Restenosis after coronary angioplasty

Coronary angioplasty is used to treat coronary disease in many patients. Indications for angioplasty have expanded since it was first performed, mainly as a result of improvement in equipment and techniques. One problem with coronary angioplasty is the phenomenon of renarrowing of the treated coronary lesion, a process called restenosis. The events that constitute restenosis appear to be a universal response to the arterial wall injury of angioplasty. They are currently characterized as follows: platelet adhesion and aggregation on the damaged endothelium and within deep splits into the tunica media; release of platelet-derived growth factors; inflammation of the mechanically injured medial zone; transformation of smooth muscle cells of the tunica media after their activation by several of the growth-promoting substances; migration and proliferation of transformed smooth muscle cells, with secretion of copious amounts of extracellular matrix material; and, finally, termination of the growth process with regrowth of endothelium over the injured area. A decade of research work has helped identify clinical correlates of restenosis after coronary angioplasty procedures. This work is hindered by lack of a uniform angiographic definition of restenosis. In addition, much of the information has come from small studies, with incomplete follow-up and retrospective orientation. Nevertheless, some data are available. Patient-related correlates include male gender, unstable angina, diabetes, and continued smoking after angioplasty. Lesion-related correlates include multilesional and multivessel procedures, higher postangioplasty residual stenosis, proximal vessel location, location in the left anterior descending artery, location in a vein graft, long lesions, and total occlusions. The only consistent procedure-related correlate has been incorrect sizing of the angioplasty balloon to the treated artery. For the purposes of individual patient care, clinical correlates are not helpful. No group of variables has been found to be associated with complete freedom from restenosis, and no group is completely predictive of restenosis. All patients undergoing angioplasty procedures require some follow-up through subsequent months and years. Symptom status and the results of noninvasive studies have been investigated for purposes of follow-up. Symptoms are virtually useless by themselves for predicting restenosis or its absence. When symptom status is combined with exercise thallium 201 scintigraphy performed 4 to 6 months after an angioplasty procedure, the two factors are less than ideal but have a negative predictive value of more than 90%. This means that more than 90% of patients who have neither symptoms nor evidence of ischemia by thallium 201 scintigraphy will not have angiographic restenosis.(ABSTRACT TRUNCATED AT 400 WORDS)     

Restenosis, the Achilles' heel of coronary angioplasty

Coronary angioplasty is widely performed for the management of symptomatic coronary artery disease. With improvements in technique, operator experience, and tools, more complex lesions are being treated. Unfortunately, luminal renarrowing continues to limit the long-term success of the procedure, resulting in the need for repeat revascularization in approximately 30% of patients within 6 months. As the pathophysiologic process of restenosis is better defined, various pharmacologic and mechanical interventions have been tried to attenuate the process. Some agents are antithrombotics, antiplatelets, angiotensin-converting enzyme inhibitors, lipid-lowering drugs, and calcium channel blockers. Improvement has been noted with the newer glycoprotein IIb- and IIIa-blocking agents, mechanical stents, and radioactive materials. Whether these new compounds will withstand the test of time is unknown.     

Restenosis and remodeling after percutaneous transluminal carotid angioplasty

INTRODUCTION: The characteristics of restenosis and remodeling after carotid percutaneous transluminal angioplasty (PTA) were badly known. OBJECTIVE: To describe these characteristics in our series of carotid PTA. PATIENTS AND METHODS: A total of 78 cases of PTA for symptomatic > 70% atherosclerotic stenosis of the extracranial internal carotid artery, were selected from our series of PTA if follow-up was > 12 months. All of them were followed with extracranial continuous-wave Doppler. RESULTS: Restenosis of any degree was found in 17 cases (21.79%) and always asymptomatic. A restenosis > or = 70% was found in 5 cases (6.4%). Restenosis was mainly found in cases without residual stenosis nor dissection after PTA (p = 0.002). Restenosis was found in 16 cases (94.11%) in the first 6-months, with no progression thereafter. Remodeling of residual stenosis was frequent (17 cases; 53.11%) and found mainly during the first month after PTA. Its incidence was highest in patients with dissection treated with heparin. In cases with restenosis, remodeling was infrequent, incomplete and occurred after 18-24 months. CONCLUSIONS: 1. Significant restenosis after PTA due to myointimal proliferation, was infrequent. All cases were asymptomatic, under antiplatelet treatment. A new interventional procedure might not be necessary. 2. Complete remodeling was frequently found after 1-month control, mainly in arteries with some residual stenosis and dissection after PTA.     

Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial

OBJECTIVES: The Probucol Angioplasty Restenosis Trial was a prospective, randomized, controlled study that investigated the effectiveness of probucol therapy in reducing the rate of restenosis after percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Antioxidants have an inhibitory effect on smooth muscle cell growth in experiments in vitro and in vivo, which suggests a possible pharmacologic effect on restenosis after PTCA. METHODS: One hundred one patients were randomly assigned to receive 1,000 mg/day of probucol or control (no lipid-lowering) therapy 4 weeks before PTCA. After 4 weeks of premedication, both groups underwent PTCA. Probucol was continued until follow-up angiography 24 weeks after PTCA. Angiographic results were analyzed at a core laboratory by quantitative coronary angiography. RESULTS: Dilation was successful in 46 of 50 patients in the probucol group and 45 of 51 in the control group. At follow-up angiography 24 weeks after angioplasty, angiographic restenosis occurred in 9 (23%) of 40 patients in the probucol group and 22 (58%) of 38 in the control group (p = 0.001). Minimal lumen diameter was 1.49 +/- 0.75 mm (mean +/- SD) in the probucol group and 1.13 +/- 0.65 mm in the control group (p = 0.02). Percent diameter stenosis at follow-up angiography in the probucol group was significantly lower than that in the control group (43.9% vs. 56.4%, p = 0.009). The late loss was 0.37 +/- 0.69 mm in the probucol group and 0.60 +/- 0.62 mm in the control group (p = 0.13). The loss/gain ratio was 0.32 +/- 0.74 in the probucol group and 0.56 +/- 0.81 in the control group (p = 0.059). Net gain was greater in the probucol group than in the control group (0.77 +/- 0.70 vs. 0.48 +/- 0.59 mm, p = 0.053). CONCLUSIONS: Probucol administered beginning 4 weeks before PTCA appears to reduce restenosis rates.     

Restenosis rate after intravascular ultrasound-guided coronary stent implantation

This study was designed to test the hypothesis that patients fulfilling intravascular ultrasound (IVUS) criteria for optimal coronary stent implantation show a reduction in the restenosis rate at 6 months. IVUS guidance for stent dilation may be associated with facilitated stent implantation and an increased acute luminal gain, but it has not yet been determined, whether and to what extent this procedure is associated with a reduction in the restenosis rate. IVUS-guided optimization of Palmaz-Schatz stent placement was performed in 125 consecutive patients, 64 of whom fulfilled IVUS-criteria for optimal stent placement. Another 125 patients served as the non-IVUS control group. In 107 patients (86%) of the non-IVUS control group and 105 patients (84%) of the IVUS group, angiographic follow-up was performed. The IVUS group of patients revealed a significantly lower restenosis rate of 20.9% as compared with 29.9% in the control group (P = 0.033). Patients that met IVUS criteria for optimal stent placement had a larger minimal lumen diameter immediately after stent implantation (3.13 +/- 0.44 vs. 2.95 +/- 0.47 mm; P = 0.045) and at 6-month follow-up (2.23 +/- 0.78 vs. 1.87 +/- 0.76 mm; P = 0.019) as well as a significantly lower restenosis rate (13.5% vs. 28.3%; P = 0.038) as compared with patients that did not fulfil these criteria. Our data suggest that patients fulfilling IVUS criteria for optimal stent placement demonstrate a reduced risk for the development of restenosis. Thus, IVUS investigation identifies factors predictive of restenosis after coronary stent placement.     

