Drug-Eluting Stent EndotheliumPresence or Dysfunction*
Heleen M.M. van Beusekom, PhD*,
Patrick W. Serruys, MD, PhD
Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands
Key Words: drug-eluting stents • endothelium • endothelial function • endothelial progenitor cells
 |
The Rosy Prophesy
|
|---|
Drug-eluting stents (DES) have considerably improved the treatment of coronary artery disease since their introduction in 2001 due to the reduction of in-stent restenosis. It seemed for a while that the rosy prophecy made in 2000 was true.
|
First Cracks
|
|---|
In 2004, however, the first report on late stent thrombosis (LST) was published by McFadden et al. (1). More followed, including reports on delayed healing from autopsy (2) and atherectomy specimen (3). Meta-analyses now indicate that, indeed, this therapy is associated with an increased risk of late stent thrombosis in some DES and applications. Daemen et al. (4) report an incidence of 0.6% per year, with a cumulative incidence of 2.4% at 4 years or higher in an all-comers population. With 3 million stents being implanted worldwide each year, the risk of stent thrombosis is becoming a problem of public health proportions.
|
Delayed Endothelialization
|
|---|
Finn et al. (5) from CVPath Institute Inc. point toward delayed endothelialization as the main cause for late stent thrombosis based on autopsy and pre-clinical studies using denuded rabbit iliac arteries. This observation has not been consistently reproduced by other investigators or in other models (e.g., after direct stenting of swine coronary arteries) (6,7).
In this issue of JACC: Cardiovascular Interventions, Nakazawa et al. (8) describe capture of CD34-positive cells via Genous stent (GS) technology (OrbusNeich Medical, Fort Lauderdale, Florida) to enhance early endothelialization of sirolimus-eluting stents (SES) in swine coronary arteries. Scanning electron microscopy was used to assess endothelial presence and confocal microscopy to assess endothelial function and maturity (CD31 expression). Stent endothelialization was studied in single and overlapping GS and SES as well as in GS-modified SES.
They found that overlapping GS and SES increased the percentage stent strut endothelialization at 14 days as compared with SES alone (55% to 79%), but remained lower than GS alone (99%). In other words, SES endothelialization can indeed be enhanced by GS technology, but this endothelium is still sensitive to sirolimus. Indeed, overlapping SES and GS did not improve the number of functional endothelial cells at all as CD31 expression in both SES and GS–SES was the same: 40%. Interestingly, overlapping 2 GS also decreased the number of functional endothelial cells (58% vs. 98%), despite the GS technology.
The direct modification of SES by the GS technology did improve stent strut endothelialization and the number of functional endothelial cells. Each was improved by 30% as compared with SES alone. These numbers, however, remained lower than in the GS alone group, confirming yet again the sensitivity of these cells for sirolimus.
Nakazawa et al. (8) conclude that: "These studies demonstrated that antibody-mediated endothelial progenitor cell capture can enhance endothelial cell coverage and maturation of endothelial cells on DES and may provide a new therapeutic approach."
|
Endothelial Presence or Endothelial Dysfunction?
|
|---|
What can we learn from this study? The first phase of the study shows that improving endothelial capture is not synonymous to improving endothelial function. It also shows that overlapping a stent causes endothelial dysfunction, even with GS. The second phase of the study shows that in a less injurious setting, GS technology does increase endothelialization in an SES environment and improves the number of functional endothelial cells in terms of CD31 expression. However, the endothelial layer remains incomplete, and endothelial dysfunction is still present. Whether GS technology is able to enhance late endothelialization at a time when the antibody against CD34 is likely covered by a proteinaceous layer (9) is not known.
|
Chronic Vascular Irritation
|
|---|
Taking into account that not all DES that show delayed healing cause LST (2,3), and that LST occurs at a steady rate long after the drugs have eluted from the stent, we have to appreciate that there is more to LST than merely a partial absence of endothelial cells. Chronic vascular or endothelial dysfunction, either stent-, drug-, or coating-induced, may play a more important role than is often suspected (10,11). Indeed, the fact that DES are also associated with endothelial dysfunction of the coronary artery distal to the stent, even after all drug has been released (12–15), indicates the chronic and extensive nature of this phenomenon.
|
Improving Endothelial Function
|
|---|
While the GS technology enhances endothelialization of SES, endothelial function remains impaired, and its long-term fate remains to be determined. We can expect that improving endothelialization will not be enough to prevent LST as illustrated by the occurrence of LST even with GS (16). The future will lie in improving endothelial function. However, one can only improve that which is present. To that end, enhancing endothelialization by any means is an important first step.
|
Footnotes
|
|---|
* Editorials published in JACC: Cardiovascular Interventions reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Interventions or the American College of Cardiology. 
