Review Article Acta Cardiol Sin 2005;21:177-89 Coronary Restenosis Chao-Chien Chang and Eng-Thiam Ong Percutaneous coronary interventions represent an attractive alternative to surgical revascularization; nevertheless, these techniques continue to be characterized by their propensity to elicit restenosis. Until now, the only widely accepted way to reduce restenosis rate has been the stent. However, clinical restenosis still represents the major limitation of this technology. Despite this limitation, angioplasty has become the most common revascularization procedure for coronary artery disease. Although the advent of coronary stents has reduced the incidence of restenosis, the problem still occurs in 20% to 30% of stented vessels.1 Restenosis is the principal drawback of percutaneous coronary interventions. Furthermore, the numerous drugs and mechanical interventions that have been used to address restenosis have had minimal success. Restenosis severely limits the benefits of angioplasty in many patients, particularly those with diabetes or multivessel coronary artery disease. Despite an exhaustive search for an effective pharmacotherapy to treat or prevent restenosis, hundreds of clinical trials have failed to identify an agent with proven therapeutic benefit. Recently, however, the Food and Drug Administration approved intracoronary radiation (brachytherapy) and drug-eluting stents as viable therapeutic options for in-stent restenosis. In addition, recent randomized trials have shown encouraging results with drug-eluting stents. This article reviews the pathophysiology and molecular mechanism of restenosis, along with current and future treatment options. Key Words: Coronary restenosis · Pathophysiology and molecular mechanism of restenosis INTRODUCTION gioplasty5 or rotational atherectomy6 have not been shown to reduce restenosis. Since its invention more than 20 years ago by Despite this limitation, angioplasty has become Grunt- zig,2 percutaneous transluminal coronary the most common revascularization procedure for cor- angioplasty (PTCA) has been established as an alterna- onary artery disease. Coronary stenting has been tive treatment for coronary artery disease. Restenosis found to be effective in preventing coronary dissec- remains as the major limiting factor for its use. The tions, impending occlusions, and acute elastic recoil. restenosis rate after PTCA has been reported to vary The restenosis rate is reduced after stent implantation from 17% to 61% depending on the nature of the le- for new coronary stenosis. Although the advent of cor- sions and the patient subgroups, such as those with onary stents has reduced the incidence of restenosis, diabetes or uremia.3 The use of other adjunctive the problem still occurs in 20% to 30% of stented techniques such as directional atherectomy,4 laser an- vessels.1 Furthermore, the numerous drugs and me- chanical interventions that have been used to address restenosis have had minimal success. Restenosis se- Received: November 4, 2004 Accepted: March 30, 2005 verely limits the benefits of angioplasty in many From the Section of Cardiology, Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan. patients, particularly those with diabetes or mul- Address correspondence and reprint requests to: Dr. Eng-Thiam Ong, tivessel coronary artery disease. Section of Cardiology, Department of Internal Medicine, Cathay It is the purpose of this article to review the patho- General Hospital, No. 280, Sec. 4, Jen-Ai Road, Taipei 10650, Taiwan. Tel: 886-2-2708-2121 ext. 3116; Fax: 886-2-2707-4949; physiology and molecular mechanism of in-stent rest- E-mail: [email protected] enosis and approaches to therapy with drug-eluting 177 Acta Cardiol Sin 2005;21:177-89 Chao-Chien Chang et al. stents. these restenosis cascades, two major processes can be discerned: arterial remodeling and neointimal hyperpla- sia. PATHOPHYSIOLOGY Arterial remodeling Restenosis is considered a local vascular manifesta- Vascular remodeling occurs naturally in atheroscle- tion of the general biologic response to injury.7 (Figure 1) rosis. Glagov et al. noted that human coronary arteries Post-balloon angioplasty (PTCA) restenosis is thought to often enlarge in response to plaque formation as a com- involve primarily negative remodeling and, partially, pensatory response that limits narrowing of the vessel neointimal hyperplasia.8 Histologically, however, in-stent lumen.10 This so-called positive remodeling can occur af- restenosis is quite distinct from restenosis after PTCA ter angioplasty, but negative remodeling can also ensue, (Figure 2). In fact, intravascular ultrasound (IVUS) stud- contributing to restenosis. Mintz et al. utilized serial ies suggest that coronary stents provide mechanical