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2P-0370 Effect of serum total homocysteine levels on the extent of coronary artery disease
Tuesday September 30, 2003: Poster Session Homocysteines and other risk factors
120
Triglyceride, mmol/L Cholesterol, mmol/L Homocysteine, µmol/L Lp(a), g/L Glucose, mmol/L
Negative stress test N = 54
Positive stress test N = 33
p
1.75 (0.4-7.02) 5.27 (2.2-8.99) 11.1 (5.4-27.8) 0.38 (0.21-1.40) 5.2 (4-10.9)
2.04 (0.91-8.1) 5.75 (3.8-10.35) 12.45 (6.3-32.7) 0.51 (0.23-1.40) 5.9 (4.3-12.9)
-1.73 0.083 -0.131 0.0892 -1.09 0.276 -1.86 0.049 -2.57 0.012
Our results show that elevated concentration of Lp(a) in serum is risk factor. Lp(a) is correlated with positive stress test. Concentration of homocystein did not correlate with positive stress test in test group. We think that it would be desirable to determine concentration of Lp(a) in serum among other risk factors. 2P-0369
The release of extracellular superoxide dismutase with hyperhomocysteinemia in human coronary atherosclerosis
H. Tasaki 1 , S. Nihei 1 , K. Yamashita 1 , Y. Nakashima 2 , T. Adachi 3 . 1 2nd Internal Medicine, Univ. Occup. Environ. Health, Kitakyushu; 2 2nd Int. Med. Occup. Environ. Health; 3 Lab. Clin. Pharmaceutics, Gifu Pharmaceutical Univ., Japan Background: The mechanism in atherogenicity by hyperhomocysteinemia is supposed to be related with oxygen radical species. In hyperhomocysteinuria, extracellular superoxide dismutase (EC-SOD) was released from endothelium. In this paper, we attempted to elucidate whether its relation was recognized in patients with coronary artery disease. Methods: Consecutive 154 male patients, undergone coronary angiographies, were measured serum homocysteine (HPLC method) and EC-SOD (ELISA). EC-SOD was measured before (basal) and after heparin-injection intravenously (post). The ratio of endothelium-bound EC-SOD (post minus basal) to basal EC-SOD was the index of binding capacity onto endothelium of EC-SOD. Patients were divided by the presence (stenosis group) and the absence (control group) of significant stenosis (AHA class 75%). Moreover, atherosclerosis was also evaluated by coronary score. Results: Plasma homocysteine was significantly increased in stenosis gr. (n=98, 12±4.6 µM/l) compared to in control gr. (n= 57, 10.2±3.0) and was also correlated with coronary score (P<0.01 by Spearman’s rank correlation). As for EC-SOD, plasma homocysteine was positively correlated with basal EC-SOD (r=0.377, P<0.0001) and inversely correlated with was EC-SOD ratio (r=0.199, p<0.05). Subdivided into 4 groups according to the levels of homocysteine and EC-SOD ratio, patients with high homocysteine level and high ratio had significant less coronary score than those with high homocysteine and low EC-SOD ratio (p=0.006 by Mann-Whitney rank analysis). Conclusions: We concluded that high level of plasma homocysteine is associated with increase of EC-SOD released from endothelium, resulting in the lowering defensive capacity of EC-SOD against oxygen free radicals. 2P-0370
Effect of serum total homocysteine levels on the extent of coronary artery disease
G. Vrentzos 1 , J. Papadakis 1 , N. Maliaraki 2 , E. Zacharis 3 , K. Katsogridakis 1 , E. Ganotakis 1 . 1 Dept of Internal Medicine; 2 Dept of Clinical Chemistry; 3 Dept of Cardiology, University of Crete, University Hospital of Crete, Greece Background: High total homocysteine (tHcy) levels increase coronary disease risk. Therefore we examined the relation between tHcy levels and the number of stenotic arteries in patients with coronary artery disease (CAD). Methods: We enrolled 155 patients with CAD (135 men) who underwent selective coronary angiography during the previous two years. These patients were divided into four groups according to the number of vessels (0, 1, 2 and 3) with > 70% stenosis. We also reviewed the major coronary risk factors for each patient (age, gender, hypertension, diabetes mellitus, dyslipidaemia, cigarette smoking, obesity), and measured serum levels of tHcy, folate, vitamin B12 and lipids. Results: There was a significant positive correlation (rs = 0.19; P = 0.017; n = 155) between tHcy serum concentration and the extent of coronary atherosclerosis, expressed by the number of coronary arteries with significant stenosis. Moreover, the number of affected vessels displayed a significant positive correlation with the presence of diabetes mellitus (rs = 0.30; P < 0.0001; n = 155), and serum levels of lipoprotein (a) (rs = 0.25; P < 0.05; n = 67) and a negative correlation with apolipoprotein A-I serum concentration (rs = -0.27; P < 0.01; n = 67).