Restenosis after percutaneous coronary angioplasty--cause, prevention strategies

PTCA is a new method of invasive cardiology. Restenosis is an important limitation of efficacy of this method. It occurs in 20-45% of patients. Pathomechanism of the restenosis is not clear. It is assumed, that restenosis is an answer of the endothelium to the procedure. This response consists of the inflammation, platelet primary adhesion and aggregation, proliferation of smooth muscle cells and intercellular matrix production. These changes together with old atheroma and thrombus create a new stenosis. There were many attempts to prevent restenosis based on the pathophysiology, but so far no successful method has been found.     

Peter B. Samuels Award. Restenosis after percutaneous transluminal angioplasty

This study investigated the regional distribution of fatty and lean tissue in long-distance runners, and the relation to training, sex hormones, and serum lipids. One hundred and twenty lean men (22 elite, 86 recreational runners and 12 non-running controls) aged 32 +/- 8.1 years (mean +/- SD) participated. Body composition (adipose and lean tissue) was measured by dual-energy x-ray absorptiometry in the total body and in the abdomen, the arms and the legs. Regional and total body fat correlated inversely with the performance at an incremental treadmill exercise test (-0.61 < r < -0.52, P < 0.0001), and the fat percentage in the abdomen and in the legs was 42% and 36% lower in the elite runners in comparison with the non-running controls. Sex hormonal status and serum lipids were unrelated to training. After multiple regression analysis the most significant determinant of the fat percentage in the legs was the weekly distance run (partial r = -0.40, P < 0.0001), whereas in the abdominal region the free testosterone index also contributed strongly (partial r = 0.39, P < 0.0001). In conclusion, long-distance runners had very low amounts of fatty tissue in the abdomen and in the extremities, and the fat percentages in the abdomen and in the legs were associated with both the training intensity and androgenic activity. Since the abdominal fatty tissue is a significant risk factor for cardiovascular disease, running may have a positive impact on the long-term risk.     

Restenosis rates in diabetic patients: a comparison of coronary stenting and balloon angioplasty in native coronary vessels

BACKGROUND: Diabetes is a major risk factor for restenosis after coronary balloon angioplasty. Recent studies have shown that coronary stenting significantly reduces restenosis compared with balloon angioplasty alone. However, limited information is available on the effect of coronary stenting in diabetic patients. METHODS AND RESULTS: We designed this study to analyze the effect of diabetes on restenosis in patients treated with either balloon angioplasty or coronary stenting who were enrolled in a 6-month angiographic follow-up program. Three hundred consecutive patients, 19% of whom were diabetics, who underwent coronary stent implantation during a single-vessel procedure on native coronary vessels and who had 6-month angiographic follow-up constituted the study group (stent group). Three hundred consecutive patients who underwent 6-month angiographic follow-up after single-vessel conventional balloon angioplasty served as control patients (balloon group). Preprocedural, postprocedural, and follow-up angiograms were analyzed with quantitative angiography. In the balloon group, the restenosis rate was almost twofold higher in diabetic than in nondiabetic patients (63% versus 36%; P=.0002) owing to both a greater late loss (0.79+/-0.70 versus 0.41+/-0.61 mm, respectively; P<.0001) and a higher rate of late vessel occlusion (14% versus 3%, respectively; P<.001). In the stent group, restenosis rates were similar in diabetics and nondiabetics (25% versus 27%, respectively). Furthermore, in the stent group, late loss (0.77+/-0.65 versus 0.79+/-0.57 mm, respectively) and the rate of late vessel occlusion (2% versus 1%, respectively) did not differ significantly between diabetic and nondiabetic patients. CONCLUSIONS: Although diabetics have increased rates of restenosis and late vessel occlusion after simple balloon angioplasty, they have the same improved outcome with coronary stenting that has been documented in nondiabetic patients.     

