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 . However, clinical restenosis still represents the major limitation of this technology. Despite this limitation, has become the most common revascularization procedure for coronary disease. Although the advent of coronary 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 . 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 .7 (Figure 1) rosis. Glagov et al. noted that human coronary 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 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 adhesion and activation. The activated creases the volume of the extracellular matrix,16 whereas, 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 af- pathways that multiple receptors employ to transmit finity for guanosine triphosphate (GTP) and is defective

(A) Growth factors (B) Hormones

Figure 3. Schematic diagram of the main intracellular pathways regulating vascular smooth muscle cell proliferation.18-20 Two main signaling pathways from the membrane to the nucleus are discussed. On the extracellular side of the plasma membrane are shown (A) growth factors binding tyrosine kinase (TK) receptors and (B) hormones that bind seven-loop receptors that signal to the heterotrimeric G proteins. Grb-2: growth factor receptor bound-2; SOS: Son of Sevenless; GTP: guanosine triphosphate; MEKK or MAPKKK: mitogen-activated protein kinase kinase kinase; MAPKK/MEK: mitogen activated protein kinase kinase; SEK: Stress activated protein kinase kinase; SAPK: Stress activated protein kinase; cAMP: cyclic adenosine monophosphate; AC: adenylate cyclase; PKA: protein kinase A; CREB: cAMP-responsive element binding protein.

Acta Cardiol Sin 2005;21:177-89 180 Coronary Restenosis, Pathophysiology and Molecular Mechanism of Restenosis in the final step of the exchange process, displacement of ulated by the assembly and phosphorylation of G1 cyclin- guanine-exchange factor (GEF) by GTP, and sequester- cyclin-dependent kinase (CDK) complexes, predomi- ing of GEFs into dead-end complexes.7 This mutant has nantly cyclin D-CDK and cyclin E-CDK-2 in VSMCs.23 been used to remove GEF activity from cells so that acti- Endogenous inhibitors of the cyclin-CDK complexes are vation of endogenous ras proteins cannot occur. Indolfi termed the CDK inhibitors (CKIs). Two groups of CKIs et al. investigated the role of ras proteins in the vascular are dominant in cardiovascular biology: the CDK inhibi- response to arterial injury in vivo by inactivating cellular tor protein (CIP/KIP) family, which includes p21Cip1 and ras function in rats in which the common carotid artery p27Kip1, and the INK4 family, which includes p16Ink4a.23 was subjected to balloon injury.18 In animals treated with Cells in the late S or G2/M phase do not migrate. There Nl7 H-ras, a significant reduction of neointimal forma- is a window of opportunity in the G1-to-G1/S transition tion (-55%) was observed 14 days after balloon injury during which VSMCs are able to migrate in response to compared with animals treated with RSV-LacZ.18 A sim- mitogenic stimuli. Therefore, proteins such as the CKIs ilar effect on neointimal formation after vascular injury that regulate G1 cell cycle progression are likely candi- was observed with the inhibition of MAPKKinase by a dates to regulate the initiation of migration as well. The dominant inhibitor mutant gene.19 protein p27Kip1 is one important candidate, given that it Activation of cAMP–protein kinase A signaling in- is tightly regulated by mitogens. p27Kip1 is an important hibits neointimal formation after balloon injury regulator of the mammalian cell cycle.23 An increase in cAMP is involved in the regulation of a variety of p27Kip1 causes proliferating cells to exit from the cell cy- cellular functions, such as cell proliferation and differenti- cle, whereas a decrease in p27Kip1 is required for quiescent ation. Hormone-activated receptors increase the intra- cells to resume cell division.24 Low levels of p27Kip1 are cellular cAMP by inactivating the subunit of the trimeric associated with excessive cell proliferation in pathologic G-protein complex (Gas), which stimulates adenylate conditions such as inflammation and restenosis.25 High cyclase (Figure 3). To evaluate the effects of cAMP on levels of p27Kip1 are observed in conditions of dimin- VSMC proliferation, Indolfi et al. treated cultures of these ished cell proliferation, such as in the late stages of cells in vitro with different concentrations of 8-Br-cAMP arterial wound repair in and restenosis.26 and analyzed cell growth at different treatment periods.20 Notably, Indolfi et al. demonstrated that A-kinase anchor They found cAMP markedly inhibited VSMC prolifera- protein (AKAP), downstream molecules of the cAMP- tion. At the time of balloon injury, they locally delivered PKA cascade, inhibits VSMC proliferation in vivo by in- 8-Br-cAMP. In the 8-Br-cAMP group, a significant reduc- creasing p27Kip1 protein levels.27 tion of neointima (-54%) was observed 14 days after vascular injury compared with the control group.20 An in- hibition of neointimal formation after vascular injury also RISK FACTORS was observed in other experiments,21 in which systemic administration of 8-Cl-cAMP reduced protein kinase A Independent risk factors for restenosis are a recent (PKA) RIa-subunit expression and upregulated PKA history of pectoris and a previous myocardial in- RIIb-subunit expression. farction. Other predictors of restenosis include stenosis Cyclin-dependent kinase complexes of longer length,28 chronic total occlusions,29 and angi- The cell cycle is a key regulator of the described ographically identifiable .30 Disease in saphenous intracellular signals and has direct effects on multiple vein grafts31 and in small native vessels (less than 3.0 cell processes, including VSMC proliferation and cell mm)32 is associated with higher rates of restenosis. One migration.22 VSMCs within the media of adult arteries of the leading predictors of angiographic stenosis after normally are quiescent, proliferate at low rates, and exist angioplasty is postprocedural diameter.1 Structural risk in the G0 phase of the cell cycle. Upon stimulation by factors, such as a large degree of luminal narrowing be- growth factors or after arterial injury, VSMCs exit the fore angioplasty, a small diameter of the reference quiescent stage G0 and progress through the G1 and segment, a symmetric lesion, an extensive area of plaque, G1/S transitions of the cell cycle. G1 progression is reg- and residual stenosis, have been identified.33-35 After

