EDITORIAL COMMENT
Endothelial Dysfunction Associated With Drug-Eluting StentsWhat, Where, When, and How?*
Joseph B. Muhlestein, MD, FACC*
Division of Cardiology, Intermountain Medical Center, Murray, Utah.
* Reprint requests and correspondence: Dr. Joseph B. Muhlestein, Division of Cardiology, Intermountain Medical Center, 5121 South Cottonwood Street, Murray, Utah 84107. (Email: ldbmuhle{at}ihc.com).
The advent of drug-eluting stents (DES) into the practice of interventional cardiology has had a tremendous impact. After their demonstration of a significant reduction in restenosis in randomized trials and U.S. Food and Drug Administration approval for their use in 2003, the incorporation of DES into clinical practice was rapid and extensive. However, beginning in 2004, a variety of reports began to circulate documenting an increased incidence of early, late, and very late stent thrombosis after DES implantation, especially after discontinuation of dual antiplatelet therapy (1). This was proposed to be caused by impaired endothelialization of the vessel at the site of stent deployment because of the presence of either the drug, the stent polymer, or both (2). Shortly thereafter, several studies reported another, more distant, effect of both sirolimus-coated and paclitaxel-coated stents, that of long-term endothelium-related vascular dysfunction detected in nonstented segments of the coronary artery (3–6). Although the precise mechanism of this distant vascular phenomenon was not known, because it was not apparent in vessels receiving bare-metal stents (BMS), it was presumed to be secondary to the presence of either the antiproliferative drug itself or its associated polymeric DES coating. Two important articles published in this issue of the Journal address these issues. One evaluates the effect on vascular function of chronic exposure to sirolimus (7). The other reports the results of a new DES, with both a different drug and a different polymeric coating, that does not seem to induce endothelial dysfunction (8). Although neither study completely answers all possible questions regarding this issue, they both contribute to our understanding of the underlying pathophysiology of the process and offer hope for a resolution of the problems with next-generation DES.
In the article by Jabs et al. (7), a 7-day continuous infusion of sirolimus into Wistar rats produced a marked degree of endothelial dysfunction as well as a desensitization of the endothelium-independent vasodilator nitroglycerin, showing that the drug may play a specific role. The investigators also reported a possible mechanism, that of sirolimus increasing the production of vascular superoxide, with the result being a loss of vascular nitric oxide bioavailability. Although their rat model was one of prolonged systemic exposure to sirolimus, they proposed that these processes could contribute to the observed endothelial dysfunction noted after deployment of sirolimus-coated stents. There are several other important limitations to this study. First, it is not certain whether the sirolimus dosing in the rat study is comparable at the vascular level to that of a coronary artery containing a DES. Second, in the rat model, the presence of sirolimus adversely affected both endothelium-dependent and endothelium-independent vascular function. In the clinical studies of DES, it was only the endothelium-dependent vascular function that was adversely affected. Third, the hypothesis that it is the effect of the sirolimus that results in long-term endothelial dysfunction must be contrasted with the fact that vascular dysfunction after sirolimus-eluting stent deployment has been reported long after the drug is gone. If the drug is still the cause, this implies that its effect must persist beyond drug exposure. In the rat model, the exposure of sirolimus continued to the end of the study, so we cannot tell whether endothelial dysfunction was persistent or not. Therefore, although the drug may play some role, it is still possible that the polymer may also be important.
Both the sirolimus-coated Cypher (Cordis Corporation, Miami Lakes, Florida) and paclitaxel-coated Taxus DES (Boston Scientific Corporation, Natick, Massachusetts) have similar permanent, nonbioabsorbing polymer coatings, including poly-n-butyl methacrylate plus polyethylene-vinyl acetate for Cypher and poly [styrene-isobutyl-styrene] for Taxus (9). These polymer layers are used both as drug reservoirs and as nondrug top-coated films to achieve optimal drug release kinetics. Both have been shown to produce, in some patients, a hypersensitivity response that could contribute to downstream vascular dysfunction (2). In the article by Hamilos et al. (8), the investigators report the results of a second-generation DES with a bioabsorbable polymer that may eliminate the endothelial dysfunction produced by earlier stent designs. In this clinical study evaluating the new Nobori biolimus A9-eluting stent (Terumo Corporation, Tokyo, Japan), vascular reactivity at 9 months was preserved in the biolimus stent when compared with the Cypher stent. The Nobori stent is different from the Cypher stent in several ways. First, it has a different drug, biolimus A9, which is apparently more lipophilic and binds more rapidly to its tissue target. This may assist in limiting the drug's presence strictly to the stent deployment site, thereby preventing its spread to more distant vascular sites where it might contribute to vascular dysfunction. Second, the drug is placed only on the vessel side of the stent, thus reducing the amount of drug released into the peripheral circulation and potentially minimizing any distant drug effect. Third, the biolimus stent has different drug-release kinetics, which may reduce the magnitude of exposure of the drug to surrounding tissues at any given time. Fourth, the Nobori stent coating itself is not permanent and is expected to be absorbed within a few months, leaving a simple BMS remaining. Which of these differences between the Nobori and Cypher stents is most important to the present study's findings related to long-term vascular function is not known, but it is certainly possible that timely resorption of the polymer is critical to the maintenance of long-term healthy vascular function.
