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Ann Thorac Surg 2000;70:1763-1764
© 2000 The Society of Thoracic Surgeons
a Department of Surgery, University of Pennsylvania, 6 Silverstein, 3400 Spruce St, Philadelphia, PA 19104, USA,
e-mail: cbridges{at}mail.med.upenn.edu
To the Editor
I appreciate Dr Lansing’s kind comments regarding the review article [1]. As discussed in the review, the available data support Dr Lansing’s observations. The Holmium-YAG laser appears to cause more tissue damage than the CO2 laser [1, 2]. His observations regarding VEGF levels are also provocative. The fact that Rosengart and associates did not observe a similar increase in systemic VEGF levels after injection of adenovirus encoding VEGF into the myocardium [3] implies that the tissue injury associated with TMR is the likely cause of the observed increase in VEGF levels. Certainly, this latter view is bolstered by the experimental studies performed in Dr Chiu’s lab, where sufficient needle injury of the myocardium in a porcine model resulted in an identical increase in the density of VEGF-positive vessels as TMR, using anti-VEGF immunostaining [4]. Whether or not the increase in systemic levels of VEGF correlates with the effect on angiogenesis is not clear. In the case of an adenovirus encoding VEGF, the expression of the VEGF cDNA may lead to local, intracellular myocyte VEGF expression, while TMR may induce VEGF production at other sites leading to differential systemic VEGF levels. Because the important impact of VEGF expression on myocardial angiogenesis is likely to be related to local tissue concentration, systemic VEGF levels may be poorly or possibly even inversely correlated with local myocardial tissue levels. Thus, Dr Lansing’s conclusion that "[The local increase in VEGF concentration associated with TMR] must be much greater than that administered in direct injections ... " may not be valid. In any case, Dr Lansing’s observations are important as we critically evaluate therapeutic modalities including direct growth factor injection into the myocardium [5], injection of naked (plasmid) DNA encoding VEGF [6], and adenovirus encoding VEGF into the myocardium [3] in efforts to induce angiogenesis.
In fact, there is a growing body of evidence that VEGF, although important in the angiogenic response, may be less relevant than growth factors such as angiopoietin-1, whose expression is required for the development of mature vessels. Transgenic mice overexpressing VEGF alone in the skin develop nests of immature "leaky" vessels that resemble capillaries. In contrast, transgenic mice overexpressing angiopoietin-1 develop larger vessels with normal vascular permeability, which appear more likely to have an impact on blood flow in patients with macroscopic arterial-occlusive disease such as coronary artery disease [7]. Thus, VEGF may not be the critical, rate-limiting growth factor in the development of clinically significant new blood vessels. His comments regarding the absence of "tumors or retinopathy" in these patients deserve emphasis as well. As we move forward with these innovative therapies, patients must be closely monitored for the development of complications related to the local and systemic effects of stimulating angiogenesis.
References
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