The Effects of Hyperhomocysteinemia on the Presence, Extent, and Severity of Coronary Artery Disease

The Effects of Hyperhomocysteinemia on the Presence, Extent, and Severity of Coronary Artery Disease Abdi BOZKURT, 1 MD, Hale TOYAKSI, 2 MD, Esmeray ACARTÜRK, 1 MD, Abdullah TULI, 2 MD, and Murat ÇAYLI, 1 MD SUMMARY Most cross-sectional and case-control studies indicate that an increased plasma total homocysteine (thcy) level is an independent risk factor for coronary artery disease (CAD). However, this is still a controversial issue. Recently, it was reported that the level of thcy is related to the extent and severity of CAD. This study was designed to investigate the relationship between plasma thcy levels and the presence, extent, and severity of CAD. Three hundred and forty-one patients who underwent coronary angiography were included in the study. Of these patients, 195 had CAD and 146 had normal coronary arteries (control group). The mean thcy level was found to be higher in patients with significant CAD (16.4 ± 7.4µmol/L vs 13.2 ± 3.6 µmol/l, P ). This group also had a higher rate of hyperhomocysteinemia (HHcy) (22.6% vs 5.5%, P ). There were positive relationships between thcy levels and male gender (P = 0.03, r = 0.16), smoking (P, r = 0.19), hyperlipidemia (P = 0.006, r = 0.15), and hypertension (P, r = 0.20). Using regression analysis HHcy was determined to be an independent risk factor for CAD (OR = 3.69, CI 95% 1.51-9.06, P = 0.004). However, HHcy was not an independent risk factor in patients with low cardiovascular risk profiles. There was no relationship between the level of thcy and the severity, extent, and vessel scores of CAD. On the other hand, age and diabetes mellitus were related with all scores of CAD. In conclusion, although hyperhomocysteinemia is an independent risk factor for CAD in our region, it appears to be unrelated to the extent and severity of the disease. (Jpn Heart J 2003; 44: 357-368) Key words: Hyperhomocysteinemia, Risk factor, Coronary artery disease THERE are several risk factors for CAD. In recent years, a high plasma total homocysteine (thcy) level has been proposed as another important risk factor. The mechanism by which high thcy levels lead to CAD remains unclear. Some of the suggested mechanisms are the damaging effects of thcy on endothelium, platelets, coagulation factors, and smooth muscle of the vessel wall, and oxida- From 1 Departments of Cardiology and 2 Departments of Biochemistry, School of Medicine, Çukurova University, Adana, Turkey. Address for correspondence: Abdi Bozkurt, MD, Assistant Professor of Cardiology, Department of Cardiology, School of Medicine, Çukurova University, 01330 Adana, Turkey. Received for publication September 5, 2002. Revised and accepted November 1, 2002. 357

358 BOZKURT, ET AL Jpn Heart J May 2003 tive modification of the LDL-cholesterol. 1,2) The main factors affecting the plasma thcy levels are age, gender, smoking, physical activity, genetic enzyme disorders, race, and nutrition. 3-6) There are controversial results with regard to both thcy being an independent risk factor as well as its effects on the extent and severity of CAD. 7-12) This study was designed to investigate the relationship between plasma thcy levels and CAD in patients from the Southern part of Turkey. METHODS Patients: Three hundred and forty-one patients who underwent coronary angiography were included in the study. Informed consent was obtained from each patient and the study protocol was approved by the Ethics Committee. Major risk factors for CAD like age, gender, family history, hyperlipidemia, hypertension, and diabetes mellitus were determined. Advanced age was defined as an age > 45 years in men and > 55 years in women. A positive family history was defined as coronary artery disease in a parent or sibling noted under the age of 55 for men and 65 for women. Hyperlipidemia was defined as a plasma total cholesterol level 200 mg/dl and/or a LDL-cholesterol level 130 mg/dl or using lipid lowering drugs at the time of investigation. 13) A sustained blood pressure greater than 140 mmhg systolic and 90 mmhg diastolic or the use of antihypertensive drugs at the time of investigation was defined as hypertension. Diabetes mellitus was considered to be present if there was a history of diabetes, fasting blood glucose 126 mg/dl, or the use of an antidiabetic medication. 14) Patients were classified into two risk groups according to their major risk factors as low risk (with 2 or less) and high risk (with 3 and more). Patients who had cancer, hepatic or renal failure (serum creatinine > 1.5 mg/dl), or were using drugs which affect plasma thcy levels such as multivitamins or anticancer agents were excluded. Plasma homocysteine level measurement: Blood was collected from the antecubital vein after a rest period of 30 minutes in the supine position following a 12- hour fast prior to the coronary angiography. Following coagulation for 1 hour at room temperature the samples were centrifuged at 3000 rpm. The plasma was collected and kept at -70 C until analysis. Total L-homocysteine levels were quantified using a fluorescent polarization immunoassay (FIPA) and an Abbott IMX analyzer. Hyperhomocysteinemia (HHcy) was taken as the mean value plus two standard deviations of the control group and defined separately for each gender. 15) Coronary angiography: Coronary angiography and ventriculography were performed by the Judkins technique. Angiographies were interpreted by two cardiologists. Coronary artery disease was defined as a 50% reduction in the internal

