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Objective: Restenosis is the main drawback of percutaneous coronary intervention (PCI). Inherited factors may explain part of the risk of restenosis. Recently, the vitamin D receptor (VDR) has been shown to be involved not only in bone metabolism but also in modulating immune responses and cell proliferation. Since the inflammatory response is implicated in restenosis, VDR-gene variants could therefore contribute to the risk of restenosis., Methods/results: Systematic genotyping for 15 haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene was performed with the high throughput TaqMan allelic discrimination assays in the Genetic Determinants of Restenosis (GENDER) population. A haplotype-based survival analysis revealed an association of haplotypes in blocks 2, 3 and 4 of the VDR-gene with the risk of clinical restenosis (p-values 0.01, 0.04 and 0.02 respectively). After adjustment for clinical risk factors for restenosis, the individual effect of the block 2 AA haplotype (p = 0.011) persisted., Conclusions: The present study indicates that VDR plays a role in restenosis after PCI. Therefore, VDR genotype may be used as risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice.

Variation in the NOS3 gene has been related to the development of restenosis. The Glu298Asp polymorphism has previously been investigated for its effect on NO levels and the development of restenosis. However, the variability of findings gave rise to the hypothesis that the functional significance of this polymorphism may only become manifest under conditions of endothelial dysfunction. Since patients with the metabolic syndrome are known to have endothelial dysfunction, we aimed to investigate if the significance of NOS3 polymorphisms may depend on the presence of the metabolic syndrome. We examined the impact of the -949 A/G, the -716 C/T and the Glu298Asp polymorphisms in the NOS3 gene on the risk of clinical restenosis in a previously described subpopulation of the GENDER-study, a multicenter prospective study design that enrolled consecutive patients after successful PCI. This subpopulation consisted of 901 patients of whom sufficient data were available to establish absence or presence of the metabolic syndrome. Of these patients, 448 had the metabolic syndrome. Clinical restenosis, defined as target vessel revascularization (TVR), was the primary endpoint. We demonstrated that the minor -949G, -716T and 298Asp alleles were associated with a significantly increased risk of TVR in patients with the metabolic syndrome (HR: 1.58 [95%CI: 1.04-2.40], HR: 1.95 [95%CI: 1.02-3.70] and HR: 1.67 [95%CI: 1.09-2.54], respectively). In the group without the metabolic syndrome we observed no association between the three polymorphisms and TVR.

Since activation of the haemostatic system is an important feature of the wound healing response triggered by arterial injury, variations in genes involved in thrombus formation may play a role in restenosis after percutaneous coronary interventions (PCI). Therefore, our aim was to examine the relationship between polymorphisms that are known to play a role in the haemostatic system and the risk of clinical restenosis in the GENetic DEterminants of Restenosis (GENDER) study, a multicenter prospective study design that enrolled 3,104 consecutive patients after successful PCI. Target vessel revascularization (TVR) was the primary endpoint. All patients were genotyped for six polymorphisms in the Factor II, Factor V, Factor VII and PAI-1 genes. The PAI-1 4G variant was associated with an increased risk of TVR. When compared to 5G/5G homozygotes, heterozygous patients were at higher risk for TVR (HR: 1.46, 95% CI: 1.05-2.03), whereas patients with the 4G/4G genotype had an even further increased risk (HR: 1.69, 95% CI: 1.19-2.41). In contrast, the factor V 506Gln (factor V Leiden) amino acid substitution was associated with a decreased risk of TVR (HR: 0.41, 95% CI: 0.19-0.86). Our findings indicate that polymorphisms in the factorV and PAI-1 genes may play a role in the process of restenosis.

