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(Circulation. 1997;95:308-310.)
© 1997 American Heart Association, Inc.

Articles

Intravascular Stent Endothelialization

A Goal Worth Pursuing?

Darren B. Schneider, MD; David A. Dichek, MD

the Gladstone Institute of Cardiovascular Disease and the Daiichi Research Center, University of California, San Francisco.

Correspondence to David A. Dichek, MD, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100. E-mail david_dichek{at}quickmail.ucsf.edu

Key Words: Editorials • stents • endothelium • thrombosis • endothelium-derived factors

	Introduction

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 
The explosive growth of interventional cardiology has been accompanied by a proliferation of devices designed both to eliminate coronary stenoses and to prevent their recurrence. The intravascular stent is certainly one of the most successful of these devices. First deployed in humans in 1986¹ and approved by the FDA in 1993, an estimated 100 000 intracoronary stents per year are deployed in the United States (personal communication, Martin B. Leon, MD, Washington Hospital Center, Washington, DC). No interventional facility in 1996 can be without the capability for stent deployment. Stents are useful both for acute closure and for improving the long-term success of balloon angioplasty. In selected populations, stent deployment decreases the rate of restenosis after coronary angioplasty, as demonstrated by the STRESS² and Benestent³ trials.

Despite their utility, intracoronary stents have been plagued by two problems during their development: acute occlusion due to thrombosis and the persistent occurrence of restenosis. Initial reports of intracoronary stent deployment in humans noted stent-related thrombosis rates of 3% to 4% under elective conditions,^{2 3} rising to 8% to 16% in bailout or emergency situations.⁴ These unacceptably high rates were initially combated with aggressive drug therapy, including both anticoagulant and antiplatelet agents. This therapy decreased stent thrombosis but did so at a cost of additional hours of patient care as well as increased vascular and bleeding complications, leading to longer hospital stays and higher hospital bills.^{2 3} In-stent restenosis remains a significant clinical problem, with rates of 13% even in the more optimistic studies.⁵

More progress has been made in combating stent thrombosis than in decreasing the rate of in-stent restenosis. Colombo et al⁶ found that if stents were appropriately deployed, thrombosis rates of <1% could be achieved with antiplatelet therapy alone. Schomig et al⁷ reported elimination of both stent-related thrombosis and hemorrhagic complications with only antiplatelet therapy (ticlopidine and aspirin). In an early report from the Benestent II pilot study, use of a heparin-coated stent and oral antiplatelet agents also eliminated both stent-related thrombosis and bleeding complications.⁵

In this issue of Circulation, Van Belle et al⁸ describe an alternative strategy to decrease stent thrombosis. This strategy relies on local delivery of vascular endothelial growth factor (VEGF), an endothelial cell mitogen. The hypotheses underlying this strategy are that single-dose local VEGF delivery will speed endothelialization and that endothelium will provide a nonthrombogenic coating of exposed stent surfaces, thereby reducing stent thrombosis and potentially decreasing or eliminating the need for antithrombotic therapy. To test these hypotheses, Van Belle et al deployed Palmaz-Schatz stents in the iliac arteries of nonatherosclerotic rabbits and then delivered a single 100-µg dose of recombinant human VEGF to the vessel wall with a channel balloon catheter. Stent endothelialization was evaluated 4 and 7 days later by planimetry of images acquired with both light microscopy and scanning electron microscopy. Thrombus deposition was measured by visual identification of thrombus and planimetry of thrombus-covered surface. VEGF infusion increased stent endothelialization at both 4 and 7 days and decreased stent surface area covered by thrombus on day 7. The authors concluded that local delivery of recombinant VEGF to the wall of a stented vessel is feasible and that VEGF both promotes stent endothelialization and reduces stent thrombosis.

This study raises four general questions concerning its interpretation and significance: (1) Is expeditious stent endothelialization required to decrease stent thrombosis? (2) Is expeditious stent endothelialization consequent to VEGF delivery desirable for any other purpose, such as to decrease in-stent restenosis? (3) Can the results of this study be extrapolated beyond this model, and will they eventually be applicable to humans? (4) Is local, catheter-mediated drug delivery to the coronary arterial wall ready for clinical application?