Vol 44 No 3 HYPERHOMOCYSTEINEMIA AND CORONARY ARTERY DISEASE 359 diameter of the left anterior descending, right or circumflex coronary artery, or their primary branches. Patients without angiographic lesions were considered to be without CAD. Vessel score: Scoring was based on the number of vessels involved and ranged from 0 to 3. Left main coronary artery stenosis was scored as 1 vessel disease. 16) Extent score: This score was developed by Negri, et al 17) and modified by Birnie, et al. 18) The coronary circulation was divided into 15 segments, 8 of which were classified as first-order segments: left main coronary artery, proximal, middle, and distal left anterior descending, proximal, and middle right coronary artery, and proximal and distal circumflex coronary artery. There are 7 secondorder segments: distal right coronary artery, posterior descending branch, obtuse marginal, and posterolateral branches of the circumflex, and the first 2 diagonal branches of the left anterior descending coronary artery. The 8 first-order segments received a score of 1 if there was any evidence of atherosclerosis, and the second-order segments scored 0.5. The overall score was the sum of the individual segment scores and the maximum score was 11.5. Stenosis score: This was a modified Gensini score, which has been described previously. 19-21) The most severe stenosis in each of 8 segments was graded according to severity, that is: a grade of 1 for 1% to 49%, 2 for 50% to 74%, 3 for 75% to 99% reduction in lumen diameter, and 4 for total occlusion. The scores were added together to give a total score out of a theoretical maximum of 32. Statistical analysis: The results were recorded on a 9.0 SPSS statistical program and defined as the mean ± standard deviation. Student s t test was used to analyze the mean age and thcy levels among the groups. The chi-square test was used to analyze other risk factors. The relationship between the risk factors and thcy levels was determined by Pearson's correlation analysis. The parameters showing uneven distribution were analyzed by Spearman's correlation analysis. Multiple logistic regression analysis was used to determine the relationship between the risk factors, HHcy, and CAD. Linear regression analysis was used to determine the angiographic scoring of CAD and related factors. A P value < 0.05 was considered significant. RESULTS Demographic specifications of the patients and levels of thcy: Among the study population, 195 patients had CAD and 146 had normal coronary arteries (control group). The mean age of the patients with CAD were significantly higher than the patients in the control group (52.3 ± 9.8 vs 50.2 ± 9.6, P = 0.046). All the major risk factors leading to CAD were also higher in the CAD group compared to the control group. The mean thcy level was also higher in the CAD group than in the