Coronary-artery stenting compared with balloon angioplasty for restenosis after initial balloon angioplasty. Restenosis Stent Study Group

BACKGROUND: Intracoronary stenting reduces the rate of restenosis after angioplasty in patients with new coronary lesions. We conducted a prospective, randomized, multicenter study to determine whether intracoronary stenting, as compared with standard balloon angioplasty, reduces the recurrence of luminal narrowing in restenotic lesions. METHODS: A total of 383 patients who had undergone at least one balloon angioplasty and who had clinical and angiographic evidence of restenosis after the procedure were randomly assigned to undergo standard balloon angioplasty (192 patients) or intracoronary stenting with a Palmaz-Schatz stent (191 patients). The primary end point was angiographic evidence of restenosis (defined as stenosis of more than 50 percent of the luminal diameter) at six months. The secondary end points were death, Q-wave myocardial infarction, bypass surgery, and revascularization of the target vessel. RESULTS: The rate of restenosis was significantly higher in the angioplasty group than in the stent group (32 percent as compared with 18 percent, P= 0.03). Revascularization of the target vessel at six months was required in 27 percent of the angioplasty group but in only 10 percent of the stent group (P=0.001). This difference resulted from a smaller mean (+/-SD) minimal luminal diameter in the angioplasty group (1.85+/-0.56 mm) than in the stent group (2.04+/-0.66 mm), with a mean difference of 0.19 mm (P=0.01) at follow-up. Subacute thrombosis occurred in 0.6 percent of the angioplasty group and in 3.9 percent of the stent group. The rate of event-free survival at 250 days was 72 percent in the angioplasty group and 84 percent in the stent group (P=0.04). CONCLUSIONS: Elective coronary stenting was effective in the treatment of restenosis after balloon angioplasty. Stenting resulted in a lower rate of recurrent stenosis despite a higher incidence of subacute thrombosis.     

Apoptosis and cell proliferation after porcine coronary angioplasty

BACKGROUND: Angioplasty initiates a number of responses in the vessel wall including cellular migration, proliferation, and matrix accumulation, all of which contribute to neointima formation and restenosis. Cellular homeostasis within a tissue depends on the balance between cell proliferation and apoptosis. METHODS AND RESULTS: Profiles of apoptosis and proliferation were therefore examined in a porcine PTCA injury model over a 28-day period. Forty-two arteries from 21 pigs, harvested at the site of maximal injury at 1, 6, and 18 hours, and 3, 7, 14, and 28 days after PTCA, were examined (n=3 animals per time point). Uninjured arteries were used as controls. Apoptosis was demonstrated by the terminal uridine nick-end labeling (TUNEL) method, transmission electron microscopy (TEM), and DNA fragmentation. Cells traversing the cell cycle were identified by immunostaining for proliferating cell nuclear antigen (PCNA). Apoptosis was not detected in control vessels at all time points nor at 28 days after PTCA. Apoptotic cells were identified at all early time points with a peak at 6 hours (5.1+/-0.26%; compared to uninjured artery, P<0.001) and confirmed by characteristic DNA ladders and TEM findings. Regional analysis showed apoptosis within the media, adventitia, and neointima peaked at 18 hours, 6 hours, and 7 days after PTCA, respectively. In comparison, PCNA staining peaked at 3 days after PTCA (7.16+/-0.29%; compared to 1.78+/-0.08% PCNA-positive cells in the uninjured artery, P<0.001). Profiles of apoptosis and cell proliferation after PTCA were discordant in all layers of the artery except the neointima. These profiles also differed between traumatized and nontraumatized regions of the arterial wall. Immunostaining with cell-type specific markers and TEM analysis revealed that apoptotic cells included vascular smooth muscle cells (VSMCs), inflammatory cells, and adventitial fibroblasts. CONCLUSIONS: These results suggest that the profile of apoptosis and proliferation after PTCA is regional and cell specific, and attempts to modulate either of these events for therapeutic benefit requires recognition of these differences.     

