Angiotensin I-converting enzyme (ACE) inhibitors and restenosis after coronary artery stenting in patients with the DD genotype of the ACE gene

OBJECTIVES: We tested the hypothesis that patients with the DD genotype of the angiotensin I-converting enzyme (ACE) gene who are treated with ACE inhibitors are at a higher risk of restenosis after coronary stent placement than patients who do not receive ACE inhibitors. BACKGROUND: Two recent studies with a limited series of patients carrying the DD genotype suggested an unfavorable impact of the use of ACE inhibitors on the restenotic process after implantation of stents in coronary arteries. Because these findings may question the use of ACE inhibitors after coronary stenting, we examined this important issue in a large series of patients. METHODS: We determined the ACE gene I/D genotype of 2,222 consecutive patients with symptomatic coronary artery disease who underwent stent implantation. The patients with the DD genotype (n = 612) constituted the study population. The primary end point was in-stent restenosis, which was assessed as angiographic restenosis (> or =50% diameter stenosis at six-month follow-up) and clinical restenosis (need for target vessel revascularization due to symptoms or signs of ischemia in the presence of angiographic restenosis over one year after the intervention). RESULTS: Of the 612 patients with the DD genotype, 403 (65.8%) were treated with ACE inhibitors and 209 (34.2%) did not receive ACE inhibitors. The angiographic and clinical restenosis rates were not significantly different between the group treated with ACE inhibitors and the group not receiving ACE inhibitors (p = 0.55). Continuous measures of restenosis, minimal lumen diameter, diameter stenosis, late lumen loss, and loss index were also similar in both groups (p > or = 0.55). In addition, one-year survival free of myocardial infarction was not significantly different between the two groups (p = 0.27). CONCLUSIONS: In contrast to previous reports, our study provides evidence that patients carrying the DD genotype are not exposed to an increased risk of restenosis after stent placement when treated with ACE inhibitors.     

Ace D/I polymorphism and incidence of post-PTCA restenosis: a prospective, angiography-based evaluation

Early restenosis is the major complication of percutaneous transluminal coronary angioplasty (PTCA), occurring in approximately 30% of all initially successful procedures. The D/I polymorphism of the ACE gene, which has variably been reported to represent a risk factor for manifestations of ischemic heart disease, has recently been implicated in the pathophysiology of restenosis after PTCA by some investigators but not by others. All studies conducted thus far involved relatively small sample sizes. We investigated the possible association of ACE D/I genotype and post-PTCA restenosis in a large, prospective sample of patients followed by quantitative coronary angiography. The ACE D/I gene polymorphism was characterized in a cohort of 779 patients, of whom 342 (cases) had developed restenosis (as defined by >50% loss of lumen compared with immediate postprocedure results) at repeat quantitative coronary angiography at 6 months after PTCA. Allele frequencies for the ACE D and I: alleles were 0.58 and 0.42 in cases and 0.58 and 0.42 in control subjects. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and restenosis or degree of lumen loss. The data from this largest study of its kind conducted so far provide no evidence for an association of the ACE D/I allelic polymorphism with incidence of restenosis after PTCA. On the basis of the power of this study, we conclude that in a general population, the ACE D/I polymorphism is not a useful marker to assess risk of post-PTCA restenosis.     

Stent implantation reduces restenosis in patients with suboptimal results following coronary angioplasty.

BACKGROUND: Primary intracoronary stenting reduces the rate of restenosis when compared with balloon angioplasty (PTCA) in selected patients. The strategy of PTCA followed by provisional stent placement for suboptimal PTCA results may be preferable to universal stenting but has not yet been tested in a randomized trial. METHODS: An attempt was made to obtain an optimal result with PTCA alone in 143 patients. Stenting was required in 50 patients (35%) for significant coronary dissection or PTCA failure. In the remaining 93 patients, the angiographic result was assessed immediately using on-line quantitative coronary angiography and classified as either optimal (<15% residual stenosis) or suboptimal (>/=15% residual stenosis). Sixteen patients (11%) had an optimal result from PTCA. The remaining 77 (54%) patients had a suboptimal result and were immediately randomized either to no further treatment or to the placement of a stent. The primary end-point was the rate of restenosis (>50% stenosis), assessed by quantitative coronary angiography, at 6 months. RESULTS: Angiographic follow-up was completed in 132 patients. Restenosis occurred in 53 (36,69)% of patients with a suboptimal result randomized to PTCA alone compared with 24 (12,41)% of patients randomized to stent (P=0.023). There was no significant difference in minimal luminal diameter at follow-up between the randomized groups. The rate of restenosis was 14 (2,43)% in patients with an optimal PTCA result and 14 (5,28)% in those that required stenting. CONCLUSIONS: Optimal angiographic results following conventional PTCA are rare and the restenosis rate following suboptimal results is high. The strategy of stenting suboptimal results is associated with a significant reduction in the rate of stenosis.     