Objectives: Genetic factors appear to be important in the development of restenosis after percutaneous coronary intervention, as well as in the process of inflammation, a pivotal factor in restenosis. Caspase-1, interleukin-1-receptor and protein tyrosine phosphatase nonreceptor type 22 are important mediators in the inflammatory response and caspase-1 also in apoptosis. Therefore, we examined whether polymorphisms in these candidate genes are related to the risk of developing restenosis after percutaneous coronary intervention., Methods: The GENetic DEterminants of Restenosis-project is a multicenter prospective follow-up study. The 5352G/A (L235L) caspase-1-polymorphism, the 7464C/G (A124G) interleukin-1r-polymorphism and the 1858C/T (R620W) protein tyrosine phosphatase nonreceptor type 22-polymorphism were genotyped. To examine the functional effect of the caspase-1 polymorphism, mature plasma interleukin-1beta levels were measured by enzyme-linked immunosorbent assay in lipopolysaccharide-stimulated whole blood from a subpopulation of patients., Results: A total of 3104 patients, age 62.1+/-10.7 years, were included after successful percutaneous coronary intervention. A significant association between the 5352AA genotype of the caspase-1 gene and target vessel revascularization (relative risk 2.2, 95% confidence interval 1.32-3.76) was observed after correcting for clinical variables. Angiographic analysis of a subgroup of patients (N=478) also showed an increased risk for developing restenosis for patients having the 5352GA/AA genotype (P=0.001). The results were corroborated, although they were not statistically significant, by somewhat higher mature interleukin-1beta levels in patients with the 5352AA genotype., Conclusions: The present study shows that patients with the 5352AA genotype in the caspase-1 gene are at increased risk of developing restenosis. If confirmed by other studies, screening patients for this genotype can lead to better risk stratification and provide indications for improving individual treatment; for instance, by providing a new target for drug-eluting stents.

Objectives: The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems., Methods: The GENDER project is a multicenter prospective follow-up study, including 3146 patients after successful PCI. Genotyping in these patients was performed for the ACE gene insertion/deletion, the angiotensinogen 235Met/Thr, T174M and A(-6)G, the angiotensin-II type 1 receptor (AT1R) 1166A/C and T810A, the angiotensin-II type 2 receptor (AT2R) 1675G/A and 3123A polymorphisms and the length polymorphism in the HO-1 promoter region., Results: A total of 3104 patients were followed for 10 months. In 2975 patients at least one of the nine genotypes could be determined. The AT1R 1166 CC genotype showed a significant association with TVR; the other polymorphisms did not. RAS-inhibitory drugs were not associated with the incidence of TVR, nor did they interact with any of the investigated polymorphisms. Patients with the ACE I/I polymorphism showed a trend towards a better outcome if they had a short number of repeats in the HO-1 promoter. This relationship was inversely present in carriers of the ACE D/D polymorphism., Conclusion: We could only establish a role for the AT1R 1166A/C polymorphism in restenosis after PCI. However, significant gene-gene interaction was suggested for the ACE gene and the HO-1 promotor. The RAS and HO-1 relation in restenosis merits further investigation.

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFalpha, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNFalpha gene was performed. The role of TNFalpha in restenosis was also assessed in ApoE*3-Leiden mice, TNFalpha knockout mice, and by local delivery of a TNFalpha biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNFalpha gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNFalpha mRNA was significantly time-dependently up-regulated. Mice lacking TNFalpha or treated locally with thalidomide showed a reduction in reactive stenosis (P=0.01 and P=0.005, respectively). Clinical and preclinical data indicate that TNFalpha plays an important role in restenosis. Therefore, TNFalpha genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNFalpha may be an anti-restenotic target strategy.

Background: Restenosis is a negative effect of percutaneous coronary intervention (PCI). No clinical factors are available that allow good risk stratification. However, evidence exists that genetic factors are important in the restenotic process as well as in the process of inflammation, a pivotal factor in restenosis. Association studies have identified genes that may predispose to restenosis, but confirmation by large prospective studies is lacking. Our aim was to identify polymorphisms and haplotypes in genes involved in inflammatory pathways that predispose to restenosis., Methods and Results: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter prospective study, including 3104 consecutive patients after successful PCI. Forty-eight polymorphisms in 34 genes in pathways possibly involved in the inflammatory process were analyzed. The 16Gly variant of the beta2-adrenergic receptor gave an increased risk of target vessel revascularization (TVR). The rare alleles of the CD14 gene (-260T/T), colony-stimulating factor 2 gene (117Thr/Thr), and eotaxin gene (-1328A/A) were associated with decreased risk of TVR. However, through the use of multiple testing corrections with permutation analysis, the probability of finding 4 significant markers by chance was 12%., Conclusions: Polymorphisms in 4 genes considered involved in the inflammatory reaction showed an association with TVR after PCI. Our results may contribute to the unraveling of the restenotic process. Given the explorative nature of this analysis, our results need to be replicated in other studies.

