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(Circulation. 2002;105:2932.)
© 2002 American Heart Association, Inc.

Editorial

What Is "The Matter" With Restenosis in 2002?

J. Eduardo Sousa, MD, PhD; Marco A. Costa, MD, PhD; Amanda G.M.R. Sousa, MD, PhD

From the Institute Dante Pazzanese of Cardiology (J.E.S., A.G.M.R.S.), São Paulo, Brazil; and the University of Florida-Shands (M.A.C.), Jacksonville, Fla.

Correspondence to Prof J. Eduardo Sousa, MD, PhD, Director of the Institute Dante Pazzanese of Cardiology, Av. Dr Dante Pazzanese, 500 - Ibirapuera 04012180, São Paulo, SP, Brazil. E-mail jesousa{at}uol.com.br

Key Words: Editorials • restenosis • stents

Undoubtedly, we have come a long way since the introduction of intracoronary stents, but restenosis continues to plague cardiologists. Much research has been devoted to the pathophysiology and treatment of in-stent restenosis. However, we still do not yet fully understand the "matter" of restenosis, and it is possible that we never will. The detailed pathological investigation by Farb et al¹ published in this issue of Circulation elegantly portrays a putative novel mechanism related to the initiation of restenosis.

See p 2974

Farb and colleagues¹ previously described recognized mechanisms of in-stent restenosis,² disruption of the internal elastic lamina, and protrusion of stent struts into lipid-laden portions of the plaque, as well as the presence of neovascularization in the neointima, which had not previously been defined. Peri-strut neoangiogenesis was weakly correlated with mean in-stent neointimal thickness but was strongly correlated with inflammation. Because the time course of neovascularization and neointimal hyperplasia is unknown, a causal relationship between the development of new blood vessels and clinical restenosis cannot be firmly established. In addition, angiogenic properties of vascular endothelial growth factors may have the dual role of inhibiting the formation of intimal hyperplasia³ and promoting its growth.⁴

The findings of Farb et al¹ challenge the clinical paradigm that "bigger is better" in percutaneous coronary interventions, in which a larger lumen after angioplasty diminishes angiographic and clinical restenosis.⁵ The "bigger is better" adage may also reflect a rather simple, but still important, aspect of the pathophysiology of restenosis, which is the idea of "the bigger the vessel, the better the outcome."⁶ After analyzing 116 stents in 56 individuals, the authors of the present study verified previous findings of greater neointimal exuberance with deeper medial penetration²; in order words, "the more you gain, the more you lose."⁷ Similarly, the authors here describe a greater intimal growth when stent struts penetrate the lipid cores of the plaque to a greater depth.¹

Such unquestionable scientific data represent a dilemma for the interventional cardiologist in the treatment of a wide variety of plaque morphologies. The coexistence of calcific, fibrotic, and soft tissues within the same diseased segment has been demonstrated by 3D intravascular ultrasound (IVUS) imaging.⁸ Angioplasty likely has disparate traumatic effects on such different tissue types. Medial penetration is more likely to occur in softer, less fibrotic tissues, whereas dissections are more likely in areas adjacent to calcified plaque. Although the low pressure of balloon inflation may result in less disruption, stents are currently deployed at high pressure to prevent the dreaded stent malposition and ultimately subacute thrombosis.⁹ IVUS can characterize plaque morphology but has limited ability to direct stent strut penetration into the lipid portions or into the medial layer. Consequently, the interventional cardiologist is faced with a struggle with the "matter": optimization of vessel lumen dimensions with high-pressure stent implantation to reduce clinical restenosis at the expense of a greater degree of intimal hyperplasia volume at follow-up. In fact, this has been the most successful percutaneous approach to prevent restenosis over the past decade.

Recently, the antirestenosis paradigm has undergone a tremendous shift. Mechanical approaches to vessel lumen enlargement are recognized as too simplistic to combat the complex process of restenosis. New, sophisticated antiproliferative strategies targeting cell cycle division have been developed. Ionizing radiation and, later, immunosuppressive agents have been shown to diminish restenosis.¹⁰ Interfering with basic cell division is a much more effective way to alter the healing process after angioplasty. With the introduction of these new techniques, inflammation associated with stent struts or due to cellular necrosis after antiproliferative therapy may play an even larger role in how and when restenosis occurs. Indeed, restenosis after radiation therapy seems to have a completely different time course¹⁰ and pathological characteristics, as IVUS already elicited the echolucent tissue, dubbed the "black hole," as a significant component of neointimal hyperplasia after brachytherapy.¹¹ The pathophysiology of restenosis in this new era will need further investigation to determine its relationship, if any, to the "matter" of plain old intimal hyperplasia in metallic stents.

Sirolimus-eluting stents appear to drastically eliminate the problem of in-stent restenosis^12,13 and may further change our perception of the restenosis "matter." None of the first 30 patients who received these stents more than 2 years ago have developed restenosis.¹⁴ Patients enrolled in the sirolimus-stent arm of the Randomized Study With the Sirolimus-Eluting Bx Velocity Balloon-Expandable Stent (RAVEL) trial have now completed 1-year follow-up without restenosis.¹⁵ This multicenter, multinational large trial confirmed the virtual absence of in-stent intimal hyperplasia in the first year after placement of the rapamycin-eluting stents. Clinical and pathological predictors of restenosis will undoubtedly be altered completely. One can imagine, however, that some restenosis will probably occur and will be more related to technical and operator-dependent characteristics than ever. Short, unstented segments or gaps between apparently overlapped stents, underdeployed stents, and diseased or traumatized segments that remain unstented, a modified "geographical miss,"¹⁶ may be prone to intimal hyperplasia at follow-up. We will need to treat complex lesions such as chronic total occlusions, bifurcation, long lesions, and left main disease prudently with these new stents. In addition, manufacturing issues such as incorrect drug dosing and strut thickness may also predispose to intimal proliferation in certain arterial segments.

Although the new era of drug-eluting stents may drastically reduce the "matter" of restenosis, old lessons must not be forgotten. Diligent stent placement in various plaque morphologies may be more important than ever in preventing restenosis. Disruption of the media and neovascularization have predicted restenosis after placement of our current bare stents, but these mechanisms may be altered by the presence of cell cycle inhibitors and will need to be studied in the future. Although the field of interventional cardiology had a previous dilemma between acute gain and late loss, restenosis will likely have a new face. The drug-eluting stent will provide maximum benefit and proof that restenosis in 2002 does not "matter" only if we pay attention to the previous lessons learned and carefully monitor its potential new appearance in the future.

Footnotes

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

References

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