ACE基因I/D多态性与冠状动脉支架内再狭窄相关性研究

目的研究冠状动脉内行药物洗脱支架置入术患者,术后支架内再狭窄发生情况与ACE基因I/D多态性的关系。方法所有患者行冠状动脉造影检查,PCR方法测定ACE基因型。根据血管造影结果分为再狭窄组（病变狭窄≥50%）和无再狭窄组（病变狭窄〈50%）。采用SPSS18.0软件比较再狭窄组与无再狭窄组的临床基本特征、冠脉造影资料,以及与ACE基因型的关系。结果此次研究共纳入396名行药物洗脱支架置入术的冠心病患者,支架内再狭窄发生40例,再狭窄率为10.1%。再狭窄组与无再狭窄组的临床基本资料、冠脉造影资料均无显著性差异（P〉0.05）。再狭窄组的ACEDD基因型35.56%、ACEDI基因型16.39%、ACEII基因型3.85%。再狭窄组与ACE基因I/D多态性具有相关性（P〈0.001）。结论冠状动脉内行药物洗脱支架置入术患者术后支架再狭窄发生与ACEDD基因型具有显著相关性。     

Risk factors for later restenosis after successful coronary angioplasty: Mitsui Memorial Hospital experience]

To determine the risk factors for restenosis, 170 patients with 245 stenotic lesions who underwent follow-up coronary angiography after successful coronary angioplasty (PTCA) were evaluated. The mean angiographic follow-up period was 116 +/- 39 days (+/- SD). Restenosis was defined according to 3 criteria: 1) greater than or equal to 50% loss of the gain achieved by PTCA, 2) greater than or equal to 60% stenosis at follow-up, 3) greater than or equal to 30% increase in stenosis from post-PTCA. The rate of restenosis was 41.2% by criterion 1), 32.2% by criterion 2) and 34.3% by criterion 3). By univariate analysis of 12 clinical, 9 angiographic and 8 procedural factors, 6 factors were significantly associated with restenosis: 1) left anterior descending artery, 2) severe stenosis before PTCA, 3) long lesions, 4) calcified lesions, 5) maximal inflation pressure greater than or equal to 100 psi, 6) number of inflations greater than or equal to 6 times. No clinical factors were suggested to have significant influence on restenosis. Multivariate analysis (stepwise method) revealed independent 6 factors related to restenosis in the following order of importance: 1) number of inflations, 2) maximal inflation pressure, 3) presence of calcification, 4) vessel dilated at PTCA, 5) diabetes mellitus, 6) lesion length. The residual stenosis had no significant influence on restenosis. This may have been due to a small number (14.7%, 36 lesions) of prominent residual stenoses (greater than or equal to 40%) in this study. The presence or absence of intimal disruptions had no significant influence on restenosis. It was suggested that restenosis after successful PTCA may be influenced mainly by "local factors" related to regions.     

