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2P-0373 Acute hyperhomocysteinemia induces myocardial malperfusion in CAD-patients
Tuesday September 30, 2003: Poster Session Homocysteines and other risk factors 2P-0373
Acute hyperhomocysteinemia induces myocardial malperfusion in CAD-patients
O. Stanger 1 , B. Hackel 2 , P. Rehak 3 , R. Konetschny 4 , B. Rigler 5 , R. Rienmüller 6 . 1 Dept Cardiac Surgery, Atherosclerosis Research, Landeskrankenhaus Salzburg, Salzburg; 2 Dept. of Radiology, Cardiac Imaging; 3 Dept. of Biomedical Engineering, Computing and Statistics; 4 Dept. of Cardiac Surgery, Landeskliniken Salzburg; 5 Dept. of Cardiac Surgery, Graz; 6 Dept. of Radiology, Cardiac Imaging, Graz, Austria Objectives: Hyperhomocysteinemia (HHcy) impairs endothelial dysfunction (ED) of conduit vessels. Organ perfusion is regulated at the level of resistance vessels. We hypothesized resistance vessel dysfunction and myocardial malperfusion following acute HHcy. Methods: 50 male subjects with coronary artery disease (CAD) were randomly assigned to undergo an oral methionine loading test (oMLT, n=30) or intake of placebo (n=20) in a double-blind design. Myocardial perfusion was measured non-invasively at baseline and after 4 hours through electronbeam-computed-tomography (EBCT) using multi slice flow mode with 3 target-rings and administrations of contrast agent administered intravenously. Blood pressure (BP) and a heart rate (HR) variance of max. ± 5% was tolerated for analyses. Results: Age, calcification scores, ejection fraction, ventricle volumes, major risk factors and lipid parameters did not differ between groups, and BP was unchanged in all subjects between baseline and the second investigation. Following oMLT, Hcy increased 3.2fold and myocardial perfusion (ml/min/100g left ventricular mass) decreased significantly (-6.6%). Hcy remained unchanged in the placebo group with increase of myocardial perfusion (+5.2%). The effect of HHcy on myocardial perfusion remained significant between groups after correcting for changes in HR (P=0.03). Conclusion: Our results demonstrate impairment of myocardial perfusion in CAD-patients through acute HHcy, most likely explained by endothelial dysfunction of resistance vessels. The D.A.CH.-LIGA homocysteine (German, Austrian and Swiss Homocysteine Society). Guidelines and recommendations on homocysteine measurement and use of folic acid and B-vitamins in cardiovascular and thrombotic disease
O. Stanger 1 , B. Fowler 2 , W. Herrmann 3 , K. Pietrzik 4 , J. Geisel 3 , J. Dierkes 5 , M. Weger 6 . 1 Cardiac Surgery, Atherosclerosis Research, Salzburg, Landeskrankenhaus Salzburg, Salzburg, Austria; 2 University Children‘s Hospital of Basel (UKBB), Basel, Schweiz; 3 Central Laboratory, Universitätskliniken des Saarlandes, Homburg; 4 Institute of Nutrition Science, Rheinische Friedrichs-Wilhelm-Universität, Bonn; 5 Institute of Clinical Chemistry, Otto-von-Guericke-Universität Magdeb, Germany; 6 Dept. of Ophthalmology, Karl-Franzens-University, LKH Graz, Austria Interest in new risk factors for atherothrombotic diseases, the leading cause for morbidity and mortality, such as homocysteine has increased dramatically. However despite extensive research in the field and general access to diagnostic and therapeutic options, clear and easy to follow information on indications for measurement and management of this risk factor is unavailable. We therefore developed a consensus on proposed recommendations for the rational clinical investigation of homocysteine and use of folic acid and B vitamins. The proposed guidelines cover definition of risk groups, cut off values for action and treatment strategies. They are presented as a basis for discussion in the debate on when to measure homocysteine and how to treat elevated levels in general practice. The potential benefit for a large number of patients and the positive costbenefit-ratio make vitamin supplementation an attractive option with current emphasis on the selection of high-risk groups at least until prospective studies lead to general preventive strategies such as food fortification. 2P-0375
Homocysteine activates nuclear factor kappa-B in endothelial cells: Role of oxidative stress
