Serum Homocysteine and Traditional Cardiovascular Risk Factors in Atherosclerosis of the Coronary and Carotid Arteries

Transcription

1 [Original Article] 77 Serum Homocysteine and Traditional Cardiovascular Risk Factors in Atherosclerosis of the Coronary and Carotid Arteries Tsui-Yen Chang 1 and Jong-Dar Chen 1,2 Background: The present study was conducted to evaluate the association between total homocysteine (thcy) and traditional cardiovascular risk factors and atherosclerosis in the carotid and coronary arteries. Methods: This was a cross-sectional study of 1884 patients presenting to a medical center in north Taiwan with varying degrees of chest pain between January 2006 and September Patients were referred for a comprehensive cardiovascular health checkup that included 256-slice multi slice computer tomography (MSCT) and carotid duplex scans. Traditional cardiovascular risk factors and serum thcy levels were measured to determine the association between thcy and atherosclerosis. Results: The mean age of the patients was 54.7 years, and 64.7% of the participants were men. Overall, 34% had coronary artery stenosis and 52% had plaque deposits in their carotid arteries. After using multiple logistic regression analysis to control for the effect of traditional cardiovascular risk factors, the odds ratio (OR) for atherosclerosis increased along with the increasing levels of thcy. These findings were observed in both the carotid and coronary arteries. thcy quartiles 3 and 4 were significantly associated with a greater OR for carotid plaque formation (1.5 and 2.1, respectively), while the fourth quartile of thcy showed a higher OR for coronary stenosis (OR = 1.5, as compared to the first quartile of thcy). Conclusion: Elevated thcy is independently associated with an increased risk of atherosclerosis in the carotid and coronary arteries identified via carotid duplex and 256-slice MSCT scans. (Taiwan J Fam Med 2017; 27: 77-88) DOI: / Key words: carotid duplex, carotid plaque, computed tomography angiography, coronary artery stenosis, homocysteine 1 Department of Family Medicine, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan. 2 School of Medicine, Fu Jen Catholic University, Taipei, Taiwan. Correspondence to: Dr. Jong-Dar Chen, Department of Family Medicine and Center for Environmental and Occupational Medicine, Shin Kong Wu Ho-Su Memorial Hospital, No.95 Wen Chang Road, Shih Lin, Taipei 111, Taiwan. Received: March 25, 2016; Revised: May 27, 2016; Accepted: July 28, 2016.

2 Taiwan J Fam Med 78 Homocysteine and atherosclerosis 2017 Vol.27 No.2 INTRODUCTION Atherosclerosis is a leading cause of coronary artery disease (CAD) and stroke, which is in turn a significant cause of worldwide mortality. The association between traditional cardiovascular risk factors and atherosclerosis has been well established in previous studies [1,2]. In recent decades, many studies have focused on discovering new biomarkers for atherosclerosis in order to improve diagnostic efficacy. In addition, newly developed techniques for the noninvasive assessment of coronary vessel stenosis, such as 256-slice multi slice computer tomography (MSCT) can provide a reliable and highly accurate diagnosis of CAD [3]. Homocysteine is a sulfur-containing amino acid, the level of which is determined by both genetic and nutritional factors [4]. Increased levels of total homocysteine (thcy) promote CAD by exerting a direct cytotoxic effect on the endothelium and increasing platelet aggregation, thus leading to a hypercoagulable state. Several studies have described that thcy is an independent risk factor for the development of atherosclerosis, which further contributes to CAD [5,6], stroke [7], peripheral artery disease [8], and extracranial carotid artery stenosis. However, most of the available results are derived primarily from Western populations. Only a few studies have explored the association between thcy and atherosclerosis in Asian populations [9-13]. The aim of the present study was to investigate the association between thcy and traditional cardiovascular risk factors and atherosclerosis in the carotid and coronary arteries of Taiwanese patients. The degree of stenosis was directly evaluated using MSCT and carotid duplex scans. MATERIAL AND METHODS Subjects This was a cross-sectional study conducted as a part of the health examination program in a medical center in north Taiwan from January 2006 to September A total of 1884 patients presenting with chest pain symptoms of varying degrees of typicality were referred for a comprehensive cardiovascular health check-up which included a 256-slice MSCT and carotid duplex scan. All subjects provided details of their medical and family histories regarding known CAD risk factors (hypertension, diabetes mellitus, and dyslipidemia), smoking habits and current medication use through a self-reported questionnaire. Patients were excluded if they had a history of adverse reactions to iodinated contrast medium or if they had elevated serum creatinine levels (>1.5 mg/ dl). Measurements Anthropometric measurements for each subject were obtained by trained nurses. Height and weight were measured with a foot-to-foot bioelectrical impedance analyzer (BF-220, Tanita Corp., Tokyo, Japan) with the subjects wearing light clothes. Body mass index (BMI) was

