JACC
HOME SUBSCRIPTIONS CURRENT ISSUE PAST ISSUES CARDIOSOURCE SEARCH HELP FEEDBACK
QUICK SEARCH:   [advanced]


     

J Am Coll Cardiol, 2002; 39:183-193
© 2002 by the American College of Cardiology Foundation
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lowe, H. C.
Right arrow Articles by Khachigian, L. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lowe, H. C.
Right arrow Articles by Khachigian, L. M.

REVIEW ARTICLE

Coronary in-stent restenosis: Current status and future strategies

Harry C. Lowe, FRACP, PhD*{dagger}, Stephen N. Oesterle, MD, FACC* and Levon M. Khachigian, PhD{dagger},*

* Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
{dagger} The Centre for Thrombosis and Vascular Research, University of New South Wales, Sydney, Australia

Manuscript received July 11, 2001; revised manuscript received October 4, 2001, accepted October 26, 2001.

* Reprint requests and correspondence: Associate Professor Levon M. Khachigian, Centre for Thrombosis and Vascular Research, School of Pathology, University of New South Wales, Sydney NSW 2052, Australia.
L.Khachigian{at}unsw.edu.au


   Abstract
Top
 Abstract
Animal models of ISR
 Treatments for ISR
 Strategies for prevention of...
 Conclusions
 References
 
In-stent restenosis (ISR) is a novel pathobiologic process, histologically distinct from restenosis after balloon angioplasty and comprised largely of neointima formation. As percutaneous coronary intervention increasingly involves the use of stents, ISR is also becoming correspondingly more frequent. In this review, we examine the available studies of the histology and pathogenesis of ISR, with particular reference to porcine and other animal models. An overview of mechanical treatments is then provided, which includes PTCA, directional coronary atherectomy and high speed rotational atherectomy. Radiation-based therapies are discussed, including a summary of current problems associated with this modality of treatment. Finally, novel strategies for the prevention of ISR are addressed, including novel developments in stents and stent coatings, conventional drugs, nucleic acid-based drugs and gene transfer. Until recently, limited pharmacologic and mechanical treatment options have been available for both treatment and prevention of ISR. However, recent advances in gene modification and gene transfer therapies and, more particularly, in local stent-based drug delivery systems make it conceivable that the incidence of ISR will now be seriously challenged.

Abbreviations and Acronyms
  ARTIST
  Angioplasty Versus Rotational Atherectomy for Treatment of In-Stent Restenosis trial
  AS
  antisense
  DCA
  directional coronary atherectomy
  DNA
  deoxyribonucleic acid
  DZ
  deoxyribonucleic acid enzyme
  HSRA
  high-speed rotational atherectomy
  Ir
  iridium
  ISR
  in-stent restenosis
  NI
  neointima
  P
  phosphorus
  PRESTO
  Prevention of Restenosis with Tranilast and its Outcomes trial
  PREVENT
  Proliferation Reduction with Vascular Energy Trial
  PTCA
  percutaneous transluminal coronary angioplasty
  RAVEL
  Rapamycin-eluting versus Plain Polymer Stents trial
  RNA
  ribonucleic acid
  ROSTER
  Randomized Trial of Rotational Atherectomy versus Balloon Angioplasty for In-Stent Restenosis
  RZ
  ribozyme
  SCRIPPS
  Scripps Coronary Radiation to Inhibit Proliferation Post Stenting trial
  SMC
  smooth muscle cell
  Sr-90
  strontium90
  START
  Stents And Radiation Therapy Trial
  WRIST
  Washington Radiation for In-Stent Restenosis Trial

Restenosis, defined as "the arterial healing response after injury incurred during transluminal coronary revascularization" (1) has been the principal drawback of coronary angioplasty since its inception nearly 25 years ago. The only widely accepted means of reducing restenosis has been the coronary stent, and the last five years have seen a prompt and widespread adoption of coronary stents, following the demonstration of reduced restenosis rates compared with percutaneous transluminal coronary angioplasty (PTCA) alone for comparable lesions (2–4). Coronary revascularization now generally involves the use of a stent in more than 70% of cases (5). Coincident with this increased stent use has been the more widespread treatment of more complex lesions and the realization that in-stent restenosis (ISR) occurs in 10% to 50% of cases currently treated in everyday practice and estimated to have occurred in 150,000 patients in 1999 in the U.S. alone (6–9). Therefore, the problem of ISR is becoming at least as important as restenosis after PTCA.

In-stent restenosis has been classified on the basis of length of restenosis in relation to stented length (10). Four types of ISR have been defined: I) focal (≤10 mm length); II) diffuse (ISR >10 mm within the stent); III) proliferative (ISR >10 mm extending outside the stent); and IV) occlusive ISR. Type I has been further subdivided into types IA to ID based on the site of focal ISR in relation to the stent (10). An additional type of ISR has been proposed, that of "aggressive ISR," defined as ISR that is longer and/or more severe than the original lesion (9). This type is noteworthy in that the clinical course is not benign, with patients more likely to have more severe symptoms and higher rates of myocardial infarction (9).

Histologically, ISR is quite distinct from restenosis after balloon angioplasty (1,11,12). Postangioplasty restenosis is thought to involve vessel elastic recoil, negative remodelling or contraction, thrombus at the site of injury, smooth muscle cell (SMC) proliferation and migration and excessive extracellular matrix production. These last two processes contribute to neointima (NI) formation (1,13). In contrast, intravascular ultrasound studies suggest that stenting virtually eliminates vessel elastic recoil and negative remodelling and that ISR is largely a result of NI formation alone (12,14,15). Neointima is composed principally of proliferating SMC (16,17) and extracellular matrix (18). Peristent thrombus has not been thought to play an important role in NI formation—at least in the pig model of stenting (19)—although recent observations suggest it may have some influence, particularly in the setting of hyperglycemia (20–22).

A number of variables are known to increase the risk of ISR. Patients with diabetes or a history of prior restenosis have a higher rate of ISR (23,24). There is some evidence that genetic factors play a role, examples being the PIA polymorphism of glycoprotein IIIa and a mutant form of methylenetetrahydrofolate reductase that appear to increase the risk of ISR, whereas allele 2 of the interleukin IL-1ra gene appears to be protective (25–28). Patients positive for allergic patch-test reactions to the stent components nickel and molybdenum also appear to have increased rates of ISR (29). Procedural-related variables have also been implicated. For example, the greater the stented length, the number of stents used or lesions in vessels that are small, occluded, at vessel ostia or in vein grafts are all associated with increased ISR rates (30–35). The postprocedural minimal lumen diameter is also an important, well-documented predictor of subsequent ISR rates (36).


   Animal models of ISR
Top
 Abstract
 Animal models of ISR
Treatments for ISR
 Strategies for prevention of...
 Conclusions
 References
 
Animal models have provided insights into the mechanisms of ISR and are widely used to evaluate candidate drug inhibitors of ISR (1,37). The principal model currently used is that of porcine coronary stenting (38), although stenting of the porcine carotid and iliac arteries has been described (39,40), and similar models have also been proposed in the rat, rabbit and primate (41–43). These small animal models of rat carotid and rabbit iliac stenting have the advantages of availability and low cost but are in peripheral vessels, histologically quite distinct from human coronaries, and are not widely used (37). Large animal models of nonhuman primates have also been proposed as models of ISR, given that many species develop spontaneous atherosclerosis with lesions similar to humans (44,45), but animals are expensive and difficult to maintain (37), and most studies have been reported using peripheral vessels (46,47).