Relation between the insertion/deletion polymorphism of the angiotensin I converting enzyme gene and restenosis after coronary stenting

BACKGROUND: Observations with intravascular ultrasound demonstrated that neointimal hyperplasia is the predominant factor responsible for in-stent restenosis. Experimental data suggest that angiotensin I converting enzyme (ACE) plays a role in the thickening of neointima after balloon denudation. Insertion/deletion (I/D) polymorphism of the ACE gene is significantly associated with plasma level of ACE and subjects with D/D genotype have significantly higher plasma levels of ACE than normal. OBJECTIVE: To investigate whether this polymorphism influences the risk of restenosis after coronary stenting. METHODS: We genotyped 158 patients who had undergone single-vessel coronary stenting for the ACE I/D polymorphism. RESULTS: Of the 158 patients, 56 (35%) had the D/D genotype, 71 (45%) had the I/D genotype and 31 (20%) had the I/I genotype. Prevalences of genotypes were compatible with Hardy-Weinberg equilibrium and distributions of ACE genotype among patients and 132 healthy controls from the same geographic area did not differ. At follow-up (after a median duration of 5.4 months), overall rates of angiographic restenosis and of revascularization of target lesion (RTL) were 32.3 and 22.8%, respectively. Of 51 patients with angiographic restenosis, 31 (60.8%) had focal and 20 (39.2%) had diffuse patterns of restenosis. Diffuse in-stent restenosis was significantly more prevalent among patients with D/D genotype (P = 0.016). Multiple stepwise logistic regression analysis identified ACE I/D polymorphism as the independent predictor of angiographic restenosis and RTL. Relative risk of angiographic restenosis was 6.29 [95% confidence interval (CI), 1.80-22.05, P = 0.0004] for D/D genotype and 3.88 (95% CI 1.11-13.12, P = 0.029) for I/D genotype, whereas relative risk of RTL was 7.44 (95% CI 1.60-34.58, P = 0.01) for D/D genotype and 3.88 (95% CI 0.083-18.15, P = 0.085) for I/D genotype. CONCLUSIONS: The ACE I/D polymorphism is significantly associated with risk of angiographic and clinical restenosis after coronary stenting. Angiographic pattern of restenosis is also significantly associated with I/D polymorphism, diffuse type being more prevalent among subjects with D/D genotype.     

Pharmacogenetic analysis of the effect of angiotensin-converting enzyme inhibitor on restenosis after percutaneous transluminal coronary angioplasty.

Angiotensin-converting enzyme (ACE) inhibitors are reported to prevent neointimal formation after balloon injury in animal models, but in most prospective studies in humans, ACE inhibitors failed to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA). The ACE genotype assigned by an insertion/deletion (I/D) polymorphism is known to affect the potency of ACE inhibitors in several renal diseases. The authors attempted to clarify whether the effect of ACE inhibitors on restenosis might be modified by the ACE genotype. A total of 126 patients was randomly and prospectively assigned to the control group and the imidapril group. In the imidapril group, patients received 5 mg imidapril daily, starting 1 day before PTCA and continuing for 3 to 6 months. Forty-six control (65 vessels) and 32 imidapril patients (43 vessels) completed the study. The minimal lumen diameter before and after the procedure did not differ significantly among the groups with the three genotypes (II, ID, and DD) in both the control and imidapril groups. Late luminal loss during the follow-up period was not related to the ACE genotype in the control group but was significantly related in the imidapril group (II, 0.63+/- 0.19 mm; ID + DD, 1.12+/-0.14 mm, p<0.05). Furthermore, in the II genotype, imidapril significantly reduced late loss and restenosis rate as defined by most of the frequently used definitions. In conclusion the ACE I/D polymorphism may influence the effect of ACE inhibitors in preventing restenosis after PTCA.     

Restenosis after successful percutaneous transluminal coronary angioplasty: the Montreal Heart Institute experience

Repeat coronary angiography was performed within 6 months after successful percutaneous transluminal coronary angioplasty (PTCA) in 178 of our first 181 patients (98%). The remaining 3 patients were symptom free, had negative treadmill exercise test results and were considered not to have had restenosis. A second follow-up angiogram was performed in 107 patients (59%), including all patients with persistent or recurrent anginal symptoms, between 7 and 18 months after PTCA. Fifty-one of the 181 patients (28%) had restenosis on 51 of 205 successfully dilated segments (25%). The stenosis was greater than or equal to 70% in 49 of these 51 segments; it was 65% and 55%, respectively, in the 2 remaining patients. Restenosis was documented angiographically at a median time of 4.7 +/- 4 months. However, 47 patients (92%) had restenosis documented within 6 months, 2 between 7 and 12 months and 2 between 13 and 18 months after PTCA. Stepwise logistic regression analysis selected the following factors as independent predictors of restenosis after PTCA: variant angina, multivessel disease, severity of residual stenosis and less reduction in the diameter of the stenosis on the angiogram immediately after PTCA. Of these 4 factors, the degree of residual stenosis immediately after PTCA was by far the most significant. It is concluded that restenosis occurs in approximately 25% of patients, almost always within the first 6 months, after successful PTCA. The degree of residual stenosis after PTCA is the most important predictor of restenosis. Increased experience and improved instrumentation may eventually lead to less residual stenosis and better late results after PTCA.     