3 Chang TY, Chen JD 79 calculated as body weight in kilograms divided by height in meters squared (kg/ m 2 ). Blood pressure (BP) was recorded in a sitting position after sufficient rest, using the automated oscillometric blood pressure recorder Dinamap DPC 100X-EN (GE Medical System, Milwaukee, Wisconsin, USA). Waist circumference (WC) was obtained at the midpoint between the anterior superior iliac crest and lower rib after normal expiration. Blood samples for biochemical analysis were collected from the subjects after an eight-hour overnight fast. Serum levels of fasting glucose (FG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), and HbA1c were measured by an automated Hitachi 7600 clinical analyzer (Hitachi, Ltd., Japan). thcy was measured by using the Architect i2000sr analyzer (Abbott, Illinois, USA). Computed tomographic angiography All patients underwent computed tomographic angiography (CTA) using a 256-slice MSCT system (Brilliance ict, Philips, Eindhoven, The Netherlands). The scan settings were 120-kVp tube voltage, 270-ms gantry rotation, 925-mA tube current-time product with prospective electrocardiogram gating when the heart rate was <70/min, and 592-mA tube current-time product with retrospective electrocardiogram gating when the heart rate was >70/min. A beta-blocker (propranolol 40 mg, oral) was prescribed to subjects whose heart rate was >90/min. Cross-sectional images were reconstructed with a section thickness of 0.9 mm at mm intervals. All images were interpreted by 2 radiologists who had at least 5 years of cardiac computed tomography experience. Subjects were classified into two categories based on the maximum percent diameter stenosis of the diseased artery: <50% coronary stenosis (-) or 50% coronary stenosis (+). Carotid ultrasonography Duplex examination was performed with a 3- to 9 MHz linear array transducer, using an ie33 diagnostic ultrasound system (Philips ultrasound, Bothell, WA, USA). All patients underwent carotid duplex scanning of the left and right common, internal, and external carotid arteries by two technicians at the health center. A plaque was defined as intima-media thickness (IMT) exceeding 1.2 mm or as local thickening of the IMT of >50% compared to the surrounding vessel wall. Subjects were classified into two categories based on the presence of carotid plaque by a neurologist Statistical analysis The subjects were divided into quartiles according to their thcy serum levels. Student s t-test was used to compare the continuous variables. The associations among thcy, coronary artery stenosis, and carotid plaque were analyzed using a multiple logistic regression model. A p value <0.05 was considered statistically significant.

4 Taiwan J Fam Med 80 Homocysteine and atherosclerosis 2017 Vol.27 No.2 Ethical considerations The ethical committee of our institute approved the study protocol and all patients provided written informed consent (EC/IRB number: R). RESULT Baseline characteristics of the study participants are presented in Table 1. The mean age of the participants was 54.7 years and 64.7% of the participants were male. Overall, 34% had coronary artery stenosis and 52% had plaque deposits in their carotid arteries. FG, TG, and systolic BP were increased in subjects with coronary artery stenosis. Similarly, FG and systolic BP were elevated in subjects with carotid plaque. Subjects with stenosis or plaque had a higher levels of thcy compared to those who did not ( vs μmol/l, and vs μmol/l, respectively). High-sensitivity (hs) C-reactive protein (CRP) did not differ among subjects with or without stenosis or plaque. Table 1. Basic Characteristics of the Study Participants Stenosis Plaque No Yes No Yes (n=1,241) (n=643) (n=902) (n=982) Age (years) * * Male (%) 68 85* Smoker (%) BMI (kg/m 2 ) * WC (cm) * * SBP (mmhg) * DBP (mmhg) * FG (mg/dl) * HbA1c (%) * * TC (mg/dl) * HDL-C (mg/dl) * LDL-C (mg/dl) TG (mg/dl) hs CRP (mg/dl) Homocysteine (μmol/l) * * *p<0.05 BMI, body mass index; WC, waist circumference; FG, fasting glucose; TC, total cholesterol; HDL-C, highdensity lipoprotein; LDL-C, low-density lipoprotein; TG, triglyceride; SBP, systolic blood pressure; DBP, diastolic blood pressure; hs CRP, high-sensitivity C-reactive protein

