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492 FABP4 PREDICTS ATHEROGENIC DYSLIPIDEMIA DEVELOPMENT. THE PREDIMED STUDY
79th EAS Congress
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
indicators of the biological age of an individual, and thus may be associated with increased risk of cardiovascular disease. Objective: We examined the hypothesis that presence of common aging signs are associated with increased risk of ischemic heart disease (IHD), myocardial infarction (MI), ischemic cerebrovascular disease (ICVD) and ischemic stroke (IS) in the general population. Methods: Facial wrinkles, greying of hair, and baldness were registered at baseline in 10,928 individuals from the Danish general population. Of these, 3,360 developed IHD, 1,700 developed MI, 1,549 developed ICVD and 1,347 developed IS during up to 34 years of follow-up. Results: Presence of common aging signs predicted hazard ratios of 1.21 (1.02–1.42) for IHD, 1.54 (1.22–1.94) for MI, 1.56 (1.23–2.00) for ICVD and 1.57 (1.20–2.04) for IS for individuals with 4 versus 0 common aging signs after adjustment for chronological age and sex. Conclusions: Common aging signs predict risk of IHD, MI, ICVD and IS in the general population independent of chronological age. In societies where other cardiovascular risk factors cannot be readily measured, presence of common aging signs may therefore be useful in identifying individuals with increased risk of cardiovascular disease. 492 FABP4 PREDICTS ATHEROGENIC DYSLIPIDEMIA DEVELOPMENT. THE PREDIMED STUDY A. Cabre´ 1 , N. Babio2 , I. Lazaro1 , M. Bullo´ 2 , A. Garcia-Arellano3 , L. Masana1 , J. Salas-Salvado´ 2 . 1 Unitat de Medicina Vascular i Metabolisme, Unitat de Recerca de L´ıpids i Arteriosclerosi, Hospital Universitari Sant Joan, IISPV, Universitat Rovira i Virgili, CIBERDEM, 2 Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, CIBER Fisiopatologia ´ (CIBERObn), Instituto de Salud Carlos III, Reus, de la Obesidad y Nutricion 3 Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain Aims: Atherogenic dyslipidemia (AD), characterized by high plasma triglycerides and low HDL particles, is considered one of the main effectors of vascular damage associated with obesity, metabolic syndrome (MS) and type 2 diabetes (T2D). The adipose Fatty Acid Binding Protein (FABP4) plasma concentrations have been linked to metabolic alterations that are associated with adiposity, such as MS, T2D and AD. The aim of this work was to prospectively study the predictive value of baseline FABP4 plasma concentrations on the development of AD. Methods and Results: A nested study within the PREDIMED trial, a multicenter dietary interventional project. Prospectively, we have analyzed the baseline plasma FABP4 levels and the incidence of AD over a six-year follow-up period (median 4 [IQR, 3−5 years]). We included 578 volunteers who visited their general practitioners because of their cardiovascular risk factors. During follow-up, 103 individuals developed AD. Baseline plasma FABP4 levels were associated with new onset AD over the follow-up period. An increase of 1 unit in baseline plasma FABP4 concentrations was associated with a 3% higher risk of developing AD (OR 1.03 [95% IC, 1.01–1.05], P= 0.008). This increased risk was observed in women but not in men. Among women, those in the highest tertile of FABP4 had a 92% increased relative risk of developing AD compared to the lowest tertile (HR 1.92 [95% CI, 1.03–3.58], P for trend = 0.039). Conclusion: Elevated plasma FABP4 concentrations should be considered as a marker of metabolic derangement, which may predict the development of AD in women. 493 THE APPLICATION OF RESEQUENCING MICROARRAY IN THE SCREENING OF FAMILIAL HYPERCHOLESTEROLEMIA M.-J. Charng1 , K.-R. Chiou2 . 1 Medicine, Taipei Veterans General Hospital/ National Yang-Ming University, Taipei, 2 Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan R.O.C. Background: Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. Methods and Results: We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes − LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) − and 290 known insertion/deletion mutations on LDLR. We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis.