Conclusions: In this study, the serum levels of tHcy correlate with the extent of coronary atherosclerosis, independently of other classical risk factors, with the exception of diabetes mellitus. 2P-0371
The role of homocysteine from endothelial cells in LDL oxidation
E. Nakano 1 , D. Nugent 2 , F. Taiwo 2 , H. Powers 1 . 1 University of Sheffield; Montfort University, United Kingdom
2 de
Objectives: Total homocysteine (tHcy) is a risk factor for atherosclerosis and cardiovascular disease, but the explanation is still not clear. Here we investigate the hypothesis that endothelial cells continuously produce homocysteine, which is oxidised to produce free radicals, that then go on to oxidise LDL. Methods: Human umbilical vein endothelial cells (HUVECs) were collected and cultured. Human LDL was purified from blood using a rapid method that generates pure LDL in less than 5 hours. HUVECs were grown for up to 48 hours in the presence of LDL. LDL oxidation was measured using the TBARS assay, and free radicals were characterised using EPR. Results: HUVECs secreted homocysteine in a methionine-dependent manner, at approximately constant rate for at least 72 hours. Homocysteine secretion was inhibited by folinic acid. LDL was oxidised in the presence of cells at a much faster rate than in their absence. The amount of LDL oxidation measured was increased slightly in the presence of anti-CD36 antibody, suggesting that oxidised LDL is taken up by scavenger receptors on the HUVECs. In the presence of L-NAME (an inhibitor of endothelial nitric oxide synthase), LDL oxidation increases, suggesting that peroxynitrite is not a significant pro-oxidant. LDL oxidation was partially inhibited by the addition of glutamate to the medium, which acts to block uptake of cystine into the cells (and therefore cysteine export). The main free radical generated by the HUVECs is hydroxyl. Conclusions: The results support the hypothesis, although cysteine is evidently also an important factor in determing LDL oxidation. 2P-0372
Fenofibrate but not simvastatin increases serum homocysteine and creatinine in patients with type 2 diabetes mellitus
T. Stulc 1 , R. Ceska 1 , V. Kozich 2 , J. Skrha 1 . 1 3rd Department of Internal Medicine; 2 Institute of Inherited Metabolic Diseases, 1st School of Medicine, Charles University, Czech Republic Objective: Fibrates (but not statins) increase plasma homocyteine (HCys) in nondiabetic subjects. Fibrates are often used in diabetic dyslipidemia; the fibrate-induced HCys increase might be particularly harmful in these high-risk patients. We have therefore compared the effect of fenofibrate and simvastatin treatments on plasma HCys in patients with type 2 diabetes mellitus (DM). Methods: 20 patients with DM and mixed hyperlipidemia were sequentially treated with fenofibrate (200mg/day) and simvastatin (20mg/day) in a cross-over study (12 weeks each treatment). Laboratory examinations were done at baseline and at the end of each treatment. Baseline values were compared to those of 26 healthy controls. Results: Levels of HCys, Cys and creatinine (Creat) were significantly higher in DM patients than in controls. All these parameters significantly increased after fenofibrate treatment, but were not influenced by simvastatin (Table 1). Proportion of patients with mild hyperhomocyteinemia (HCys > 15 µmol/l) increased from 20% at baseline to 60% after fenofibrate. Control (C)
Baseline (B)
Feno (F)
Simva (S)
p (B/C)
p (F/B)
p (S/B)
HCys [µmol/l] 9.0±3.0 12.4±3.6 16.7±3.9 11.5±3.3 0.0072 0.0001 0.3549 Cys [µmol/l] 264±37 302±75 341±65 308±52 0.0396 0.0135 0.8871 Creat [µmol/l] 86±8 95±15 105±17 93±17 0.0193 0.0001 0.1474
Conclusions: Fenofibrate significantly increased HCys levels in patients with DM; simvastatin had no effect on HCys levels. Intervention to reduce plasma HCys should therefore be considered in fibrate-treated patients with DM.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
120
Triglyceride, mmol/L Cholesterol, mmol/L Homocysteine, µmol/L Lp(a), g/L Glucose, mmol/L
Negative stress test N = 54
Positive stress test N = 33
p
1.75 (0.4-7.02) 5.27 (2.2-8.99) 11.1 (5.4-27.8) 0.38 (0.21-1.40) 5.2 (4-10.9)