Objectives: We sought to identify polymorphisms in genes that predispose to restenosis., Background: Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined by target vessel revascularization [TVR]) in a large patient population undergoing percutaneous coronary intervention (PCI). A mouse model for restenosis was used to further investigate LPL's role in restenosis., Methods: The GENetic DEterminants of Restenosis (GENDER) project is a multicenter, prospective study design that enrolled 3,104 consecutive patients after successful PCI. These patients were genotyped for four different LPL gene polymorphisms. In apolipoprotein E (ApoE)*3-Leiden transgenic mice, arterial messenger ribonucleic acid (mRNA) was used to assess LPL expression during a cuff-induced restenotic process., Results: Using multivariable analysis, carriers of the 447Ter allele of the LPL enzyme showed a lower risk of TVR compared with 447Ser homozygotes (p = 0.005). In the mouse model, LPL mRNA levels were increased 40-fold compared with control arteries at 6 h after cuff placement., Conclusions: The LPL C/G polymorphism (Ser447Ter), resulting in a truncation of the two C-terminal amino acids of the mature LPL protein, appears to be an important protective factor for TVR in humans. The role of LPL in this process was further established in a mouse model, where LPL expression was very strongly up-regulated in the target arterial wall, suggesting a contribution of this lipolytic enzyme to restenosis. Possibly, LPL Ser447Ter genotyping may lead to better risk stratification and tailored therapy in the prevention of restenosis after PCI.

Objective: Patients with metabolic syndrome have increased risk of cardiovascular events. The number of patients with metabolic syndrome is rapidly increasing, and these patients often need revascularization. However, only limited data are available on the effect of metabolic syndrome on restenosis in patients undergoing percutaneous coronary intervention (PCI)., Research Design and Methods: To assess the role of metabolic syndrome in the development of restenosis, we performed an analysis in a population of patients from the GENetic DEterminants of Restenosis (GENDER) study. The GENDER project, a multicenter prospective study, included consecutive patients after successful PCI and was designed to study the predictive value of various genetic and other risk factors for subsequent clinical restenosis, defined as target vessel revascularization (TVR) or combined end point of death, myocardial infarction, and TVR. This subpopulation of GENDER consisted of 901 patients, 448 of whom (49.7%) had metabolic syndrome., Results: On multivariable Cox regression analysis, controlling for age, sex, previous myocardial infarction, stent length, current smoking, and statin therapy, there was no association between increased risk of TVR (hazard ratio 1.03 [95% CI 0.68-1.57]) or the combined end point (1.05 [0.71-1.55]) and the presence of metabolic syndrome., Conclusions: This study demonstrates that metabolic syndrome is not associated with TVR or the combined end point after PCI. Furthermore, accumulating characteristics of metabolic syndrome were neither associated with increased risk of TVR nor with the combined end point. Therefore, PCI has equal beneficial results in patients with or without metabolic syndrome. This is important information in light of the pandemic proportion of metabolic syndrome that the medical community will face.

