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(Circulation. 1996;94:1199-1202.)
© 1996 American Heart Association, Inc.

Articles

Hoop Dreams

Stents Without Restenosis

Elazer R. Edelman, MD, PhD; Campbell Rogers, MD

the Department of Medicine (Coronary Care Unit and Cardiac Catheterization Laboratory, Brigham and Women's Hospital), Harvard Medical School, Boston, Mass; and Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass.

Correspondence to Elazer R. Edelman, MD, PhD, Biomedical Engineering Center, Bldg 20A-127, Massachusetts Institute of Technology, Cambridge, MA 02139. E-mail eedelman@mit.edu.

Key Words: Editorials • stents • restenosis • angioplasty • pathology • ultrasonics

	Introduction

Top Introduction Vascular Injury/Vascular Repair:... Evaluating Vascular Reactions to... Future Directions References

 
Spanning ribs enable canoes and massive sailing ships to float and withstand the battering of the seas. Bronze-age huts were supported by massive wooden hoops embedded in the walls, and the great cathedrals of Europe rose only by virtue of innovative buttress supports. Endovascular stents were designed with the expectation that they would similarly buttress the collapsible artery against deforming stress with the hope that they might break the vicious cycle of arterial stenosis, intervention, and restenosis. As these devices stretch vessels to their greatest extent, they represent the extreme of the notion that "bigger is better." This prevailing paradigm in interventional cardiology holds that relative restenosis is minimized by maximization of the initial lumen diameter; the larger the diameter is immediately after any form of angioplasty, the greater is the degree but the less is the impact of luminal encroachment from elastic recoil, thrombosis, intimal hyperplasia, and matrix remodeling.¹

The attraction of this paradigm arises in part from frustration with attempted control of the vascular response to injury. To date, even the most promising pharmacological agents have failed to stem the tide of restenosis, and the most sophisticated of mechanical interventions have, if anything, exacerbated the problem. Only the simplest approach beyond balloon angioplasty, endovascular stenting, now appears to offer some relief,^{2 3 4 5} yet even these devices are limited by the vascular counterreaction they elicit. If the "bigger is better" paradigm holds true, the only recourse is to use larger stents expanded to their maximal extent. Furthermore, if size alone dictates restenosis, no single stent design should be superior to any other.

Extensive experimental data, however, suggest that the pathobiological response to implantation of an endovascular device involves a complex interplay among design, material, and deployment technique. Reconciling clinical dogma with experimental observations will require transference of relevant mechanisms from basic studies to rigorous trials in patients. In this issue of Circulation, Hoffmann and coworkers⁶ present an important step forward in this regard. With the use of intravascular ultrasound (IVUS), they report the spatial patterns of restenosis along the length of Palmaz-Schatz metal stents implanted in either native coronary arteries or stenosed saphenous vein bypass grafts. Their findings will force us to reconsider accepted notions of stent pathobiology.

	Vascular Injury/Vascular Repair: Balloons and Stents

Top Introduction Vascular Injury/Vascular Repair:... Evaluating Vascular Reactions to... Future Directions References

 
Vascular injury caused by insertion of an indwelling endovascular stent differs from that of simple balloon angioplasty in at least four ways. First, the struts of the expanding stent impose focal deep vascular trauma in comparison to the less-controlled stretching and fracturing of the vessel wall caused by balloon inflation alone (Figure). Second, extensive early thrombus generated within days of stenting may serve as a nidus and scaffold for subsequent cell proliferation and neointimal hyperplasia. Third, permanent rather than transient strain is applied to the vessel wall, producing lasting changes in vessel geometry. Fourth, foreign material remains in the injured artery. Each of these factors is potentially mutable through intentional changes in stent geometry, material, design, or use. If the determinants and biological basis of the response to stent-imposed injury can be understood, it may be possible to guide stent design from first principles and to develop an optimal stent for each specific clinical need.

View larger version (36K): [in this window] [in a new window]   Figure 1. Divergent processes of vascular repair after balloon angioplasty and stenting of an atherosclerotic vessel. Balloon angioplasty (top) compresses and fractures the atherosclerotic plaque (light gray) and tunica media (black), slightly enlarging the artery. After a few days, a thin layer of platelet-rich thrombus (dark gray) lines the lumen and fills the dissection plane. The lumen shrinks from combined effects of early elastic recoil and later formation of a fibrocellular neointima (speckled area). Stent deployment after angioplasty (bottom) compresses the dissection plane and enlarges the lumen while stretching the artery with minimal elastic recoil. Within hours to days after stenting, caps of thrombus infiltrated with inflammatory cells (dark gray) form over stent struts (black rectangles), particularly abundant at sites of deep injury. Over ensuing weeks, a neointima forms (speckled area), thicker where injury is more severe. Although intimal growth after stenting is greater than after balloon angioplasty, the residual lumen is also larger, as the scaffolding of the stent maintains luminal dimensions. Late changes in arterial size are not depicted because the contribution of remodeling to restenosis after angioplasty or stenting remains incompletely characterized. (Figure prepared by James Squire.)

