ability to detect myocardial hypoperfusion and thereby allows early cardiac rehabilitation.
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