The effect of preprocedural fibrinogen levels on in-stent restenosis is largely unknown. The -455G/A polymorphism of the fibrinogen beta-gene is associated with baseline plasma level or acute phase increase of fibrinogen. Therefore, we hypothesized that there is a relationship between this polymorphism and preprocedural fibrinogen level and clinical restenosis at follow-up among patients with coronary stent placement. The GENetic DEterminants of Restenosis (GENDER) project is a multicenter follow-up study that enrolled 3,146 consecutive patients after successful percutaneous coronary intervention. A coronary stent was placed in 2,309 patients. Of these, 2,257 (97.7%) patients were successfully genotyped for the -455G/A polymorphism. Plasma fibrinogen levels were measured at baseline in a subpopulation of 623 stented patients with the von Clauss method and patients were grouped into tertiles according to fibrinogen levels. Primary endpoint was target vessel revascularization (TVR); secondary combined endpoint was defined as death presumably from cardiac causes, MI not attributable to another coronary artery than the target vessel, and TVR. No association was observed between the -455G/A polymorphism and TVR or combined endpoint (p=0.99, p=0.97, respectively). Multivariate regression analysis revealed that the risk of TVR and combined endpoint was not higher for patients in the highest tertile for fibrinogen versus the lowest tertile (RR=0.60, 95% CI: 0.26-1.37 for TVR, RR=0.64, 95% CI: 0.29-1.44 for combined endpoint). In conclusion, the presence of -455G/A polymorphism in the fibrinogen beta-gene and preprocedural fibrinogen level is not associated with an increased risk of TVR or combined endpoint in a patient population with coronary stent placement. Therefore, these parameters are not worthwhile for stratifying patients at risk for restenosis pre-stenting.

Aims: To document the practice of interventional cardiology and the clinical restenosis rate, as well as the risk factors for clinical restenosis in an unselected population of patients in daily practice and to provide a perspective for the need of new devices such as drug-eluting stents., Methods and Results: A total of 3177 consecutive patients, who underwent successful percutaneous transluminal coronary angioplasty (PTCA) in the Netherlands, were included. Patients with acute myocardial infarction were excluded. The pre-defined end-point of clinical restenosis was defined as cardiac death, myocardial infarction and revascularisation of the target vessel. Follow-up (9.6 months, IQR 3.9) was complete in 3146 (99.3%) patients with a mean age of 62.1+/-10.7 years. Of them 896 (28.5%) were female, 459 (14.6%) had diabetes and 1459 (46.4%) had multi-vessel disease. Most patients (2105, 66.9%) were treated for stable angina. Of all patients, 819 (26.0%) were treated for multiple lesions, 2340 (74.4%) underwent stenting and 820 (26.1%) received glycoprotein IIb/IIIa inhibitors. All stented patients received life-long aspirin and ticlopidin/clopidogrel during at least 1 month after the procedure. Target vessel revascularisation during follow-up by either coronary artery by-pass grafting (CABG) or PTCA was necessary in 304 patients (9.7%). Thirty-three (1.1%) patients died of cardiac disease and 22 (0.7%) patients suffered from myocardial infarction (MI) attributable to the originally treated vessel. Overall, the need for revascularisation, or the incidence of cardiac death or MI occurred in 346 patients (11.0%), at 9 and 12 months these event-rates were 10.2% and 12.0%, respectively. Diabetes, hypertension, peripheral vessel disease, multi-vessel disease and treatment of type C lesions prevailed as independent risk factors for clinical restenosis. Longer stents and smaller minimal stent diameter were risk factors for in-stent stenosis., Conclusion: In this unselected series of consecutive patients treated for stable and unstable angina in everyday clinical practice in the pre-drug-eluting stent era, clinical restenosis after 9 and 12 months follow-up of the patients occurred in 10.2% and 12.0%, respectively. The risk varies from 8.3% to 17.6% depending on the number of risk factors. A proper selection of patients that benefit from new devices warranted, since the vast majority are well-treated with standard techniques and proper assignment of expensive new devices is obviously of importance for overall health care.