The porcine model of ISR is currently and widely used (37). In this model, oversized metallic stents are placed into the coronary arteries of domestic crossbred swine. A thick NI is reliably induced by 28 days (Fig. 1). The model is attractive for a number of reasons; the response to deep injury is very similar between domestic pig and normal human coronary arteries (48), and the adaptive response in the pig is more profound in pigs fed a hypercholesterolemic diet (49). Moreover, since the size and anatomic distribution of porcine coronary arteries are similar to those of the human, angiography, intravascular ultrasound, instrumentation and stent deployment are all similar to the clinical situation.



View larger version (178K):
[in this window]
[in a new window]
  		Figure 1 In-stent restenosis after porcine coronary stenting. Nonatherosclerotic porcine coronary artery 30 days after stenting with oversized balloon. Vessel excised, processed in methylmethacrylate, cut, polished and stained with haemotoxylin and eosin (originally at 2x magnification). The injury score for each stent strut is shown according to the definitions: 0 = internal elastic lamina (IEL) intact, endothelium denuded, media compressed but not lacerated; 1 = IEL lacerated, media compressed but not lacerated; 2 = IEL lacerated, media lacerated, external elastic lamina (EEL) compressed but not lacerated; 3 = EEL lacerated, media contains large lacerations, stent strut may extend into the adventitia. The injury score for the vessel section is calculated as (total of individual stent strut injury scores) / (number of stent struts in section) and equals 21/10 = 2.1 based on the original description (38). L = lumen; M = media; N = neointima; S = stent strut; Th = thrombus.

 
The porcine model is also useful in that the degree of injury can be quantitated. The anatomic depth to which the stent strut penetrates the vessel wall has been correlated with the induced NI thickness (38). For stents with multiple struts, an "injury score" can be derived for each strut and a mean score for the vessel as a whole (Fig. 1). Injury score can then be correlated to the vessel cross-sectional mean NI area (38) or percent stenosis (50). More recently, in addition to the injury score an "inflammation score" has also been described (50). This is derived from the extent and severity of inflammatory cell infiltrate around the stent struts. A correlation exists between the inflammatory score and the degree of arterial injury and with NI thickness, suggesting inflammation also plays an important role in this model (50).

There is a time-dependent progression in the cellular response to stenting in the pig model (19). At 24 h after stenting, immediately adjacent to the stent struts, there are acute inflammatory cells and thrombus, containing platelets and fibrin (19). At one week, this thrombus has become organized, and macrophages are evident. By two to four weeks, although some chronic inflammatory cells remain, the predominant cell type is the fully differentiated SMC (19). Although histologic studies in the human are necessarily less detailed, a similar progression of thrombus formation, inflammatory cell and SMC infiltration has been observed from postmortem studies (22).

Despite these similarities, the pig model, like other models, has limitations. The preinjured arteries are normal, nonatherosclerotic vessels (38). In the pig, the stent struts induce injury directly, by medial cell compression or laceration (38). In the human, direct medial injury occurs by only 32% of stent struts, with most struts being in contact with atheromatous plaque and not media (22). Thus, in the human, a stent strut "injury score" is not a practical calculation, but it is noteworthy that the amount of NI formation increases with increasing stent area relative to proximal reference lumen area (22). Another difference between the models is that in the pig the degree of ISR is examined at one month, compared with the three to six months that is the peak period of ISR development in humans (3,51). Despite these limitations, the porcine coronary model has gained the most widespread use of any of the large animal models (37) and continues to be used to evaluate potential new antirestenotic drugs (52), gene-based (53) and radiation-based therapies (54).


   Treatments for ISR
Top
 Abstract
 Animal models of ISR
 Treatments for ISR
Strategies for prevention of...
 Conclusions
 References
 
In any discussion of the modalities of treatment for ISR it should be pointed out that many of these modalities can also be used in combination with stenting of de novo coronary lesions and, therefore, can also be viewed as preventing ISR. For the most part, mechanical and radiation-based therapies have been used to treat ISR, whereas drug and stent-based therapies have been used in de novo lesions to try to prevent ISR. The discussion in the subsequent text follows this pattern.

Mechanical treatments.   PTCA
Percutaneous transluminal coronary angioplasty—redilating within the segment of ISR—is the most commonly available treatment. The procedure is technically straightforward but usually does not achieve a lumen diameter as large as that achieved at the time of original stent deployment, even using larger balloons at high pressures (55). It has been suggested that 56% of the achieved lumenal enlargement occurs through additional stent expansion, and 44% is due to a reduction or compression of NI tissue (55). Intravascular ultrasound studies have suggested that this NI tissue may undergo reintrusion through stent struts soon after initial balloon expansion, leading to an acute loss of benefit (56). In patients with ISR lesions <10 mm in length (type I or II) treated with PTCA alone, recurrence of restenosis occurs in 19% to 35%; for types III or IV, treated with PTCA in combination with other therapies, recurrence rates are 50% and 83%, respectively (10,55). In view of these generally poor results, therefore, attention has focused on mechanical techniques that involve removal of tissue.

Directional coronary atherectomy (DCA).   Directional coronary atherectomy is an attractive option for the treatment of ISR in that there is some evidence that pre-existing plaque burden contributes to ISR (57) so that plaque debulking before stenting using DCA has been proposed as a technique to lower ISR (58). Directional coronary atherectomy has been demonstrated to remove NI tissue within the stent and results in an acute gain in lumen diameter (57,59). In a small series of 45 patients undergoing DCA for diffuse ISR, there was a low rate of target lesion revascularization at 12 months of 28.3% (60). However, concerns over increased morbidity in general after DCA (61) and specific concerns over stent strut fracture and disruption after DCA for ISR (62) have hindered broad adoption of this technique.

High speed rotational atherectomy (HSRA).   High speed rotational atherectomy results in the efficient removal of NI, and, if followed by PTCA, these acute outcomes can be improved additionally by further stent expansion and tissue extrusion. Initial registry data suggest this technique is feasible and safe, resulting in restenosis rates of 28% at 13-month follow-up (63). However, results of two subsequent randomized trials have provided conflicting data. The first of these, the Randomized Trial of Rotational Atherectomy Versus Balloon Angioplasty for In-Stent Restenosis (ROSTER), was a single center trial comparing 75 patients undergoing PTCA with 75 patients undergoing HSRA and found clinical restenosis rates of 20% versus 43% (p = 0.01), respectively (64). These findings were supported by registry data suggesting improved one-year outcomes for HSRA compared with PTCA (65) and satisfactory outcomes in patients with proximal left anterior descending lesions treated with HSRA with adjunctive intravascular ultrasound (66). However, the Angioplasty Versus Rotational Atherectomy for Treatment of In-Stent Restenosis Trial (ARTIST) demonstrated the opposite effect. For patients with diffuse ISR (10 mm to 50 mm length), 146 patients undergoing PTCA had an angiographic restenosis rate of 51.2% compared with 152 patients undergoing HRSA with a restenosis rate of 64.8% (p = 0.04) (67).