Mechanisms and prevention of restenosis after coronary angioplasty]

The success of PTCA is limited by late restenosis, which occurs in 30-50% of all cases, chiefly within the first six months after the intervention. Restenosis is due to the proliferation of smooth muscle cells and especially to overproduction of extracellular matrix in the arterial wall. The coronary intervention is followed by a not fully defined constrictive process of wound healing, so-called remodeling. Various alternative intervention techniques were investigated but did not show any clear advantage concerning restenosis compared to PTCA. Although the rate of restenosis is reduced by stent implantation, which hinders remodeling, the remaining intimal hyperplasia often leads to restenosis. In spite of promising results in animal models, to date no effective human pharmacological therapy has been found to prevent restenosis. To determine whether antioxidants, endovascular radiation or gene therapy show any benefit will require further, larger trials.     

Remodeling after directional coronary atherectomy (with and without adjunct percutaneous transluminal coronary angioplasty): a serial angiographic and intravascular ultrasound analysis from the Optimal Atherectomy Restenosis Study

Expression of DNA topoisomerase IIalpha protein varies through the cell cycle with its peak in G2/M. This cell-cycle-dependent expression depends on changes in topoisomerase IIalpha mRNA stability as well as promoter activity. We isolated the 3' genomic region of the mouse topoisomerase IIalpha gene and investigated whether or not the 3' untranslated region (UTR) of the topoisomerase IIalpha mRNA participates in the cell-cycle-dependent mRNA stability. Interestingly, genomic- and RT-PCR analyses revealed that the topoisomerase IIalpha 3' UTR is formed via splicing in mouse, but not in human and hamster. Comparison of the mouse 3' region with the human and hamster regions suggests that this mouse-specific splicing has resulted from an accidental acquisition of the consensus 5' splice site. The minority of the non-spliced topoisomerase IIalpha 3' UTR in mouse was confirmed by Northern blot analysis. We performed transient expression assays using luciferase constructs with the mouse topoisomerase IIalpha 3' genomic region, or the major spliced form of the 3' UTR. However, neither construct affected the cell-cycle-dependent expression of the reporter gene driven by the topoisomerase IIalpha promoter. Our results strongly suggest that the mouse topoisomerase IIalpha 3' UTR by itself is not involved in the cell-cycle-dependent mRNA stability.     

Prospects of prevention of restenosis after coronary angioplasty

The prevention of restenosis after coronary angioplasty has been marked over recent years by the failure of trials of drug treatment based on inhibition of arterial smooth muscle cell proliferation. This failure could be due to an insufficient concentration of the orally or intravenously administered drug in the lesion to be treated. Another reason for this failure of drug treatment could be the nonexclusive role of intimal hyperplasia in the pathophysiology of restenosis, which also appears to be related to a education of the overall calibre of the artery at the site of dilatation. The pathogenesis of this phenomenon, called "remodelling", remains obecure and is only partly prevented by insertion of stents, which is currently the only treatment able to decrease the number of new revascularization procedures for restenosis. This benefit is related to optimization of the initial result (stents avoiding early "recoil", secondary to the elastic recoil forces of the arterial wall), and possibly to prevention of late remodelling of the vessel at the site of dilatation, either tonic (vasomotor) or trophic. On the other hand, the benefit related to the absence of "remodelling" of the stended lesions is partly limited by intimal hyperplasia, exacerbated by the presence of the stent. The future therapeutic strategy could combine insertion of stents and prevention of smooth muscle cell proliferation by new treatment strategies acting at the molecular level. Encouraging preliminary results have already been obtained in animals with chimeric toxins, antisense strategies and especially gene therapy using defective adenoviral vectors for replication.     