360 BOZKURT, ET AL Jpn Heart J May 2003 control group (16.4 ± 7.4µmol/L vs 13.2 ± 3.6 µmol/l, P ). Hyperhomocysteinemia values were calculated differently for each gender. The cut-off values were determined to be 21.3 µmol/l for males and 17.9 µmol/l for females, and higher levels were considered to be HHcy. Hyperhomocysteinemia was more prevalent in the CAD group than in the control group (22.6% vs 5.5%, P ). The demographic characteristics and cardiovascular risk factors for the patients and controls are shown in Table I. thcy level and hyperhomocysteinemia in patient population subgroups: The mean thcy levels were higher in both the male (P = 0.001) and female (P = 0.002) subgroups of the CAD patients compared to the control group. The thcy levels were higher in males than females in both groups (16.9 ± 7.8 µmol/l vs 14.8 ± 5.7 µmol/l, P = 0.04 and 14.0 ± 3.7 µmol/l vs 12.0 ± 3.0 µmol/l, P = 0.001, respectively). The prevalence of HHcy was the same in the male and female groups (21.7% vs 25.0%, P = 0.6). Regardless of age, the mean plasma thcy levels in the patients were higher than the control group. There was no relation between age and thcy levels in the patients and the control group. In the CAD group, the mean levels of thcy were significantly different in the patients who had previous myocardial infarction (n = 68) and the patients who did not (n = 127) (17.1 ± 8.2 µmol/l and 15.0 ± 5.2 µmol/l respectively, P = 0.03). However, there was no relationship between the prevalence of HHcy and Table I. Controls Demographic Characteristics and Cardiovascular Risk Factors of the Patients and the Patients (n = 195) Controls (n = 146) P Age (years) Gender (female/male) Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglyceride (mg/dl) Homocysteine (µmol/l) Male (n = 237) Female (n = 104) 50 age (n = 163) > 50 age (n = 178) Hyperhomocysteinemia 52.3 ± 9.8 52/143 118 (60.5 %) 68 (34.9 %) 32 (16.4 %) 115 (59.0 %) 72 (36.9 %) 207.4 ± 72.5 121.9 ± 42.3 42.7 ± 8.9 195.7 ± 124.7 16.4 ± 7.4 16.9 ± 7.8 14.8 ± 5.7 16.4 ± 7.7 16.4 ± 7.0 44 (22.6 %) 50.2 ± 9.6 52/94 52 (35.6 %) 30 (20.5 %) 5 (3.4 %) 30 (20.5 %) 10 (6.8 %) 186.3 ± 39.2 110.0 ± 32.8 45.5 ± 9.6 154.9 ± 63.3 13.2 ± 3.6 14.0 ± 3.7 12.0 ± 3.0 13.4 ± 3.7 13.0 ± 3.5 8 (5.5 %) 0.04 0.09 0.003 0.002 0.005 0.004 0.001 0.002 0.001

Vol 44 No 3 HYPERHOMOCYSTEINEMIA AND CORONARY ARTERY DISEASE 361 prior MI (P = 0.4, r = 0.06) and the rate of HHcy were similar in both subgroups (24.4% vs 19.1%, P = 0.4). Relationship between risk factors and thcy level: There was a positive but weak relationship between the thcy levels and male gender (P = 0.03, r = 0.16), cigarette smoking (P, r = 0.19), hyperlipidemia (P = 0.006, r = 0.15), and hypertension (P, r = 0.20). The patients with major risk factors in the CAD group had higher levels of thcy compared to the patients in the control group with similar risk factors (Table II). Relationship between CAD and HHcy and major risk factors: Using regression analysis, HHcy was determined to be an independent risk factor for CAD (OR = 3.69, CI 95% 1.51-9.06, P = 0.004) just like age, gender, smoking, DM, family history, and hyperlipidemia (Table III). When patients were analyzed according to their gender, HHcy was found to be an independent risk factor for both males (OR = 3.62, 95% CI = 1.23-10.63, P = 0.02) and females (OR = 6.4, 95% CI = 1.07-38.55, P = 0.004). However, in the subgroup analysis the mean thcy levels of the patients (n = 42) and control group (n = 92) with low risk profiles were similar (14.0 ± 4.9 µmol/l vs 12.8 ± 3.4 µmol/l, P = 0.1). HHcy was not an independent risk factor for the low risk group (OR = 1.32, CI95% 0.3-5.6, P = 0.7). Relationship between plasma thcy levels and other risk factors with the extent, severity, and vessel scoring of the CAD: It was found that age (P = 0.001, r = 0.25), DM (P = 0.004, r = 0.21), and hypertension (P = 0.02, r = 0.17) were related to the vessel score whereas thcy (P = 0.3, r = 0.07) was not. In the subgroup analysis, neither the low risk (P = 0.6, r = 0.04) nor high risk group (P = 0.2, r = 0.1) thcy was related to the number of vessel involved. The mean vessel scores were 1.84 ± 0.8 and 1.77 ± 0.8 for patients with and without HHcy, respectively (P = 0.6). Patients with 3-vessel disease had significantly higher rates of Table II. Plasma Total Homocysteine Levels in the Patients and Controls with the Same Risk Factor Risk Factors Patients (n = 195) Controls (n = 146) P Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history + (170) (171) + (98) (143) + (37) (304) + (145) (196) + (82) (259) 17.4 ± 8.1 14.8 ± 5.7 18.4 ± 8.8 15.3 ± 6.3 15.0 ± 5.3 16.6 ± 7.7 16.8 ± 8.0 15.8 ± 6.3 15.8 ± 5.9 16.7 ± 8.1 13.9 ± 3.7 12.9 ± 3.5 14.4 ± 3.8 12.9 ± 3.5 11.4 ± 3.9 13.3 ± 3.6 14.4 ± 4.2 12.9 ± 3.4 13.7 ± 4.9 13.2 ± 3.5 0.01 0.002 0.1 0.003 0.2 (+): present, ( ): absent.