K. O, F.L. Sung, K.K.W. Au-Yeung, J.C.W. Yip, Y.L. Siow. University of Hong Kong, Department of Pharmacology, Faculty of Medicine, Sassoon Road, Hong Kong SAR Objective: Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated that nuclear factor kappa-B (NF-κB), a transcription factor, played an important role in homocysteine
(Hcy)-induced chemokine expression in vascular smooth muscle cell and in monocyte-derived macrophage. However, it is unclear how Hcy regulates NF-κB activity in vascular cells and whether Hcy can initiate similar changes in vivo. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-κB activation and the underlying mechanism of Hcy-induced NF-κB activation in endothelial cells. Methods: Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-κB and superoxide anions in the aortic endothelium were detected by immunohistochemical staining. The molecular mechanism of Hcy-induced NF-κB activation was further investigated in human umbilical cord vein endothelial cells. Results: The activated form of NF-κB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. Incubation of cells with Hcy (100 mmol/L) activated IκB kinases (IKKa and IKKb) as well as increased phosphorylation and degradation of IκBa. NF-κB nuclear translocation, enhanced NF-κB/DNA binding activity and increased transcriptional activity were detected. Further analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with superoxide dismutase (SOD), a superoxide anion scavenger, could prevent Hcy-induced activation of IKK kinases and NF-κB in endothelial cells. Conclusions: These results suggest that Hcy-induced superoxide anion production may play a important role for NF-κB activation in the early stages of atherosclerosis in the vascular wall via activation of IκB kinases. 2P-0376
Hyperhomocysteinemia stimulates cholesterol biosynthesis in liver
C.W.H. Woo, Y.L. Siow, K. O. Department of Pharmacology, University of Hong Kong, Hong Kong SAR Objective: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. The objective of this study was to investigate the effect of homocysteine (Hcy) on the transcriptional regulation of hepatic cholesterol synthesis. Methods: Hyperhomocysteinemia was induced in Sprague–Dawley rats after 4 weeks of a high-methionine diet. Northern immunoblotting was used to determine the mRNA expression of hepatic 3-hydroxy-3-methylglutary coenzyme A (HMG-CoA) reductase. The expressions of its transcription factor, sterol regulatory element-binding protein-2 (SREBP-2) were determined by Western immunoblotting while the co-regulators of SREBP-2, cAMP response element binding protein (CREB) and nuclear factor Y (NF-Y) for optimal HMG-CoA reductase gene expression were examined by electrophoretic mobility shift assay. Results: Increased cholesterol biosynthesis led to lipid accumulation in the livers and increased level of plasma cholesterol were observed in the hyperhomocysteinemic rats. Regulatory transcription factors for HMG-CoA reductase were activated in the liver of hyperhomocysteinemic rats. Folate supplementation not only lowered the level of plasma Hcy but also reversed hyperhomocysteinemia-induced activation of SREBP-2, CREB and NF-Y as well as HMG-CoA reductase. Conclusions – These results suggest that in the absence of other known risk factors, hyperhomocysteinemia up-regulates hepatic HMG-CoA reductase expression. Such up-regulation is mediated through the stimulation of transcriptional factors. Supported by a RGC grant. 2P-0377
Changes of homocysteine levels after administration of folic acid
S. Paximadas 1 , S.N. Pagoni 2 , M.B. Kosmidis 2 , K.A. Kanellas 2 , D.S. Moutafis 2 , N.K. Joakeimidis 2 , T.P. Gialernios 2 . 1 General Hospital of Athens ELPIS, Athens; 2 Athens, Greece Hyperhomocysteinemia is the result of a disturbed methionine metabolism. Epidemiological studies have demonstrated that elevated plasma levels of homocysteine (Hcy) are a predisposing factor for coronary artery disease and stroke. Purpose: The aim of this study was to investigate the influence of folic acid on the Hcy levels during the 4 weeks period treatment in patients with hyperhomocysteinemia. Materials and Methods: The study included 48 outpatients with elevated Hcy aged 64±10 years (34-81 years), 26 females and 22 males. Investigated the Hcy levels, lipid profile as Total Cholesterol (TC), Triglycerides (TG),
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
2P-0374
121