5 Chang TY, Chen JD 81 Table 2 shows a comparison of the odds ratio for traditional cardiovascular risk factors and homocysteine for developing atherosclerosis. High levels of thcy had a greater odds ratio for developing stenosis and plaque (OR = 1.5, 95% CI = and OR = 1.6, 95% CI = , respectively). Among the traditional cardiovascular risk factors, only high FG (defined as FG 100 mg/dl) had a greater odds ratio for atherosclerosis. The relationship between the thcy quartiles and atherosclerosis risk factors is shown in Table 3. The mean thcy in each quartile was μmol/l (first quartile), μmol/ L (second quartile), μmol/ L (third quartile), and μmol/ L (fourth quartile). thcy quartiles 3 and 4 were associated with increased WC, BMI, systolic and diastolic BP, and decreased levels of HDL-C. A concurrent increase in the OR for atherosclerosis was seen with increasing quartiles of thcy (Table 4). Quartile 1 was used as the reference group. thcy quartile 4 was significantly associated with coronary stenosis (OR = 1.5, with a 95% CI of ), while quartiles 3 and 4 were associated with carotid plaque formation (OR = 1.5 and 2.1, with a 95% CI of and , respectively). DISCUSSION The current study used multiple imaging modalities, including 256-slice MSCT and carotid duplex to investigate the associations among thcy, traditional cardiovascular risk factors, and Table 2. The Association Between Serum Homocysteine, Traditional Risk Factors and Atherosclerosis in the Coronary and Carotid Arteries Stenosis Plaque High blood pressure 1.2 ( ) 1.2 ( ) High FG 1.4 ( )* 1.4 ( )* High TG 1.1 ( ) 0.8 ( ) Low HDL-C 0.9 ( ) 1.2 ( ) High LDL-C 1.2 ( ) 1.2 ( ) High hs CRP 0.8 ( ) 0.9 ( ) High thcy 1.5 ( )* 1.6 ( )* Adjusted for age, sex, waist circumference, body mass index, smoking status and alcohol consumption. *p value <0.05 data were expressed as OR (95% CI) FG, fasting glucose; TG, triglyceride; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein; hs CRP, high-sensitivity C-reactive protein; thcy, total homocysteine High blood pressure: systolic blood pressure 130 mmhg or diastolic blood pressure 85 mmhg; High FG: FG 100 mg/dl; High TG: TG 150 mg/dl; Low HDL: HDL 40 mg/dl for men and 50 mg/dl for women; High LDL: LDL 130 mg/dl; High hs CRP: hs CRP 0.5 mg/dl; High thcy: thcy 12.3 μmol/l (Q4)

