Genetic, clinical and experimental aspects of restenosis : a biomedical perspective

This thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of PCI. Genetic variance poses an opportunity to enhance stratification of individuals who will be more prone to develop restenosis. Restenosis is a multifactorial process, therefore only limited part of the number of candidate genes that are potentially involved in restenosis can be described. Since the inflammatory reaction is known to be highly important in restenosis, our study has its main focus on inflammatory markers. To examine various candidate genes and their polymorphisms we made use of the GENetic DEterminants of Restenosis (GENDER) study, a multicenter follow-up study, including 3,104 consecutive patients, who were successfully treated with PCI. In the different chapters we describe the study population and the clinical and genetic factors investigated. Furthermore, we made use of a mouse model to improve our understanding of restenosis. Our results have contributed to a better understanding of the restenotic process, they could provide novel therapeutic targets as well as contribute to development of improved risk stratification of patients who are scheduled for elective PCI, thereby creating the opportunity to individualize treatment in the future.LEI Universiteit LeidenNederlandse Hartstichting Jacues H. de Nong Stichting Medtronic Trading Nederland B.V. St. Jude Medical Nederland Sorin Group Nederland B.V. Pfizer Nederland B.V. Merck Sharp & Dohme B.V. Boehringer Ingelheim B.V. Bristol –Myers Squibb B.V. AstraZeneca B.V. Sankyo-pharma Nederland B.V. Bayer B.V. HealthCareVasculaire biologie en interventi

The role and importance of gene polymorphisms in the development of atherosclerosis

The development of atherosclerosis is a multifactorial process. The purpose of the study was to examine three genetic polymorphisms playing a role in the metabolic processes underlying the disease. We compared the data of 348 atherosclerotic non-diabetic patients with 260 atherosclerotic diabetic patients and 384 healthy controls. We analyzed the prevalence of myocardial infarction and stroke in three different groups of patients carrying different polymorphisms. It was proved that if the mutant TT eNOS Glu298ASP variant is present, a significantly higher number of myocardial infarctions can be observed than in patients carrying heterozygote GT or normal GG genotype. We proved that in the case of MTHFR 677CT heterozygote variants, the occurrence of myocardial infarction is significantly higher and the difference is also significant in case of the 677TT homozygote variant. It was verified that among patients with the mutant TNF-α AA genotype the occurrence of cardiovascular events was significantly higher. Screening the genetically high risk groups on the long run should be considered as an early detection opportunity that may give better chances for prevention and treatment. Understanding the inflammatory mechanisms of the atherosclerosis may give new therapeutical targets to pharmacologists

Genetics of ACS and recurrent MI/cardiac death: are we getting to the heart of the (atherosclerotic) matter?

Vascular Biology and Interventio

The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice

Objective: Inflammatory factors are thought to play a regulatory role in restenosis. Interleukin-10 (IL10) is an important anti-inflammatory cytokine with anti-atherogenic potentials. The aim of this study was to assess the effects of IL10 modulation on cuff-induced neointima formation in hypercholesterolemic APOE*3-Leiden mice. Methods: The involvement of IL10 in neointima formation was studied in a hypercholesterolemic mouse model of cuff-induced stenosis of the femoral artery by IL10 knocking-out or overexpression procedures. IL10+/- mice were crossbred with APOE*3-Leiden mice to generate hypercholesterolemic APOE*3-LeidenIL10-/- mice. To achieve IL10 overexpression in APOE*3-Leiden mice, a single intramuscular injection of a murine IL10 overexpression plasmid was performed followed by electroporation. Results: Knocking-out IL10, in hypercholesterolemic APOE*3-Leiden mice, resulted in a significant 1.9-fold increase of neointima surface as compared to APOE*3-LeidenIL10+/+ littermates (p = 0.02). Conversely, a marked 45% inhibition on cuff-induced neointima formation was obtained after IL10 overexpression (p = 0.02). Electrodelivery of IL10 vector leads to detectable IL10 serum levels, with a sustained expression over the experimental period of 3 weeks. IL10 overexpression reduced plasma cholesterol levels in APOE*3-Leiden mice, whereas IL10 deficiency in these mice did not lead to altered cholesterol levels as compared to the IL10+/+ group. Finally, IL10 overexpression stimulated endogenous IL10 mRNA expression in the spleen and reduced the transcriptional responses of several pro-inflammatory cytokines. Conclusion: Here, we clearly demonstrate the role of IL10 in the development of neointima formation in hypercholesterolemic mice and the potential therapeutic effect of non-viral electrodelivery of IL10 cDNA to inhibit post-angioplasty restenosis. © 2006 Elsevier Ireland Ltd. All rights reserved