362 BOZKURT, ET AL Jpn Heart J May 2003 Table III. Risk Factors for CAD According to Multiple Logistic Regression Analysis Risk Factor Odds ratio 95% Confidence interval P Age Gender Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history HHcy 1.04 2.33 2.21 1.36 4.92 4.39 5.96 3.69 1.01-1.07 1.19-4.59 1.28-4.17 0.73-2.54 1.53-15.86 2.47-7.85 2.69-13.21 1.51-9.06 0.01 0.01 0.006 0.3 0.008 0.001 0.02 HHcy = hyperhomocysteinemia; CAD = coronary artery disease. Table IV. Comparison of Cardiovascular Risk Factors According to the Number of Stenosed Vessels in Patients with CAD Risk Factor 1 Vessel (n = 82) 2 Vessel (n = 64) 3 Vessel (n = 46) Age (years) Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history Total cholesterol (mg/dl) LDL-cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglyceride (mg/dl) thcy (µmol/l) HHcy 49.7 ± 9.8 54 (65.9 %) 23 (28 %) 8 (9.8 %) 48 (58.5 %) 27 (32.9 %) 211.6 ± 96.3 120.0 ± 39.5 41.9 ± 9.5 203.1 ± 127.7 16.0 ± 7.2 18 (22.0 %) 53.6 ± 8.5 39 (60.9 %) 20 (31.3 %) 10 (15.6 %) 34 (53.1 %) 24 (37.5 %) 200.6 ± 45.9 118.0 ± 42.5 44.1 ± 8.4 188.7 ± 88.3 16.4 ± 6.3 15 (23.4 %) 55.4 ± 10.0* 23 (50 %) 24 (52.2)* 14 (30.4 %)* 33 (77.1 %) 20 (43.5 %) 211.4 ± 2.7 131.4 ±± 46.9 41.5 ± 8.3 197.2 ± 161.7 17.1 ± 9.0 11 (23.9 %) thcy = homocysteine; HHcy: hyperhomocysteinemia; CAD = coronary artery disease. *Three-vessel versus one-vessel, P < 0.005 Three-vessel versus two vessel, P < 0.05 Two-vessel versus one-vessel, P < 0.05. major risk factors including age, hypertension, DM, and hyperlipidemia compared to patients with 1 vessel disease (Table IV). Linear regression analysis showed a significant relationship between the extent of CAD and age (P = 0.009) and DM (P = 0.006). No relationship was identified between thcy and disease scoring (Table V). The mean extent score was 2.22 ± 1.3 and 2.25 ± 1.3 in patients with and without HHcy, respectively (P = 0.8). The stenosis scoring of the CAD had a relationship with age (P = 0.007) and DM (P = 0.008), however, this relationship was not present with thcy (Table V). The stenosis scores were 6.47 ± 3.6 and 6.61 ± 3.8 for patients with and without HHcy, respectively (P = 0.8). There was no relationship between thcy and

Vol 44 No 3 HYPERHOMOCYSTEINEMIA AND CORONARY ARTERY DISEASE 363 Table V. P Values of the Relation Between Risk Factors and the Vessel, Extent, and Stenosis Scores in Patients with CAD Risk Factor Vessel score Extent score Stenosis score Age Smoking Hypertension Diabetes mellitus Hyperlipidemia Family history thcy (µmol/l) 0.001 0.09 0.02 0.004 0.3 0.2 0.3 0.009 0.4 0.4 0.008 0.2 0.4 0.7 0.007 0.8 0.4 0.006 0.9 0.4 0.4 thcy = homocysteine; CAD = coronary artery disease. extent and stenosis scoring when the patients were divided into subgroups according to age, gender, and risk profile (P > 0.05). DISCUSSION The relationship between plasma thcy and CAD is still a matter of argument. Most of the cross-sectional and case control studies indicate that the increased level of thcy is an independent risk factor for CAD. 7-8,22-26) Some prospective studies have also showed that an increase in thcy is an indicator for cardiovascular mortality and new coronary artery events. 24-25) However, in some case controlled and prospective studies it was reported that there is no relationship between thcy and CAD. 9-11,27) In this study, we determined that HHcy, similar to known major risk factors, is an independent risk factor for CAD and increases the risk of CAD by 3.69 fold. This result is consistent with the literature indicating a 1.3 to 5.2 fold increase in the risk. 28) HHcy was found to be an independent risk factor for both males and females in the subgroup analyses. There are many possible reasons for the controversial results on the relation between HHcy and CAD. First, the factors affecting the level of thcy are different in every population. Factors like nutrition habits, genetic factors, life styles, and race can affect thcy levels. 3-6) Also, both the thcy level and CAD to which is related are multifactorial. In a study conducted in India, patients with and without CAD were found to have similar levels of thcy of around 18 µmol/l. 9) However, among Indians living in England, although in both the CAD and control groups the levels of thcy were determined to be lower (12.0 µmol/l and 10.8 µmol/l), it was concluded that thcy was an independent risk factor. 23) A second reason is the difference in the methodology of the studies. Although in most studies the diag-