Other devices.   Given the lack of a clear benefit for any of the above techniques, a number of other devices have been tested in the treatment of ISR. These include laser angioplasty, helical atherectomy and the cutting balloon (67–70). The cutting balloon used for treatment of ISR has been associated with improved clinical and angiographic variables at follow-up in a matched comparison with HSRA, PTCA and stenting and is currently widely used in a number of centers (70). Additional stenting within the region of ISR has also been proposed. This is a straightforward technique generally giving an improved angiographic result compared with PTCA alone (71). However, additional stenting may result in greater procedural creatine kinase-MB release (72), and the longer-term results are similar to angioplasty alone (73,74).

Radiation treatment for ISR.   Radiation therapy (or brachytherapy from the Greek "brakhus" meaning short, referring to the short distance between the intravascular radiation source and target cells) (75,76) is a recently proposed therapy for ISR, currently the subject of a number of clinical trials and debate (77,78). Intravascular radiation is thought to disrupt cellular deoxyribonucleic acid (DNA) and actively dividing intimal and medial cells (79). This mechanism is analogous to radiation therapies used in conditions of neoplastic and non-neoplastic proliferative diseases (80). Since a large number of the SMCs contained in ISR lesions are proliferating, as assessed by immunohistochemistry for proliferating cell nuclear antigen and other markers of proliferation (16), this approach has been enthusiastically explored.

Radiation therapy has been tested from two main sources: {gamma} and ß (Table 1) (81). To date, the principal {gamma} source tested has been a locally delivered 132Iridium (Ir) wire (6,82,83); ß sources include a 32Phosphorus (P) wire (84) and a 32P-ß-emitting stent (85). ß-radiation derives from particulate energy in the form of electrons and, therefore, has limited penetration, with most therapeutic benefit gained within 2 mm to 3 mm of the source. In contrast, {gamma}-radiation is in the form of photons, penetrates well beyond the vessel wall and is not thought to be completely shielded by standard lead aprons and shields used in catheterization laboratories, although the amount of extra shielding required depends on the total {gamma}-radiation dose and is currently the matter of some debate (76,78,86).


View this table:
[in this window]
[in a new window]
  		Table 1 Radiation Treatment for ISR: Clinical Trials

 
Most clinical experience has been with the {gamma} source using a 132Ir wire or ribbon (6,82,83). The GAMMA-I trial and {gamma}-Washington Radiation for In-Stent Restenosis (WRIST) trials randomized 252 and 130 patients with ISR, respectively, to receive percutaneous coronary intervention with either 132Ir wire or placebo (6,82). The Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial randomized 26 patients to 132Ir wire and 29 patients to placebo after stenting for restenosis following coronary intervention, 62% of which was ISR (83). In all three studies, there were significantly reduced rates of angiographic ISR at six months (21.6% vs. 50.5%; 29.2% vs. 67.7%; 17% vs. 54%, respectively, all p = ≤ 0.01). Subsequent trials in selected subgroups have demonstrated similar effects (Table 1). The benefit beyond six months, however, appears less robust. At three-year follow-up of patients in the SCRIPPS trial, a reduction in ISR for the treatment group was still evident (33.3% vs. 63.6%, p < 0.05), though the magnitude was less at three years than it was at six months (48% vs. 69%). There was a continuing loss of lumenal diameter confined to the treatment group out to three years, raising the possibility that {gamma}-radiation may simply delay ISR rather than reduce it (87).

To date, there is more limited experience using ß-radiation, though there are a number of trials ongoing at the time of writing (81,88). ß sources include strontium90 (Sr-90), 90Yttrium (89) and a 32P source wire (84). In the Stents And Radiation Therapy (START) trial, 485 patients with ISR <20 mm in length were treated with angioplasty and irradiation with Sr-90/Y or placebo (81). Angiographic restenosis at eight months was improved with radiation (29% vs. 45%, p = 0.001), and there was no stent thrombosis in the treatment group (81). 90Yttrium has been used in a dose-finding study in 181 patients after PTCA of de novo lesions, with stenting performed in 28%. There was a significant, dose-dependent decrease in restenosis rates up to the maximum used dose of 18 Gy, without an increase in late complications (89). This source has yet to be used for the treatment of ISR. In the Proliferation Reduction with Vascular Energy Trial (PREVENT), a 32P source wire on a centering catheter was used in three doses of 16 Gy, 20 Gy and 24 Gy compared with control in a heterogenous group of 105 patients with ISR (25), post-PTCA restenosis (7) or de novo lesions (73) treated with either stenting (61%) or PTCA (39%). In this diverse patient group, restenosis rates were reduced (8% vs. 39%, p = 0.012) with similar effects across the radiation doses (84). A 32P-ß-emitting stent implanted for 91% to 93% de novo lesions at a number of doses reduces intrastent ISR at six months but is associated with high rates of stent-edge restenosis—the so-called "candy wrapper" effect (85). Recent data in 22 patients examining the effects at one year demonstrate ongoing intrastent luminal loss, suggesting 32P-ß-emitting stents may also be simply delaying but not preventing ISR (90).

Problems with radiation therapy.   Despite recent Food and Drug Administration approval for two intracoronary radiation delivery devices, there remain a number of concerns (78,91). The optimal dosage for either {gamma}- or ß-based radiation therapy is not known (92). Doses given in clinical trials have largely been based on pig studies of stenting or angioplasty alone, which have suggested that a mean dose of 12 Gy to 18 Gy at a depth of 2 mm is optimal (77). This issue is important, since these studies in pigs have suggested that a dose of <10 Gy may even be stimulatory (93), and prior clinical experience indicates that doses >50 Gy for Hodgkin’s disease may be associated with late coronary aneurysm formation or further coronary disease (94). Practical considerations such as local anatomy and difficulty centering delivery devices often mean dosing is variable along the course of a vessel (77,92,95)—concerns recently born out by clinical trial evidence showing that {gamma}-radiation may be less effective in treating long lesions (96). Similar practical considerations include "geographic miss," a term adopted from radio-oncology to describe the development of a new stenosis at the edge of an irradiated area. This is reported to be due to the combination of injury and low-dose radiation and includes the "candy wrapper" effect observed in relation to 32P-ß-emitting stents (97,98).

Another alternative method of delivery is a liquid 188Refilled balloon, which avoids centering difficulties but carries its own risks (99). Late stent thrombosis has also been reported in a number of radiation trials, of concern because of the frequency (6% to 7%) and the timing (>3 months) (77). The Beta-Cath trial documented a stent thrombosis rate of 6.6% (100); the {gamma}-WRIST trial reported rates of 7% (82). Neither trial gave prolonged antiplatelet therapy, and subsequent approaches of six months and one year antiplatelet treatment may reduce rates of stent thrombosis (101,102), although it is notable that in the WRIST PLUS trial a relatively high rate of 2.5% late stent thrombosis was still observed with a six month course of clopidogrel and aspirin (103). There is some evidence that this risk is reduced if further stenting is not performed after irradiation (100,104). Other findings within six months of coronary radiation therapy include coronary aneurysms (105,106) and acellular, necrotic areas of tissue—so-called "black holes." These "black holes" are significant, at least in part, because they contain proteoglycan and other prothrombotic material (Serruys PW, unpublished data, 2001) (107). Thus, coronary radiation for ISR appears to show promising early benefit. The long-term benefits and associated risks, however, remain unclear (78).