Deep Injury
Through rigorous histological examination of stented porcine coronary arteries, Schwartz and coworkers⁷ have shown how acute vascular injury by stent struts predicts subsequent neointimal hyperplasia. Intimal thickening over each strut was commensurate with the depth of strut penetration, and the integrated extent of restenosis for entire arterial cross sections correlated well with the average injury imposed by all struts. There is, however, a marked heterogeneity to strut-related injury and therefore to vascular repair within each arterial cross section. The intentional oversizing or postdilation of stents with high-pressure balloon inflations, as is performed to limit subacute thrombosis,⁸ will worsen deep injury. This in turn may provoke greater intimal growth.

Cellular Responses
We and others have found angioplastied and stented arteries to be fertile places in which to examine the pathology of vascular injury and repair. Within minutes of endothelial denudation, a monolayer of platelets lines the arterial lumen. After several days, smooth muscle cells proliferate and migrate from the tunica media to the intima.^{9 10} Stent deployment produces a completely different pattern.^{7 11 12} Thick platelet-rich mural thrombi form over stent struts. Inflammatory cells from the circulation and adventitial vasa vasorum line the lumen and migrate into the thrombus. Later, smooth muscle cells migrate to and proliferate within the neointima, with intimal size and proliferative rate directly commensurate with the severity of early inflammatory cell recruitment.^{12 13} Both the rate and duration of cell proliferation and the contribution of mononuclear cells after stenting exceed those accompanying balloon injury alone.^{13 14 15 16 17}

Mechanical Strain
Balloon angioplasty applies a transient strain to the vessel wall, whereas stent deployment transfixes the artery in a permanently altered shape. The cellular proliferation known to be induced by transient strain¹⁸ may be further potentiated by the more-prolonged stimulus of stenting. The shape change imposed on the artery is somewhat analogous to that observed in interposition vascular grafts. The junctions of stented and native arterial segments are subject to abrupt transitions in diameter, contour, and rigidity. As is the case with vascular grafts, disruption of flow patterns at these sites may influence repair and restenosis.

Materials
The effect of residual foreign material may be the most critical difference between stent implantation and simple balloon angioplasty. The profound impact of an indwelling material on the vasculature has been demonstrated most clearly in experimental systems with stents constructed from polymer materials. These stents, intended to be gradually resorbed and serve potentially as platforms for the local delivery of polymer-incorporated drugs, can produce a severe inflammatory response, remarkable degrees of neointimal hyperplasia, and even complete arterial occlusion within 4 to 6 weeks of implantation.¹⁹ It remains to be seen whether removal of the material is a priority or a luxury and whether the process of resorption may exacerbate rather than alleviate disease.

	Evaluating Vascular Reactions to Endovascular Implants

Top Introduction Vascular Injury/Vascular Repair:... Evaluating Vascular Reactions to... Future Directions References

 
The central role of material in eliciting a vascular reaction and the initiation of vascular responses at sites of deep strut injury forces the following questions: Do different stent designs provoke different responses? And if so, can a stent be constructed with less vascular reactivity? In experimental animals, the answer is clearly yes,^{13 20} but clinical validation is still lacking despite the exponential growth in the use of various stent designs by interventional cardiologists. Several techniques may be applied to study these questions in humans (Table), and the safe and effective treatment of patients requires critical and rigorous application of these tools.

View this table: [in this window] [in a new window]   Table 1. Clinical Tools for Studying In-Stent Restenosis

Histopathology
Extensive histopathological and immunohistochemical examination of animal arteries has revealed specifics of the cellular response to stenting and the effects of stent design on this response.^{7 11 12} When animals were implanted with stents of identical material, weight, and surface area but with different configurations, a twofold difference in intimal growth was observed.¹³ Primary stenting without arterial predilation limited the extent of endothelial ablation and reduced neointimal hyperplasia still further.²¹ Two limited reports of human pathology after stenting have been presented,^{22 23} but rigorous histological examination of stented human vessels must be pursued as more tissue becomes available at autopsy or through surgical explantation of stented bypass grafts. Atherectomy also offers a unique ability to examine tissue without loss of the stent, but examination is limited to the neointima formed between and/or above stent struts. In animal models, this zone is transformed early and rapidly from a rich cellular reaction into a bland, relatively acellular, matrix-rich material.^{11 12 24} Most late cellular activity in stented vessels resides in the areas immediately around and beneath the stent struts, fields that can be examined only at autopsy or after full surgical excision. Unfortunately, such specimens are by their nature the worst of the lot, often reflecting progression of disease in nonstented arteries or stent failure in patients who have died or require further intervention. Nevertheless, stent-specific histology may open further vistas for experimental pathobiology, much like precise examination of human restenotic lesions after balloon angioplasty did 10 to 15 years ago.^{25 26}

Clinical End Points
At the other end of the spectrum from pathological evaluation are purely clinical end points. The information gleaned from patient performance can guide informed decisions by patients and physicians alike and can be used to formulate cost-benefit analyses for diagnostic or treatment algorithms. The shortcoming of the use of only clinical end points, however, is the limited way in which they reflect biological or pathophysiological information. Nowhere do clinical and biological data diverge more than in trials of coronary interventions. The prevalence of coronary heart disease renders evidence-based clinical decision analysis a key public health and economic concern. However, the multicentric nature of coronary disease makes clinical failure from restenosis difficult to distinguish from progressive disease elsewhere. It is precisely for this reason that imaging studies such as that of Hoffmann and coworkers⁶ are so essential.

