- Email: [email protected]
2P-0590 Effect of statin on promoter activity of human serum paraoxonase 1 gene
Tuesday September 30, 2003: Poster Session Therapy 2P-0589
Influence of apolipoprotein E polymorphisms on coronary artery disease and on the efficacy of HMG-CoA reductase inhibitors in men
A.H. Maitland-van der Zee 1 , J.W. Jukema 2 , A.H. Zwinderman 2 , D.M. Hallman 3 , J.C. Seidell 4 , A. De Boer 1 , J.J.P. Kastelein 5 , P. De Knijff 6 , G.K. Hovingh 2 . 1 Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University; 2 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; 3 Human Genetics Center, University of Texas Health Science Centre, Houston, USA; 4 Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and Environmental Protection; 5 Department of Vascular Medicine, Academic Medical Center, Amsterdam; 6 Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
2P-0590
Effect of statin on promoter activity of human serum paraoxonase 1 gene
K. Ota, K. Arii, T. Suehiro, Y. Ikeda, Y. Kumon, K. Hashimoto. Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi, Japan Objective: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has various pleiotropic effects of anti-atherosclerosis in addition to cholesterol lowering effect. Human serum paraoxonase 1 (PON1) is associated with HDL particle and inhibits the oxidative modification of LDL. We investigated whether stain has an effect on promoter activity of PON1 gene. Materials and methods: HepG2 cells were transfected with constructions of plasmid pGL3 luciferase reporter vector containing PON1 promoter region (-6/-587). Pitavastain, atrovastain or simvastain was added, and after 24 hrs, luciferase activity was measured as promoter activity. Results and Discussion: Pitavastain increased the promoter activity in a dose dependent manner. Atrovastatin and simvastain also increased the PON1 promoter activity. Mevalonate and farnesyl pyrophosphate (FPP) restored the stain effect on PON1 promoter activity, but geranylgeranyl pyrophosphate did not. These results suggest that not only pitavastain but also other stains induce PON1 promoter activation, and the inhibition of FPP pathway is a key mechanism of the promotive effect of statin on PON1 promoter activity. Conclusion: Stain activated the transcription of PON1 gene and inhibition of FPP pathway is involved in this effect. It is supposed that the statin-induced promoter activation of PON1 gene is one of anti-atherosclerotic effects of statin.
Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia
C. Otto 1 , P. Kern 2 , R. Bambauer 3 , S. Kallert 2 , P. Schwandt 4 , K.G. Parhofer 1 . 1 Medical Department 2, University Hospital, Munich; 2 Franz-von-Prümmer-Klinik, Bad Brückenau; 3 Institute for Blood Purification, Homburg/Saar; 4 Arteriosclerosis Prevention Institute, Munich, Germany Objective: LDL apheresis is an extracorporal modality to lower LDL cholesterol. While most of the devices eliminate LDL particles from plasma, a recently introduced whole blood perfusion column (DALI) adsorbs lipoproteins directly from whole blood. Methods: In a multicenter trial we investigated the efficacy and safety of a new whole-blood LDL apheresis system (Liposorber D) in 10 patients with severe hypercholesterolemia and coronary heart disease who had already been treated regularly with another LDL apheresis technique before. In the Liposorber D, positively charged atherogenic lipoproteins (LDL, VLDL, lipoprotein(a)) are adsorbed by negatively charged dextran sulfate. Results: In 93 LDL aphereses, the mean reduction in LDL cholesterol and lipoprotein(a) was 62.2±11.5% and 55.6±16.9%, respectively (p<0.01). If hemodilution during apheresis was considered, the reductions were 58.0±10.9 and 55.3±10.9%, respectively (p<0.01), while HDL cholesterol did not change significantly. Fibrinogen concentration was lowered by 12% during a single LDL apheresis (p<0.01). Treatment time of a single apheresis procedure was 112±22 minutes. When safety parameters before the first apheresis were compared with parameters before the final apheresis no significant changes were observed with the exception of a lower blood glucose before the final apheresis (86±25 vs. 94±29 mg/dl, p<0.05). Three mild episodes of hypocalcemia and two mild episodes of arterial hypotension were observed, however, LDL apheresis could be continued in each case. Conclusion: The new whole blood LDL apheresis with Liposorber D is a safe, simple and useful modality to reduce LDL cholesterol and lipoprotein(a) in cardiovascular high risk patients. 2P-0592