   Strategies for prevention of ISR
Top
 Abstract
 Animal models of ISR
 Treatments for ISR
 Strategies for prevention of...
Conclusions
 References
 
Stents.   There has been great interest in the nature of stents themselves and the means used to implant them as stimuli for ISR (108,109). Stent design, composition, length, as well as stent guidance strategies, such as intravascular ultrasound and measures of coronary flow have received considerable attention and are fully discussed elsewhere (51,110). More recently, there has been great interest in the possibility that stents may be coated with slowly eluting antirestenotic agents (111). Polymer-coated stents initially provoked excessive reactions (112), but subsequent coatings using phosphorylcholine-based polymers have not had this effect and may prove a useful drug delivery platform (113). A number of diverse agents have been shown to elute slowly from polymer coatings and are associated with reduced NI formation in animal models (Table 2A). Two agents in particular have undergone pilot studies in humans (114,115). The first, sirolimus, is a naturally occurring compound derived from the streptomyces fungus and stimulates p27kip1 levels causing cyclin-Cdk complex inhibition and cell cycle arrest (116). In two groups of 15 patients treated with a sirolimus-coated stent (140 µg/cm2), either as a fast (15 day) or slow (>28 day) release formulation, negligible NI regrowth was observed at four months (114). The recently reported Rapamycin-Eluting Versus Plain Polymer Stents (RAVEL) trial randomized 238 patients to a sirolimus-coated stent or conventional stent for de novo coronary lesions and found a zero restenosis rate in the sirolimus group (vs. 26%, p < 0.0001), clearly a finding of huge implications. Similarly, paclitaxel, a naturally occurring compound from the Pacific yew tree with potent antiproliferative effects, thought to be due to an alteration in microtubular function, has shown promising early results in 14 patients stented with a paclitaxel derivative impregnated sleeve incorporated into a stent design (117). Both agents have now proceeded to clinical trials (Table 2B) (115,117,118). Clearly there remain questions as to the most suitable agent, toxicity and how multiple or overlapping drug-eluting stents can be used safely (119). There has also been the observation that stent-based drug delivery results in marked spatial variations in delivered drug dose (120) and reports of late stent thrombosis associated the paclitaxel stents, although it is unclear whether this is due to the drug or the polymer sleeve (121).


View this table:
[in this window]
[in a new window]
  		Table 2 Stent-Based Local Drug Delivery for ISR

 
Conventional drugs.   A large number of conventional, systemically delivered drugs have reduced NI formation in a variety of animal models, but, with the exceptions of probucol, these have not translated to reduced restenosis after PTCA in the human (37,122,123). However, as previously discussed, ISR is comprised principally of NI formation, whereas restenosis after PTCA is multifactorial (12). Therefore, drugs inhibiting SMC proliferation and migration might be useful more specifically in reducing rates of ISR. One such agent is troglitazone, which appeared to reduce NI formation in a small series of 52 patients (124). Another agent is tranilast, which has multiple effects, including inhibition of SMC proliferation and migration (125), reduces ISR in the porcine coronary model (126) but appears to show no benefit in recently completed large Phase III Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial (127).

Nucleic acid-based drugs.   Nucleic acid-based drugs provide novel therapeutic options for the treatment of restenosis as well as other conditions (128). The broad principal behind nucleic acid-based drugs is to specifically target and inhibit a regulatory gene that plays an important role in a pathogenic process, classically by creating a molecule of ribonucleic acid (RNA) or DNA that undergoes complementary base pairing with its endogenous target (129). Nucleic-acid based drugs can broadly be divided into three main types: antisense (AS), ribozymes (RZs) and DNAzymes (DZs). Antisense molecules are single-stranded DNA molecules that form an RNA-DNA duplex with target messenger RNA (130). Antisense oligodeoxynucleotides targeting the proto-oncogenes c-myb and c-myc inhibit NI formation in rat and pig models of injury (131–133), including stenting (134). However, to date, the only reported use of AS to prevent ISR in humans using a locally delivered AS molecule targeting c-myc showed no benefit (135). Ribozymes are RNA-based molecules with the advantage of the ability to cleave their target messenger RNA in an enzymatic fashion (136,137). An RZ targeting c-myb inhibits SMC proliferation and NI formation after balloon injury to the rat carotid artery (138). Similarly, RZs targeting transforming growth factor-ß1 also inhibit NI formation in the rat model (139). A chimeric DNA/RNA hammerhead RZ targeting proliferating cell nuclear antigen reduces NI formation by 28% in the pig coronary stent model (140).

A further refinement to nucleic acid gene targeting strategies has been the development of DZs. These are single-stranded DNA molecules with catalytic domains capable of RNA cleavage at high efficiencies, with added stability conferred by their DNA structure and base modifications (141,142). Locally delivered DZs targeting the zinc finger transcription factor Egr-1 inhibit NI formation in the rat carotid injury model by more than 50%, the first such demonstration of the use of DZs in vivo (143). More recently, DZs targeting the human version of Egr-1 have been shown to inhibit ISR in the porcine coronary stent model (144).

Recently, the expression profile of a large number of known genes was identified in human in-stent restenotic tissue at the time of revascularization (145). One gene upregulated was FK506 binding protein 12, the receptor for sirolimus, an intriguing finding given the low rates of ISR recently reported using sirolimus-coated stents (114,146). A number of other genes were also identified, raising the possibility that key mediators of NI formation upregulated in ISR could systematically be targeted with gene-specific strategies such as nucleic acid-based methodologies.

Gene transfer.   Gene transfer is defined as the direct introduction of a desirable gene into a local environment, with the aim of increasing the function of that gene to gain pathophysiologic benefit (147). As such, gene transfer has been viewed as having the potential to be more specifically targeted and more suited to local therapy than conventional drug treatment. The first description of direct gene transfer into the vasculature was over a decade ago (148) and has since been described in a number of cardiovascular contexts including atherosclerosis, angiogenesis and ischemia (149–151). Restenosis or ISR, in many ways, has been seen as an ideal pathogenic process to be treated by gene transfer in that the onset of the restenotic process is largely known and the site of restenosis is localized and readily accessible (152,153).

A large number of gene products have been investigated as potential targets for gene transfer and tested in both animals and in preliminary studies in humans (Table 3).
Human Studies
Gene Target
Lac Z
VEGF


These genes have been selected to attempt modification of a number of processes focusing on SMC proliferation but including cell migration, thrombosis and endothelial function (151,153). Studies have shown a generally consistent effect in the order of 30% to 70% inhibition of NI formation and, significantly, a number of these approaches have entered phase I human trials. Early reports suggest this approach is well tolerated (154).