	Is Expeditious Stent Endothelialization Required to Decrease Stent Thrombosis?

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 
It is likely that the study by van Belle et al⁸ was conceived and initiated before the publication of the recent advances in stent deployment and antithrombotic therapy discussed above.^{5 6 7} If stent thrombosis rates of <1% continue to be found in larger clinical studies, then the problem of stent thrombosis in humans may well be solved. A large and costly clinical trial would be necessary to document that any therapeutic intervention decreased stent thrombosis below this low level.

More importantly, the assumption that stent endothelialization is required to decrease stent thrombosis may not be accurate. Data from animal models of arterial injury suggest that the thrombogenicity of an injured artery may decrease in the absence of endothelialization.^{9 10} Exposed smooth muscle cells in balloon-injured rat carotid arteries are able to maintain a relatively nonthrombogenic surface.¹⁰ In balloon-injured rabbit aortas, platelet deposition occurs within minutes but does not increase over the subsequent 24 hours. Over the next week, in the absence of endothelialization, the number of vessel-associated platelets actually decreases, indicating that thrombogenicity decreases before endothelial regrowth.⁹ Indeed, data in the study by Van Belle et al suggest that VEGF delivery could decrease thrombus formation by a mechanism other than expedited endothelialization. Although these data reveal a statistically significant inverse correlation between stent endothelialization and the development of organized thrombus,⁸ the strength of this correlation was somewhat low, and endothelialization accounted for only 52% (r²=.52) of thrombus suppression.¹¹ If endothelialization accounts for a 52% reduction in the amount of organized thrombus, then at least one other factor contributes 48% of this effect. Identification of the additional factor(s) may ultimately be critical to understanding how VEGF appears to decrease thrombus formation.

	Is Expeditious Stent Endothelialization Consequent to VEGF Delivery Desirable for Any Other Purpose, Such as to Decrease In-Stent Restenosis?

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 
If expeditious endothelialization is not required to limit stent thrombosis, then perhaps rapid endothelialization remains a desirable goal for the purpose of decreasing in-stent restenosis. Because a rigid stent prevents luminal loss due to vascular remodeling,^{12 13} in-stent restenosis occurs solely as a result of neointimal accumulation.¹⁴ If an intact endothelium prevents neointimal accumulation, rapid endothelialization of stented arteries would be an important goal. A recent publication reported that VEGF-induced endothelialization of balloon-injured rat carotid arteries was associated with a decrease in neointimal accumulation.¹⁵

The premise that regrowth of endothelium will limit neointimal accumulation, however, is inconsistent with the results of several independent lines of investigation. In gently denuded rat aortas, smooth muscle cell proliferation is not increased subjacent to the areas of endothelial loss.¹⁶ In rat carotid arteries, neointimal accumulation after arterial injury is more a function of medial injury than of endothelial loss.¹⁷ In balloon-injured rabbit ileofemoral arteries, early restoration of endothelium by autologous endothelial seeding does not decrease neointimal accumulation.¹⁸ Human atherosclerosis develops below morphologically intact endothelium,¹⁹ and endothelialized human coronary stents also contain substantial neointimal mass.²⁰ The presence of endothelium and a resistance to intimal growth do not appear to be inextricably linked.

If, as suggested by Van Belle et al,⁸ VEGF-mediated endothelialization limits neointimal accumulation, perhaps VEGF is acting by a mechanism other than simply promoting endothelial regrowth. Moreover, VEGF-mediated endothelialization may limit neointimal accumulation only in a model- or species-specific manner. A recent report of VEGF delivery in a canine model of arterial injury revealed that VEGF administration resulted in increased neointimal accumulation.²¹ Thus, VEGF-mediated acceleration of endothelial regrowth might actually come at the expense of luminal diameter. The benefits of VEGF administration might also be achieved at the expense of plaque stability. Local vascular delivery of a related endothelial mitogen, basic fibroblast growth factor, enhances neoangiogenesis in adventitial vasa vasorum,²² which could potentially lead to plaque hemorrhage.²³ Delivery of VEGF to atherosclerotic arteries might prove to have certain benefits, but there could be risks in this approach.