364 BOZKURT, ET AL Jpn Heart J May 2003 nosis of CAD was made with criteria of 50% stenosis of vessel diameter, in others this value was considered to be 70% - 75%. 7,9,22,23) Also, some subjects did not undergo coronary angiography. 7,9) One other important point is the difference in the definition of HHcy. In many studies HHcy is accepted as being greater than the sum of the mean value of the normal population and 2 standard deviations. 15,28) However, in some studies HHcy was defined as the thcy level, which is above the 75% or 90% percentile of the normal population. 7,11) Furthermore, the clinical condition of the patient during the measurement of thcy levels is an important factor. In some studies it was reported that these levels were measured during acute coronary events and this could affect the results. 28) In a recent study it was shown that in patients with premature CAD, although the thcy levels were not higher than normal controls, HHcy and a history of myocardial infarction (MI) were found to be related and it was proposed that HHcy might be important not in the development of CAD, but rather in acute coronary thrombosis. 10) Ethnic and geographic differences, nutritional habits, and genetic polymorphism are factors which can affect the results. 3-6,29) In our population there is a relationship between thcy and CAD independent of age and gender. Furthermore, HHcy appears to be the fourth major risk factor following family history, DM, and hyperlipidemia. Donner, et al 30) have found that in low risk patient groups and patients under the age of 50 the incidence of HHcy was not significantly high. They concluded that the CAD and HHcy relationship reported in other studies was actually a result of other primary risk factors. A meta-analysis showed that although the effect of HHcy in the development and progression of CAD might be less important in the long term, it is still too early to conclude that HHcy is not an important risk factor. It was also stated that the effects of thcy could be masked by other risk factors. 12) We also found that in low risk profile patients the thcy levels were not higher than the control group and HHcy was not an independent risk factor. But this subgroup consisted of only a few patients. The mean thcy level of the patients than smoke or have hypertension or hyperlipidemia was higher than that of the control subjects with the same risk factors. For these reasons, in patients with a low risk profile it may not be appropriate to conclude that HHcy is not an independent risk factor for CAD. Also, in a study involving a small patient population formed of low risk profile patients, there was a significant relationship between thcy levels and CAD. 31) However, in the literature there are no adequate data to support that HHcy is an independent risk factor in patients with a low risk profile. The normal plasma thcy level is accepted to be 5-15 µmol/l although in many studies a range between 8.5-13.5 µmol/l is commonly used. 27,32) In the patient populations this value was found to be between 7.6 and 16.4 µmol/l. 5,32)