181 Acta Cardiol Sin 2005;21:177-89 Chao-Chien Chang et al. adjustment for other risk factors, such as diabetes mellitus coronary atherectomy catheter, developed in the early and proximal lesions in the left anterior descending cor- 1980s, which allows shaving and extraction of plaque onary artery, there is only a slight difference in the rate from the diseased vessel wall. Comparisons of direc- of restenosis between first and successive coronary tional coronary atherectomy and standard angioplasty for .28,34 Genetic factors may also be involved, the treatment of de novo lesions have shown similar including polymorphisms for the D/D genotype of the rates of restenosis between the two procedures.1 angiotensin-converting enzyme (ACE) receptor,36 glyco- The was designed to reduce restenosis. protein receptor IIIa PIA1/PIA2,37 4G/5G promoter of It has been demonstrated by IVUS that there are two ma- the plasminogen activator inhibitor 1,38 and haptoglobin jor components which contribute to restenosis following 2/2.39 Additionally, a clinical presentation with unstable successful PTCA.43 One is the vascular remodeling which angina enhances the likelihood of restenosis after occurs by recoiling of the outer vessel wall, and the other angioplasty.40 Plasminogen activator inhibitor 1, uro- one is intimal hyperplasia.44 Coronary stenting has been kinase plasminogen activator, and tissue factor have shown to prevent vascular remodeling and to hinder vas- also been demonstrated to be risk factors.41,42 cular re-narrowing by allowing more room for intimal hyperplasia. Newer stents were designed taking these fac- tors into consideration; they were designed for better TREATMENT scaffolding and less intimal prolapse. In the BElgian NEtherlands Stent (BENESTENT)45 and Stent Restenosis Shortly after the phenomenon of restenosis was rec- (STRESS) trials,46 patients with de novo lesions were ran- ognized, investigators sought to develop devices that domly assigned to either angioplasty or stenting. Stenting could more completely debulk the plaque burden at the was associated with a lower rate of restenosis as com- time of intervention. The rationale was to maximize the pared with placebo in both the BENESTENT (22% vs. postprocedural vessel diameter, thereby reducing the 32%) and STRESS trials (31.6% vs. 42%). This benefi- rates of restenosis. One such device was the directional cial effect has been confirmed in other randomized trials,

Acta Cardiol Sin 2005;21:177-89 182 Coronary Restenosis, Pathophysiology and Molecular Mechanism of Restenosis