Restenosis after percutaneous transluminal coronary angioplasty (PTCA): A report from the PTCA registry of the national heart, lung, and blood institute

The results of follow-up angiography in patients from 27 clinical centers enrolled in the PTCA Registry were analyzed to evaluate restenosis after PTCA. Of 665 patients with successful PTCA, 557 (84%) had follow-up angiography (median follow-up 188 days). Restenosis, defined as an increase of at least 30% from the immediate post-PTCA stenosis to the follow-up stenosis or a loss of at least 50% of the gain achieved at PTCA, was seen in 187 patients (33.6%). The incidence of restenosis in patients who underwent follow-up angiography was highest within the first 5 months after PTCA. Restenosis was found in 56% of patients with definite or probable angina after PTCA and in 14% of patients without angina after PTCA. Twenty-four percent of patients with restenosis did not have either definite or probable angina. Multivariate analysis selected 4 factors associated with increased rate of restenosis: male sex, PTCA of bypass graft stenosis, severity of angina before PTCA and no history of MI before PTCA.     

Angiotensin-converting enzyme insertion/deletion polymorphism does not influence the restenosis rate after coronary stent implantation

BACKGROUND: Experimental studies have shown an activation of the angiotensin-converting enzyme (ACE) system as a response to endothelial injury. Recent publications have elucidated the hypothesis that the ACE gene polymorphism may influence the level of late luminal loss after coronary stent implantation. It is still unclear whether the polymorphism of the angiotensin gene is a major predictor of the extent of neointimal hyperplasia. In this multicenter study, we therefore tested the relationship between the ACE gene polymorphism and the restenosis rate after coronary stent implantation. METHODS: As a substudy of the optimization with intracoronary ultrasound (ICUS) to reduce stent restenosis (OPTICUS) study, we analyzed ACE serum levels and the ACE gene polymorphism in 154 patients at 9 different centers. All patients underwent elective coronary stent implantation in a stenosis of a major coronary vessel. Balloon inflations were repeated until a satisfactory result was achieved in on-line quantitative coronary angiography or ICUS fulfilling the OPTICUS study criteria. After follow-up of 6 months, all patients underwent reangiography under identical projections as the baseline procedure. A blinded quantitative analysis of the initial procedure as well as the follow-up examinations were performed by an independent core laboratory. ACE gene polymorphism and ACE serum activity were measured at the 6-month follow-up in a double-blinded setting. RESULTS: With respect to the ACE gene polymorphism, there were three subgroups: DD genotype (48 patients), ID (83 patients) and II (23 patients). The subgroups did not differ in regard to age, gender, extent of coronary artery disease, stenosis length, initial degree of stenosis or degree of stenosis after stent implantation. In all, 39 patients (25.3%) had significant restenosis: 12 DD patients (25.0%), 18 ID patients (21.7%) and 9 II patients (39.1%) (odds ratio 2.164, 95% confidence interval 0.853-5.493). We obtained the following results for ACE serum levels: 0.53 micromol/l/s in the DD subgroup, 0.29 micromol/l/s in the ID subgroup and 0.09 micromol/l/s in the II subgroup (p < 0.001). Multivariate logistic regression analysis of the influence of ACE gene polymorphism on the restenosis rate after coronary stent implantation adjusted for lesion length (>12 mm), ACE inhibitor or hydroxymethylglutaryl coenzyme A reductase (CSE) inhibitor treatment, age, male gender, diabetes mellitus, hypertension, high cholesterol, family history, smoking and three-vessel disease did not uncover any statistic significance. CONCLUSIONS: In contrast to other study groups, we were unable to disclose that the DD polymorphism of the ACE gene was associated with a higher rate of restenosis after coronary stent implantation in this multicenter study. In addition, patients with higher ACE serum levels did not show a higher restenosis rate in this trial. We conclude that the pathogenesis of restenosis is a multifactorial process involving various genetic and nongenetic factors.     