Acute hyperhomocysteinemia induces myocardial malperfusion in CAD-patients
O. Stanger 1 , B. Hackel 2 , P. Rehak 3 , R. Konetschny 4 , B. Rigler 5 , R. Rienmüller 6 . 1 Dept Cardiac Surgery, Atherosclerosis Research, Landeskrankenhaus Salzburg, Salzburg; 2 Dept. of Radiology, Cardiac Imaging; 3 Dept. of Biomedical Engineering, Computing and Statistics; 4 Dept. of Cardiac Surgery, Landeskliniken Salzburg; 5 Dept. of Cardiac Surgery, Graz; 6 Dept. of Radiology, Cardiac Imaging, Graz, Austria Objectives: Hyperhomocysteinemia (HHcy) impairs endothelial dysfunction (ED) of conduit vessels. Organ perfusion is regulated at the level of resistance vessels. We hypothesized resistance vessel dysfunction and myocardial malperfusion following acute HHcy. Methods: 50 male subjects with coronary artery disease (CAD) were randomly assigned to undergo an oral methionine loading test (oMLT, n=30) or intake of placebo (n=20) in a double-blind design. Myocardial perfusion was measured non-invasively at baseline and after 4 hours through electronbeam-computed-tomography (EBCT) using multi slice flow mode with 3 target-rings and administrations of contrast agent administered intravenously. Blood pressure (BP) and a heart rate (HR) variance of max. ± 5% was tolerated for analyses. Results: Age, calcification scores, ejection fraction, ventricle volumes, major risk factors and lipid parameters did not differ between groups, and BP was unchanged in all subjects between baseline and the second investigation. Following oMLT, Hcy increased 3.2fold and myocardial perfusion (ml/min/100g left ventricular mass) decreased significantly (-6.6%). Hcy remained unchanged in the placebo group with increase of myocardial perfusion (+5.2%). The effect of HHcy on myocardial perfusion remained significant between groups after correcting for changes in HR (P=0.03). Conclusion: Our results demonstrate impairment of myocardial perfusion in CAD-patients through acute HHcy, most likely explained by endothelial dysfunction of resistance vessels. The D.A.CH.-LIGA homocysteine (German, Austrian and Swiss Homocysteine Society). Guidelines and recommendations on homocysteine measurement and use of folic acid and B-vitamins in cardiovascular and thrombotic disease
O. Stanger 1 , B. Fowler 2 , W. Herrmann 3 , K. Pietrzik 4 , J. Geisel 3 , J. Dierkes 5 , M. Weger 6 . 1 Cardiac Surgery, Atherosclerosis Research, Salzburg, Landeskrankenhaus Salzburg, Salzburg, Austria; 2 University Children‘s Hospital of Basel (UKBB), Basel, Schweiz; 3 Central Laboratory, Universitätskliniken des Saarlandes, Homburg; 4 Institute of Nutrition Science, Rheinische Friedrichs-Wilhelm-Universität, Bonn; 5 Institute of Clinical Chemistry, Otto-von-Guericke-Universität Magdeb, Germany; 6 Dept. of Ophthalmology, Karl-Franzens-University, LKH Graz, Austria Interest in new risk factors for atherothrombotic diseases, the leading cause for morbidity and mortality, such as homocysteine has increased dramatically. However despite extensive research in the field and general access to diagnostic and therapeutic options, clear and easy to follow information on indications for measurement and management of this risk factor is unavailable. We therefore developed a consensus on proposed recommendations for the rational clinical investigation of homocysteine and use of folic acid and B vitamins. The proposed guidelines cover definition of risk groups, cut off values for action and treatment strategies. They are presented as a basis for discussion in the debate on when to measure homocysteine and how to treat elevated levels in general practice. The potential benefit for a large number of patients and the positive costbenefit-ratio make vitamin supplementation an attractive option with current emphasis on the selection of high-risk groups at least until prospective studies lead to general preventive strategies such as food fortification. 2P-0375
Homocysteine activates nuclear factor kappa-B in endothelial cells: Role of oxidative stress
K. O, F.L. Sung, K.K.W. Au-Yeung, J.C.W. Yip, Y.L. Siow. University of Hong Kong, Department of Pharmacology, Faculty of Medicine, Sassoon Road, Hong Kong SAR Objective: Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases. Our previous studies demonstrated that nuclear factor kappa-B (NF-κB), a transcription factor, played an important role in homocysteine