6 Taiwan J Fam Med 82 Homocysteine and atherosclerosis 2017 Vol.27 No.2 Table 3. The Distribution of Traditional Cardiovascular Risk Factors in Quartiles of Homocysteine Q1 Q2 Q3 Q4 (n=474) (n=468) (n=471) (n=471) Homocysteine (μmol/l) Age (years) Male (%) Smoker (%) WC (cm) * 89 9* 90 9* BMI (kg/m 2 ) * 26 4* 26 4* FG (mg/dl) HbA1c TC (mg/dl) HDL-C (mg/dl) * 48 13* 47 13* LDL-C (mg/dl) TG (mg/dl) * SBP (mmhg) * * DBP (mmhg) * 78 12* hs CRP (mg/dl) *p value <0.05, as compared to Q1 (Student's t-test) BMI, body mass index; WC, waist circumference; FG, fasting glucose; TC, total cholesterol; HDL, highdensity lipoprotein; LDL-C, low-density lipoprotein; TG, triglycerides; SBP, systolic blood pressure; DBP, diastolic blood pressure; hs CRP, high-sensitivity C-reactive protein Table 4. The Association Between Serum Homocysteine and Atherosclerosis in Coronary Artery Stenosis and Carotid Plaque (Adjusted for Age, Sex, BP, FG, TG, LDL, HDL, Smoking, and Alcohol Consumption) Q1 Q2 Q3 Q4 Stenosis ( ) 1.1 ( ) 1.5 ( )* Plaque ( ) 1.5 ( )* 2.1 ( )* *p value <0.05 data were expressed as OR (95% CI) BP, blood pressure; FG, fasting glucose; TG, triglyceride; LDL-C, low-density lipoprotein; HDL-C, highdensity lipoprotein atherosclerosis in the coronary and carotid arteries of Taiwanese patients. The OR for atherosclerosis increased along with increasing levels of thcy after controlling for the traditional cardiovascular risk factors. These findings were observed in both the carotid and coronary arteries. thcy quartiles 3 and 4 were significantly

7 Chang TY, Chen JD 83 associated with a greater OR for carotid plaque formation (OR = 1.5 and 2.1, respectively), and the fourth quartile of thcy also showed higher OR for coronary stenosis (OR = 1.5, as compared to the first quartile of thcy). Previous studies have shown that elevated thcy is strongly associated with CAD events, peripheral artery disease [14], and ischemic stroke [15]. However, most of the available data are limited to a predominantly Caucasian population. Only a few studies have explored the association between thcy and cardiovascular disease in the Asian population [9-13]. thcy was associated with a 10-year CAD risk on using the Framingham risk score, modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) in Korean populations [9]. The OR in quartile 4 to quartile 1 was 5.1 (95% CI = ). Furthermore, our current results also indicate that elevated thcy is an independent risk factor for atherosclerosis in the Taiwanese population. Instead of using the Framingham risk score to determine the risk of CAD, our study utilized MSCT for the direct detection of atherosclerosis in the coronary arteries. MSCT has been in use for many years as a non-invasive diagnostic tool for evaluating the presence and severity of coronary vessel stenosis. The 256-slice CTA has been proven to be both reliable and accurate in the diagnosis of CAD. In addition, results from our own institute and others have previously shown a powerful correlation with invasive coronary angiography [3,16]. The sensitivity and specificity were 94.3% and 87.3%, respectively, with vessel-based analysis. We have shown that elevated thcy is an independent risk factor for occlusive CAD, confirming the results from previous studies. A meta-analysis by Wald et al. [17] showed that each 3 μmol/l decrease in thcy level reduced the relative risk for CAD by 16%, for deep vein thrombosis by 25% and for stroke by 24%. According to the recommendations by the U.S. Preventive Services Task Force, an increase in thcy levels of 5 μmol/l confers an approximate 20% increase in the risk of CAD events [18]. In the present study, thcy levels appeared to be higher than those reported for Caucasians [14]. Similar findings have been reported in other Asian populations [19]. Chambers et al. [19] found that the mean thcy concentrations were 6% higher in Indians than in Europeans, which may account for the twice as many CAD deaths in this population. thcy levels may be determined by genetic and nutritional factors, including deficiencies of folate, vitamin B6, and vitamin B [4] 12. Prolonged cooking of vegetables, which is a common practice in many Chinese households, may destroy the folate content [20]. In addition, our study population was symptomatic and thus more likely to have higher thcy levels. Despite the higher level of thcy, the mean thcy was relatively low in our atherosclerotic subjects compared to the levels previously cited for Caucasians [14]. Mean fasting thcy levels in CAD cases were 12.9 to 16.4 μmol/l in previous studies and 11.6 μmol/l in the current study. There is still no consensus