View this table:
[in this window]
[in a new window]
  		Table 3 Gene Transfer Therapies for Restenosis

 
Most studies have used adenovirus vectors to achieve gene transfection, although plasmid DNA, either naked or with a carrier (usually lipid) molecule, has also been employed (153). Other alternatives are retroviruses and adeno-associated viruses (153). Adenoviruses have the advantage as vectors in that they can produce large amounts of highly purifed recombinant virus (155). However, there have been recent concerns that adenoviruses may induce inflammation, particularly when introduced via the intraluminal route (156,157) and may promote thrombus formation (158). These concerns have not yet been reported using naked plasmid DNA. As to the question of how to achieve local delivery, catheter-based delivery devices for vascular gene transfer have been investigated for restenosis, all with important limitations (159–161). More recently, a high transfection efficiency has been achieved with a DNA-eluting polylactic-polyglycolic acid-coated stent in porcine arteries (53), suggesting that local gene transfer may be possible using a coated stent.

While studies of gene transfer for restenosis are still at an early stage, the results of preliminary human trials are promising. Moreover, the potential advantages of using local gene delivery to treat a local iatrogenic process are significant and likely to see continued research effort (152).

Other treatments.   There is the recent suggestion that novel physical therapies may be useful in the treatment of ISR: two examples being high-frequency ultrasound and low-power red laser light (162,163). Ultrasound can inhibit vascular SMC migration and proliferation, and intravascular ultrasound at 700 kHz delivered to porcine coronary arteries for 5 min after stenting reduces cell proliferation at seven days, and NI thickness at 28 days (162). Low-power red laser light enhances endothelial cell growth in vitro and in vivo, and preliminary studies suggest that it is associated with low rates of ISR (163).


   Conclusions
Top
 Abstract
 Animal models of ISR
 Treatments for ISR
 Strategies for prevention of...
 Conclusions
References
 
In-stent restenosis is an emerging pathobiologic process, histologically comprised largely of NI formation with, until recently, limited treatment options available for both treatment and prevention. Recent advances in gene modification and gene transfer therapies and, more particularly, in local stent-based drug delivery systems make it conceivable that the incidence of ISR—currently the Achilles’ heel of interventional cardiology—will now be seriously challenged.


   Footnotes
 
Associate Professor Khachigian is supported by project grants from the NHMRC, National Heart Foundation and NSW State Government, Australia. Dr. Lowe is a CI Martin Fellow of the NHMRC, Australia.


   References
Top
 Abstract
 Animal models of ISR
 Treatments for ISR
 Strategies for prevention of...
 Conclusions
 References
 

