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Ann Thorac Surg 1996;62:1058
© 1996 The Society of Thoracic Surgeons
DR TODD K. ROSENGART (New York, NY): I congratulate you on a very interesting paper and certainly an innovative approach to enhancing the potential of transmyocardial revascularization. I will briefly present some information that my associates and I have developed regarding the angiogenic potential of vascular endothelial growth factor (VEGF) in vivo. Before we went to studies examining VEGF delivery in the myocardium, we wanted first to assess its angiogenic potential when delivered using an adenovirus vector. We used retroperitoneum as a target site for a number of reasons, including the fact that this tissue possesses a very low baseline level of vascularization.
In these experiments, we delivered 109 pfu/100 µL of adenovirus encoding for VEGF, which yielded VEGF tissue concentrations of about 5 ng/mL. We were able to demonstrate about a fivefold increase in vascularization grossly and similar results histologically without much inflammation or fibrosis 30 days after viral administration. The administration of a null virus yielded minimal neovascularization. As mentioned in your discussion, the method of delivery of the VEGF is very important, and a number of previous studies suggest that sustained tissue exposure to VEGF is probably critical to stimulating angiogenesis. I think that providing sustained VEGF delivery using a viral vector may be a useful means of accomplishing this goal, a means that may also prove clinically useful in inaccessible internal organs such as the heart.
DR CRAIG R. SMITH (New York, NY): At Columbia-Presbyterian, for several years, we have been looking at the effect of carbon dioxide lasers and holmium–yttrium-aluminum garnet lasers in animal hearts and more recently in human hearts. This is the first report of which I am aware that suggests that the histology we are observing may be the rule rather than the exception. The channels you discussed are exactly like those we have been seeing.
I agree with Dr Rosengart that it might be premature to give up on a role for growth factors. We have done a series of experiments in normal canine hearts in which each laser channel was filled with a Teflon stent coated with Matrigel containing 100 ng/mL of beta fibroblast growth factor. The animals were sacrificed at 2 weeks and the hearts examined histologically. At lower power, we saw a channel in cross section containing remnants of the stent surrounded by a flare of inflammation. At higher power, we saw that most of the darker-staining surrounding area was an inflammatory infiltrate similar to what you presented. However, in a paler-staining area adjacent to the channel, there was a substantial proliferation of endothelial cells in nests and whorls. This lay outside the core of the channel itself, which is where we typically see small, endothelium-lined spaces in unmodified channels. This implies that our stent-Matrigel-FGF combination successfully stimulated angiogenesis outside the channel.
You anticipated my first question by indicating your plans to do an ischemic model. Perhaps an ischemic heart will provide an opportunity to see more effects from the VEGF if there is a less pronounced increase in vascularity from the laser alone.
My second question has to do with other mechanisms. I think you were very perceptive in your choice of three histologic grading criteria because fibrosis, inflammation, and vascularity are certainly the three poles of a healing reaction that may be important to manipulate. If vascularity proves less manipulatable than we would like, have you considered adding factors that would interfere with fibrosis and that might also contribute to a better result?
DR FLEISCHER: To date, we have not tried any adjunctive interventions except VEGF and the adenovirus encoding for the profilin gene reported in this study.
Related Article
Ann. Thorac. Surg. 1996 62: 1051-1058.
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