Quantitatively assessed coronary collateral circulation and restenosis following percutaneous revascularization.

AIMS: A high degree of collateral supply to a vascular area where a percutaneous transluminal coronary angioplasty (PTCA) has been performed represents a haemodynamic force competing with the antegrade flow through the dilated lesion. Therefore, our purpose was to determine whether patients with restenosis following PTCA have a higher collateral flow to the recipient vessel than patients without restenosis. METHODS AND RESULTS: In 200 consecutive PTCA patients, an intracoronary pressure-derived collateral flow index (CFI) was determined quantitatively during balloon occlusion, using simultaneous measurements of the mean aortic pressure (P(ao)) and of the intracoronary pressure distal to the occluded stenosis (P(occl)), as well as the estimated central venous pressure (CVP=5 mmHg): CFI=(P(occl)-CVP)/(P(ao)-CVP). Sixty-four patients had an angiographic follow-up examination after at least 2 months, and were subdivided into patients with restenosis (>50% diameter stenosis, n=34) and patients without restenosis (n=30). Patients with restenosis had a significantly higher collateral flow index at the initial coronary angiography than patients without restenosis (0.26 +/- 0.14 vs 0.12 +/- 0.09; P<0.0001). CONCLUSIONS: Patients with restenosis after PTCA show a more extended collateral supply to this recipient area than patients without restenosis. Well developed collaterals to a revascularized region are a risk factor for restenosis of the treated lesion.     

Prior cytomegalovirus infection and the risk of restenosis after percutaneous transluminal coronary balloon angioplasty

BACKGROUND: Restenosis is a common problem after all revascularization procedures in atherosclerotic coronary arteries. Reactivated human cytomegalovirus (CMV) has been detected in tissues of restenotic vascular lesions and was hypothesized to be a contributing pathogenic factor. Recent data suggest an association of restenosis after optimal coronary atherectomy with CMV serostatus, and a possible role of antiviral therapy was discussed. We therefore tested the hypothesis that prior CMV infection might be a risk factor for restenosis after conventional coronary balloon angioplasty (PTCA). METHODS AND RESULTS: We analyzed 92 consecutive patients who had been admitted for control angiography after previous PTCA within a mean interval of 6 months. Anti-CMV antibodies were measured as an indicator of prior CMV infection and latency. The coronary angiograms before PTCA, directly after, and 6 months later were analyzed quantitatively. Sixty-five percent of the patients were CMV-positive. Before PTCA, the degree (mean+/-SD) of stenosis was 69+/-10% in CMV-positive and 68+/-8.3% in CMV-negative subjects. PTCA resulted in a residual stenosis of 39% in both groups. After 6 months, the late losses of luminal diameter in the CMV-positive and -negative groups were 11+/-13% and 12+/-15%, respectively (P=0.658). In an ANCOVA with 25 potential risk factors for restenosis, CMV serostatus was not significantly associated with restenosis development. CONCLUSIONS: Our data indicate that prior CMV infection, in contrast to optimal atherectomy, is not associated with chronic restenosis after conventional coronary balloon angioplasty. The results do not support a possible benefit from antiviral therapy.     

Importance of stenosis morphology in the estimation of restenosis risk after elective percutaneous transluminal coronary angioplasty