  1. Schwartz RS. Animal models of human coronary restenosis. Topol EJ. Textbook of Interventional Cardiology. 2nd ed. Philadelphia, PA: W.B. Saunders; 1994. p. 365–381
  2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease: stent restenosis study investigators. N Engl J Med. 1994;331:496–501[Abstract/Free Full Text]
  3. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable stent implantation with balloon angioplasty in patients with coronary artery disease: Benestent study group. N Engl J Med. 1994;331:489–489[Abstract/Free Full Text]
  4. Lane DM. Dramatic increase in the use of coronary stents. Am J Cardiol. 1999;84:1141[Medline]
  5. Faxon DP, Williams DO, Yeh W, Mehra A, Houbokov R, Detre K. Improved in-hospital outcome with expanded use of coronary stents: results from the NHLBI dynamic registry. J Am Coll Cardiol. 1999;33(Suppl A):91A
  6. Leon MB, Teirstein PS, Moses JW, et al. Localized intracoronary gamma-radiation therapy to inhibit the recurrence of restenosis after stenting. N Engl J Med. 2001;344:250–256[Abstract/Free Full Text]
  7. Al Suwaidi J, Berger P, Holmes DR. Coronary artery stents. JAMA. 2000;284:1828–1836[Abstract/Free Full Text]
  8. Till FV, Aliabadi D, Kinn JW, Kaplan BM, Benzuly KH, Safian RD. Real life stenting: a comparison of target vessel revascularization in Benestent-stress lesions to non-Benestent-stress lesions (abstr). Circulation. 1996;94:I332
  9. Goldberg SL, Loussararian A, De Gregorio J, Di Mario C, Albiero R, Colombo A. Predictors of diffuse and aggressive intrastent restenosis. J Am Coll Cardiol. 2001;37:1019–1025[Abstract/Free Full Text]
  10. Mehran R, Dangas G, Abizaid A, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100:1872–1878[Abstract/Free Full Text]
  11. Moreno PR, Palacios IF, Leon MN, Rhodes J, Fuster V, Fallon JT. Histopathologic comparison of human coronary in-stent and post-balloon angioplasty restenotic tissue. Am J Cardiol. 1999;84:462–466[CrossRef][Medline]
  12. Mach F. Toward new therapeutic strategies against neointimal formation in restenosis. Atheroscler Thromb Vasc Biol. 2000;20:1699–1700[Free Full Text]
  13. Mintz GS, Popma JJ, Pichard AD, et al. Arterial remodelling after coronary angioplasty: a serial intravascular ultrasound study. Circulation. 1996;94:35–43[Abstract/Free Full Text]
  14. Mudra H, Regar E, Klauss V, et al. Serial follow-up after optimized ultrasound guided deployment of Palmaz-Schatz stents. Circulation. 1997;95:363–370[Abstract/Free Full Text]
  15. Hoffman R, Mintz GS, Dussaillant RG, et al. Patterns and mechanisms of in-stent restenosis: a serial intravascular ultrasound study. Circulation. 1996;94:1247–1254[Abstract/Free Full Text]
  16. Kearney M, Pieczek A, Haley L, et al. Histopathology of in-stent restenosis in patients with peripheral artery disease. Circulation. 1997;95:1998–2002[Abstract/Free Full Text]
  17. Grewe PH, Deneke T, Machraoui A, Barmeyer J, Muller K-M. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol. 1999;35:157–163
  18. Virmani R, Farb A. Pathology of in-stent restenosis. Curr Opin Lipidol. 1999;10:499–506[CrossRef][Medline]
  19. Carter AJ, Laird JR, Farb A, Kufs W, Wortham DC, Virmani R. Morphological characteristics of lesion formation and time course of smooth muscle cell proliferation in a porcine proliferative restenosis model. J Am Coll Cardiol. 1994;139:1398–1405
  20. Carter AJ, Bailey L, Devries J, Hubbard B. The effects of uncontrolled hyperglycemia on thrombosis and formation of neointima after coronary stent placement in a novel diabetic porcine model of restenosis. Coron Artery Dis. 2000;11:473–479[CrossRef][Medline]
  21. Lowe HC, Chesterman CN, Khachigian LM. Does thrombus contribute to in-stent restenosis in the porcine coronary stent model? Thromb Haemost. 2001;85:1117–1118[Medline]
  22. Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999;99:44–52[Abstract/Free Full Text]
  23. Abizaid A, Kornowski R, Mintz GS, et al. The influence of diabetes mellitus on acute and late outcomes following coronary stent implantation. J Am Coll Cardiol. 1998;32:584–589[Abstract/Free Full Text]
  24. Mittal S, Weiss DL, Hirshfeld JWJ, Kolansky DM, Herrmann HC. Comparison of outcome after stenting for de novo versus restenotic narrowings in native coronary arteries. Am J Cardiol. 1997;80:711–715[CrossRef][Medline]
  25. Kosokabe T, Okumura K, Sone T, et al. Relation of a common methylenetetrahydrofolate reductase mutation and plasma homocysteine with intimal hyperplasia after coronary stenting. Circulation. 2001;103:2048–2054[Abstract/Free Full Text]
  26. Kastrati A, Schoming A, Seyfarth M, et al. PIA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation. 1999;99:1005–1010[Abstract/Free Full Text]
  27. Kastrati A, Koch W, Berger PB, et al. Protective role against restenosis from an interleukin-receptor antagonist gene polymorphism in patients treated with coronary stenting. J Am Coll Cardiol. 2000;36:2168–2173[Abstract/Free Full Text]
  28. Kastrati A, Dirschinger J, Schomig A. Genetic risk factors and restenosis after percutaneous coronary interventions. Herz. 2000;25:34–46[Medline]
  29. Koster R, Vieluf D, Kiehn M, et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet. 2000;356:1895–1897[CrossRef][Medline]
  30. Dangas G, Mehran R, Lansky AJ, et al. Acute and long-term results of treatment of diffuse in-stent restenosis in aortocoronary saphenous vein grafts. Am J Cardiol. 2000;86:777–779[CrossRef][Medline]
  31. Kobayashi Y, De Gregorio J, Kobayashi N, et al. Stented segment length as an independent predictor of restenosis. J Am Coll Cardiol. 1999;34:651–659[Abstract/Free Full Text]
  32. Elezi S, Kastrati A, Neumann FJ, Hadamitzky M, Dirshinger J, Schomig A. Vessel size and long-term outcome after coronary stent placement. Circulation. 1998;98:1875–1880[Abstract/Free Full Text]
  33. Kastrati A, Schomig A, Elezi S, et al. Predictive factors of restenosis after coronary stent placement. J Am Coll Cardiol. 1997;30:1428–1436[Abstract]
  34. Sirnes PA, Golf S, Myreng Y, et al. Stenting In Chronic Coronary Occlusion (SICCO): a randomised, controlled trial of adding stent implantation after successful angioplasty. J Am Coll Cardiol. 1996;28:1444–1451[Abstract]
  35. Heidland UE, Heintzen MP, Michel CJ, Strauer BE. Risk factors for the development of restenosis following stent implantation of venous bypass grafts. Heart. 2001;85:312–317[Abstract/Free Full Text]
  36. Fitzgerald PJ, Oshima A, Hayase M, et al. Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study. Circulation. 2000;201:523–530
  37. Johnson GJ, Griggs TR, Badimon L. The utility of animal models in the preclinical study of interventions to prevent human coronary artery restenosis: on behalf of the Subcommittee on Animal, Cellular and Molecular Models of Thrombosis and Haemostasis of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 1999;81:835–843[Medline]
  38. Schwartz RS, Huber KC, Murphy JG, et al. Restenosis and the proportional neointimal response to coronary artery injury: results in a porcine model. J Am Coll Cardiol. 1992;19:267–274[Abstract]
  39. Muller DW, Golomb G, Gordon D, Levy RJ. Site-specific dexamethasone delivery for the prevention of neointimal thickening after vascular stent placement. Coron Artery Dis. 1994;5:435–442[Medline]
  40. Verheye S, Salame MY, Robinson KA, et al. Short- and long-term histopathologic evaluation of stenting using a self-expanding nitinol stent in pig carotid and iliac arteries. Cathet Cardiovasc Diagn. 1999;48:316–323
  41. Indolfi C, Esposito G, Stabile E, et al. A new rat model of small vessel stenting. Basic Res Cardiol. 2000;95:179–185[CrossRef][Medline]
  42. Robinson KA, Roubin GS, Siegel RJ, Black AJ, Apkarian RPKing SB III. Intra-arterial stenting in the atherosclerotic rabbit. Circulation. 1988;78:646–653[Abstract/Free Full Text]