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Conclusions: The high-throughput FH resequencing array detects LDLR, APOB, and PCSK9 with high efficiency and accuracy and identifies diseasecausing mutations cost-effectively. Thus, it facilitates large-scale screening of the heterogeneous FH populations. 494 ASSOCIATION OF ANTIBODY AGAINST HEAT SHOCK PROTEIN-27 AND PRO-OXIDANT-ANTIOXIDANT BALANCE WITH THE SEVERITY OF CORONARY ARTERY DISEASE AND METABOLIC SYNDROME M. Ghayour-Mobarhan1 , H. Pourghadamyari2 , M. Moohebati2 , S.M.R. Parizadeh2 , S. Tavallaie2 , A. Sahebkar2 , A. Rahsepar2 , R. Paydar2 , G. Ferns3 . 1 Biochemistry and Nutrition Research Center & Cardiovascular Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, 2 Mashhad University of Medical Sciences, Mashhad, Iran, 3 Institute for Science and Technology in Medicine, University of Keele, Guy Hilton Research Centre, Thornburrow Drive, Stoke on Trent, Staffordshire, UK Objectives: Antibody titers to several heat shock proteins (anti-Hsps) and oxidative stress have been reported to be associated with the severity and progression of cardiovascular disease. However, there are little data regarding anti-Hsp27 titers and pro-oxidant antioxidant balance (PAB) in patients with coronary artery disease (CAD) and metabolic syndrome. Methods: A total of 400 patients with suspected CAD were recruited. Based on the results of coronary angiography, these patients were classified into CAD+ (n = 300) and CAD− (n = 100) groups defined as patients with 50% and <50% stenosis of any major coronary artery, respectively. Eighty three healthy subjects were also recruited as the control group. Results: CAD+ patients had significantly higher anti-Hsp27 titers and PAB compared to both CAD- and control groups. Anti-Hsp27 titers and PAB were also higher in the CAD− group compared to the control group. With regard to the number of affected vessels in the CAD+ group, patients with 3 vessel disease (3VD) had higher anti-Hsp27 titers compared to both 2VD and 1VD subgroups, PAB did not differ significantly among patients with different vascular disease (SVD, 2VD and 3VD). Furthermore, the CAD+ patients were divided into metabolic syndrome and nonmetabolic syndrome patients. Metabolic syndrome patients had significantly higher anti-HSP27 titer than non metabolic syndrome patients (P = 0.021). However, PAB did not differ significantly between them (P = 0.85). Conclusions: Anti-Hsp27 titers may be associated with the presence and severity of CAD and metabolic syndrome. However, PAB may be associated with the present of CAD, but not for the severity of CAD. 495 ARTIFICIAL NEURAL NETWORK SYSTEM PREDICTS 6-YEAR INCIDENCE OF METABOLIC SYNDROME USING SERUM MARKERS FOR ATHEROSCLEROSIS H. Hirose1,2 , T. Takayama2 , S. Hozawa2 , I. Saito1,2 . 1 Health Center, Keio University, 2 Internal Medicine, Keio University School of Medicine, Tokyo, Japan Aims: Metabolic syndrome (MetS) is known as an important risk factor for atherosclerosis and cardiovascular diseases. Although insulin resistance and serum adiponectin level are closely related to the occurrence of MetS, it is difficult to predict the onset of MetS in clinical practice. The aims of this study were to predict the 6-year incidence of MetS using an artificial neural network (ANN) system based serum markers for atherosclerosis, including the insulin resistance index calculated by homeostasis model assessment (HOMA-IR), HDL-cholesterol and adiponectin levels. Methods: Subjects were recruited among the participants of annual health check-ups in 2000 and 2006. A total of 410 Japanese male teachers and workers at our Institute, aged 30 to 59 years at baseline, were participated in this retrospective cohort study. Clinical parameters were randomly divided into a training data set and a validation data set, and the ANN system and multiple logistic regression (MLR) analysis were used to predict the individual incidences. Results: The sensitivity of the prediction was 0.27 for the MLR models and 0.93 for the ANN, while the specificity was 0.95 for the MLR and 0.91 for the ANN. Sensitivity analysis of the ANN identified the BMI, age, diastolic blood pressure, HDL-cholesterol, LDL-cholesterol, and HOMA-IR as important predictive factors, suggesting that these factors are non-linearly related to the outcome. Conclusion: We successfully predicted the 6-year incidence of MetS using an ANN system based on clinical data, including HOMA-IR, serum HDL-cholesterol and adiponectin levels, in Japanese male subjects.