Genetic factors appear to be important in the restenotic process after percutaneous coronary intervention (PCI), as well as in inflammation, a pivotal factor in restenosis. TNFα, a key regulator of inflammatory responses, may exert critical influence on the development of restenosis after PCI. The GENetic DEterminants of Restenosis (GENDER) project included 3104 patients who underwent a successful PCI. Systematic genotyping for six polymorphisms in the TNFα gene was performed. The role of TNFα in restenosis was also assessed in ApoE*3-Leiden mice, TNFα knockout mice, and by local delivery of a TNFα biosynthesis inhibitor, thalidomide. The -238G-1031T haplotype of the TNFα gene increased clinical and angiographic risk of restenosis (P=0.02 and P=0.002, respectively). In a mouse model of reactive stenosis, arterial TNFα mRNA was significantly time-dependently up-regulated. Mice lacking TNFα or treated locally with thalidomide showed a reduction in reactive stenosis (P=0.01 and P=0.005, respectively). Clinical and preclinical data indicate that TNFα plays an important role in restenosis. Therefore, TNFα genotype may be used as a risk marker for restenosis and may contribute to individual patient screening prior to PCI in clinical practice. Inhibition of TNFα may be an anti-restenotic target strategy. [ABSTRACT FROM AUTHOR]

Background: A high throughput animal model may enhance pathophysiological studies to mechanisms of in-stent restenosis (ISR). More and appropriate antibodies and transgenic and knockout strains are available in rats. Consequently, a model for ISR in the rat would be convenient for pathobiological studies. Here we present the full characteristics of a rat ISR model suitable for high throughput stent research. Methods: The abdominal aorta of rats was separated from surrounding tissue and a BeStent™ 2 or a Cypher™ sirolimus-eluting stent was locally inserted. After 1, 3, 7, 28 and 56 days, the aortas were harvested, fixed, embedded and cut. Morphometric analysis was performed and inflammation scored. Results: The neointimal area increased to a maximum after 28 days (0.55 ± 0.08 mm2). Subsequently, the neointimal area slightly decreased. The injury score and the neointimal area were linearly correlated (r = 0.85, p < 0.01). Thrombus formation was present after 1 day. Leukocyte adherence was evident after 1 day, maximal after 3 days (93 ± 21 cells/section) and decreased thereafter. The inflammation score increased after 3 days to a maximum after 7 days (1.37 ± 0.06) and declined thereafter. After 28 days the Cypher sirolimus-eluting stent decreased the stenosis in comparison to the BeStent 2 (10.2 ± 0.85 vs. 18.0 ± 2.0%, respectively, p < 0.01). Conclusions: Stent deployment in the rat abdominal aorta results in thrombus formation, inflammation and neointimal formation. Moreover, there is a linear correlation between the injury score and the neointimal area. These responses resemble ISR events as seen in other animal models. Moreover, a known anti-restenotic stent also reduces neointimal formation in this model. Rat abdominal aorta stenting is a promising animal model for ISR, it is suitable for testing commercially manufactured stents and studying the pathophysiology of ISR. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Different components of the renin–angiotensin system (RAS) have been demonstrated in atherosclerotic plaques. However, the involvement of the RAS in in-stent restenosis is not clear. We studied the differential immunolocalisation of angiotensin converting enzyme (ACE) and the angiotensin II type 1 (AT1) receptor in de-novo stenotic lesions and in-stent restenotic lesions in human coronary arteries. Methods: Using a pullback atherectomy catheter, biopsies from de-novo coronary lesions (n=19) and in-stent restenotic lesions (n=19) were obtained. The biopsies were immunostained for vascular smooth muscle cells (VSMCs), macrophages, ACE and the AT1 receptor. Results: In biopsies from de-novo stenotic lesions ACE-positive macrophages were more numerous than in in-stent restenotic lesions (P=0.002). Moreover, in the latter lesions, ACE-positive macrophages decreased when the time interval of stent implantation was longer. On the other hand, in-stent restenotic lesions contained predominantly young VSMCs, which abundantly expressed AT1 receptors. Conclusions: Lesional ACE expression is not a prominent feature of in-stent restenotic lesions. In contrast, AT1 receptors are abundantly expressed on young VSMCs. In de-novo lesions ACE and AT1 receptors were found on macrophages and VSMCs, which were present in all specimens. [Copyright &y& Elsevier]