Coronary Imaging
The two tools available for in vivo follow-up of coronary repair after intervention are quantitative coronary angiography (QCA) and IVUS. Angiography has become a point of reference because of its familiarity and availability. The seminal randomized clinical trials demonstrating less critical lumen encroachment after stenting compared with balloon angioplasty had QCA as a primary end point.^{4 5} Recent long-term sequential QCA evaluation of stented vessels has also provided the important finding that progression of restenosis beyond 6 months after implantation is rare.²⁷ Unfortunately, QCA provides only a small window on vascular repair, outlining luminal contours but looking no deeper into the vessel wall. Correlation between QCA and histological events is rough, reflecting inconsistencies in tissue preparation and histological analysis as well as limitations in sensitivity and precision of two-dimensional angiography.

Intravascular ultrasound affords the opportunity to see beyond the luminal lining, albeit at some cost and risk. Three-dimensional reconstruction of diseased arteries before and after intervention has become possible.^{28 29} Motorized pullback devices and ever smaller and higher-frequency probes will increase the accuracy with which plaque composition, procedural damage, and arterial geometry can be gauged sequentially. The immediate implications of this information as a guide to therapy are unproven, but as a research tool the information is invaluable.

Hoffmann and coworkers⁶ used IVUS to examine the fate of Palmaz-Schatz stents in 115 native coronary artery or saphenous vein bypass graft lesions over a mean follow-up period of 5.4 months. Although the stent metal impaired ultrasound penetration beyond the device, the accumulation of tissue within the stent proved to be the main contributor to lumen loss. The pattern of this loss was not uniform along the stent but increased significantly where the two halves of the stent were joined by a bridging articulation. Of particular interest, when two stents were placed in sequence without overlap (but also without an articulation), no corresponding increase in tissue accumulation was found. The seemingly minor addition of a bridge, constraining one degree of freedom for the stent, contributed substantially to reparative events and restenosis. Therefore, there is good reason to expect that further changes in stent design may have an even greater impact on in-stent restenosis in humans, just as they do in experimental models. A second important insight from this study is the similarity of responses in saphenous vein grafts and native coronary arteries after stenting. No significant differences in luminal loss were seen between the two vessel types, which is in contradistinction to historic data attesting to the aggressiveness of balloon angioplasty restenosis in vein grafts.³⁰ By eliminating elastic recoil and perhaps remodeling, leaving only the interactions of struts, vessel wall, and circulating elements as determinants of repair, stents may in effect equalize vessel types and negate differences in chronic responses between native coronary arteries and saphenous vein bypass grafts.

A minor limitation of the study is its inability, for methodological reasons, to differentiate neointimal hyperplasia from remodeling. By using the stent itself as a surrogate for the outer boundary of the artery, what the authors call remodeling is actually stent collapse. Remodeling may still be occurring, with tissue growing through the stent interstices from without, joining intimal hyperplasia to make a composite neointima. Further technical developments in IVUS may resolve this issue.

	Future Directions

Top Introduction Vascular Injury/Vascular Repair:... Evaluating Vascular Reactions to... Future Directions References

 
The benefits of coronary stenting are only beginning to be realized. Stents will be used in longer and more complex lesions, in patients with acute ischemic syndromes, and in smaller arteries. The expanding use of these devices requires that we clearly define the pathobiological principles that govern reaction to their insertion before safe and effective stent designs can be optimized for all clinical indications. Evidence abounds in animals and is rapidly accumulating in humans that stent design and use can determine the form of response and extent of repair. In animal studies, we must continue to scrutinize the cellular and molecular events that accompany material/tissue interactions. Clinical trials should follow the lead of Hoffmann and coworkers⁶ and not neglect biological end points for the sake of purely clinical ones. Long-term follow-up studies with coronary imaging may be used to mitigate concern over delayed repair and prolonged injury. Preclinical and clinical trials that directly compare stent designs and deployment protocols will be essential as the number of stent designs grows and the potential adverse effects of subtle changes in design are recognized. Pharmacological interventions that take into account specific aspects of stent-induced vascular injury and repair must be pursued. Finally, optimal treatment for in-stent restenosis, whether with balloon dilation, ablative techniques, repeat stenting, or bypass surgery, must be elevated from the realm of anecdote to formal study. As study of the vascular biology of endovascular stents lets us dream of stents without restenosis, the old adage that "bigger is better" may need to be amended to "only better is better."

	Footnotes

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

	References

Top Introduction Vascular Injury/Vascular Repair:... Evaluating Vascular Reactions to... Future Directions References

 
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