Cost-effectiveness of screening for abdominal aortic aneurysm Japan-based estimates
S. Ishikawa, T. Takahasi, K. Oshima, J. Mohara, Y. Morishita. 2nd Department of Surgery, Gunma University Hospital, Japan Objective: The detection rate of AAA in our study was less than a half of that in European countries. The purpose of this study is to evaluate the cost-effectiveness of this screening procedure in Japan particularly focusing the screening cost and the hospital cost for AAA surgery. Methods: A total of 10,057 residents, who are 60 years of age or more, participated in a abdominal aortic aneurysm (AAA) screening test using ultrasound, which included 4247 males and 5810 females. Aneurysm was detected in 34 out of 10,057 participants, including 32 males and two females. The mean age of patients with AAAs was 74 years ranging from 62 to 90. The detection rate of AAA was 0.8% in males, 0.03% in females and 0.3% in total. Results: It took eight dollars for screening each participant, and a cost for detecting each aneurysm was estimated at 1,250 dollars in males, 23,240 dollars in females and 2,366 dollars in total. The mean hospital cost was significantly (p<0.01) higher in our recent patients with ruptured AAA than in those with non-ruptured AAA (37,583 vs. 15,750 dollars). The size of aneurysm detected in the screening test was less than 40 mm in 22 (65%) out of 34. It was estimated 920 dollars to study a patient with small aneurysm using US every six months for a ten-year follow-up period. Male, obesity and smoking habits were significant factors in patients with AAA than in participants without AAA. There were no significant differences between patients with AAA and participants without AAA in the frequency of hypertension, ischemic heart disease, diabetes mellitus or hyperlipidemia. Conclusion: A screening for AAA using US is useful not only for the early detection of AAA but also for the reduction of overall medical cost in Japan.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Aim: To study the influence of APOE polymorphisms on risk of coronary atherosclerosis among normolipidaemic males and on efficacy of statins towards lipids, lipoproteins and angiographic parameters. Methods: APOE genotypes were studied in a group (n = 815) of well characterised male CAD patients who participated in the lipid lowering regression study “REGRESS”. Results were compared with two control groups (n=280 and 1801). Results: No significant differences regarding APOE allele or genotype frequencies were observed between patients and controls. CAD patients with APOE2+ had lower total (-0.04%, p=0.04)) and LDL-cholesterol levels (-0.07%, p=0.002) and lower LDL/HDL ratio (-0.08%, p=0.002), lower HDL-cholesterol (+5.6%, p=0.03) and higher triglycerides (+10.7%, p=0.04) when compared with CAD patients with APOE4+. In contrast no significant differences were observed in angiographic parameters. There was a significant interaction between treatment (placebo/pravastatin) and APOE genotype considering lipid levels, APOE2+ carriers had the largest improvement of HDL levels (+0.15 mmol/l) and LDL/HDL ratio’s (-0.60) compared with APOE3+ (+0.06 mmol/l, -0.043 respectively) and APOE4+ carriers (+0.07mmol/l, -0.040). In contrast APOE2+ allele carriers had less effect in terms of angiographic parameters although not statistically significant. Conclusions: APOE influences lipid and lipoprotein levels, but is not associated with the extent or prevalence of coronary atherosclerosis in normolipidemic males with CAD. The effects of statins in subjects with different APOE genotypes were different with regard to lipoprotein profile, but not with regard to angiographic parameters. This study was financially supported by the Netherlands Heart Foundation, Grant No. 2000.170. REGRESS was sponsored by Bristol Myers Squibb.