Figure 4. Cell cycle in which restenosis rates were reduced by 25% to 50% 16-gray, 20-gray, or 24-gray radiotherapy (intracoronary as compared with angioplasty alone.1 The benefits of 32P).49 Radiotherapy reduced the restenosis at the target stenting are attributed to larger lumen gain, elimination site as compared with placebo (8% vs. 39%, p=0.01). of vessel recoil, and prevention of negative remodel- The angiographic and clinical benefits, however, were ing.1 Unfortunately, neointimal hyperplasia remains a limited by restenosis adjacent to the target site (14% in problem after stenting.47 The most recent advances in the treated group vs. 11% in the placebo group) and by the treatment of restenosis include intracoronary radia- late thrombotic events in the treated group. More re- tion (brachytherapy) and drug-coated stents (Table cently, in the Stents and Radiation Trial (START),50 1)(Figure 4). patients with in-stent restenosis were randomly assigned to brachytherapy or placebo after receiving mechanical Brachytherapy treatment (primarily angioplasty) for in-stent restenosis. In animals, intracoronary radiation reduces neointimal Restenosis within the entire segment treated with radia- proliferation after angioplasty, presumably by decreasing tion was reduced in 45% of controls and 29% of treated smooth muscle cell mitosis and by inducing apoptosis.48 patients at 8 months (p=0.001). Because of this trial, Investigators have used both beta and gamma radiation the FDA has approved beta radiation for the treatment of for this purpose. in-stent restenosis. Beta particles are emitted electrons from a radioac- In the Intimal Hyperplasia Inhibition With Beta tive isotope. The most extensively studied isotopes Instent (INHIBIT) trial,51 patients with in-stent restenosis have been phosphorus 32 (32P) and strontium 90. In the who had been treated with repeat percutaneous interven- Proliferation Reduction with Vascular Energy Trial tion were randomly assigned to beta radiation or placebo. (PREVENT), patients with native or restenotic lesions Angiographic restenosis was lower in the radiation group who had been treated with stenting or balloon angioplasty (26%) than in the placebo group (52%, p < 0.0001). In a were randomly assigned to intervention with placebo or trial of escalating doses of beta radiation after angioplasty

183 Acta Cardiol Sin 2005;21:177-89 Chao-Chien Chang et al. alone for de novo lesions, restenosis occurred in 4% of late was reported in only 3% of patients who patients who had been treated with the highest radiation had undergone prolonged antiplatelet therapy (6 months dose.52 Conversely, the preliminary results from the ran- of clopidogrel in addition to aspirin),56 similar to the pla- domized BETA-CATH trial did not show beta radiation cebo historical control group from WRIST. Longer to be beneficial as a primary intervention strategy in de therapy with clopidogrel (12 months) did not reduce the novo lesions.53 The study randomly assigned 1455 pa- incidence of late thrombosis, but decreased the number of tients who had been treated with angioplasty, with or major cardiac events and rate of repeat revascularization.58 without stenting, to beta radiation or placebo. At 8 Finally, follow-up duration of these patients has been months, restenosis rates in the analysis segment (treated short, and it is unclear whether untoward effects of radi- segment plus 5 mm on both sides) did not differ signifi- ation, including the potential for fibrosis and oncogenesis, cantly between radiation and placebo groups (31% vs. might emerge. 36%, p=0.3). Gamma radiation entails photon emission by radio- Drug-coated stents isotopes such as iridium 182, which has shown efficacy The most promising prospect for reducing restenosis in reducing restenosis in the Scripps Coronary Radiation has been the recent development of drug-coated stents. to Inhibit Proliferation Post Stenting (SCRIPPS) trial,54 Several drugs are being tested for local delivery through the Washington Radiation for In-Stent Restenosis Trial eluting stents, including estradiol and . The (WRIST),55 WRIST PLUS,56 and Gamma-1 trial.57 The most extensively studied, to date, is sirolimus (rapamycin). FDA approved gamma radiation for the treatment of Sirolimus is an immunosuppressive drug that is tradi- in-stent restenosis based on the Gamma-1 trial results.57 tionally used to prevent organ transplant rejection. In this investigation, 252 patients with instent restenosis Within the last 10 years, animal experiments have dem- were randomly assigned to either a placebo “hot wire” or onstrated its efficacy in reducing restenosis, and recently an iridium 192 “hot wire” after undergoing angioplasty, human clinical trials have been completed. In the Ran- atherectomy, or laser angioplasty. At 6 months, the inci- domized Double-Blind Study with the Sirolimus-Eluting dence of restenosis was 55% in the placebo group and BX Velocity Balloon-Expandable Stent in the Treatment 32% in the treated group. of Patients with De Novo Native Coronary Lesions These results indicate that brachytherapy is benefi- (RAVEL), patients were randomly given a sirolimus- cial, albeit with several limitations. The procedure is eluting stent or placebo.59 The restenosis rate at 6 months expensive, inconvenient, and requires the services of a was 0% in the sirolimus group compared with 26% in radiation oncologist. Also, use of gamma radiation re- the placebo group (p < 0.001). In the subgroup of dia- quires that personnel leave the room during the 20 betic patients, none of the patients with drug-coated minutes of radiation exposure. The increased incidence stents had restenosis compared with 42% of those with of late thrombosis and is a major bare metal stents (p < 0.002). Preliminary results were concern. In the Gamma-1 trial, for example, there was a recently presented for the Sirolimus-coated BX Velocity trend toward late thrombosis (5% vs. 0.8%, p=0.07) Balloon-expandable Stent in the Treatment of Patients and myocardial infarction (10% vs. 4.2%, p=0.09) in with De Novo Coronary Artery Lesions (SIRIUS) trial.60 the treated group when compared with the placebo In this trial, 1058 patients were randomly given a group. All of the late thrombosis events occurred in stent sirolimus-coated stent or a bare stent. At angiographic recipients. Specifically, 6% of patients who received follow-up at 8 months, in-segment restenosis (stent plus new stents at the time of intervention had late thrombo- 5-mm proximal and distal borders) occurred in 9% of sis as opposed to none of the nonstented patients. sirolimus-coated stent patients compared with 36% of Similarly, late thrombosis occurred in 10% of treated pa- control group patients (p < 0.001). Adverse effects did tients in PREVENT, 3% of treated patients in the not differ between two groups, including stent thrombo- INHIBIT trial, and 6% in the BETA-CATH trial. Pro- sis (0.6% in the sirolimus group vs. 1.1% in the placebo longed antiplatelet therapy might ameliorate these group) and formation (0.6% in the sirolimus adverse effects. In the nonrandomized WRIST PLUS, group vs. 1.1% in the placebo group). Recently, paclitaxel-