To determine the importance of predilatation stenosis morphology on the risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA), 500 procedures were randomly chosen for analysis from 3,839 consecutive successful PTCA procedures. Angiographic follow-up was available for 308 patients (62%) at a mean of 7.3 +/- 3.4 months after PTCA. One dilated site was randomly chosen per procedure. One hundred and one sites had documented restenosis (greater than or equal to 50% mean diameter stenosis from multiple projections) by quantitative angiography (33% of all sites restudied and 20% of all sites dilated). Twenty-eight morphologic variables and 20 other angiographic, clinical and procedural variables were analyzed by an observer blinded to clinical outcome. Univariate analysis found post-PTCA percent stenosis greater than 30% (p = 0.005), bend point location (p = 0.01), post-PTCA gradient greater than 15 mm Hg (p = 0.02), angina class III to IV (p = 0.03), age (p = 0.04) and the absence of dissection (p = 0.04) to predict restenosis. Multivariate analysis found only 2 significant (p less than 0.05) independent predictors of restenosis: post-PTCA percent stenosis greater than 30% and bend point location. Restenosis occurred in 41% of lesions located at an end-diastolic vessel angle greater than or equal to 45 degrees compared with 28% in lesions on lesser bends. Thus, only 1 predilatation morphologic characteristic, stenosis location at a bend point, was an important independent predictor of restenosis, and should be considered when assessing patients for PTCA.     

Angiographic restenosis after successful Wallstent stent implantation: an analysis of risk predictors.

Follow-up angiographic study was performed in 86 patients after initially successful Wallstent stent (Medinvent, Lausanne, Switzerland) implantation between April 1986 and October 1990. The stent angiographic restenosis rate was 16% at a mean of 8 months after stenting despite the inclusion of a substantial number of patients at high risk of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Of a total 15 variables analyzed, only suboptimal stent placement was found to be a significant predictor of stent restenosis. Age; gender; baseline New York Heart Association functional class; previous PTCA; indication for stenting; left ventricular ejection fraction; preangioplasty and immediate postangioplasty diameter stenosis severity; stented vessel site, lesional morphology; number, diameter, and length of stents implanted; and the interval between stenting and follow-up angiographic restudy were not significant risk factors of stent restenosis. Our study suggests that intracoronary stent implantation with the Wallstent may be a useful and promising adjunctive option after PTCA, particularly in patients at high risk of restenosis after PTCA. However, because of the significantly enhanced risk of restenosis after suboptimal stent implantation, we strongly recommend the selection and placement of Wallstent stents that adequately cover the entire length of the dilated coronary segment.     

Risk factors for progression of atherosclerosis six months after balloon angioplasty of coronary stenosis

To assess the possible progression of coronary artery disease after percutaneous transluminal coronary angioplasty (PTCA) and its relation to risk factors and restenosis, 124 patients who underwent a first successful PTCA were studied. All had routine follow-up angiography 5 to 8 months after PTCA. Restenosis was defined as a 30% decrease in diameter stenosis or a return to greater than 50% stenosis, and progression (in any nondilated site) as a 20% decrease in diameter stenosis, assessed by a video-densitometric computer-assisted technique. Univariate and multivariate analysis with respect to progression was carried out for age, sex, initial unstable angina, previous myocardial infarction, diabetes mellitus, hypertension, hypercholesterolemia (greater than or equal to 6.2 mmol), smoking habits, Jenkins' score, dilated artery and restenosis. Forty-one patients (33%) had restenosis, and 23 (19%) had evidence of progression; 20 (87%) of these latter patients had restenosis and 3 (13%) did not. Univariate correlates of progression were: previous myocardial infarction (p less than 0.05), higher Jenkins' score (p less than 0.0003) and restenosis (p less than 0.0001). Restenosis was the only multivariate correlate (p less than 0.00003). Progression at routine angiography after PTCA is not rare, and appears to be related to both the initial extent of coronary artery disease and restenosis.     

Lack of association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and vasospastic angina

Background and hypothesis: It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary atherosclerosis and myocardial infarction, but its relation to vasospastic angina has not been fully proven. In the present study, we investigated the possible relationship between the ACE I/D genotype and vasospastic angina. Methods: We explored the distribution of the ACE genotype in 20 patients with vasospastic angina without fixed coronary artery stenosis, 55 angina patients with fixed coronary artery stenosis, and 30 control subjects without coronary artery disease. Results: The frequency of the DD genotype in patients with vasospastic angina (DD: 30.0%, ID: 20.0%, II: 50.0%) did not differ from that in the control subjects (DD: 23.3%, ID: 26.7%, II: 50.0%), while the frequency in patients with coronary artery stenosis (DD: 43.7%, ID: 21.8%, II: 34.5%) was significantly higher than that in the control subjects. The frequency of the D allele also did not differ between patients with vasospastic angina (0.40) and control subjects (0.37), while the frequency was significantly higher in patients with coronary artery stenosis (0.55). Conclusions: These findings suggest that the ACE DD genotype is a potent genetic risk factor for organic coronary artery disease, while it confers no appreciable increase in risk of vasospastic angina. These results also suggest the diversity of the pathogenesis of vascular lesions in these two types of coronary artery disease.     