2.04 (0.91-8.1) 5.75 (3.8-10.35) 12.45 (6.3-32.7) 0.51 (0.23-1.40) 5.9 (4.3-12.9)
-1.73 0.083 -0.131 0.0892 -1.09 0.276 -1.86 0.049 -2.57 0.012
Our results show that elevated concentration of Lp(a) in serum is risk factor. Lp(a) is correlated with positive stress test. Concentration of homocystein did not correlate with positive stress test in test group. We think that it would be desirable to determine concentration of Lp(a) in serum among other risk factors. 2P-0369
The release of extracellular superoxide dismutase with hyperhomocysteinemia in human coronary atherosclerosis
H. Tasaki 1 , S. Nihei 1 , K. Yamashita 1 , Y. Nakashima 2 , T. Adachi 3 . 1 2nd Internal Medicine, Univ. Occup. Environ. Health, Kitakyushu; 2 2nd Int. Med. Occup. Environ. Health; 3 Lab. Clin. Pharmaceutics, Gifu Pharmaceutical Univ., Japan Background: The mechanism in atherogenicity by hyperhomocysteinemia is supposed to be related with oxygen radical species. In hyperhomocysteinuria, extracellular superoxide dismutase (EC-SOD) was released from endothelium. In this paper, we attempted to elucidate whether its relation was recognized in patients with coronary artery disease. Methods: Consecutive 154 male patients, undergone coronary angiographies, were measured serum homocysteine (HPLC method) and EC-SOD (ELISA). EC-SOD was measured before (basal) and after heparin-injection intravenously (post). The ratio of endothelium-bound EC-SOD (post minus basal) to basal EC-SOD was the index of binding capacity onto endothelium of EC-SOD. Patients were divided by the presence (stenosis group) and the absence (control group) of significant stenosis (AHA class 75%). Moreover, atherosclerosis was also evaluated by coronary score. Results: Plasma homocysteine was significantly increased in stenosis gr. (n=98, 12±4.6 µM/l) compared to in control gr. (n= 57, 10.2±3.0) and was also correlated with coronary score (P<0.01 by Spearman’s rank correlation). As for EC-SOD, plasma homocysteine was positively correlated with basal EC-SOD (r=0.377, P<0.0001) and inversely correlated with was EC-SOD ratio (r=0.199, p<0.05). Subdivided into 4 groups according to the levels of homocysteine and EC-SOD ratio, patients with high homocysteine level and high ratio had significant less coronary score than those with high homocysteine and low EC-SOD ratio (p=0.006 by Mann-Whitney rank analysis). Conclusions: We concluded that high level of plasma homocysteine is associated with increase of EC-SOD released from endothelium, resulting in the lowering defensive capacity of EC-SOD against oxygen free radicals. 2P-0370
Effect of serum total homocysteine levels on the extent of coronary artery disease
G. Vrentzos 1 , J. Papadakis 1 , N. Maliaraki 2 , E. Zacharis 3 , K. Katsogridakis 1 , E. Ganotakis 1 . 1 Dept of Internal Medicine; 2 Dept of Clinical Chemistry; 3 Dept of Cardiology, University of Crete, University Hospital of Crete, Greece Background: High total homocysteine (tHcy) levels increase coronary disease risk. Therefore we examined the relation between tHcy levels and the number of stenotic arteries in patients with coronary artery disease (CAD). Methods: We enrolled 155 patients with CAD (135 men) who underwent selective coronary angiography during the previous two years. These patients were divided into four groups according to the number of vessels (0, 1, 2 and 3) with > 70% stenosis. We also reviewed the major coronary risk factors for each patient (age, gender, hypertension, diabetes mellitus, dyslipidaemia, cigarette smoking, obesity), and measured serum levels of tHcy, folate, vitamin B12 and lipids. Results: There was a significant positive correlation (rs = 0.19; P = 0.017; n = 155) between tHcy serum concentration and the extent of coronary atherosclerosis, expressed by the number of coronary arteries with significant stenosis. Moreover, the number of affected vessels displayed a significant positive correlation with the presence of diabetes mellitus (rs = 0.30; P < 0.0001; n = 155), and serum levels of lipoprotein (a) (rs = 0.25; P < 0.05; n = 67) and a negative correlation with apolipoprotein A-I serum concentration (rs = -0.27; P < 0.01; n = 67).
