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613 THE PREVALENCE OF POLYMORPHISMS PROTROMBOGENIC FACTORS IN PATIENTS WITH CORONARY HEART DISEASE
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
concentrations are associated with long-term mortality following ischemic stroke. Methods: In 244 patients with acute ischaemic stroke (age: 69±13 years), samples of ALCAM were obtained serially from presentation to day 5 and after half a year. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause mortality as the sole end-point. Results: At follow-up 72 patients (29%) had died. Patients with ALCAM in the fourth quartile (>46.8 ng/mL) at admission had a significantly poorer survival rate on univariate analysis (P < 0.001); other time-points did not add further but provided similar prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels and heart and/or renal failure, ALCAM levels above the fourth quartile remained an independent predictor of long-term mortality (adjusted hazard ratio, 2.05; 95% CI: 1.11 to 3.76; P = 0.021). Conclusions: ALCAM levels measured at admission of acute ischemic stroke are associated with long-term mortality. 611 DEVELOPMENT OF GENDER PRESPECIFIED PREDICTION MODEL BASED ON BAYESIAN BELIEVE NETWORKS METHOD FOR RISK ESTIMATION AFTER ACUTE CORONARY SYNDROME M.A. Evdokimova1 , I.V. Uporov2 , I.N. Kurochkin2 , A.V. Sulimov2 , D.N. Vtyurina2 , V.V. Nosikov3 , D.A. Zateyshchikov1 . 1 FSI Educational Scientific Medical Centre of the General Management Department of the President of Russian Federation, 2 Lomonosov Moscow State University, 3 National Research Centre “GosNII Genetika”, Moscow, Russia Clinical course prediction in patients undergoing acute coronary syndrome is a very important and only partial resolved clinical problem. The aim of the study was to develop the new model with includes clinical, genetic and instrumental date. 1190 patients (63.3% men) from 7 regions of Russia were involved in the study on the 10-th day after ACS in stable condition. We registered the following endpoints − unstable angina, fatal and nonfatal myocardial infarction and stroke and death for other reasons. The follow-up time was 18 mouths. The database contains 407 variables − clinical, life style, instrumental characteristics, 30 polymorphic markers of genes encoding haemostatic inflammation and lipids transport proteins. Bayesian believe networks (BN) method was used for evaluation outcome probabilities. A binary presentation of patient status has been employed − “sick” one, if endpoint occurred in less than 18 months after release from hospital, otherwise patient considered as “healthy”. We have carried out survival curve analysis (SCA) and determined the set of factors affecting patient outcomes. A current predictive BN demonstrate a satisfactory prognosis (AUC=0.59). The SCA also revealed that some factors (for example FGB-455G/A genotype) demonstrate opposite effect on outcome for men and women. Therefore one can conclude that prognosis method should take into account a gender difference between patients Quality of prognosis can be improved by building a separate BNs for men (AUC=0.67) and for women (AUC=0.63). Thus, gender prespecified Bayesian believe networks model can be useful for unfavorable outcome assessment for patients after ACS. 612 OVEREXPRESSION OF b2 -GLYCOPROTEIN I THAT INHIBITS CELL MIGRATION IN HUMAN AORTIC ENDOTHELIAL CELLS W.-C. Chiu1 , W.H.-H. Sheu2 , S.-Y. Lin2 , A.-N. Chiang1 . 1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 2 Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan R.O.C. Introduction: b2 -glycoprotein I (b2 -GPI), also known as apolipoprotein H, is a plasma glycoprotein with poorly defined function in vascular cells. Objectives: To clarify the role of oxidative stress in b 2 -GPI gene regulation and determine the effect of b2 -GPI on cell migration in human aortic endothelial cells (HAECs). Results: We demonstrate that expression of b2 -GPI at both protein and mRNA levels was significantly elevated in Huh7 cells treated with hydrogen peroxide (H2 O2 ). Knockdown of the c-Jun, c-Fos, p65, and p50 genes using small interfering RNAs (siRNAs) indicate that AP-1 and NF-úB may play an essential role in the H2 O2 -induced b2 -GPI expression. We found that positive immunostaining for b2 -GPI was occurred in the endothelium of human atherosclerotic plaque. Using wound-healing assay, we found that HAECs treated with b2 -GPI resulted in a dose-dependent decrease in endothelial cell migration and anti-b2 -GPI antibody significantly restored the anti-migration effect of b2 -GPI. Moreover, overexpression of b2 -GPI by transient infection of HAECs with adenoviral reporter or empty vector also revealed that b2 -GPI inhibited cell migration. We assessed the events in response to b2 -GPI-treated HAECs by immunofluorescence microscopy. Consistent with the idea shown above, b2 -GPI ameliorated actin distribution in response to wound healing. Conclusions: Our findings provide new insight suggesting that b2 -GPI expression is up-regulated in hepatocytes under oxidative stress through stress sensing pathways and b2 -GPI possesses anti-migration properties in human endothelial cells.