Acta Cardiol Sin 2005;21:177-89 184 Coronary Restenosis, Pathophysiology and Molecular Mechanism of Restenosis coated stents have also shown benefit in reducing duced neointimal formation without affecting endothelial restenosis. In a randomized study involving patients as- regeneration with potential benefit in the prevention signed to low-dose paclitaxel-coated stents, high-dose and treatment of in-stent restenosis.64 Recent data have paclitaxel-coated stents, or placebo,61 restenosis occurred shown that estradiol-eluting phosphorylcholine-coated in 27% of patients in the control group, 12% in the stents that were implanted in porcine low-dose group, and 4% in the high-dose group at 4- to reduced neointimal hyperplasia by 40% compared with 6-month follow-up. After nine months follow-up, the control stents. The Estrogen And Stent To Eliminate rate of angiographic restenosis was reduced from 26.6% Restenosis (EASTER) study was a single-center feasi- to 7.9% with the paclitaxel-eluting stent (relative risk, bility study testing 17-beta-estradiol-eluting BiodivYsio 0.30; 95% confidence interval, 0.19 to 0.46; p < 0.001). (Abbott, Abbott Park, Illinois) stents in 30 patients with The nine-month composite rates of death from cardiac de novo coronary lesions. Stents were loaded on-site by causes or myocardial infarction (4.7% and 4.3%, respec- immersion in a solution of estradiol. Late loss was 0.32 tively) and stent thrombosis (0.6% and 0.8%, respectively) mm in lesion and 0.57 mm in stent. Neointimal hyper- were similar in the group that received a paclitaxel- plasia, detected using IVUS, was 23.5%. At six months, eluting stent and the group that received a bare-metal there were no deaths or stent thromboses, and only one stent.62 patient underwent repeat revascularization. A second phase of the EASTER study has recently concluded, Healing-enhancing stents and results are not available. Vascular endothelial growth factor-eluting stents Stents attracting endothelial cells (ECs) Despite promising results with local delivery of the Stents may be used to attract circulating ECs. R vascular endothelial growth factor (VEGF) to the site of stents (Orbus Medical Technologies, Fort Lauderdale, vascular injury, a recently conducted experimental study Florida) coated with antibodies to CD34 receptors on of VEGF-eluting stents failed to demonstrate a beneficial progenitor circulating ECs have been implanted in pig effect on endothelization or on intimal hyperplasia. These coronary arteries. These non drug-eluting stents would VEGF-eluting stents did not accelerate endothelization or ultimately promote the elution of biologically active sub- inhibit restenosis, but they did reduce the stent thrombosis stances through a functioning endothelium monolayer. rate, which may make them less thrombogenic.63 Acceler- The effects of these novel stents on restenosis remain to ated endothelialization by local delivery of endothelial- be demonstrated. Kutryk et al.67 proposed the seeding of specific growth factors could constitute an attractive alter- intravascular stents by the xenotransplantation of geneti- native to direct antiproliferative strategies. cally modified ECs, which were capable of modifying Estradiol-eluting stents the pathophysiologic response to vessel wall damage and Estradiol may improve vascular healing, reduce provide controllable levels of active compounds. The smooth muscle cell (SMC) migration and proliferation, feasibility and potential of this method has been demon- and promote local angiogenesis. Several animal and hu- strated in animal studies. There are also preliminary man studies have demonstrated a protective effect of data68 suggesting that endoluminal seeding of syngeneic estrogen on coronary circulation.64 Estrogen appears SMCs can be effective in reducing intimal hyperplasia in not only to have a beneficial effect on lipids but also a restenosis animal model and in arterial allografts. stimulates NO production by endothelial cells (ECs), as well as inhibits the expression of the proto-oncogene c-myc, which is implicated in the development of CONCLUSION intimal hyperplasia.65 Estradiol may also contribute to vascular healing and prevent restenosis by improving Given the prevalence of coronary artery disease and re-endothelization (estrogen receptor alpha-activation) the widespread dissemination of technology and exper- and by decreasing SMC migration and proliferation (es- tise, the number of percutaneous coronary interventions trogen receptor beta-activation).66 This explains why will continue to increase aggressively. Interventional car- 17-beta-estradiol-eluting stents are associated with re- diologists will treat more patients, including those with

