Perivascular Treatment with Azathioprine Reduces Neointimal Hyperplasia in Experimental Vein Grafts
DOI:
https://doi.org/10.1532/HSF98.20051168Abstract
Background. Azathioprine is an immunosuppressive and anti-inflammatory drug, and it has been shown to induce apoptosis in human T-lymphocytes. We investigated whether local treatment with azathioprine can inhibit neointimal hyperplasia in experimental vein grafts.
Methods. C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a cuff technique. In the treatment group azathioprine was perivascularly applied. The control group did not receive local treatment. Vein grafts were harvested at 1 and 2 weeks postoperatively and underwent morphometric analysis as well as immunohistochemical analysis for apoptosis (TUNEL).
Results. In grafted veins without treatment (controls), neointimal thickness was 10 m m (range, 6-29 m m), and 12 m m (range, 8-40 m) at 1 and 2 weeks postoperatively, respectively. In azathioprine-treated grafts, the neointimal thickness was 2 m m (range, 1-5 m m) and 4 m m (range, 3-11 m m) at 1 and 2 weeks postoperatively, respectively. This reduction of neointimal thickness was significant at 1 week (P = .001) and 2 weeks (P = .016) postoperatively.
Azathioprine-treated vein grafts showed an increased rate of apoptosis in the vascular wall as compared with controls (593 [range, 26-783] versus 45 [range, 0-106] apoptotic cells/mm2 at 1 week, P = .063; and 656 [range, 327-1270] versus 19 [range, 0-79] apoptotic cells/mm2 at 2 weeks, P = .016).
Conclusion. We conclude that treatment of experimental vein grafts with azathioprine is associated with a reduction of neointimal hyperplasia and an increased apoptosis rate in the vascular wall. These results suggest that azathioprine may be useful for the prevention of vein graft disease after coronary artery bypass grafting.
References
Belgi G, Friedmann PS. 2002. Traditional therapies: glucocorticoids, azathioprine, methotrexate, hydroxyurea. Z Hautkr 77:624-32.nMaltzman JS, Koretzky GA. 2003. Azathioprine: old drug, new actions. J Clin Invest 111:1122-24.nMingoli A, Edwards JD, Feldhaus RJ, et al. 1996. Fresh vein allograft survival in dogs after cyclosporine treatment. J Surg Res 62:95-102.nSchachner T, Zou Y, Oberhuber A, et al. 2004. Local application of rapamycin inhibits neointimal hyperplasia in experimental vein grafts.nAnn Thorac Surg 77:1580-85.nZou Y, Dietrich H, Hu Y, Metzler B, Wick G, Xu Q. 1998. Mouse model of venous bypass graft disease. Am J Pathol 153:1301-10.nSchachner T, Oberhuber A, Zou Y, et al. 2005. Rapamycin treatment is associated with an increased apoptosis rate in experimental vein grafts. Eur J Cardio Thorac Surg 27:302-6.nSchachner T, Zou Y, Oberhuber A, et al. 2004. Perivascular application of C-type natriuretic peptide attenuates neointimal hyperplasia in experimental vein grafts. Eur J Cardiothorac Surg 25:585-90.nSchwab M, Herrlinger K, Schaeffeler E, Stange EF. 2003. Therapiechronisch entzündlicher darmerkrankungen mit azathioprin, 6-Mercaptopurin und 6-Thioguanin [in German]. Dtsch Med Wochenschr 128:378-85.nTiede I, Fritz G, Strand S, et al. 2003. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest 111:1133-45.nArruda JA, Costa MA, Brito FS, et al. 2003. Effect of systemic immuno suppression on coronary in-stent intimal hyperplasia in renal transplant patients. Am J Cardiol 91:1363-5.n
Published
How to Cite
Issue
Section
Author Disclosure & Copyright Transfer Agreement
In order to publish the original work of another person(s), The Heart Surgery Forum® must receive an acknowledgment of the Author Agreement and Copyright Transfer Statement transferring to Forum Multimedia Publishing, L.L.C., a subsidiary of Carden Jennings Publishing Co., Ltd. the exclusive rights to print and distribute the author(s) work in all media forms. Failure to check Copyright Transfer agreement box below will delay publication of the manuscript.
A current form follows:
The author(s) hereby transfer(s), assign(s), or otherwise convey(s) all copyright ownership of the manuscript submitted to Forum Multimedia Publishing, LLC (Publisher). The copyright transfer covers the exclusive rights to reproduce and distribute the article and the material contained therein throughout the world in all languages and in all media of expression now known or later developed, including but not limited to reprints, photographic reproduction, microfilm, electronic data processing (including programming, storage, and transmission to other electronic data record(s), or any other reproductions of similar nature), and translations.
However, Publisher grants back to the author(s) the following:
- The right to make and distribute copies of all or part of this work for use of the author(s) in teaching;
- The right to use, after publication in The Heart Surgery Forum, all or part of the material from this work in a book by the author(s), or in a collection of work by the author(s);
- The royalty-free right to make copies of this work for internal distribution within the institution/company that employs the author(s) subject to the provisions below for a work-made-for-hire;
- The right to use figures and tables from this work, and up to 250 words of text, for any purpose;
- The right to make oral presentations of material from this work.
Publisher reserves the right to grant or refuse permission to third parties to republish all or part of the article or translations thereof. To republish, such third parties must obtain written permission from the Publisher. (This is in accordance with the Copyright Statute, United States Code, Title 17. Exception: If all authors were bona fide officers or employees of the U.S. Government at the time the paper was prepared, the work is a “work of the US Government” (prepared by an officer or employee of the US Government as part of official duties), and therefore is not subject to US copyright; such exception should be indicated on signature lines. If this work was prepared under US Government contract or grant, the US Government may reproduce, royalty-free, all or portions of this work and may authorize others to do so, for official US Government purposes only, if the US Government contract or grant so requires.
I have participated in the conception and design of this work and in the writing of the manuscript and take public responsibility for it. Neither this manuscript nor one with substantially similar content under my authorship has been published, has been submitted for publication elsewhere, or will be submitted for publication elsewhere while under consideration by The Heart Surgery Forum, except as described in an attachment. I have reviewed this manuscript (original version) and approve its submission. If I am listed above as corresponding author, I will provide all authors with information regarding this manuscript and will obtain their approval before submitting any revision. I attest to the validity, accuracy, and legitimacy of the content of the manuscript and understand that Publisher assumes no responsibility for the validity, accuracy, and legitimacy of its content. I warrant that this manuscript is original with me and that I have full power to make this Agreement. I warrant that it contains no matter that is libelous or otherwise unlawful or that invades individual privacy or infringes any copyright or other proprietary right. I agree to indemnify and hold Publisher harmless of and from any claim made against Publisher that relates to or arises out of the publication of the manuscript and agree that this indemnification shall include payment of all costs and expenses relating to the defense of any such claim, including all reasonable attorney’s fees.
I warrant that I have no financial interest in the drugs, devices, or procedures described in the manuscript (except as disclosed in the attached statement).
I state that the institutional Human Subjects Committee and/or the Ethics Committee approved the clinical protocol reported in this manuscript for the use of experimental techniques, drugs, or devices in human subjects and appropriate informed consent documents were utilized.
Furthermore, I state that any and all animals used for experimental purposes received humane care in USDA registered facilities in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” prepared by the Institute of Laboratory Animal Resources and published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).