Restenosis and its determinants in first and repeat coronary angioplasty

Restenosis is the main problem limiting long-term success ofpercutaneous transluminal coronary angioplasty (PTCA) and ismost accurately evaluated by follow-up angiography. We comparedthe primary and long-term results of angioplasty in 268 consecutivepatients (293 segments) with first PTCA (PTCA 1, angiographicfollow-up 98%) and in 66 patients (76 segments) with repeatPTCA after restenosis (PTCA 2, angiographic follow-up 92%).Forty clinical, angiographic and procedural factors were assessedin relation to outcome. Primary success rate was higher in PTCA2 (91% vs 67.5%) and major complications were fewer (4.5% vs16%).Higher inflation pressure (7.9 ± 2.3 vs 6.8 ±1.8 atm, P<0.005) and larger balloons (3.5 ± 0.5 vs3.2 ± 0.5mm, P< 0.005) were used for PTCA 2, resultingin lesser residual stenosis (33 ± 16± vs 40 ±18%, P <0.05). Restenosis rate (>70%) after PTCA 1 andafter PTC A 2 (27% vs 36%, P = NS) and the mean time to recurrence(4.7 vs 5.3 months, P = NS) were similar. Procedural factorswere the main determinants of long-term success in primary PTCA.The restenosis risk was independently related to residual stenosis>45% (P<0.001), variant angina (P<0.05) and multivesseldisease (P<0.05) after PTCA 1 and to male sex (P<0.001)and higher inflation pressure (P<0.05) after PTCA 2. Mildto moderate intimal tearing was associated with less restenosisafter PTC A 1, but not after PTCA 2. Including 9 patients (10segments) with a third PTCA, 70% of the 66 patients with repeatPTCA had a successful long-term outcome. Repeat angioplastyshould therefore be considered as an integral part of PTCA therapy.Restenosis however remains a major concern. An optimal primaryresult with a minimal residual stenosis is decisive for firstPTCA, whereas avoidance of a dissection by using lower inflationpressure on a restenosis might improve the long-term outcomeof repeat PTCA.     

Prevention of restenosis after coronary balloon angioplasty: Rationale and design of the fluvastatin angioplasty restenosis (FLARE) trial

Prevention of restenosis after successful percutaneous transluminal coronary balloon angioplasty (PTCA) continues to present the greatest therapeutic challenge in interventional cardiology. Experimental and pathological studies describe restenosis as no more than the biologic healing response to arterial injury. Studies of serial quantitative coronary angiography have demonstrated that this biologic process may be measured as the loss in minimal luminal diameter (MLD) from post-PTCA to follow-up angiography and that it is essentially ubiquitous and normally distributed. Thus, quantitative coronary angiography has become the gold standard for evaluation of the angiographic outcome of clinical trials of new agents and devices aimed at prevention of restenosis. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors inhibit biosynthesis of mevalonate, a precursor of nonsterol compounds involved in cell proliferation, and thus may control the neointimal response, which forms the kernel of restenosis. Experimental evidence suggests that fluvastatin may exert a greater direct inhibitory effect on proliferating vascular myocytes than other HMG-CoA reductase inhibitors, independent of any lipid-lowering action. The Fluvastatin Angioplasty Restenosis (FLARE) Trial was conceived, in collaboration between the Thoraxcenter, Erasmus University, Rotterdam, The Netherlands, and Sandoz Pharma, to evaluate the ability of fluvastatin 40 mg twice dally to reduce restenosis after successful single-lesion PTCA. Treatment of suitable patients begins 2 weeks before PTCA and continues after successful PTCA (residual diameter stenosis <50%, without major cardiac complications) to follow-up angiography at 26 ± 2 weeks. Restenosis is measured by quantitative coronary angiography at a core laboratory as the loss in MLD from post-PTCA to follow-up angiography. It is calculated (90% power, α = 0.05) that 730 evaluable patients will be needed to test the hypothesis that fluvastatin will reduce the expected post-PTCA loss in MLD by 40%. Serial lipid analysis will be carried out at a central laboratory. Trial evaluation is focused on the primary endpoint (change in MLD) but includes primary clinical end-points (death, myocardial infarction, or the need for coronary artery bypass graft surgery or reintervention up to 40 weeks after PTCA) as well as secondary and tertiary clinical, angiographic, and laboratory endpoints. According to this methodologic approach, the effect of fluvastatin on luminal renarrowing and clinical events after successful PTCA as well as possible associations of lipid parameters with restenosis can be comprehensively investigated.     

