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(Circulation. 2005;112:e153.)
© 2005 American Heart Association, Inc.

Correspondence

Letter Regarding Article by Luo et al, "Adenovirus-Mediated Expression of ß-Adrenergic Receptor Kinase C-Terminus Reduces Intimal Hyperplasia and Luminal Stenosis of Arteriovenous Polytetrafluoroethylene Grafts in Pigs"

Joris I. Rotmans, MD, PhD; Erik S.G. Stroes, MD, PhD

Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands

Gerard Pasterkamp, MD, PhD

Experimental Cardiology Laboratory, University Medical Center, Utrecht, The Netherlands

To the Editor:

With great interest we have read the article by Luo and coworkers¹ in which they described a reduction of intimal hyperplasia and luminal stenosis after adenoviral transduction of ßARKct in a pig model of ePTFE arteriovenous (AV) graft failure. This study confirms the potential of gene therapeutic approaches to prevent stenosis in AV grafts for hemodialysis.² An intriguing finding was the very low patency rate in the control group, which declined to 37.5% after 4 weeks. This is in sharp contrast to the 100% patency rate after 4 weeks in similar experiments performed in our laboratory.³ The authors propose that "different structure" of the AV grafts between the studies may have contributed to the unexpectedly large discrepancy in patency rates. We believe, however, that other differences in methodology more likely explain the differences in patency rates. First, Luo and coworkers constructed 1 AV graft between the carotid artery and the contralateral jugular vein, whereas we constructed 2 bilateral AV grafts in each pig. The setup used by Luo et al is likely to be accompanied by significantly lower graft flow in view of the longer grafts (15 cm versus 7.5 cm in our experiments). Lower graft flow accelerates graft thrombosis, as reduction in flow is the best single predictor for graft thrombosis.⁴ Second, another pivotal observation is the absence of any newly formed thrombotic lesions in the histological sections, compatible with the onset of thrombosis between 1 and 2 weeks after implantation. In this respect, it is significant to note that no mention is made regarding the antiplatelet regimen in the thrombogenic pig model. In our experience, it is of the utmost importance to institute the use of both clopidogrel and acetylsalicylic acid to prevent early graft thrombosis in this AV graft model in the pig. It has been acknowledged generally that the most prevalent cause of early graft thrombosis pertains to technical failures rather than graft failure due to progressive stenosis at the venous outflow tract. Studies with low patency rates such as those reported by Luo et al¹ should be interpreted carefully, because early graft thrombosis and not gradual intimal hyperplasia may have been the main determinant of lumen loss during follow up.

	References

Top References References

 

1. Luo Z, Akita GY, Date T, Treleaven C, Vincent KA, Woodcock D, Cheng SH, Gregory RJ, Jiang C. Adenovirus-mediated expression of ß-adrenergic receptor kinase C-terminus reduces intimal hyperplasia and luminal stenosis of arteriovenous polytetrafluoroethylene grafts in pigs. Circulation. 2005; 111: 1679–1684.[Abstract/Free Full Text]
   
2. Rotmans JI, Verhagen HJ, Velema E, de Kleijn DP, van den Heuvel M, Kastelein JJ, Pasterkamp G, Stroes ES. Local overexpression of C-type natriuretic peptide ameliorates vascular adaptation of porcine hemodialysis grafts. Kidney Int. 2004; 65: 1897–1905.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Rotmans JI, Velema E, Verhagen HJ, Blankensteijn JD, Kastelein JJ, de Kleijn DP, Yo M, Pasterkamp G, Stroes ES. Rapid, arteriovenous graft failure due to intimal hyperplasia: a porcine, bilateral, carotid arteriovenous graft model. J Surg Res. 2003; 113: 161–171.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Neyra NR, Ikizler TA, May RE. Change in access blood flow over time predicts vascular access thrombosis. Kidney Int. 1998; 54: 1714–1719.[CrossRef][Medline] [Order article via Infotrieve]
   

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Response

Zhengyu Luo, MD; Geoffrey Y. Akita, DVM, PhD; Taro Date, MD, PhD; Christopher Treleaven, BSc; Karen A. Vincent, PhD; Denise Woodcock, AS; Seng H. Cheng, PhD; Richard J. Gregory, PhD; Canwen Jiang, MD, PhD

Genzyme Corporation, Framingham, Mass

We appreciate Drs Rotmans, Pasterkamp, and Stroes’ interest and comments on the patency rate in our pig model of arteriovenous ePTFE graft failure.¹ Compared with their earlier report, the patency rate 4 weeks after the construction of the arteriovenous ePTFE grafts was much lower in our study.² They suggest that the longer length of our ePTFE grafts and slower blood flow contributed to the lower patency rate. As stated in our article, Rotmans et al constructed 2 bilateral PTFE AV grafts in each pig in their study, whereas only a single AV shunt between the left common carotid artery and right external jugular vein was created in our study, owing to concerns of cerebral ischemia. In addition to the difference over the graft length, the angle (25° to 30° in our study versus 45° in theirs) by which the ePTFE graft was cut and anastomosed to the external jugular vein was also different. We reasoned that the different structure and resultant flow velocity may have contributed to the discrepancy in patency rate.¹ They also speculate that thrombotic lesions might have accelerated graft failure in our study. Our study was not designed to examine the relative contribution of early thrombosis and gradual intimal hyperplasia to graft failure in the absence of an antiplatelet regimen. Although no antiplatelet regimen was used, the pigs were treated with a bolus dose of heparin (100 IU/kg) before graft implantation. It is possible that early thrombosis accelerates intimal hyperplasia and graft failure.³ On the basis of angiographic and histological assessments, however, there was no evidence that early graft thrombosis rather than progressive intimal hyperplasia at the ePTFE/vein anastomosis determined graft patency.

	Acknowledgments

 
Disclosure

The authors are employees of Genzyme, which sponsored the research under discussion.

	References

Top References References

 

1. Luo Z, Akita GY, Date T, Treleaven C, Vincent KA, Woodcock D, Cheng SH, Gregory RJ, Jiang C. Adenovirus-mediated expression of ß-adrenergic receptor kinase C-terminus reduces intimal hyperplasia and luminal stenosis of arteriovenous polytetrafluoroethylene grafts in pigs. Circulation. 2005; 111: 1679–1684.[Abstract/Free Full Text]
   
2. Rotmans JI, Velema E, Verhagen HJ, Blankensteijn JD, Kastelein JJ, de Kleijn DP, Yo M, Pasterkamp G, Stroes ES. Rapid, arteriovenous graft failure due to intimal hyperplasia: a porcine, bilateral, carotid arteriovenous graft model. J Surg Res. 2003; 113: 161–171.[CrossRef][Medline] [Order article via Infotrieve]
   
3. Pakala R, Willerson JT, Benedict CR. Effect of serotonin, thromboxane A2, and specific receptor antagonists on vascular smooth muscle cell proliferation. Circulation. 1997; 96: 2280–2286.[Abstract/Free Full Text]
   

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This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rotmans, J. I. Articles by Jiang, C. Search for Related Content PubMed PubMed Citation Articles by Rotmans, J. I. Articles by Jiang, C. Related Collections Gene therapy Platelet function inhibitors Restenosis Animal models of human disease CV surgery: other Related Article