	Can the Results of This Study Be Extrapolated Beyond This Model, and Will They Eventually Be Applicable to Humans?

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 
In other words, is it appropriate to use these rabbit studies to design clinical protocols for stent endothelialization in humans? The answer to this question appears to be no. Van Belle et al found that complete endothelialization after balloon injury and stent deployment in rabbit external iliac arteries required 28 days; VEGF therapy resulted in near-complete endothelial coverage in 7 days.⁸ In contrast, stented coronary arteries in a porcine model endothelialized within 7 days without exogenous VEGF.²⁴ Limited autopsy data from humans also suggest that endothelialization occurs within 2 weeks after coronary stent implantation.²⁰ Rapid endothelialization of human coronary stents may not require a pharmacological stimulus. Until substantial animal data support a consensus that VEGF delivery expedites coronary stent endothelialization above the rate expected in humans, a clinical trial may be premature.

	Is Local, Catheter-Mediated Drug Delivery to the Coronary Arterial Wall Ready for Clinical Application?

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 
Local delivery of high concentrations of a drug directly to the arterial wall, which would minimize systemic effects, is an attractive goal. The channel balloon catheter used by Van Belle et al consists of a central angioplasty balloon surrounded by 24 channels through which a drug can be delivered to the luminal surface of a vessel.²⁵ Local-delivery catheters can deliver proteins directly to the vessel wall, but they can also cause vascular trauma.²⁶ The use of infusion balloon devices in the coronary arteries poses the additional risk of occluding a functional end artery, resulting in acute tissue ischemia. The prolonged balloon inflation time in the present study (15 minutes) might indeed cause myocardial ischemia. Other factors absent in the rabbit model may complicate infusion into human coronary artery lesions, including fibrous atherosclerotic plaque, plaque dissections produced during angioplasty, and numerous side branches along the infusion site. Each of these factors could preclude effective drug delivery to the target lesion. Alternative approaches to local balloon infusion, such as bonding of drugs to the stent^{5 27} or the use of radioactive stents (reported to decrease neointimal accumulation without delaying endothelialization^{28 29} ), must also be considered.

In demonstrating a powerful effect of local VEGF delivery on stent endothelialization in the rabbit, the study by Van Belle et al,⁸ challenges us to reconsider our assumptions about adjunctive therapy for stent placement and, indeed, about VEGF itself as a therapeutic agent. Is stent thrombosis still a clinical problem? Is more expeditious stent endothelialization a desirable goal? Can stent endothelialization be expedited in humans? What are the risks of VEGF infusion, and are these risks justified by the potential benefits of decreased stent thrombosis and restenosis? By what molecular and cellular pathways does VEGF actually promote endothelialization and decrease thrombosis? By what mechanisms in this rabbit model does a single bolus of VEGF produce biological effects that last for weeks? Are these underlying cellular mechanisms also present in atherosclerotic human arteries, thus supporting the use of VEGF? Despite promising preclinical studies with VEGF, these questions remind us that we have much to learn both about basic mechanisms of human restenosis and about VEGF biology. Substantial progress in both of these areas may eventually pave the way for the rational application of VEGF therapy to human disease.

Note Added in Proof
In a recent report (Lindner and Reidy, Circ Res. 1996;16:1399-1405), VEGF delivery did not accelerate endothelial regrowth in rat or mouse models of arterial injury. Further investigations of the reproducibility, species specificity, and mechanisms of VEGF action are clearly warranted.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top Introduction Is Expeditious Stent... Is Expeditious Stent... Can the Results of... Is Local, Catheter-Mediated Drug... References

 

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