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J Thorac Cardiovasc Surg 2003;126:122-123
© 2003 The American Association for Thoracic Surgery
Cardiopulmonary support and physiology |
Dr T. Rosengart (Evanston, Ill). I congratulate the authors on a beautiful presentation. They certainly are pioneers in the field, together with Dick Weisel and Philippe Menasche, and really have led a growing body of evidence suggesting some very exciting work in the possibility of cell transplant.
I have four questions for Dr. Saito. The first question involves the use of 5-azacytidine to drive differentiation. Your histology very elegantly shows apparent differentiation of cell lines based upon the localization either to scar or periscar, appearing to go to a myocyte differentiation or a fibroblast differentiation. Based upon these findings, do you think that additional 5-azacytidine would be efficacious or a more prolonged predifferentiation prior to transplant?
In contrast, there certainly are a number of studies now suggesting that undifferentiated cells, bone marrow or otherwise, may equally be efficacious in driving myocardial remodeling. Given concerns potentially by the US Food and Drug Administration or other regulatory agencies in going to clinical trials in terms of mutations, potential mutations, and complications using 5-azacytidine, how do you see the role of using this or other differentiating factors?
Dr Saito. We have not seen it.
Dr Rosengart. Do you think that the azacytidine plays an important role, or do you think that simply transplanting undifferentiated cells will be as efficacious?
Dr Saito. Yes, I think so. We have never seen myotube formation or pulsating cells in a culture dish even after treatment with 5-azacytidine. Possibly I don’t think 5-azacytidine worked. Therefore, we reconfirmed the importance of a microenvironment.
Dr Rosengart. The second question involves the vascular delivery, the arterial delivery, and certainly this has advantages in terms of global dissemination, spreading of the cells throughout the myocardium. The concern, of course, as you have shown in your histology, is the risk of microembolization. Have you looked at creatine kinase levels or other evidence of myocardial injury? Is that a potential disadvantage of this delivery technique?
Dr Saito. Yes, it is a very important point. Actually we have never checked the creatine kinase level, but if we infused more number of cells, the mortality was much higher. For example, if I infused 5 million cells as a preliminary study, more than half of the animals died immediately after cell infusion. That was I think due to microembolization. I have never seen a creatine kinase level.
Dr Rosengart. The third question involves your echo data, and it appears very clear that when you look at your ejection fraction and your end-diastolic and systolic volumes that you do have what appears to be a stabilization of geometry or compliance. When you look at your fractional shortening data at the 8-week time point, you appear to have an improvement in function that is not consistent with your other parameters. Do you have any explanation why these parameters appear to be different?
Dr Saito. Ejection fraction was calculated using LVEDd and LVEDs. That was presented. But when calculated, I also don’t understand why only at 8 weeks marrow stromal cells show, how to say, very improved cardiac function. But basically this value, fractional shortening, was calculated from EDd and EDs. So I don’t know why.
Dr Rosengart. Thank you. And my final question involves mechanism of action. On your 8-week histology it would appear that there are a relatively sparse number of cells. I don’t know if you have an estimation of how many cells you actually have. As you know, obviously the two or three major mechanisms being considered are stabilization of compliance and angiogenesis, and then obviously the possibility that these are actually contractile cells. It would appear based upon your cell number that stabilization of compliance is not an obvious mechanism; certainly angiogenesis is a possibility, but your echo data would again suggest that maybe this is stabilizing compliance.
Do you have any theories right now which is the more likely explanation of why this is potentially working?
Dr Saito. That is the limitation of our study, to explain the exact mechanism. What I can do is just speculate. As you suggested, we actually found some marrow stromal cells integrated into the vascular wall, so I think some of them participated in angiogenesis, and obviously it had a positive impact on cardiac function. Another thing is probably that numerous cells in the infarcted area contributed to avoid scar thinning and chamber dilatation. So probably improvement was obtained from a combination of those factors. I can’t say clearly.
Dr J. Chachques (Paris, France). I want to congratulate you for this research and study. I want to point also that for this cell therapy there are two indications: one is ischemic disease and the other can be also idiopathic dilated cardiomyopathy. In our group we are working on both approaches experimentally.
The goal of this cell therapy in your model is to improve the condition of the ischemic area. If you have occlusion of the artery that will irrigate this infarction area, the cells will not arrive toward this area, and so the cell therapy will not be efficient to replace the dead cells. Perhaps the best indication for cell therapy delivered through the coronary arteries is idiopathic dilated cardiomyopathy. In this case you can have the cell therapy through the whole myocardium, and I think that in your case you don’t have cells into the infarct. Can you make a quantitative analysis of the cells that you find into the myocardium?
Dr Saito. Thank you very much for your comment and the question. Actually we estimated the number of cells in the infarcted area harvested at 8 weeks after cell infusion; that was approximately 3 million cells. That was 3 times more than that of injury infused. At the time of cell infusion it was 2 weeks after left coronary artery ligation, and the scar formation had not been completed. Of course there is some ischemic area, but along with the completion of scar formation, oxygen supply and demand level would be stabilized. And also, although left coronary ligation was performed permanently, the resultant myocardial infarction was rather heterogeneous; I mean, some cells survived, some vessels were patent, and that is why they could survive even in the middle of the scar.
Related Article
J. Thorac. Cardiovasc. Surg. 2003 126: 114-122.
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