Clinical Restenosis after Coronary Stent Implantation Is Associated with the Heme Oxygenase-1 Gene Promoter Polymorphism and the Heme Oxygenase-1 99G/C Variant Talin Gulesserian, 1,2† Catharina Wenzel, 4† Georg Endler, 1 Raute Sunder-Plassmann, 1 Claudia Marsik, 1 Christine Mannhalter, 1 Nelly Iordanova, 4 Mariann Gyo¨ ngyo¨ si, 3 Johann Wojta, 3 Stefan Mustafa, 1 Oswald Wagner, 1* and Kurt Huber 4 Background: Vascular remodeling after percutaneous coronary stent implantation frequently leads to resteno- sis. Heme oxygenase 1 (HO-1) is involved in the gener- ation of the endogenous antioxidant bilirubin and car- bon monoxide, both of which exert antiinflammatory and antiproliferative effects. The aim of the present study was to evaluate the influence of genetic risk factors combined with the conventional risk factors on the development of coronary restenosis after percutane- ous coronary intervention (PCI) with stent implantation. Methods: The HO-1 gene GT dinucleotide repeat pro- moter polymorphism and HO-1 99G/C variant were evaluated in 199 patients with coronary artery disease after coronary stent implantation and control angiogra- phy at 6 months after the intervention. Coronary reste- nosis was confirmed by quantitative angiography. Results: Carriers of the long allele of the HO-1 gene promoter (>29 repeats) had a significantly higher risk of developing restenosis after PCI than noncarriers [odds ratio (OR)  1.9; 95% confidence interval (95% CI), 1.0 –3.4; P  0.04]. Interestingly, the allele longer than 29 repeats conferred a significantly higher risk of develop- ing restenosis (OR  3.4; 95% CI, 1.2–9.1; P  0.017) in nonsmokers than in smokers (OR  2.0; 95% CI, 0.7–5.2; P  0.18). Conclusions: The long allele of the HO-1 gene promoter (>29 repeats) polymorphism, which leads to low HO-1 inducibility, may represent an independent prognostic marker for restenosis after PCI and stent implantation. The effect of the >29 repeat allele is attenuated in smokers, who have chronic exogenous CO exposure. © 2005 American Association for Clinical Chemistry Atherosclerotic vascular disease, including coronary ar- tery disease, and its complication myocardial infarction (MI) 5 are the major causes of morbidity and mortality in industrialized countries. Endogenous and exogenous risk factors, such as smoking, hyperlipidemia, diabetes melli- tus (DM), and hypertension (1), significantly increase the individual risk for MI. Although new treatment strategies such as percutaneous coronary intervention (PCI) fol- lowed by stent implantation of acute and chronic coro- nary vessel occlusions have significantly reduced morbid- ity and mortality, in a considerable number of patients, in-stent restenosis after stent implantation significantly diminishes the success of revascularization. Over the past decade, several experimental approaches have been used to study the cardioprotective role of endogenous specific stress proteins, including heme oxy- genase (HO), which is part of the physiologic vascular 1 Clinical Institute of Medical and Chemical Laboratory Diagnostics, 2 Di- vision of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, and 3 Department of Cardiology, Medical University of Vienna, Vienna, Austria. 4 3rd Department of Medicine (Cardiology and Emergency Medicine), Wilhelminenhospital, Vienna, Austria. †These authors contributed equally to the present work. *Address correspondence to this author at: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Wa¨hr- inger Gu¨ rtel 18-20, 1090 Vienna, Austria. Fax 43-1-40400-5389; e-mail Oswald.Wagner@meduniwien.ac.at. Received March 23, 2005; accepted June 2, 2005. Previously published online at DOI: 10.1373/clinchem.2005.051581 5 Nonstandard abbreviations: MI, myocardial infarction; DM, diabetes mellitus; PCI, percutaneous coronary intervention; HO-1, heme oxygenase-1; OR, odds ratio; and 95% CI, 95% confidence interval. Clinical Chemistry 51:9 1661–1665 (2005) Lipids, Lipoproteins, and Cardiovascular Risk Factors 1661 Downloaded from https://academic.oup.com/clinchem/article/51/9/1661/5629912 by guest on 17 July 2022