Angiographic patterns of restenosis after angioplasty of multiple coronary arteries

To assess angiographic patterns of restenosis after percutaneous transluminal coronary angioplasty (PTCA) of multiple coronary arteries, angiograms were reviewed in 40 patients with clinical recurrence after PTCA of multiple arteries. Clinical recurrence was defined as return of symptoms after successful PTCA of more than 1 major artery or branch and angiographic evidence of restenosis of 1 or more lesions. In these 40 patients, 83 arteries (2.1 arteries per patient) and 103 narrowings (2.6 narrowings per patient) were successfully dilated. Restenosis developed in 57 of 83 arteries at risk (69%): 23 patients (58%) had restenosis in only 1 artery and 17 (42%) in 2 arteries. Restenosis occurred in 63 of 103 lesions at risk (61%): 20 patients (50%) had restenosis of 1 narrowing, 17 (43%) had restenosis of 2 narrowings and 3 (7%) had recurrence of 3 narrowings. Only 13 patients (33%) had restenosis of all narrowings dilated. Predictors of restenosis of individual narrowings were: higher pre-PTCA percent stenosis (87 +/- 10% in narrowings with restenosis vs 82 +/- 10% in narrowings without, p less than 0.02), and higher degree of residual stenosis after PTCA (46 +/- 13% in narrowings with restenosis vs 36 +/- 12% in narrowings without, p less than 0.001). Balloon size or inflation pressure did not predict recurrence of narrowings. Repeat PTCA was successful in 97% of cases attempted (33 of 34), 3 patients underwent elective bypass surgery and 3 were managed with medical therapy. Most patients with clinical recurrence after PTCA of multiple arteries do not have restenosis of multiple arteries or narrowings, and only one-third will have recurrence of all narrowings.(ABSTRACT TRUNCATED AT 250 WORDS)     

The 5A/6A polymorphism of the stromelysin-1 gene and restenosis after percutaneous coronary interventions.

AIMS: Matrix metalloproteinase stromelysin-1 has been implicated in the process of exaggerated lumen re-narrowing after primarily successful interventions in coronary arteries. We examined the possibility that the 5A/6A promoter polymorphism of the stromelysin-1 gene is associated with restenosis after stenting or percutaneous transluminal coronary angioplasty (PTCA). METHODS AND RESULTS: The study included 3333 consecutive patients with symptomatic coronary artery disease who were treated with stent implantation (n=2857) or PTCA (n=476). Primary end-point was angiographic restenosis, defined as >/=50% diameter stenosis at 6-month follow-up angiography. Restenosis rates were 28.1%, 27.8%, and 29.5% in carriers of the stromelysin-1 genotypes 5A5A, 5A6A, and 6A6A, respectively (P=0.71). The incidence of death or myocardial infarction and the need for revascularization at the site of the intervention due to symptoms or signs of ischaemia in the presence of angiographic restenosis were not significantly different between the genotype groups at 1 year. Separate analysis of the patients who underwent stenting and the patients who were treated with PTCA did not indicate the existence of a treatment type-related association between the 5A/6A polymorphism and restenosis. CONCLUSION: Our data strongly suggest that the 5A/6A polymorphism of the stromelysin-1 gene is not related to angiographic restenosis or the 1-year clinical outcome after interventions in coronary arteries.