Regardless of the mechanisms of the reduction of vascular function after DES deployment, the following questions remain: what is the clinical relevance of this finding and what can be done about it? Certainly, in many circumstances, reduced endothelial function has been shown to correlate with increased atherogenesis, as well as cardiovascular risk (10). Whether DES-induced endothelial dysfunction produces a similar risk is not known. However, one disappointing finding in most long-term follow-up studies comparing the use of DES with BMS is the general lack of improvement in the hard outcomes of death and myocardial infarction (11). Indeed in several studies, the risk of death is increased with the use of DES over and above what might be expected from the documented risk of stent thrombosis (12). It is possible that an increased cardiovascular risk from DES-associated endothelial dysfunction may help to explain these findings. In addition, it is not yet known how generalized the effect of DES-induced endothelial dysfunction is. Most published studies have only looked at the target vessel. In the present study by Hamilos et al. (8), endothelial dysfunction was noted in the target vessel both proximal as well as distal to the site of Cypher stent deployment. This implies that the effect did not require a downstream relationship to have an impact. Although this has not yet been studied, it does seem possible that DES-associated endothelial dysfunction may be generalized to other coronary arteries aside from the specific one where the DES was placed. If this is the case, then much of the potential clinical benefit from presently available DES, occurring as a result of a reduced incidence of in-stent restenosis, might be offset by the adverse clinical effects of DES-associated endothelial dysfunction.
Finally, if DES-associated endothelial dysfunction is a real and harmful phenomenon, what can be done about it? As shown in this issue of the Journal, newer, perhaps better, second-generation DES are presently being designed and tested that may eliminate this adverse effect. However, in the meantime, for the millions of patients in whom first-generation DES have already been deployed, aggressive efforts to improve general endothelial function could be helpful. Aggressive lipid management with statins has been shown to improve vascular reactivity (13). Other lipid therapies such as niacin and fibrates also may contribute (14,15). The recently released highly selective beta-1 receptor antagonist nebivolol has also been shown to improve vascular function, potentially through a nitric oxide–mediated mechanism (16). All of these approaches may mitigate against the possible adverse clinical effects of DES-associated vascular dysfunction.
In summary, DES-associated endothelial dysfunction seems to be a real and potentially significant, fascinating, and unexpected phenomenon. Further research, such as reported in the 2 articles presented in this issue of the Journal (7,8), is needed to gain a fuller understanding of its clinical relevance.
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Footnotes
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Dr. Muhlestein has received research funds from Boston Scientific and Cordis Corporations in relationship to stent research.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy Lancet 2004;364:1519-1521.[CrossRef][Web of Science][Medline]2. Lüscher TF, Steffel J, Eberli FR, et al. Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications Circulation 2007;115:1051-1058.[Abstract/Free Full Text] 3. Togni M, Raber L, Cocchia R, et al. Local vascular dysfunction after coronary paclitaxel-eluting stent implantation Int J Cardiol 2007;120:212-220.[CrossRef][Web of Science][Medline] 4. Hofma S, Van der Giessen W, Van Dalen B, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation Eur Heart J 2006;27:166-170.[Abstract/Free Full Text] 5. 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] 6. Fuke S, Maekawa K, Kawamoto K, et al. Impaired endothelial vasomotor function after sirolimus-eluting stent implantation Circ J 2007;71:220-225.[CrossRef][Web of Science][Medline] 7. Jabs A, Göbel S, Wenzel P, et al. Sirolimus-induced vascular dysfunction: increased mitochondrial and nicotinamide adenosine dinucleotide phosphate oxidase-dependent superoxide production and decreased vascular nitric oxide formation J Am Coll Cardiol 2008;51:2130-2138.[Abstract/Free Full Text] 8. Hamilos MI, Ostojic M, Beleslin B, et al. NOBORI CORE Investigators Differential effects of drug-eluting stents on local endothelium-dependent coronary vasomotion J Am Coll Cardiol 2008;51:2123-2129.[Abstract/Free Full Text] 9. Otsuka Y, Chronos NAF, Apkarian RP, Robinson KA. Scanning electron microscopic analysis of defects in polymer coatings of three commercially available stents: comparison of BiodivYsio, Taxus and Cypher Stents J Invasive Cardiol 2007;19:71-76.[Medline] 10. Schachinger V, Britten MB, Zeiher A. Impaired epicardial coronary vasoreactivity predicts for adverse cardiovascular events during long-term follow-up Circulation 2000;101:1899-1906.[Abstract/Free Full Text] 11. Stettler C, Wandel S, Allemann S, et al. Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis Lancet 2007;370:937-948.[CrossRef][Web of Science][Medline] 12. Lagerqvist B, James SK, Stenestrand U, et al. SCAAR Study Group Long-term outcomes with drug-eluting stents versus bare-metal stents in Sweden N Engl J Med 2007;356:1009-1019.[Abstract/Free Full Text] 13. Wassmann S, Laufs U, Bäumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species Hypertension 2001;37:1450-1457.[Abstract/Free Full Text] 14. Vaccari CS, Hammoud RA, Nagamia SH, et al. Revisiting niacin: reviewing the evidence J Clin Lipidol 2007;1:248-255.[CrossRef] 15. Koh KK, Han SH, Quon MJ, Ahn JY, Shin EK. Beneficial effects of fenofibrate to improve endothelial dysfunction and raise adiponectin levels in patients with primary hypertriglyceridemia Diabetes Care 2005;28:1419-1424.[Abstract/Free Full Text] 16. Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study Circulation 2001;104:511-514.[Abstract/Free Full Text]
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