  43. Krupski WC, Bass A, Kelly AB, Hanson SR, Harker LA. Reduction in thrombus formation by placement of endovascular stents at endarterectomy sites in baboon carotid arteries. Circulation. 1991;84:1749–1757[Abstract/Free Full Text]
  44. Muller DWM, Ellis SG, Topol EJ. Experimental models of coronary artery restenosis. J Am Coll Cardiol. 1992;19:418–432[Abstract]
  45. Vesselinovich D. Animal models and the study of atherosclerosis. Arch Pathol Lab Med. 1988;112:1011–1017[Medline]
  46. Geary RL, Adams MR, Benjamin ME, Williams JK. Conjugated equine estrogens inhibit progression of atherosclerosis but have no effect on intimal hyperplasia or arterial remodelling induced by balloon catheter injury in monkeys. J Am Coll Cardiol. 1998;31:1158–1164[Abstract/Free Full Text]
  47. Geary RL, Williams JK, Golden D, Brown DG, Benjamin ME, Adams MR. Time course of cellular proliferation, intimal hyperplasia, and remodelling following angioplasty in monkeys with established atherosclerosis: a nonhuman primate model of restenosis. Atheroscler Thromb Vasc Biol. 1996;16:34–43[Abstract/Free Full Text]
  48. Schwartz RS, Murphy JG, Edwards WD, Camrud AR, Vlietstra RE, Holmes DRJ. Restenosis after balloon angioplasty: a practical proliferative model in porcine coronary arteries. Circulation. 1990;82:2190–2200[Abstract/Free Full Text]
  49. Rodgers GP, Minor ST, Robinson K, et al. Adjuvant therapy for intracoronary stents: investigations in atherosclerotic swine. Circulation. 1990;82:560–569[Abstract/Free Full Text]
  50. Kornowski R, Hong MK, Fermin OT, Bramwell O, Wu H, Leon MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointima hyperplasia. J Am Coll Cardiol. 1998;31:224–230[Abstract/Free Full Text]
  51. Hoffman R, Mintz GS. Coronary in-stent restenosis—predictors, treatment and prevention. Eur Heart J. 2000;21:1739–1749[Free Full Text]
  52. Alt E, Haehnel I, Beilharz C, et al. Inhibition of neointima formation after experimental coronary stenting. Circulation. 2000;101:1453–1458[Abstract/Free Full Text]
  53. Klugherz BD, Jones PL, Cui X, et al. Gene delivery from a DNA controlled-release stent in porcine coronary arteries. Nature Biotech. 2000;18:1181–1184[CrossRef][Medline]
  54. Waksman R, Bhargava B, Saucedo JF, et al. Yttrium-90 delivered via a centering catheter and afterloader, given both before and after stent implantation, inhibits neointima formation in porcine coronary arteries. Cardiovasc Radiat Med. 2000;2:11–17[CrossRef][Medline]
  55. Mehran R, Mintz GS, Popma J, et al. Mechanisms and results of balloon angioplasty for the treatment of in-stent restenosis. Am J Cardiol. 1996;78:618–622[CrossRef][Medline]
  56. Shirian A, Mintz GS, Waksman R, et al. Early lumen loss after treatment of in-stent restenosis. Circulation. 1998;98:200–203[Abstract/Free Full Text]
  57. Hoffman R, Mintz GS, Mehran R, et al. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz-Schatz stents. J Am Coll Cardiol. 1998;31:43–49[Abstract/Free Full Text]
  58. Moussa I, Moses J, Di Mario C, et al. Stenting after Optimal Lesion Debulking (SOLD) registry. Circulation. 1998;98:1604–1609[Abstract/Free Full Text]
  59. Strauss B, Umans V, Van Suylen RJ, et al. Directional atherectomy for treatment of restenosis within coronary stents: clinical, angiographic and histologic results. J Am Coll Cardiol. 1992;20:1465–1473[Abstract]
  60. Mahdi NA, Pathan AZ, Harrell L, et al. Directional coronary atherectomy for the treatment of in-stent restenosis. Am J Cardiol. 1998;82:1345–1351[CrossRef][Medline]
  61. Harrington RA, Lincoff AM, Califf RM, et al. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol. 1995;25:1693–1699[Abstract]
  62. Meyer T, Schmidt T, Buchwald A, Wiegand V. Stent wire cutting during coronary directional atherectomy. Clin Cardiol. 1993;16:450–452[Medline]
  63. Sharma SK, Duvvuri S, Dangas G, et al. Rotational atherectomy for in-stent restenosis: acute and long-term results of the first 100 cases. J Am Coll Cardiol. 1998;32:1358–1365[Abstract/Free Full Text]
  64. Sharma SK, Kini A, King T, Dangas G, Cocke TP. Randomised Trial of Rotational Atherectomy versus Balloon Angioplasty for In-Stent Restenosis (ROSTER): interim analysis of 150 cases (abstr). Eur Heart J. 1999;20:281A
  65. Goldberg SL, Berger P, Cohen DJ, et al. Rotational atherectomy or balloon angioplasty in the treatment of intra-stent restenosis: BARASTER multicenter registry. Cathet Cardiovasc Intervent. 2000;51:407–413[CrossRef][Medline]
  66. Moreno PR, Garcia E, Soriano J, Acosta J, Abeytua M. Long-term outcome of patients with proximal left anterior descending coronary artery in-stent restenosis treated with rotational atherectomy. Cathet Cardiovasc Intervent. 2001;52:435–442[CrossRef][Medline]
  67. vom Dahl J, Silber S, Buettner HJ, et al. Rotational atherectomy versus balloon angioplasty for diffuse in-stent restenosis: preliminary results of a randomised multicentre trial (ARTIST trial). Am J Cardiol. 1999;84(Suppl 6A):237A[CrossRef]
  68. Giri S, Ito S, Lansky AJ, et al. Clinical and angiographic outcome in the Laser Angioplasty for Restenotic Stents (LARS) multicenter registry. Cathet Cardiovasc Diagn. 2001;52:24–34
  69. Albiero R, Nishida T, Karvouni E, et al. Cutting balloon angioplasty for the treatment of in-stent restenosis. Cathet Cardiovasc Diagn. 2000;50:452–459
  70. Adamian M, Colombo A, Briguori C, et al. Cutting balloon angioplasty for the treatment of in-stent restenosis: a matched comparison with rotational atherectomy, additional stent implantation and balloon angioplasty. J Am Coll Cardiol. 2001;38:672–679[Abstract/Free Full Text]
  71. Alfonso F, Gomez-Recio M, Cequier A, et al. Final angiographic results of the restenosis intra-stent: balloon angioplasty versus elective stenting (RIBS) randomised study. Eur Heart J. 2001;22:1264A
  72. Mehran R, Dangas G, Abizaid A, et al. Treatment of focal in-stent restenosis with balloon angioplasty alone versus stenting: short- and long-term results. Am Heart J. 2001;141:610–614[CrossRef][Medline]
  73. Di Mario C, Marsico F, Adamian M, Karvouni E, Albiero R, Colombo A. New recipes for in-stent restenosis: cut, grate, roast, or sandwich the neointima? Heart. 2000;84:471–475[Free Full Text]
  74. Alfonso F, Cequier A, Zueco J, et al. Stenting the stent: initial results and long-term clinical and angiographic outcome of coronary stenting for patients with in-stent restenosis. Am J Cardiol. 2000;85:327–332[CrossRef][Medline]
  75. Anonymous. The New Oxford Dictionary of English. 1st ed. Oxford: Clarendon Press; 1998.
  76. Waksman R, Serruys PW. Handbook of Vascular Brachytherapy. 1st ed. London: Martin Dunitz Ltd; 1998.
  77. Kuntz RE, Baim DS. Prevention of coronary restenosis: the evolving evidence base for radiation therapy. Circulation. 2000;101:2130–3133[Free Full Text]
  78. Sheppard R, Eisenberg MJ. Intracoronary radiotherapy for restenosis. N Engl J Med. 2001;344:295–297[Free Full Text]
  79. Munro TR. The relative radiosensitivity of the nucleus and cytoplasm of Chinese hamster fibroblasts. Radiat Res. 1970;42:451–470[Medline]
  80. Escarmant P, Zimmermann S, Amar A, et al. The treatment of 783 keloid scars by iridium 192 interstitial irradiation after surgical excision. Int J Radiat Oncol Biol Phys. 1993;26:245–251[Medline]
  81. Ajani A, Kim H-S, Waksman R. Clinical trials of vascular brachytherapy for in-stent restenosis: update. Cardiovasc Radiat Med. 2001;2:107–113[CrossRef][Medline]
  82. Waksman R, White RL, Chan RC, et al. Intracoronary gamma-radiation therapy after angioplasty inhibits recurrence of in-patients with in-stent restenosis. Circulation. 2000;101:2165–2171[Abstract/Free Full Text]