Endovascular beta-irradiation after percutaneous transluminal coronary balloon angioplasty

PURPOSE: Intraluminal beta-irradiation has been shown to markedly decrease fibrointimal proliferation after arterial injury in experimental models. With the aim of reducing the incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA), we undertook a pilot clinical evaluation to assess both the technical feasibility and the clinical safety of this treatment after balloon coronary angioplasty. METHODS AND MATERIALS: Between June 21 and November 15, 1995, 15 patients (6 women and 9 men, aged 72 +/- 5 years) underwent intracoronary beta-irradiation immediately after a conventional PTCA procedure. Both the PTCA and irradiation procedure were done in a conventional catheterization laboratory, using an endoluminally centered pure metallic 90Y source, a newly developed technique of intracoronary beta-irradiation. This was done after documenting the ability of the system to generate reproducible dose delivery to the arterial wall. RESULTS: Both the PTCA and the irradiation procedure were technically feasible in all attempted cases, and a dose of 18 Gy was delivered with a local exposure time of 391 +/- 206 s (range 153-768). In four patients, the intervention was completed by intraarterial stent implantation because of dissection induced by the initial PTCA. No in-hospital complications occurred, and serial creatine kinase measurements remained within the normal range in all cases. CONCLUSION: Our early experience thus suggests that reliable and reproducible dose delivery can be achieved, and that coronary endoluminally centered beta-brachytherapy is both feasible and safe on a short-term basis in the clinical setting. Whether this novel mode of therapy will favorably influence post-PTCA restenosis in patients, as it does in experimental models, must await long-term angiographic follow-up of the present series as well as further clinical study.     

Prevention and treatment of restenosis after percutaneous transluminal coronary angioplasty

Restenosis is a clinical problem after coronary angioplasty associated with major ischemic events or repeat interventions in 20-50% of the patients undergoing this procedure. Major efforts have been undertaken in the past decade to successfully prevent or treat restenosis but no pharmacologic approach to the problem has as yet been identified to be effective enough in clinical conditions. New strategies to cope with restenosis are targeted by local application of ionizing radiation which markedly reduces cell proliferation after angioplasty in animal experiments. Preliminary clinical trials indicate that endovascular radiation therapy is a safe and effective means to treat restenosis. Randomized, multicenter studies with long follow-up periods are needed to support these early results.     

Prevention of restenosis by bezafibrate after successful coronary angioplasty

BACKGROUND: To study the role of bezafibrate in prevention of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA), we evaluated the incidence of restenosis and its correlation with serum lipid levels and effects on the coagulation-fibrinolytic system. METHODS: Subjects who had undergone successful elective PTCA were classified into three groups based on their triglyceride level and whether or not bezafibrate was administered. Fifty-two patients who had a triglyceride level < 150 mg/dl were classified as group A. Those with a triglyceride level +/- 150 mg/dl were randomly and prospectively allocated to receive either bezafibrate (group B, n = 21), or no lipid-lowering treatment (group C, n = 22). The restenosis rates in all three groups were subsequently monitored and correlated with serum levels of lipids and coagulation-fibrinolytic system markers. RESULTS: In the bezafibrate group, three of 21 patients (14%) had restenosis compared with 12 of 22 (55%) in group C and 18 of 52 (35%) in group A. In groups A and C, fibrinogen and triglyceride levels were significantly higher in the patients with restenosis. At the time of re-evaluation, serum triglyceride, fibrinogen, and plasminogen activator inhibitor type 1 (PAI-1) levels were lower and high-density lipoprotein (HDL) cholesterol levels were higher in the bezafibrate group than in group C. By logistic regression analysis, triglyceride and PAI-1 were found to be significant risk factors for postangioplasty restenosis. CONCLUSIONS: Triglyceride is a risk factor for post-PTCA restenosis, and bezafibrate reduces the post-PTCA restenosis rate in patients with a high triglyceride level. In the bezafibrate group, a significant decrease in PAI-1 was observed in association with a decrease in triglyceride level and an elevation of HDL cholesterol level. This suggests that improvement in fibrinolytic capacity is involved in the mechanism of decrease in the rate of restenosis.