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613 THE PREVALENCE OF POLYMORPHISMS PROTROMBOGENIC FACTORS IN PATIENTS WITH CORONARY HEART DISEASE G.A. Chumakova1,2 , A.A. Kozarenko1,2 , N. Veselovskaya2,3 . 1 Internal Medicine, Altay State Medical University, Barnaul, 2 Multifocal Atherosclerosis, Science Research Institute of Complex Problems of Cardiovascular Diseases SD RAMS, Kemerovo, 3 Cardiologycal, Altay Regional Cardiology Dispensaries, Barnaul, Russia Objective: To study the prevalence of allelic protrombogenic polymorphisms in coronary heart disease (CHD). Design and Methods: The study included 115 patients (94 men and 21 women) aged 33 to 70 years with angina. Also examined 572 healthy adolescents. All patients were studied the carrier of polymorphisms of tissue plasminogen activator inhibitor type-I − SERPINE1; prothrombin − F2; factor V Leiden − F5, and gene polymorphism of methylenetetrahydrofolate reductase − MTHFR. Results: The overall incidence of these polymorphisms in patients with severe angina was 87%, and the group of healthy individuals − 28.8% and the combination of 3 or more polymorphisms occurred in 13.9% patients and 0% of healthy individuals. In combination of three of studied polymorphisms the clinical debut of CHD occurs on average 7 years earlier, than patients without these polymorphisms (48.2±1.0 vs. 55.2±1.2 years, p = 0.007). The clinical presentation of angina in male smokers with three protrombogenic polymorphisms appeared earlier on average 9.4 years, than in men without these polymorphisms (56±1.1 vs. 46.6±1.2 years, p < 0.000). In patients with CHD associated with the metabolic syndrome age debut of angina in the presence of three different polymorphisms protrombogenic factors was on average 7.3 years less than in patients with one of the studied polymorphisms (48.3±1.2 vs. 55.6±1.9 years; p = 0.014). Conclusions: Protrombogenic genetic polymorphisms occur among patients with CHD significantly more frequent than in the healthy population, which should be considered in of population-based prevention of atherosclerosis. 614 FATTY ACID BINDING PROTEIN 4 AS A BIOMARKER OF CAROTID ATHEROSCLEROSIS AND OUTCOME IN PATIENTS WITH ACUTE ISCHEMIC STROKE S. Holm1 , T. Ueland1 , T.B. Dahl1 , A.E. Michelsen1 , M. Skjelland1 , D. Russell1 , K. Krogh-Sørensen1 , O.P. Clausen1 , D. Atar2 , J.L. Januzzi3 , P. Aukrust1 , J.K. Jensen4 , B. Halvorsen1 . 1 Oslo University Hospital, Rikshospitalet, 2 Oslo University Hospital, Aker, Oslo, Norway, 3 Massachusetts General Hospital, Boston, MA, USA, 4 Odense University Hospital, Odense, Denmark Background and Objective: Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking, and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke. Methods: We examined FABP4 concentrations in asymptomatic and symptomatic subjects with carotid atherosclerosis, as well as in 244 subjects with acute ischemic stroke. Concentrations of FABP4 were analyzed as a function of presence and severity of carotid atherosclerosis. We also examined the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in THP-1 monocytes/macrophages. In addition, FABP4 concentrations were examined for their ability to predict mortality during longitudinal follow-up following ischemic stroke. Results: FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms (<1 month). Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in THP-1 monocytes/macrophages. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with mortality during follow-up. Conclusions: FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke. 615 GENOME ANALYSIS IS MORE EFFFECTIVE THAN SINGLE-GENE ANALYSIS IN IDENTIFYING SUBJECTS AT HIGH RISK FOR ATHEROTHROMBOSIS A. Izzotti. Health Sciences, University of Genoa, Genoa, Italy Analysis of genetic risk-factor for atherothrombosis is usually pursued by evaluating polymorphisms of single genes mainly including factor II (prothrombin) and factor V (Leiden). However, this approach explores only a small piece of the genetic information playing a role in atherothrombosis. The aim of our study was to evaluate the performance of microarray SNPs analysis in evaluating individual risk for atherothrombosis as compared to single-gene analysis in three independent studies. In the first retrospective study 4,661 subjects undergoing factor II and V analyses were followed up for 7 years without observing any influence of these genotypes on the incidence of atherohtombotic episodes, a finding likely related to the scarcity of homozigous mutants (<0.1%). In the second prospective study
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
concentrations are associated with long-term mortality following ischemic stroke. Methods: In 244 patients with acute ischaemic stroke (age: 69±13 years), samples of ALCAM were obtained serially from presentation to day 5 and after half a year. Patients with overt ischaemic heart disease and atrial fibrillation were excluded. The patients were followed for 47 months, with all-cause mortality as the sole end-point. Results: At follow-up 72 patients (29%) had died. Patients with ALCAM in the fourth quartile (>46.8 ng/mL) at admission had a significantly poorer survival rate on univariate analysis (P < 0.001); other time-points did not add further but provided similar prognostic information. In multivariate analysis, after adjustment for age, stroke severity, C-reactive protein levels, troponin T levels and heart and/or renal failure, ALCAM levels above the fourth quartile remained an independent predictor of long-term mortality (adjusted hazard ratio, 2.05; 95% CI: 1.11 to 3.76; P = 0.021). Conclusions: ALCAM levels measured at admission of acute ischemic stroke are associated with long-term mortality. 611 DEVELOPMENT OF GENDER PRESPECIFIED PREDICTION MODEL BASED ON BAYESIAN BELIEVE NETWORKS METHOD FOR RISK ESTIMATION AFTER ACUTE CORONARY SYNDROME M.A. Evdokimova1 , I.V. Uporov2 , I.N. Kurochkin2 , A.V. Sulimov2 , D.N. Vtyurina2 , V.V. Nosikov3 , D.A. Zateyshchikov1 . 1 FSI Educational Scientific Medical Centre of the General Management Department of the President of Russian Federation, 2 Lomonosov Moscow State University, 3 National Research Centre “GosNII Genetika”, Moscow, Russia Clinical course prediction in patients undergoing acute coronary syndrome is a very important and only partial resolved clinical problem. The aim of the study was to develop the new model with includes clinical, genetic and instrumental date. 1190 patients (63.3% men) from 7 regions of Russia were involved in the study on the 10-th day after ACS in stable condition. We registered the following endpoints − unstable angina, fatal and nonfatal myocardial infarction and stroke and death for other reasons. The follow-up time was 18 mouths. The database contains 407 variables − clinical, life style, instrumental characteristics, 30 polymorphic markers of genes encoding haemostatic inflammation and lipids transport proteins. Bayesian believe networks (BN) method was used for evaluation outcome probabilities. A binary presentation of patient status has been employed − “sick” one, if endpoint occurred in less than 18 months after release from hospital, otherwise patient considered as “healthy”. We have carried out survival curve analysis (SCA) and determined the set of factors affecting patient outcomes. A current predictive BN demonstrate a satisfactory prognosis (AUC=0.59). The SCA also revealed that some factors (for example FGB-455G/A genotype) demonstrate opposite effect on outcome for men and women. Therefore one can conclude that prognosis method should take into account a gender difference between patients Quality of prognosis can be improved by building a separate BNs for men (AUC=0.67) and for women (AUC=0.63). Thus, gender prespecified Bayesian believe networks model can be useful for unfavorable outcome assessment for patients after ACS. 612 OVEREXPRESSION OF b2 -GLYCOPROTEIN I THAT INHIBITS CELL MIGRATION IN HUMAN AORTIC ENDOTHELIAL CELLS W.