8 Taiwan J Fam Med 84 Homocysteine and atherosclerosis 2017 Vol.27 No.2 among clinicians regarding a threshold thcy level that would protect against CAD events. Our results suggest that the cutoff points for thcy should be different among different ethnicities. Our data also provided evidence that plasma thcy levels are associated with extracranial carotid plaque deposits. We observed that the risk of plaque formation increased significantly in quartiles 3 and 4, which were previously considered to be in the normative range for thcy. In our study, the risk of plaque formation was elevated in patients with thcy quartile 3 (mean thcy = 11.3 μmol/l). Previous studies on the association between plasma thcy level and carotid plaque showed conflicting results. Sakaki et al. evaluated the association between plasma thcy and atherosclerotic carotid plaque and lacunar infarction [11]. They found that the plaque score increased linearly with thcy. After controlling for the traditional atherosclerotic risk factors, thcy was found to be significantly associated with the plaque score, suggesting a potential effect of higher thcy on the formation of carotid atherosclerosis. A link between thcy and extracranial carotid artery stenosis has also been previously investigated by Selhub and colleagues [21]. The OR for stenosis 25% was 2.0 for elderly subjects in the highest quartile as compared to those in the lowest quartile. However, a study by Hillenbrand et al. [22] failed to demonstrate this association. Several studies have also failed to demonstrate any association between early re-stenosis following carotid endarterectomy and thcy [23,24]. This study supports the possibility of an atherogenic role for thcy in the carotid and coronary arteries. thcy can promote plaque formation through various mechanisms that are not yet fully understood. It is postulated that thcy may have a direct toxic effect on the vascular endothelium, that it may impair endothelium-related vasodilatation, as well as increase DNA synthesis in vascular smooth muscle cells and cause oxidation of LDL-C [25-28]. It may also inhibit the action of the anticoagulant proteins thrombomodulin and activated factor V; inhibit the activation of protein C; and increase platelet aggregation, thus contributing to a hypercoagulable state [29]. The hs CRP level and traditional cardiovascular risk factors (with the exception of FG) were not significantly associated with atherosclerosis in this study. This finding might be partly explained by the fact that the symptomatic study participants were referred for a cardiovascular health checkup may have had varying degree of chest pain, and may have accepted treatment for these traditional risk factors. There are some limitations of this study that should be mentioned. First, all the study subjects were referred due to varying degrees of chest pain and were able to accept medical treatment for the traditional cardiovascular risk factors. This limitation of the study protocol may have underestimated the effects of these risk factors on atherosclerosis. Second, we collected the medical history using a

9 Chang TY, Chen JD 85 self-administrated questionnaire that was incomplete in some cases, and thus we may have underestimated the effect of certain variables (ie. medication history and family history of CAD) on atherosclerosis. Third, we did not collect nutrition data or quantify serum levels of folic acid, which have been proposed in previous studies to be related to the serum level of thcy. In conclusion, directly imaging atherosclerosis of the coronary and carotid arteries in this study allowed us to clarify the association between thcy serum levels and atherosclerosis. Our study provides evidence for the association between thcy and atherosclerosis in subjects with varying degrees of chest pain, using both carotid duplex and 256-slice MSCT. Elevated thcy levels increased the risk of atherosclerosis in the carotid and coronary arteries. thcy levels in the 4th quartile were significantly associated with a greater OR for carotid plaque formation and coronary artery stenosis. Further studies are warranted to effectively design cutoff points for thcy in different ethnic groups. ACKNOWLEDGEMENTS This article was supported by the physical checkup center of Shin Kong Wu- Ho Su Memorial Hospital. REFERENCES 1. de Lemos JA, Lloyd-Jones DM: Multiple biomarker panels for cardiovascular risk assessment. N Engl J Med 2008; 358: Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB: Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: Petcherski O, Gaspar T, Halon DA, et al: Diagnostic accuracy of 256-row computed tomographic angiography for detection of obstructive coronary artery disease using invasive quantitative coronary angiography as reference standard. Am J Cardiol 2013; 111: Cooper BA, Rosenblatt DS: Inherited defects of vitamin B12 metabolism. Annu Rev Nutr 1987; 7: Clarke R, Daly L, Robinson K, et al: Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991; 324: Kawashiri M, Kanami K, Nohara A, et al: Plasma homocysteine level and development of coronary artery disease. Coron Artery Dis 1999; 10: Perry IJ, Refsum H, Morris RW, Ebrahim SB, Ueland PM, Shaper AG: Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men. Lancet 1995; 346: Taylor LM Jr, Moneta GL, Sexton GJ, Schuff RA, Porter JM: Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease. J Vasc Surg 1999; 29: 8-19; discussion Cho DY, Kim KN, Kim KM, Lee DJ, Kim BT: Combination of high-sensitivity C-reactive protein and homocysteine may predict an increased risk of coronary artery