185 Acta Cardiol Sin 2005;21:177-89 Chao-Chien Chang et al. comorbid conditions that may complicate percutaneous coronary angioplasty: a serial intravascular ultrasound study. treatment, such as diabetes, multivessel disease, and Circulation 1996;94:35-43. chronic total occlusion. Therefore, expanding our under- 12. Miano JM, Vlasic N, Tota RR, Stemerman MB. Localization of Fos and Jun proteins in rat aortic smooth muscle cells after standing of restenosis and treatment options becomes vascular injury. Am J Pathol 1993;142:715-24. more pressing. Although many patients can benefit from 13. Riessen R, Wight TN, Pastore C, et al. Distribution of hyaluronan percutaneous intervention, many can also suffer from its during extracellular matrix remodeling in human restenotic limitations, with restenosis causing recurrent angina, arteries and balloon-injured rat carotid arteries. Circulation ischemic events, and repeat interventions. 1996;93:1141-7. For these patients, there are other treatment options. 14. Ward MR, Tsao PS, Agrotis A, et al. Low blood flow after Intracoronary radiation, despite its limitations, has been angioplasty augments mechanisms of restenosis: inward vessel remodeling, cell migration, and activity of genes regulating shown to be effective in ameliorating restenosis. The migration. Arterioscler Thromb Vasc Biol 2001;21:208-13. current data regarding drug-coated stents are promising. 15. Wilcox JN, Waksman R, King SB, Scott NA. The role of the Ultimately, these advances offer great hope for markedly adventitia in the arterial response to angioplasty: the effect of lower rates of restenosis and a new era in interventional intravascular radiation. Int J Radiat Oncol Biol Phys 1996;36: cardiology. 789-96. 16. Pickering JG, Ford CM, Chow LH. Evidence for rapid accu- mulation and persistently disordered architecture of fibrillar collagen in human coronary restenosis lesions. 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Acta Cardiol Sin 2005;21:177-89 188 Review Article Acta Cardiol Sin 2005;21:177−89

冠狀動脈血管再狹窄

張釗監 王榮添 台北市 國泰綜合醫院 心臟內科

冠狀動脈疾病的介入性療法中，血管支架置放術比傳統的氣球擴張術有較令人滿意的 結果，已有多篇的文獻證實。隨著使用率的增加，血管支架置放後所遭遇的難題，如血管 再狹窄，是心臟科醫師所要面臨的一大問題。血管再狹窄的問題，尤其在有糖尿病或者 multivessel 的冠狀動脈疾病患者最為嚴重，往往限制血管成型術的好處。最近，美國食品 和藥品管理局 (FDA) 批准 brachytherapy 和 drug-eluting stents 作為在 stent 的再狹窄問題上 之可行的治療選擇。本篇文章將探討血管再狹窄問題的病理生理學和分子機轉，並回顧當 今與將來的治療選擇。

關鍵詞：冠狀動脈血管再狹窄、血管再狹窄問題的病理生理學和分子機轉。

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