-C. Chiu1 , W.H.-H. Sheu2 , S.-Y. Lin2 , A.-N. Chiang1 . 1 Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, 2 Department of Education and Research, Taichung Veterans General Hospital, Taichung, Taiwan R.O.C. Introduction: b2 -glycoprotein I (b2 -GPI), also known as apolipoprotein H, is a plasma glycoprotein with poorly defined function in vascular cells. Objectives: To clarify the role of oxidative stress in b 2 -GPI gene regulation and determine the effect of b2 -GPI on cell migration in human aortic endothelial cells (HAECs). Results: We demonstrate that expression of b2 -GPI at both protein and mRNA levels was significantly elevated in Huh7 cells treated with hydrogen peroxide (H2 O2 ). Knockdown of the c-Jun, c-Fos, p65, and p50 genes using small interfering RNAs (siRNAs) indicate that AP-1 and NF-úB may play an essential role in the H2 O2 -induced b2 -GPI expression. We found that positive immunostaining for b2 -GPI was occurred in the endothelium of human atherosclerotic plaque. Using wound-healing assay, we found that HAECs treated with b2 -GPI resulted in a dose-dependent decrease in endothelial cell migration and anti-b2 -GPI antibody significantly restored the anti-migration effect of b2 -GPI. Moreover, overexpression of b2 -GPI by transient infection of HAECs with adenoviral reporter or empty vector also revealed that b2 -GPI inhibited cell migration. We assessed the events in response to b2 -GPI-treated HAECs by immunofluorescence microscopy. Consistent with the idea shown above, b2 -GPI ameliorated actin distribution in response to wound healing. Conclusions: Our findings provide new insight suggesting that b2 -GPI expression is up-regulated in hepatocytes under oxidative stress through stress sensing pathways and b2 -GPI possesses anti-migration properties in human endothelial cells.
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613 THE PREVALENCE OF POLYMORPHISMS PROTROMBOGENIC FACTORS IN PATIENTS WITH CORONARY HEART DISEASE G.A. Chumakova1,2 , A.A. Kozarenko1,2 , N. Veselovskaya2,3 . 1 Internal Medicine, Altay State Medical University, Barnaul, 2 Multifocal Atherosclerosis, Science Research Institute of Complex Problems of Cardiovascular Diseases SD RAMS, Kemerovo, 3 Cardiologycal, Altay Regional Cardiology Dispensaries, Barnaul, Russia Objective: To study the prevalence of allelic protrombogenic polymorphisms in coronary heart disease (CHD). Design and Methods: The study included 115 patients (94 men and 21 women) aged 33 to 70 years with angina. Also examined 572 healthy adolescents. All patients were studied the carrier of polymorphisms of tissue plasminogen activator inhibitor type-I − SERPINE1; prothrombin − F2; factor V Leiden − F5, and gene polymorphism of methylenetetrahydrofolate reductase − MTHFR. Results: The overall incidence of these polymorphisms in patients with severe angina was 87%, and the group of healthy individuals − 28.8% and the combination of 3 or more polymorphisms occurred in 13.9% patients and 0% of healthy individuals. In combination of three of studied polymorphisms the clinical debut of CHD occurs on average 7 years earlier, than patients without these polymorphisms (48.2±1.0 vs. 55.2±1.2 years, p = 0.007). The clinical presentation of angina in male smokers