CORRESPONDENCE: LETTER TO THE EDITOR
Drug-Eluting Stent Implantation May Not Affect Vasomotor Function in Early Phase
Gaku Nakazawa, MD,
Qi Cheng, MD,
Xin Xu, PhD,
Aloke V. Finn, MD,
Frank D. Kolodgie, PhD and
Renu Virmani, MD*
* CVPath Institute Inc, 19 Firstfield Road, Gaithersburg, Maryland 20878 (Email: rvirmani{at}cvpath.org).
The study by Obata et al. (1) demonstrates that drug-eluting stents (DES) adversely affect endothelium-dependent vasomotor function with a reduction in vascular endothelial growth factor (VEGF). This report addressed a very important issue because it has been reported that endothelialization and its function are impaired following DES implantation (2,3). However, we are not convinced by the findings in the present study that DES affect vasomotor function 2 weeks after implantation. As we have previously reported (4), there is no histologic difference between DES and bare-metal stents (BMS) within 2 weeks following implantation. Moreover, vascular healing of the stented segment in acute myocardial infarction generally takes a much longer time to complete than stable plaques do in the case of both DES and BMS because these lesions generally contain large necrotic cores. Therefore, it is surprising that the authors report differences in response to intracoronary acetylcholine because the extent and functionality of endothelium for lesions stented with either DES or BMS lesions is not different 2 weeks after implantation. Furthermore, angiography cannot detect the underlying atherosclerotic disease in the distal segments where vasomotor function was assessed, and it is possible that the differences observed were due to differences in atherosclerotic burden between the 2 groups because endothelial function has been shown to be heavily influenced by the presence of underlying atherosclerotic disease.
The authors also speculate that lack of VEGF in DES might be responsible for impaired endothelialization or its function. As the authors mentioned in the introduction, a compensatory up-regulation of VEGF is usually observed when endothelium is denuded, whereas VEGF is down-regulated upon complete re-endothelialization (5). We do agree that high blood concentrations of sirolimus at an early time point could impair endothelial cells in the portion distal to the stent and be responsible for vasomotor dysfunction. However, the sirolimus concentration in the anterior interventricular vein is far below its IC50 (1.0 to 1.5 nmol/l) even at 3 days (0.5 nmol/l) and even further below at 2 weeks (0.2 nmol/l) following implantation. Even if sirolimus had a detrimental effect on endothelial cells in the distal vessel, the VEGF level should be higher in the presence of active ongoing arterial repair. In fact, our in vitro and in vivo data clearly showed VEGF up-regulation after endothelial injury. In our own assays, human umbilical vein endothelial cells are grown until confluence and VEGF expression is measured using Cytokine Array (RayBiotech Inc., Norcross, Georgia) in the presence and absence of scratching or treatment with everolimus (2 nmol/l) for 16 h. The VEGF was greater in the scratched and everolimus group (1.7 ± 0.4- and 1.8 ± 0.6-fold increase, respectively) as compared with the nonscratched control group. Similarly, we have observed up-regulation of VEGF messenger ribonucleic acid in the bare-metal stented rabbit iliac arteries as compared with nonstented iliac arteries at 7 days (1.4 ± 0.2-fold-increase). Thus, VEGF is up-regulated in the lesions where endothelialization is incomplete. It is hard to reconcile these findings with those of Obata et al. (1). The vascular biology of DES implantation is just being understood and larger clinical studies as well as preclinical studies are needed to deepen our understanding.
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Footnotes
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Please note: Dr. Virmani receives research support from Medtronic AVE, Abbott Vascular, Conor Medsystems, OrbusNeich, Terumo Corporation, Cordis Corporation, BioSensors International, Prescient Medical, Biotronik, and Alchimedics. She consults for Medtronic AVE, Abbott Vascular, Prescient Medical, and Biotronik.
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References
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- Obata JE, Kitta Y, Takano H, et al. Sirolimus-eluting stent implantation aggravates endothelial vasomotor dysfunction in the infarct-related coronary artery in patients with acute myocardial infarction J Am Coll Cardiol 2007;50:1305-1309.[Abstract/Free Full Text]
- Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk J Am Coll Cardiol 2006;48:193-202.[Abstract/Free Full Text]
- Togni M, Windecker S, Cocchia R, et al. Sirolimus-eluting stents associated with paradoxic coronary vasoconstriction J Am Coll Cardiol 2005;46:231-236.[Abstract/Free Full Text]
- Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing Arterioscler Thromb Vasc Biol 2007;27:1500-1510.[Abstract/Free Full Text]
- Wysocki SJ, Zheng MH, Smith A, Norman PE. Vascular endothelial growth factor (VEGF) expression during arterial repair in the pig Eur J Vasc Endovasc Surg 1998;15:225-230.[CrossRef][ISI][Medline]
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