  83. Teirstein PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit restenosis after coronary stenting. N Engl J Med. 1997;336:1697–1703[Abstract/Free Full Text]
  84. Raizner AE, Oesterle SN, Waksman R, et al. Inhibition of restenosis with beta-emitting radiotherapy: report of the Proliferation Reduction with Vascular Energy Trial (PREVENT). Circulation. 2000;102:951–958[Abstract/Free Full Text]
  85. Albiero R, Adamian M, Kobayashi N, et al. Short and intermediate term results of 32P radioactive beta-emitting stent implantation in patients with coronary artery disease. Circulation. 2000;101:18–26[Abstract/Free Full Text]
  86. Bohan M, Yue N, Nath R. On the need for massive additional shielding of a catheterization laboratory for the implementation of high dose rate 192 Ir intravascular brachytherapy. Cardiovasc Radiat Med. 2000;2:39–41[CrossRef][Medline]
  87. Teirstein PS, Massullo V, Jani S, et al. Three-year clinical and angiographic follow-up after intracoronary radiation: results of a randomised clinical trial. Circulation. 2000;101:360–365[Abstract/Free Full Text]
  88. Teirstein PS. Beta-radiation to reduce restenosis: Too little, too soon? Circulation. 1997;95:1095–1097[Free Full Text]
  89. Verin V, Popowski Y, de Bruyne B, et al. Endoluminal beta-radiation therapy for the prevention of coronary restenosis after balloon angioplasty. N Engl J Med. 2001;344:243–249[Abstract/Free Full Text]
  90. Kay IP, Wardeh AJ, Kozuma K, et al. Radioactive stents delay but do not prevent in-stent neointimal hyperplasia. Circulation. 2001;103:14–17[Abstract/Free Full Text]
  91. Kuntz RE. Stent plus radiation: no sure cure for stenosis. JAMA. 2001;285:2069[Free Full Text]
  92. Amols HI, Zaider M, Weinberger J, Ennis R, Schiff PB, Reinstein LE. Dosimetric considerations for catheter-based beta and gamma emitters in the therapy of neointimal hyperplasia in human coronary arteries. Int J Radiat Oncol Biol Phys. 1996;36:913–921[CrossRef][Medline]
  93. Weinberger J, Amols H, Ennis RD, Schwartz A, Wiedermann JG, Marboe C. Intracoronary irradiation: dose response for the prevention of restenosis in swine. Int J Radiat Oncol Biol Phys. 1996;36:767–775[CrossRef][Medline]
  94. Annest LS, Anderson RP, Li W, Haferamnn MD. Coronary artery disease following mediastinal radiation therapy. J Thorac Cardiovasc Surg. 1983;85:257–263[Abstract]
  95. Kim HS, Waksman R, Cottin Y, et al. Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis. J Am Coll Cardiol. 2001;37:1026–1030[Abstract/Free Full Text]
  96. Ahmed JM, Mintz GS, Waksman R, et al. Serial intravascular ultrasound analysis of the impact of lesion length on the efficacy of intracoronary gamma irradiation for preventing recurrent in-stent restenosis. Circulation. 2001;103:188–191[Abstract/Free Full Text]
  97. Sabate M, Costa MA, Kozuman K, et al. Geographic miss: a cause of treatment failure in radio-oncology applied to intracoronary radiation therapy. Circulation. 2000;103:E65–66
  98. Serruys PW, Kay IP. I like the candy, I hate the wrapper. Circulation. 2000;101:3–7[Free Full Text]
  99. Hoher M, Worhle J, Wohlfrom M, et al. Intracoronary beta-irradiation with a liquid (188)re-filled balloon: six-month results from a clinical safety and feasibility study. Circulation. 2000;101:2355–2360[Abstract/Free Full Text]
  100. Costa MA, Sabate M, van der Giessen WJ, et al. Late coronary occlusion after intracoronary brachytherapy. Circulation. 1999;100:789–792[Abstract/Free Full Text]
  101. Waksman R, Ajani AE, White RL, et al. Prolonged antiplatelet therapy to prevent late thrombosis after intracoronary gamma-radiation in patients with in-stent restenosis: Washington Radiation for In-Stent Restenosis Trial plus 6 months of clopidogrel (WRIST PLUS). Circulation. 2001;103:2332–2335[Abstract/Free Full Text]
  102. Silber S, Brockhoff C, Dorr R, Mugge A, Krischke I, Mainhertz T. The German IST-registry: need of one year of clopidogrel to avoid late/late stent thrombosis (abstr). J Am Coll Cardiol. 2001;37:82A
  103. Waksman R, Bhargava B, Taafe M, et al. Prolonged antiplatelet therapy to reduce late thrombosis after intracoronary gamma radiation in patients with in-stent restenosis: "plavix-wrist" (abstr). Circulation. 2000;102:II570
  104. Waksman R. Late thrombosis after radiation: sitting on a time bomb. Circulation. 1999;100:780–782[Free Full Text]
  105. Condalo JA, Waksman R, Gurdiel O, et al. Long-term angiographic and clinical outcome after percutaneous transluminal coronary angioplasty and intracoronary radiation therapy in humans. Circulation. 1997;96:727–732[Abstract/Free Full Text]
  106. Vandergoten P, Brosens M, Benit E. Coronary aneurysm five months after intracoronary beta-irradiation. Acta Cardiol. 2000;55:313–315[CrossRef][Medline]
  107. Castagna MT, Mintz GS, Weissman N, Maehara A, Finet G, Waksman R. "Black hole": echolucent restenotic tissue after brachytherapy. Circulation. 2001;5:778
  108. Rogers C, Edelman ER. Endovascular stent design dictates experimental restenosis and thrombosis. Circulation. 1995;9:2995–3001
  109. Kastrati A, Mehilli J, Dirschinger J, et al. Restenosis after coronary placement of various stent types. Am J Cardiol. 2001;87:34–39[Medline]
  110. Cantor WJ, Peterson ED, Popma JJ, et al. Provisional stenting strategies: systematic overview and implications for clinical decision making. J Am Coll Cardiol. 2001;36:1142–1151
  111. Gunn J, Cumberland D. Stent coatings and local drug delivery: state of the art. Eur Heart J. 1999;20:1693–1700[Free Full Text]
  112. van der Giesen WJ, Lincoff M, Schwartz RS, et al. Marked inflammatory sequelae to implantation of biodegradable and nonbiodegradable polymers in porcine coronary arteries. Circulation. 1996;94:1690–1697[Abstract/Free Full Text]
  113. Hofma SH, van Beusekom HM, Serruys PW, van der Giessen WJ. Recent developments in coated stents. Curr Intervent Cardiol Rep. 2001;3:28–36[Medline]
  114. Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries. Circulation. 2001;103:192–195[Abstract/Free Full Text]
  115. Grube E. Drug eluting stents: a new era in the stent technology. Cardiol Int. 2001;2:5–6
  116. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation. 1999;99:2164–2170[Abstract/Free Full Text]
  117. Honda Y, Grube E, de la Fuente LM, Yock PG, Stertzer SH, Fitzgerald PJ. Novel drug-delivery stent: intravascular ultrasound observations from the first human experience with the QP-eluting polymer stent system. Circulation. 2001;104:380–383[Abstract/Free Full Text]
  118. Colombo A, Liistro F. Antiproliferative approach to restenosis. Rothman MT. Restenosis: Multiple Strategies for Stent Drug Delivery. 1st ed. London: ReMEDICA; 2001.
  119. Drachman DE, Rogers C. Coated stents. Rothman MT. Restenosis: Multiple Strategies for Stent Drug Delivery. 1st ed. London: ReMEDICA; 2001.
  120. Hwang C-W, Wu D, Edelman ER. Stent-based delivery is associated with marked spatial variations in drug distribution. J Am Coll Cardiol. 2001;37:1A[Medline]
  121. Liistro F, Colombo A. Late acute thrombosis after paclitaxel eluting stent implantation. Heart. 2001;86:262–264[Abstract/Free Full Text]
  122. Bult H. Restenosis: a challenge for pharmacology. Trends Pharmacol Sci. 2000;21:274–279[CrossRef][Medline]
  123. Tardiff JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. N Engl J Med. 1997;337:365–372[Abstract/Free Full Text]
  124. Takagi T, Akasaka T, Yamamuro A, et al. Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with noninsulin dependent diabetes mellitus. J Am Coll Cardiol. 2000;36:1529–1535[Abstract/Free Full Text]
  125. Muranaka Y, Yamasaki Y, Nozawa Y, et al. TAS-301, an inhibitor of smooth muscle cell migration and proliferation, inhibits intimal thickening after balloon injury to rat carotid arteries. J Pharmacol Exp Ther. 1998;285:1280–1286[Abstract/Free Ful