with three protrombogenic polymorphisms appeared earlier on average 9.4 years, than in men without these polymorphisms (56±1.1 vs. 46.6±1.2 years, p < 0.000). In patients with CHD associated with the metabolic syndrome age debut of angina in the presence of three different polymorphisms protrombogenic factors was on average 7.3 years less than in patients with one of the studied polymorphisms (48.3±1.2 vs. 55.6±1.9 years; p = 0.014). Conclusions: Protrombogenic genetic polymorphisms occur among patients with CHD significantly more frequent than in the healthy population, which should be considered in of population-based prevention of atherosclerosis. 614 FATTY ACID BINDING PROTEIN 4 AS A BIOMARKER OF CAROTID ATHEROSCLEROSIS AND OUTCOME IN PATIENTS WITH ACUTE ISCHEMIC STROKE S. Holm1 , T. Ueland1 , T.B. Dahl1 , A.E. Michelsen1 , M. Skjelland1 , D. Russell1 , K. Krogh-Sørensen1 , O.P. Clausen1 , D. Atar2 , J.L. Januzzi3 , P. Aukrust1 , J.K. Jensen4 , B. Halvorsen1 . 1 Oslo University Hospital, Rikshospitalet, 2 Oslo University Hospital, Aker, Oslo, Norway, 3 Massachusetts General Hospital, Boston, MA, USA, 4 Odense University Hospital, Odense, Denmark Background and Objective: Fatty acid binding protein 4 (FABP4) has been shown to play an important role in macrophage cholesterol trafficking, and associated inflammation. To further elucidate the role of FABP4 in atherogenesis in humans, we examined the regulation of FABP4 in carotid atherosclerosis and ischemic stroke. Methods: We examined FABP4 concentrations in asymptomatic and symptomatic subjects with carotid atherosclerosis, as well as in 244 subjects with acute ischemic stroke. Concentrations of FABP4 were analyzed as a function of presence and severity of carotid atherosclerosis. We also examined the ability of different stimuli with relevance to atherosclerosis to regulate FABP4 expression in THP-1 monocytes/macrophages. In addition, FABP4 concentrations were examined for their ability to predict mortality during longitudinal follow-up following ischemic stroke. Results: FABP4 levels were higher in patients with carotid atherosclerosis, both systemically and within the atherosclerotic lesion, with particular high mRNA levels in carotid plaques from patients with the most recent symptoms (<1 month). Immunostaining of carotid plaques localized FABP4 to macrophages, while activated platelets and oxidized LDL were potent stimuli for FABP4 expression in THP-1 monocytes/macrophages. When measured at the time of acute ischemic stroke, high plasma levels of FABP4 were significantly associated with mortality during follow-up. Conclusions: FABP4 is linked to atherogenesis, plaque instability and adverse outcome in patients with carotid atherosclerosis and acute ischemic stroke. 615 GENOME ANALYSIS IS MORE EFFFECTIVE THAN SINGLE-GENE ANALYSIS IN IDENTIFYING SUBJECTS AT HIGH RISK FOR ATHEROTHROMBOSIS A. Izzotti. Health Sciences, University of Genoa, Genoa, Italy Analysis of genetic risk-factor for atherothrombosis is usually pursued by evaluating polymorphisms of single genes mainly including factor II (prothrombin) and factor V (Leiden). However, this approach explores only a small piece of the genetic information playing a role in atherothrombosis. The aim of our study was to evaluate the performance of microarray SNPs analysis in evaluating individual risk for atherothrombosis as compared to single-gene analysis in three independent studies. In the first retrospective study 4,661 subjects undergoing factor II and V analyses were followed up for 7 years without observing any influence of these genotypes on the incidence of atherohtombotic episodes, a finding likely related to the scarcity of homozigous mutants (<0.1%). In the second prospective study