IVUS to document negative remodeling in a series of scaffolding that virtually eliminates long-term negative 209 angioplasty patients11 and observed that much of the remodeling and that in-stent restenosis is largely a result lumen loss was due to vessel constriction (area circum- of vascular smooth muscle cells (VSMCs) proliferation, scribed by the external elastic lamina), rather than which is exaggerated after stent deployment due to the neointimal thickening. It is not known how much nega- high-pressure technique of stent deployment.9 Within tive remodeling contributes to restenosis, but it plays a Figure 1. Proposed mechanism of restenosis. Acta Cardiol Sin 2005;21:177-89 178 Coronary Restenosis, Pathophysiology and Molecular Mechanism of Restenosis Figure 2. Mechanisms of restenosis after balloon angioplasty and stenting. (Upper) In-stent restenosis is 100% due to smooth muscle cell proliferation; remodeling of the vessel does not occur. (Bottom) The mechanisms responsible for restenosis after balloon angioplasty are mainly the negative remodeling of vessel that accounts for 75% of the phenomenon and the proliferation of smooth muscle cells with neointimal formation that represents the other 25%. greater role in angioplasty if stenting is not performed.1 liferation and migration because healthy endothelial In-stent restenosis, in contrast, arises primarily from cells inhibit smooth muscle cell growth through nitric neointimal hyperplasia.1 oxide production.1 During the first several months fol- lowing angioplasty, the neointima expands, and the Neointimal hyperplasia additional volume comprises smooth muscle cells and Balloon inflation fractures the atherosclerotic plaque, extracellular matrix. Accumulation of collagen fibers in- invoking platelet adhesion and activation. The activated creases the volume of the extracellular matrix,16 whereas, platelets release mitogens, including thromboxane A2, in parallel, reduced degradation of collagen in the serotonin, and platelet-derived growth factor, which pro- extracellular matrix contributes to the enhanced presence mote smooth muscle cell proliferation.1 Concurrently, of collagen in the matrix. levels of mitogenic proto-oncogenes, including c-fos, c-jun, fosB, junB, and junD, increase in the smooth mus- cle cells.12 This activation of smooth muscle cells alters MOLECULAR MECHANISMS OF their phenotype from contractile to synthetic, and 20% to RESTENOSIS 40% of medial smooth muscle cells enter the cell cycle within 3 days.1 Additionally, smooth muscle cells elabo- A commonly accepted model of the response to arte- rate promigratory proteins, including CD44v6, urokinase rial injury suggests that growth factors are released after plasminogen activator receptor, integrin alpha(v)ss,13 injury, thereby changing the composition of the extracellular transforming growth factor-ss,1 MDC9, and ss-inducible matrix and triggering a proliferation and migration pro- gene h3.14 Consequently, many activated medial smooth gram. Vascular smooth muscle cells (VSMCs) undergo a muscle cells migrate to the intima.12 Although most of phenotypic modulation from a contractile to a synthetic these cells originate in the media, adventitial myofibroblasts phenotype (dedifferentiation), proliferate into the media, also migrate to the intima.15 A dysfunctional endothe- migrate from the media into the intima, and subsequently lium might also contribute to smooth muscle cell pro- form the neointima. Vascular smooth muscle cells that 179 Acta Cardiol Sin 2005;21:177-89 Chao-Chien Chang et al. form the neointimal tissue remain the main target if mitogenic signals from the membrane to the nucleus in restenosis is to be challenged. VSMCs after arterial injury, in particular, the role of the ras-raf-mitogen-activated protein kinase (MAPK) Intracellular signaling of vascular smooth pathway and the cyclicadenosine monophosphate muscle cells after vascular Injury (cAMP)- dependent signaling in activated VSMCs In the past few years, many investigators have fo- (Figure 3).7,17 cused their attention on the relative importance of single Ras-raf-MAPK signaling of smooth muscle cells receptors in the complex mechanism of vascular smooth after vascular injury muscle cell (VSMC) growth control after vascular in- Ras proteins are key transducers of mitogenic sig- jury.7 However, it is unlikely that the inhibition of only a nals from plasma membrane to the nucleus in many cell single receptor would be clinically relevant to the pre- types. Several mutants of ras (such as N17 H-ras and vention of in-stent restenosis. Therefore, in the last few L61, S186 H-ras) act in a dominant negative manner to years, Indolfi et al. have studied mainly the common block normal ras activation. N17 H-ras has reduced