2P-0591
169
Influence of apolipoprotein E polymorphisms on coronary artery disease and on the efficacy of HMG-CoA reductase inhibitors in men
A.H. Maitland-van der Zee 1 , J.W. Jukema 2 , A.H. Zwinderman 2 , D.M. Hallman 3 , J.C. Seidell 4 , A. De Boer 1 , J.J.P. Kastelein 5 , P. De Knijff 6 , G.K. Hovingh 2 . 1 Department of Pharmacoepidemiology & Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University; 2 Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands; 3 Human Genetics Center, University of Texas Health Science Centre, Houston, USA; 4 Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and Environmental Protection; 5 Department of Vascular Medicine, Academic Medical Center, Amsterdam; 6 Department of Human Genetics, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
2P-0590
Effect of statin on promoter activity of human serum paraoxonase 1 gene
K. Ota, K. Arii, T. Suehiro, Y. Ikeda, Y. Kumon, K. Hashimoto. Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi, Japan Objective: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has various pleiotropic effects of anti-atherosclerosis in addition to cholesterol lowering effect. Human serum paraoxonase 1 (PON1) is associated with HDL particle and inhibits the oxidative modification of LDL. We investigated whether stain has an effect on promoter activity of PON1 gene. Materials and methods: HepG2 cells were transfected with constructions of plasmid pGL3 luciferase reporter vector containing PON1 promoter region (-6/-587). Pitavastain, atrovastain or simvastain was added, and after 24 hrs, luciferase activity was measured as promoter activity. Results and Discussion: Pitavastain increased the promoter activity in a dose dependent manner. Atrovastatin and simvastain also increased the PON1 promoter activity. Mevalonate and farnesyl pyrophosphate (FPP) restored the stain effect on PON1 promoter activity, but geranylgeranyl pyrophosphate did not. These results suggest that not only pitavastain but also other stains induce PON1 promoter activation, and the inhibition of FPP pathway is a key mechanism of the promotive effect of statin on PON1 promoter activity. Conclusion: Stain activated the transcription of PON1 gene and inhibition of FPP pathway is involved in this effect. It is supposed that the statin-induced promoter activation of PON1 gene is one of anti-atherosclerotic effects of statin.
Efficacy and safety of a new whole-blood low-density lipoprotein apheresis system (Liposorber D) in severe hypercholesterolemia
C. Otto 1 , P. Kern 2 , R. Bambauer 3 , S. Kallert 2 , P. Schwandt 4 , K.G. Parhofer 1 . 1 Medical Department 2, University Hospital, Munich; 2 Franz-von-Prümmer-Klinik, Bad Brückenau; 3 Institute for Blood Purification, Homburg/Saar; 4 Arteriosclerosis Prevention Institute, Munich, Germany Objective: LDL apheresis is an extracorporal modality to lower LDL cholesterol. While most of the devices eliminate LDL particles from plasma, a recently introduced whole blood perfusion column (DALI) adsorbs lipoproteins directly from whole blood. Methods: In a multicenter trial we investigated the efficacy and safety of a new whole-blood LDL apheresis system (Liposorber D) in 10 patients with severe hypercholesterolemia and coronary heart disease who had already been treated regularly with another LDL apheresis technique before. In the Liposorber D, positively charged atherogenic lipoproteins (LDL, VLDL, lipoprotein(a)) are adsorbed by negatively charged dextran sulfate. Results: In 93 LDL aphereses, the mean reduction in LDL cholesterol and lipoprotein(a) was 62.2±11.5% and 55.6±16.9%, respectively (p<0.01). If hemodilution during apheresis was considered, the reductions were 58.0±10.9 and 55.3±10.9%, respectively (p<0.01), while HDL cholesterol did not change significantly. Fibrinogen concentration was lowered by 12% during a single LDL apheresis (p<0.01). Treatment time of a single apheresis procedure was 112±22 minutes. When safety parameters before the first apheresis were compared with parameters before the final apheresis no significant changes were observed with the exception of a lower blood glucose before the final apheresis (86±25 vs. 94±29 mg/dl, p<0.05). Three mild episodes of hypocalcemia and two mild episodes of arterial hypotension were observed, however, LDL apheresis could be continued in each case. Conclusion: The new whole blood LDL apheresis with Liposorber D is a safe, simple and useful modality to reduce LDL cholesterol and lipoprotein(a) in cardiovascular high risk patients. 2P-0592