(Hcy)-induced chemokine expression in vascular smooth muscle cell and in monocyte-derived macrophage. However, it is unclear how Hcy regulates NF-κB activity in vascular cells and whether Hcy can initiate similar changes in vivo. The objective of the present study was to investigate the in vivo effect of hyperhomocysteinemia on NF-κB activation and the underlying mechanism of Hcy-induced NF-κB activation in endothelial cells. Methods: Hyperhomocysteinemia was induced in Sprague-Dawley rats after 4 weeks of a high-methionine diet. The activated form of NF-κB and superoxide anions in the aortic endothelium were detected by immunohistochemical staining. The molecular mechanism of Hcy-induced NF-κB activation was further investigated in human umbilical cord vein endothelial cells. Results: The activated form of NF-κB and increased level of superoxide anions were detected in the endothelium of aortas isolated from hyperhomocysteinemic rats. Incubation of cells with Hcy (100 mmol/L) activated IκB kinases (IKKa and IKKb) as well as increased phosphorylation and degradation of IκBa. NF-κB nuclear translocation, enhanced NF-κB/DNA binding activity and increased transcriptional activity were detected. Further analysis revealed a marked elevation of superoxide anion levels in Hcy-treated cells. Treatment of cells with superoxide dismutase (SOD), a superoxide anion scavenger, could prevent Hcy-induced activation of IKK kinases and NF-κB in endothelial cells. Conclusions: These results suggest that Hcy-induced superoxide anion production may play a important role for NF-κB activation in the early stages of atherosclerosis in the vascular wall via activation of IκB kinases. 2P-0376
Hyperhomocysteinemia stimulates cholesterol biosynthesis in liver
C.W.H. Woo, Y.L. Siow, K. O. Department of Pharmacology, University of Hong Kong, Hong Kong SAR Objective: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. The objective of this study was to investigate the effect of homocysteine (Hcy) on the transcriptional regulation of hepatic cholesterol synthesis. Methods: Hyperhomocysteinemia was induced in Sprague–Dawley rats after 4 weeks of a high-methionine diet. Northern immunoblotting was used to determine the mRNA expression of hepatic 3-hydroxy-3-methylglutary coenzyme A (HMG-CoA) reductase. The expressions of its transcription factor, sterol regulatory element-binding protein-2 (SREBP-2) were determined by Western immunoblotting while the co-regulators of SREBP-2, cAMP response element binding protein (CREB) and nuclear factor Y (NF-Y) for optimal HMG-CoA reductase gene expression were examined by electrophoretic mobility shift assay. Results: Increased cholesterol biosynthesis led to lipid accumulation in the livers and increased level of plasma cholesterol were observed in the hyperhomocysteinemic rats. Regulatory transcription factors for HMG-CoA reductase were activated in the liver of hyperhomocysteinemic rats. Folate supplementation not only lowered the level of plasma Hcy but also reversed hyperhomocysteinemia-induced activation of SREBP-2, CREB and NF-Y as well as HMG-CoA reductase. Conclusions – These results suggest that in the absence of other known risk factors, hyperhomocysteinemia up-regulates hepatic HMG-CoA reductase expression. Such up-regulation is mediated through the stimulation of transcriptional factors. Supported by a RGC grant. 2P-0377
Changes of homocysteine levels after administration of folic acid
S. Paximadas 1 , S.N. Pagoni 2 , M.B. Kosmidis 2 , K.A. Kanellas 2 , D.S. Moutafis 2 , N.K. Joakeimidis 2 , T.P. Gialernios 2 . 1 General Hospital of Athens ELPIS, Athens; 2 Athens, Greece Hyperhomocysteinemia is the result of a disturbed methionine metabolism. Epidemiological studies have demonstrated that elevated plasma levels of homocysteine (Hcy) are a predisposing factor for coronary artery disease and stroke. Purpose: The aim of this study was to investigate the influence of folic acid on the Hcy levels during the 4 weeks period treatment in patients with hyperhomocysteinemia. Materials and Methods: The study included 48 outpatients with elevated Hcy aged 64±10 years (34-81 years), 26 females and 22 males. Investigated the Hcy levels, lipid profile as Total Cholesterol (TC), Triglycerides (TG),
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
TUESDAY
2P-0374
121