Atherosclerosis Supplements 12, no. 1 (2011) 13–184
indicators of the biological age of an individual, and thus may be associated with increased risk of cardiovascular disease. Objective: We examined the hypothesis that presence of common aging signs are associated with increased risk of ischemic heart disease (IHD), myocardial infarction (MI), ischemic cerebrovascular disease (ICVD) and ischemic stroke (IS) in the general population. Methods: Facial wrinkles, greying of hair, and baldness were registered at baseline in 10,928 individuals from the Danish general population. Of these, 3,360 developed IHD, 1,700 developed MI, 1,549 developed ICVD and 1,347 developed IS during up to 34 years of follow-up. Results: Presence of common aging signs predicted hazard ratios of 1.21 (1.02–1.42) for IHD, 1.54 (1.22–1.94) for MI, 1.56 (1.23–2.00) for ICVD and 1.57 (1.20–2.04) for IS for individuals with 4 versus 0 common aging signs after adjustment for chronological age and sex. Conclusions: Common aging signs predict risk of IHD, MI, ICVD and IS in the general population independent of chronological age. In societies where other cardiovascular risk factors cannot be readily measured, presence of common aging signs may therefore be useful in identifying individuals with increased risk of cardiovascular disease. 492 FABP4 PREDICTS ATHEROGENIC DYSLIPIDEMIA DEVELOPMENT. THE PREDIMED STUDY A. Cabre´ 1 , N. Babio2 , I. Lazaro1 , M. Bullo´ 2 , A. Garcia-Arellano3 , L. Masana1 , J. Salas-Salvado´ 2 . 1 Unitat de Medicina Vascular i Metabolisme, Unitat de Recerca de L´ıpids i Arteriosclerosi, Hospital Universitari Sant Joan, IISPV, Universitat Rovira i Virgili, CIBERDEM, 2 Human Nutrition Unit, IISPV, Hospital Universitari de Sant Joan, Universitat Rovira i Virgili, CIBER Fisiopatologia ´ (CIBERObn), Instituto de Salud Carlos III, Reus, de la Obesidad y Nutricion 3 Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain Aims: Atherogenic dyslipidemia (AD), characterized by high plasma triglycerides and low HDL particles, is considered one of the main effectors of vascular damage associated with obesity, metabolic syndrome (MS) and type 2 diabetes (T2D). The adipose Fatty Acid Binding Protein (FABP4) plasma concentrations have been linked to metabolic alterations that are associated with adiposity, such as MS, T2D and AD. The aim of this work was to prospectively study the predictive value of baseline FABP4 plasma concentrations on the development of AD. Methods and Results: A nested study within the PREDIMED trial, a multicenter dietary interventional project. Prospectively, we have analyzed the baseline plasma FABP4 levels and the incidence of AD over a six-year follow-up period (median 4 [IQR, 3−5 years]). We included 578 volunteers who visited their general practitioners because of their cardiovascular risk factors. During follow-up, 103 individuals developed AD. Baseline plasma FABP4 levels were associated with new onset AD over the follow-up period. An increase of 1 unit in baseline plasma FABP4 concentrations was associated with a 3% higher risk of developing AD (OR 1.03 [95% IC, 1.01–1.05], P= 0.008). This increased risk was observed in women but not in men. Among women, those in the highest tertile of FABP4 had a 92% increased relative risk of developing AD compared to the lowest tertile (HR 1.92 [95% CI, 1.03–3.58], P for trend = 0.039). Conclusion: Elevated plasma FABP4 concentrations should be considered as a marker of metabolic derangement, which may predict the development of AD in women. 493 THE APPLICATION OF RESEQUENCING MICROARRAY IN THE SCREENING OF FAMILIAL HYPERCHOLESTEROLEMIA M.-J. Charng1 , K.-R. Chiou2 . 1 Medicine, Taipei Veterans General Hospital/ National Yang-Ming University, Taipei, 2 Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan R.O.C. Background: Familial hypercholesterolemia (FH) is a heterogeneous autosomal dominant disease with a prevalence of 1 in 500. To date, over 1200 unique pathogenic mutations have been identified in at least 3 genes. The large allelic and genetic heterogeneity of FH requires high-throughput, rapid, and affordable mutation detection technology to efficiently integrate molecular screening into clinical practice. We developed an array-based resequencing assay to facilitate genetic testing in FH patients. Methods and Results: We designed a custom DNA resequencing array to detect mutations on all 3 FH-causing genes − LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 gene (PCSK9) − and 290 known insertion/deletion mutations on LDLR. We verified FH array performance by analyzing 35 previously sequenced subjects (21 with point mutations, 2 insertions, 7 deletions, and 5 healthy controls) and blindly screening 125 FH patients. The average microarray call rate was 98.45% and the agreement between microarray and capillary sequencing was 99.99%. The FH array detected mutations by using automated software analysis, followed by manual review in 28 of the 30 subjects (pickup rate, 93.3%). In the blinded study, the FH array detected at least 1 mutation in 77.5% of patients clinically diagnosed with definite FH according to Simon Broome FH criteria and in 52.9% with probable FH diagnosis.