* Reprint requests and correspondence: Dr. Heleen van Beusekom, Thoraxcenter, Room Ee2355a, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands (Email: h.vanbeusekom{at}erasmusmc.nl).
|
REFERENCES
|
|---|
- 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]
- 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]
- van Beusekom HM, Saia F, Zindler JD, et al. Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus Eur Heart J 2007;28:974-979.[Abstract/Free Full Text]
- Daemen J, Wenaweser P, Tsuchida K, et al. Early and late coronary stent thrombosis of sirolimus-eluting and paclitaxel-eluting stents in routine clinical practice: data from a large two-institutional cohort study Lancet 2007;369:667-678.[CrossRef][Medline]
- 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]
- Seifert PS, Huibregtse BA, Polovick J, Poff B. Early vascular response to overlapped paclitaxel-eluting stents in swine coronary arteries Cardiovasc Revasc Med 2007;8:251-258.[CrossRef][Medline]
- Van Beusekom HM, Sorop O, van den Heuvel M, et al. Early endothelialization in paclitaxel eluting stents is similar to other drug eluting stents but shows transient endothelial dysfunction (abstr) EuroIntervention 2009;5(Suppl E):E65.
- Nakazawa G, Granada JF, Alviar CL, et al. Anti-CD34 antibodies immobilized on the surface of sirolimus-eluting stents enhance stent endothelialization J Am Coll Cardiol Intv 2010;3:68-75.[Abstract/Free Full Text]
- Wendel HP, Avci-Adalia M, Ziemera G. Endothelial progenitor cell capture stents—hype or hope? Int J Cardiol 2009 July 2[E-pub ahead of print].
- van Beusekom HM, Whelan DM, Hofma SH, et al. Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries J Am Coll Cardiol 1998;32:1109-1117.[Abstract/Free Full Text]
- Van Beusekom HM, Ertas G, Sorop O, Peters I, Serruys PW, Van der Giessen WJ. Endothelial progenitor cell capture in stented porcine coronary arteries increases endothelialization but does not affect intimal thickening (abstr) EuroIntervention 2009;5(Suppl E):E21.
- Li J, Jabara R, Pendyala L, et al. Abnormal vasomotor function of porcine coronary arteries distal to sirolimus-eluting stents J Am Coll Cardiol Intv 2008;1:279-285.[Abstract/Free Full Text]
- Sorop O, Batenburg WW, Koopmans S-J, et al. Taxus but not Cypher drug eluting stents induce endothelial dysfunction in the distal coronary microvasculature Circulation 2007;116:293.[Abstract/Free Full Text]
- Hofma SH, van der Giessen WJ, van Dalen BM, et al. Indication of long-term endothelial dysfunction after sirolimus-eluting stent implantation Eur Heart J 2006;27:166-170.[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]
- Rossi ML, Zavalloni D, Gasparini GL, Mango R, Belli G, Presbitero P. The first report of late stent thrombosis leading to acute myocardial infarction in patient receiving the new endothelial progenitor cell capture stent Int J Cardiol 2009 Jan 8[E-pub ahead of print].
Related Article
-
Anti-CD34 Antibodies Immobilized on the Surface of Sirolimus-Eluting Stents Enhance Stent Endothelialization
- Gaku Nakazawa, Juan F. Granada, Carlos L. Alviar, Armando Tellez, Greg L. Kaluza, Margaret Yoklavich Guilhermier, Sherry Parker, Stephen M. Rowland, Frank D. Kolodgie, Martin B. Leon, and Renu Virmani
J. Am. Coll. Cardiol. Intv. 2010 3: 68-75.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
D. R. Holmes Jr, D. J. Kereiakes, S. Garg, P. W. Serruys, G. J. Dehmer, S. G. Ellis, D. O. Williams, T. Kimura, and D. J. Moliterno
Stent Thrombosis
J. Am. Coll. Cardiol.,
October 19, 2010;
56(17):
1357 - 1365.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
The Rosy Prophesy
First Cracks