Cost-effectiveness of screening for abdominal aortic aneurysm Japan-based estimates
S. Ishikawa, T. Takahasi, K. Oshima, J. Mohara, Y. Morishita. 2nd Department of Surgery, Gunma University Hospital, Japan Objective: The detection rate of AAA in our study was less than a half of that in European countries. The purpose of this study is to evaluate the cost-effectiveness of this screening procedure in Japan particularly focusing the screening cost and the hospital cost for AAA surgery. Methods: A total of 10,057 residents, who are 60 years of age or more, participated in a abdominal aortic aneurysm (AAA) screening test using ultrasound, which included 4247 males and 5810 females. Aneurysm was detected in 34 out of 10,057 participants, including 32 males and two females. The mean age of patients with AAAs was 74 years ranging from 62 to 90. The detection rate of AAA was 0.8% in males, 0.03% in females and 0.3% in total. Results: It took eight dollars for screening each participant, and a cost for detecting each aneurysm was estimated at 1,250 dollars in males, 23,240 dollars in females and 2,366 dollars in total. The mean hospital cost was significantly (p<0.01) higher in our recent patients with ruptured AAA than in those with non-ruptured AAA (37,583 vs. 15,750 dollars). The size of aneurysm detected in the screening test was less than 40 mm in 22 (65%) out of 34. It was estimated 920 dollars to study a patient with small aneurysm using US every six months for a ten-year follow-up period. Male, obesity and smoking habits were significant factors in patients with AAA than in participants without AAA. There were no significant differences between patients with AAA and participants without AAA in the frequency of hypertension, ischemic heart disease, diabetes mellitus or hyperlipidemia. Conclusion: A screening for AAA using US is useful not only for the early detection of AAA but also for the reduction of overall medical cost in Japan.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
Aim: To study the influence of APOE polymorphisms on risk of coronary atherosclerosis among normolipidaemic males and on efficacy of statins towards lipids, lipoproteins and angiographic parameters. Methods: APOE genotypes were studied in a group (n = 815) of well characterised male CAD patients who participated in the lipid lowering regression study “REGRESS”. Results were compared with two control groups (n=280 and 1801). Results: No significant differences regarding APOE allele or genotype frequencies were observed between patients and controls. CAD patients with APOE2+ had lower total (-0.04%, p=0.04)) and LDL-cholesterol levels (-0.07%, p=0.002) and lower LDL/HDL ratio (-0.08%, p=0.002), lower HDL-cholesterol (+5.6%, p=0.03) and higher triglycerides (+10.7%, p=0.04) when compared with CAD patients with APOE4+. In contrast no significant differences were observed in angiographic parameters. There was a significant interaction between treatment (placebo/pravastatin) and APOE genotype considering lipid levels, APOE2+ carriers had the largest improvement of HDL levels (+0.15 mmol/l) and LDL/HDL ratio’s (-0.60) compared with APOE3+ (+0.06 mmol/l, -0.043 respectively) and APOE4+ carriers (+0.07mmol/l, -0.040). In contrast APOE2+ allele carriers had less effect in terms of angiographic parameters although not statistically significant. Conclusions: APOE influences lipid and lipoprotein levels, but is not associated with the extent or prevalence of coronary atherosclerosis in normolipidemic males with CAD. The effects of statins in subjects with different APOE genotypes were different with regard to lipoprotein profile, but not with regard to angiographic parameters. This study was financially supported by the Netherlands Heart Foundation, Grant No. 2000.170. REGRESS was sponsored by Bristol Myers Squibb.
2P-0591
169