105
Conclusions: The high-throughput FH resequencing array detects LDLR, APOB, and PCSK9 with high efficiency and accuracy and identifies diseasecausing mutations cost-effectively. Thus, it facilitates large-scale screening of the heterogeneous FH populations. 494 ASSOCIATION OF ANTIBODY AGAINST HEAT SHOCK PROTEIN-27 AND PRO-OXIDANT-ANTIOXIDANT BALANCE WITH THE SEVERITY OF CORONARY ARTERY DISEASE AND METABOLIC SYNDROME M. Ghayour-Mobarhan1 , H. Pourghadamyari2 , M. Moohebati2 , S.M.R. Parizadeh2 , S. Tavallaie2 , A. Sahebkar2 , A. Rahsepar2 , R. Paydar2 , G. Ferns3 . 1 Biochemistry and Nutrition Research Center & Cardiovascular Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, 2 Mashhad University of Medical Sciences, Mashhad, Iran, 3 Institute for Science and Technology in Medicine, University of Keele, Guy Hilton Research Centre, Thornburrow Drive, Stoke on Trent, Staffordshire, UK Objectives: Antibody titers to several heat shock proteins (anti-Hsps) and oxidative stress have been reported to be associated with the severity and progression of cardiovascular disease. However, there are little data regarding anti-Hsp27 titers and pro-oxidant antioxidant balance (PAB) in patients with coronary artery disease (CAD) and metabolic syndrome. Methods: A total of 400 patients with suspected CAD were recruited. Based on the results of coronary angiography, these patients were classified into CAD+ (n = 300) and CAD− (n = 100) groups defined as patients with 50% and <50% stenosis of any major coronary artery, respectively. Eighty three healthy subjects were also recruited as the control group. Results: CAD+ patients had significantly higher anti-Hsp27 titers and PAB compared to both CAD- and control groups. Anti-Hsp27 titers and PAB were also higher in the CAD− group compared to the control group. With regard to the number of affected vessels in the CAD+ group, patients with 3 vessel disease (3VD) had higher anti-Hsp27 titers compared to both 2VD and 1VD subgroups, PAB did not differ significantly among patients with different vascular disease (SVD, 2VD and 3VD). Furthermore, the CAD+ patients were divided into metabolic syndrome and nonmetabolic syndrome patients. Metabolic syndrome patients had significantly higher anti-HSP27 titer than non metabolic syndrome patients (P = 0.021). However, PAB did not differ significantly between them (P = 0.85). Conclusions: Anti-Hsp27 titers may be associated with the presence and severity of CAD and metabolic syndrome. However, PAB may be associated with the present of CAD, but not for the severity of CAD. 495 ARTIFICIAL NEURAL NETWORK SYSTEM PREDICTS 6-YEAR INCIDENCE OF METABOLIC SYNDROME USING SERUM MARKERS FOR ATHEROSCLEROSIS H. Hirose1,2 , T. Takayama2 , S. Hozawa2 , I. Saito1,2 . 1 Health Center, Keio University, 2 Internal Medicine, Keio University School of Medicine, Tokyo, Japan Aims: Metabolic syndrome (MetS) is known as an important risk factor for atherosclerosis and cardiovascular diseases. Although insulin resistance and serum adiponectin level are closely related to the occurrence of MetS, it is difficult to predict the onset of MetS in clinical practice. The aims of this study were to predict the 6-year incidence of MetS using an artificial neural network (ANN) system based serum markers for atherosclerosis, including the insulin resistance index calculated by homeostasis model assessment (HOMA-IR), HDL-cholesterol and adiponectin levels. Methods: Subjects were recruited among the participants of annual health check-ups in 2000 and 2006. A total of 410 Japanese male teachers and workers at our Institute, aged 30 to 59 years at baseline, were participated in this retrospective cohort study. Clinical parameters were randomly divided into a training data set and a validation data set, and the ANN system and multiple logistic regression (MLR) analysis were used to predict the individual incidences. Results: The sensitivity of the prediction was 0.27 for the MLR models and 0.93 for the ANN, while the specificity was 0.95 for the MLR and 0.91 for the ANN. Sensitivity analysis of the ANN identified the BMI, age, diastolic blood pressure, HDL-cholesterol, LDL-cholesterol, and HOMA-IR as important predictive factors, suggesting that these factors are non-linearly related to the outcome. Conclusion: We successfully predicted the 6-year incidence of MetS using an ANN system based on clinical data, including HOMA-IR, serum HDL-cholesterol and adiponectin levels, in Japanese male subjects.