Conclusions: In this study, the serum levels of tHcy correlate with the extent of coronary atherosclerosis, independently of other classical risk factors, with the exception of diabetes mellitus. 2P-0371
The role of homocysteine from endothelial cells in LDL oxidation
E. Nakano 1 , D. Nugent 2 , F. Taiwo 2 , H. Powers 1 . 1 University of Sheffield; Montfort University, United Kingdom
2 de
Objectives: Total homocysteine (tHcy) is a risk factor for atherosclerosis and cardiovascular disease, but the explanation is still not clear. Here we investigate the hypothesis that endothelial cells continuously produce homocysteine, which is oxidised to produce free radicals, that then go on to oxidise LDL. Methods: Human umbilical vein endothelial cells (HUVECs) were collected and cultured. Human LDL was purified from blood using a rapid method that generates pure LDL in less than 5 hours. HUVECs were grown for up to 48 hours in the presence of LDL. LDL oxidation was measured using the TBARS assay, and free radicals were characterised using EPR. Results: HUVECs secreted homocysteine in a methionine-dependent manner, at approximately constant rate for at least 72 hours. Homocysteine secretion was inhibited by folinic acid. LDL was oxidised in the presence of cells at a much faster rate than in their absence. The amount of LDL oxidation measured was increased slightly in the presence of anti-CD36 antibody, suggesting that oxidised LDL is taken up by scavenger receptors on the HUVECs. In the presence of L-NAME (an inhibitor of endothelial nitric oxide synthase), LDL oxidation increases, suggesting that peroxynitrite is not a significant pro-oxidant. LDL oxidation was partially inhibited by the addition of glutamate to the medium, which acts to block uptake of cystine into the cells (and therefore cysteine export). The main free radical generated by the HUVECs is hydroxyl. Conclusions: The results support the hypothesis, although cysteine is evidently also an important factor in determing LDL oxidation. 2P-0372
Fenofibrate but not simvastatin increases serum homocysteine and creatinine in patients with type 2 diabetes mellitus
T. Stulc 1 , R. Ceska 1 , V. Kozich 2 , J. Skrha 1 . 1 3rd Department of Internal Medicine; 2 Institute of Inherited Metabolic Diseases, 1st School of Medicine, Charles University, Czech Republic Objective: Fibrates (but not statins) increase plasma homocyteine (HCys) in nondiabetic subjects. Fibrates are often used in diabetic dyslipidemia; the fibrate-induced HCys increase might be particularly harmful in these high-risk patients. We have therefore compared the effect of fenofibrate and simvastatin treatments on plasma HCys in patients with type 2 diabetes mellitus (DM). Methods: 20 patients with DM and mixed hyperlipidemia were sequentially treated with fenofibrate (200mg/day) and simvastatin (20mg/day) in a cross-over study (12 weeks each treatment). Laboratory examinations were done at baseline and at the end of each treatment. Baseline values were compared to those of 26 healthy controls. Results: Levels of HCys, Cys and creatinine (Creat) were significantly higher in DM patients than in controls. All these parameters significantly increased after fenofibrate treatment, but were not influenced by simvastatin (Table 1). Proportion of patients with mild hyperhomocyteinemia (HCys > 15 µmol/l) increased from 20% at baseline to 60% after fenofibrate. Control (C)
Baseline (B)
Feno (F)
Simva (S)
p (B/C)
p (F/B)
p (S/B)
HCys [µmol/l] 9.0±3.0 12.4±3.6 16.7±3.9 11.5±3.3 0.0072 0.0001 0.3549 Cys [µmol/l] 264±37 302±75 341±65 308±52 0.0396 0.0135 0.8871 Creat [µmol/l] 86±8 95±15 105±17 93±17 0.0193 0.0001 0.1474
Conclusions: Fenofibrate significantly increased HCys levels in patients with DM; simvastatin had no effect on HCys levels. Intervention to reduce plasma HCys should therefore be considered in fibrate-treated patients with DM.
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan