| Percutaneous coronary intervention (PCI) has become a safe and effective treatment modality for single and multivessel coronary artery disease. However, restenosis is still the major limitation of PCI, resulting from injury of the vessel wall caused by balloon dilation and stent placement. The vascular damage is characterized by irritation of endothelial and subendothelial structures and injury of medial regions with rupture of the internal elastic lamina. This damage causes segmental thrombus formation and subsequent invasion of macrophages and polymorphonuclear leukocytes, followed by expression and release of numerous growth factors and cytokines from blood cells and stretched smooth muscle cells, leading to proliferation of smooth muscle cells. Vascular inflammation thus plays an important role in this complex multifactorial phenomenon. Restenosis is a major health problem, because it occurs in 10-40% of all treated persons, depending on which technique was used and the extension of the disease. No pharmacologic strategy or new device has proven effective in preventing this phenomenon. Only coronary stenting and the upcoming drug-eluting stents (DES) have reduced the incidence of restenosis, but certainly did not abolish it. In return difficult to treat in-stent restenosis might develop. Identifying patients at increased risk for restenosis may improve stratification of patients to individually tailored treatment. Thus far, however, it has proven difficult to stratify patients with regard to risk for coronary restenosis based only upon clinical or procedural risk factors, since risk factors identified so far in relation to restenosis have not been consistently reported. There is evidence that genetic factors explain part of the excessive risk for restenosis independently of conventional clinical variables. Therefore, the purpose of this study was to evaluate in a large unselected study sample whether a variety of inflammatory genetic determinants can predict the risk of clinical restenosis after PCI. The GENetic DEterminants of Restenosis project was designed to study the association between various gene polymorphisms and clinical restenosis. It is a multicenter prospective follow-up study with both clinical and angiographic restenosis as an endpoint. All patients undergoing percutaneous coronary interventions were eligible for the study. Only, patients treated for acute ST elevation myocardial infarction (MI) were excluded. After having obtained written informed consent, blood was sampled for DNA isolation and future analysis. Clinical and procedural data were gathered prospectively. Clinical restenosis was established during a 9 month follow-up for death, myocardial infarction and target vessel revascularisation. A repeat angiographic study was performed in a subpopulation after 6 months. An independent endpoint committee evaluated all potential endpoints. As mentioned before, inflammatory responsiveness, which is highly genetically determined, plays a pivotal role in the process of restenosis. Therefore, we concentrated on inflammatory genes. We mostly selected genes, on basis of their relation to inflammation previously described in literature reports of gene associations with inflammatory diseases. Participating centers Participating centers in the GENDER project are the Leiden University Medical Center in Leiden, the Academic Medical Center in Amsterdam, The University Hospital Maastricht and the University Medical Center Groningen. The Gaubius Laboratory of TNO-PG in Leiden collected the blood samples from the participating centers and isolated DNA. DNA-analysis was executed in the University Hospital of Maastricht and in the Sylvius Laboratory Leiden. Present status In 1998 the GENDER project was designed. Approval of the Medical Ethics Committees of the participating centers was obtained. Inclusion of patients started in March 1999. In June 2001 the last patient was included in the project. DNA has been extracted for all patients and genotyping for 114 SNPs in different genes has been performed by using two different arrays (inflammation and cardiovascular), developed by Roche Molecular Systems. Furthermore, three different multiplex assays, with 17 different polymorphisms, divided over 8 different genes have been developed and executed at the Sylvius laboratory. Four other polymorphisms have been analysed by Taqman analysis also at the Sylvius laboratory. Furthermore, we used an established mouse model of restenosis to study the involvement of the significantly associated genes with restenosis. This was performed in cooperation with the Gaubius Laboratory of TNO-PG. At the moment, we are in preparation to determine several polymorphisms in different candidate genes and gene systems, which can lead to an even better understanding of the restenotic process and thereby improve risk stratification of patients even more. Present results Total follow-up was completed in 3,146 patients, after exclusion of patients who developed an event in the first 30 days, 304 (9,8%) patients developed restenosis (target vessel revascularization, TVR). Angiographic follow-up is available in 480 patients. Indeed, so far, we were able to identify 16 polymorphisms in 15 different genes associated with restenosis. Six of these genes have already been validated in an established mouse model of restenosis, where they showed time-dependent upregulation and could thus confirm a role for these genes in the restenotic process. These genes contribute to the unravelling of the process of restenosis. Furthermore, genotyping of these genes may provide a better risk stratification and lead to a more tailored therapy for patients with identified increased risk of restenosis after PCI and may serve as rationale for new anti-restenotic therapies. |