10 Taiwan J Fam Med 86 Homocysteine and atherosclerosis 2017 Vol.27 No.2 disease in Korean population. Chin Med J (Engl) 2012; 125: Matsui T, Arai H, Yuzuriha T, et al: Elevated plasma homocysteine levels and risk of silent brain infarction in elderly people. Stroke 2001; 32: Sasaki T, Watanabe M, Nagai Y, et al: Association of plasma homocysteine concentration with atherosclerotic carotid plaques and lacunar infarction. Stroke 2002; 33: Jeong SK, JY, Cho YI: Homocysteine and internal carotid artery occusion in ischemic stroke. J Atheroscler Thromb 2010; 17: Mungun-Ulzii K, Erdenekhuu N, Altantsetseg P, Zulgerel D, Huang SL: Asymptomatic Mongolian middle-aged women with high homocysteine blood level and atherosclerotic disease. Heart Vessels 2010; 25: Boushey CJ, Beresford SA, Omenn GS, Motulsky AG: A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 1995; 274: Holmes MV, Newcombe P, Hubacek JA, et al: Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials. Lancet 2011; 378: Chao SP, Law WY, Kuo CJ, et al: The diagnostic accuracy of 256-row computed tomographic angiography compared with invasive coronary angiography in patients with suspected coronary artery disease. Eur Heart J 2010; 31: Wald DS, Law M, Morris JK: Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002; 325: U. S. Preventive Services Task Force. Using nontraditional risk factors in coronary heart disease risk assessment: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 151: Chambers JC, Obeid OA, Refsum H, et al. Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian Asian and European men. Lancet 2000; 355: Dawson DW, Waters HM: Malnutrition: folate and cobalamin deficiency. Br J Biomed Sci 1994; 51: Selhub J, Jacques PF, Bostom AG, et al: Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population. J Nutr 1996; 126: 1258S-1265S. 22. Hillenbrand R, Hillenbrand A, Liewald F, Zimmermann J: Hyperhomocysteinemia and recurrent carotid stenosis. BMC Cardiovasc Disord 2008; 8: Assadian A, Rotter R, Assadian O, Senekowitsch C, Hagmuller GW, Hubl W: Homocysteine and early re-stenosis after carotid eversion endarterectomy. Eur J Vasc Endovasc Surg 2007; 33: Samson RH, Yungst Z, Showalter DP: Homocysteine, a risk factor for carotid atherosclerosis, is not a risk factor for early recurrent carotid stenosis following carotid endarterectomy. Vasc Endovascular Surg 2004; 38:

11 Chang TY, Chen JD Heinecke JW, Rosen H, Suzuki LA, Chait A. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem 1987; 262: Tsai JC, Perrella MA, Yoshizumi M, et al: Promotion of vascular smooth muscle cell growth by homocysteine: a link to atherosclerosis. Proc Natl Acad Sci U S A 1994; 91: Usui M, Matsuoka H, Miyazaki H, Ueda S, Okuda S, Imaizumi T. Endothelial dysfunction by acute hyperhomocyst(e) inaemia: restoration by folic acid. Clin Sci (Lond) 1999; 96: Wall RR, Harlan JM, Harker LA, Striker GE: Homocysteine-induced endothelial cell injury in vitro: a model for the study of vascular injury. Thromb Res 1980; 18: Lentz SR, Sadler JE: Inhibition of thrombomodulin surface expression and protein C activation by the thrombogenic agent homocysteine. J Clin Invest 1991; 88:

12 88 [ ] 1 1,2 目的 : 方法 : ,884 結果 : 34% 52% 結論 : ; 27: DOI: /