Vol 44 No 3 HYPERHOMOCYSTEINEMIA AND CORONARY ARTERY DISEASE 365 In one study this level was found to be around 18 µmol/l in both the patient and control groups and this was attributed to nutritional habits. 9) The values we present in this paper for both the CAD and the control groups are within the range found in the literature. We did not find a relationship between age and thcy levels. This might be attributed to the mean age distributions of our CAD and control groups, which were 52 and 50 years, respectively. Similarly, some studies show that there is no relationship between age and thcy levels. 7,25) Also, in these studies the mean age was around 50 to 54 years. It is known that in males the thcy levels are 11% - 22% higher than in females. 5,8) We also found that the thcy levels in males were 14% higher than in females in both the CAD and control groups. This finding is attributed to estrogen being a factor that lowers thcy levels in females. 33) The lower levels of B6, folate, and cobalamine in meles might be another reason for this phenomenon. 4) We also identified a weak relation between thcy levels and smoking. However, the mechanism by which smoking increases thcy levels is unknown. Some possible mechanisms might be decreases in plasma thiol, folate, B12, and B6 levels due to smoking. 34,35) Although most studies failed to identify a relationship between hypertension and lipid profiles with thcy, 7,8,24,25) some epidemiologic studies reported the existence of this phenomenon. 6,36) We also identified a significant but weak relationship between hypertension and high total cholesterol levels with thcy. The effect of MI on thcy is controversial. It was reported that in the first 24 hours of the MI the thcy level was 40% lower than the 72-hour value, followed by an increase after the acute phase which lasts for 6 to 8 weeks. 37) Nikfardjam, et al 10) showed a relationship between history of MI and HHcy. Nygard, et al 24) reported that in patients with a history of MI the levels of thcy were elevated and this eleration was attributed to an increase in acute events. In our study even though we found that the thcy levels were higher in patients with a history of MI, there was no difference in the rate of HHcy. In recent years, it has been reported that the level of thcy may be related to the extent, severity, and number of vessels involved in CAD and may be important in the progression of the disease. 7,38) A prospective study based on a definition of CAD of 50% stenosis showed that thcy levels are weakly related with vessel score unlike dyslipidemia which is strongly related with vessel score. 24) Montalescot, et al 38) accepted > 75% stenosis as the criteria for a diagnosis of CAD and found a weak but significant relationship between the number of vessels involved and the level of thcy. In a study involving only male patients in which the criteria for CAD was > 75% stenosis, the level of thcy was found to be higher in patients with 3 vessel disease than in patients with 1 or 2 vessel disease. 7) Chao, et al 8) accepted the border for CAD as 70% stenosis and found that the thcy levels were significantly higher in patients with 3-vessel disease than in

366 BOZKURT, ET AL Jpn Heart J May 2003 patients with 1 or 2-vessel disease. They also found a relationship between extent and stenosis scoring with the level of thcy. There are also studies stating there is no relationship between thcy levels and the extent, severity, and number of vessels involved. Kang, et al 39) who considered the CAD criteria to be > 70% stenosis and Wilcken, et al 40) who took the CAD criteria to be 50% stenosis, reported there was no relationship between thcy levels and disease severity. A study showed that thcy levels are related with the vessel and extent scores of CAD in patients with a low risk profile unlike in patients with a high risk profile. 31) In our study, we did not find a relationship between the thcy levels and the extent, severity, and number of vessels involved in the CAD. This might be due to the number of patients. However, in the literature the study group sizes vary between 70 and 201 patients. 7,31) On the other hand, there was a relationship between major risk factors such as age and DM with the scores for extent, severity, and number of vessels involved. Controversial results between plasma thcy levels and the extent and severity of CAD might be related to the different narrowing percentages for vessels used in defining CAD. Another possible reason is that the relation between the extent and severity of CAD could be dependent on geographic, demographic, nutrition, and genetic differences. On the other hand, risk factors that have an effect on the progression of CAD may differ according to the characteristics of the populations and patients groups. CONCLUSION Although hyperhomocysteinemia is an independent risk factor for CAD in our region, it appears to be unrelated to the extent and severity of the disease. REFERENCES 1. McCully KS. Homocysteine and vascular disease. Nat Med 1996; 2: 386-9. 2. Thambyrajah J, Townend JN. Homocysteine and atherothrombosis mechanisms for injury. Eur Heart J 2000; 21: 967-73. 3. Kraus JP. Biochemistry molecular genetics of cystathionine beta-synthase deficiency. Eur J Pediatr 1998; 157: S50-3. 4. Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH. Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 1993; 270: 2693-8. 5. Senaratne MP, MacDonald K, DeSilva D. Possible ethnic differences in plasma homocysteine levels associated with coronary artery disease between South Asian and East Asian immigrants. Clin Cardiol 2001; 24: 730-4. 6. Nygard O, Volsett SE, Refsum H, et al. Total plasma homocysteine and cardiovascular risk profile: the Hordaland Homocysteine Study. JAMA 1995; 274:1526-33. 7. Yoo JH, Park JE, Hong KP, et al. Moderate hyperhomocyst(e)inemia is associated with the presence of coronary artery disease and severity of coronary atherosclerosis in Koreans. Thromb Res 1999; 94: 45-52. 8. Chao CL, Tsai HH, Lee CM, et al. The graded effect of hyperhomocysteinemia on the severity and extent of coronary atherosclerosis. Atherosclerosis 1999; 147: 379-86.

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