外周动脉病在中国高血压人群中的流行病学调查及血管内皮细胞生长因子(VEGF)受体基因多态性与其发病风险的关联研究
摘要
目的外周动脉病与冠状动脉粥样硬化性心脏病及脑卒中的发病及死亡密切相关,高血压是外周动脉病的独立危险因素。然而,在中国高血压患者中,外周动脉病的发病率和危险因素还未有报道。
     方法2004-2005年,我们在中国农村7个社区对年龄40-75岁人口进行了一项横断面调查,共筛查了4,716名高血压患者和833名年龄、性别匹配的非高血压对照。外周动脉病定义为:任何一侧下肢踝臂指数(ABI)≤0.9,高血压定义为:收缩压≥140mmHg,或舒张压≥90mmHg,或既往有明确的高血压病史及服用降压药史。
     结果在高血压患者中(n=4,716)外周动脉病的患病率为8.7%(n=408),无高血压的对照组中(n=833)外周动脉病患者占5.0%(42),低于高血压患者,有统计学差异(P=0.004)。高血压患者中,有外周动脉病者与无外周动脉病者相比,年龄更大,(61±8.6 vs 58±8.6岁,P<0.01),传统心血管病危险因素携带更多,包括血压增高(170±22.6 vs 167±22.7 mmHg,P<0.01),脉压增大(72±19.7 vs 68±18.9 mmHg,P<0.01),血糖增高(5.8±2.2 vs 5.6±1.7 mmol/L,P<0.05),总胆固醇增高(5.7±1.3 vs 5.5±1.1 mmol/L,P<0.05),血浆尿酸增高(355±98.0 vs 293±86.2 mmol/L,P<0.05)。多因素logistic回归调整了年龄、性别及其他心血管病危险因素后,与外周动脉病相关的危险因素为:吸烟史(OR=1.65,95%CI 1.18-2.29),脑卒中病史(OR=1.50,95%CI 1.12-2.00),血浆尿酸(OR=1.21,95%CI 1.10-1.59),总胆固醇(OR=1.12,95%CI 1.10-1.59)。
     结论本研究第一次报道了中国高血压患者外周动脉病患病率,并且发现外周动脉病与传统心血管病危险因素独立相关。
     目的探讨中国老年人群踝臂指数(ABI)与无症状性颈动脉粥样硬化的关系。
     方法采用横断面研究方法,2005年8-11月,在参加“青岛港健康研究”的人群中,挑选年龄大于55岁,既往无冠心病,脑卒中,周围动脉病史507人,进行颈动脉超声及四肢血压的检查,同时完善心血管病危险因素的调查。颈动脉粥样硬化定义为:颈动脉内-中膜厚度(IMT)>1.0mm,或局部斑块形成;ABI<0.9定义为踝臂指数(ABI)减低。
     结果颈动脉粥样硬化的患者踝臂指数(ABI)明显减低,ABI<0.90的比例增加(P<0.05);年龄更高,收缩压,脉压增高,BMI增大,血糖增高;既往糖尿病,高血压病史增加(P<0.05),进一步调整年龄,性别,血脂,血糖,收缩压,脉压,体重指数后,踝臂指数(ABI)减低与颈动脉粥样硬化独立相关(OR=0.10,95%CI 0.02-0.42,P<0.01)。结论踝臂指数(ABI)与无症状性颈动脉粥样硬化密切相关,是其独立危险因素。
     目的外周动脉病是一种动脉粥样硬化性血管损伤性疾病,血管壁病变是其发病基础。血管内皮生长因子受体基因(VEGFR)特异地作用于血管内皮细胞,诱导内皮细胞的增生和迁移、细胞外基质的重建以及毛细血管腔的形成,并增加血管通透性,在血管发育、重构及成熟过程中起着重要的调控作用。
     方法采用病例对照的研究方法,研究对象年龄在40~75岁,均为汉族,彼此无亲缘关系,分为外周动脉病组(439人)和对照组(1,517人)。根据既往病史及踝臂指数(ABI)≤0.9诊断为外周动脉病,对照组为0.9<ABI≤1.3的“健康人”,无外周动脉病及其他类型动脉粥样硬化性疾病,性别、年龄与病例组匹配。利用PCR和限制性酶切片断长度多态性(RFLP)的方法对VEGFR-2基因2个SNPs进行基因分型,分析基因多态性与外周动脉病发病风险的关系。
     结果外周动脉病组rs2071559 C等位基因频率及TC和CC基因型频率显著高于对照组(P<0.01),rs1870377 T等位基因频率及AT和TT基因型频率也在病例组中的分布高于对照组(P<0.01)。多元logistic回归模型校正了传统危险因素的影响后,rs2071559 C等位基因及rs1870377 T等位基因仍然与增加的外周动脉病患病风险相关(OR 1.62,95%CI:1.21~2.17;OR 1.63,95%CI:1.15~2.31),P<0.01。
     结论VEGFR-2基因多态可能是外周动脉病的易感基因。
Objectives Peripheral arterial disease (PAD) is associated with morbidity andmortality of coronary heart disease and stroke. Hypertension is an independent riskfactor for peripheral arterial disease. However, the prevalence and risk factors of PADin hypertensive patients has not been studied in China.
     Methods In order to investigate the prevalence of PAD and its risk factors in China,a cross-sectional study was carried out. Total 4,716 patients with hypertension and833 age-sex matched people without hypertension were recruited; age 40-75, from 7rural communities. PAD was defined as an ankle-brachial index (ABI)≤0.9 in eitherlegs, hypertension was defined as systolic blood pressure≥140mmHg, or diastolicblood pressure≥90mmHg, or history of antihypertensive drug use.
     Results The prevalence of PAD is 8.7% (n=408) in patients with hypertension(n=4,716), higher than the people without hypertension (5.0%, n=833), P=0.004.Hypertensive patients with PAD were older (61±8.6 vs 58±8.6 years old, P<0.01), hadmore conventional cardiovascular risk factors including higher systolic blood pressure(170±22.6 vs 167±22.7 mmHg, P<0.01), pulse pressure (72±19.7 vs 68±18.9 mmHg,P<0.01), higher blood glucose (5.8±2.2 vs 5.6±1.7mmol/L, P<0.05), total cholesterol(5.7±1.3 vs 5.5±1.1 mmol/L, P<0.05), and serum uric acid (355±98.0 vs 293±86.2mmol/L, P<0.05) than the hypertensive patients without PAD. After adjusted for sex,age and other cardiovascular risk factors by using multiple logistical regressionanalysis, PAD remained associated with current smoking (OR=1.65, 95% CI1.18-2.29), history of stroke (OR=1.50, 95% CI, 1.12-2.00), serum uric acid(OR=1.21, 95% CI, 1.10-1.59), total cholesterol (OR=1.12, 95% CI, 1.10-1.59).
     Conclusion This study provides the prevalence of PAD in Chinese patients with hypertension for the first time; and PAD is independently associated withconventional cardiovascular risk factors.
     Objective The purpose of this study was to detect the relationship betweenankle-brachial index (ABI) and preclinical carotid atherosclerosis in elderly Chinese.Methods In order to investigate the association between ABI and preclinical carotidatherosclerosis in elderly Chinese, a cross-sectional study was carried out. Total 507patients older than 55 years from the health study of QingDao harbor were recruited.None of them had history of clinical coronary artery disease, stroke and peripheralartery disease. Blood pressure and ultrasound examination were performed. Carotidatherosclerosis was defined as carotid intima-media thickness (IMT)>1.0mm orcarotid plaque. Low ankle-brachial index (ABI) was defined as ABI<0.9 in eitherlegs.
     Results The higher percentage of ankle-brachial index (ABI)<0.9 and history ofdiabetic mellitus, hypertension were investigated in subjects with carotidatherosclerosis than those without carotid atherosclerosis, (p<0.05). Subjects withcarotid atherosclerosis were older, had more conventional cardiovascular risk factorsincluding higher systolic blood pressure, pulse pressure, higher blood glucose, bodymass index (BMI) than those without carotid atherosclerosis, (p<0.05). Afteradjusted for sex, age and other cardiovascular risk factors by using multiple logisticalregression analysis, ABI was negatively associated with carotid atherosclerosis(OR=0.10, 95%CI 0.02-0.42, P<0.01).
     Conclusion Low ABI is a strong predictor for preclinical carotid atherosclerosis inelderly Chinese
     Objective Peripheral arterial disease (PAD) is a kind of atherosclerotic diseaseresulted from vascular damage. The lesion in vascular wall is the underlyingpathological mechanism. Vascular endothelial growth factor (VEGF), which is apotent endothelial cell mitogen and vascular permeability-enhancing factor, plays avital role in the process of vascular development and maturation via its tyrosinekinase receptors.
     Methods A case-control study was carried out. Total 439 patients with peripheralarterial disease and 1,517 age-sex matched individuals without atheroscleroticdiseases such as stroke, coronary arterial disease and PAD were recruited. They allclaimed as Han nationality, with age 40-75 years old, without relative between eachother. PAD was defined as an ankle-brachial index (ABI)≤0.9 in either legs. In orderto determine the relationship between the polymorphisms of the VEGF-2 gene and therisk of PAD, two polymorphisms of the VEGF-2 gene were genotyped by PCR andrestriction enzyme analysis.
     Results -604C allele frequency and genotype frequencies of TC and CC in thepatients group were much higher than which in the control group (P<0.01), +1719Tallele frequency and genotype frequencies of AT and TT were also higher in thepatients group than that in the control group (P<0.01). After adjustment fortraditional cardiovascular risk factors by using multiple logistical regression analysis,allele frequencies of-604C and +1719T were associated with PAD significantly (OR1.62, 95%CI: 1.21~2.17; OR 1.63, 95%CI: 1.15~2.31, P<0.01).
     Conclusion the polymorphisms of the VEGF-2 gene is associated with the risksusceptibility to peripheral arterial disease
引文
1. Zheng ZJ, Sharrett AR, Chambless LE, et al. Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study. Atherosclerosis. May 1997;131(1):115-125.
    2. Kennedy M, Solomon C, Manolio TA, et al. Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. Arch Intern Med. Sep 12 2005;165(16): 1896-1902.
    3. Lee AJ, Price JF, Russell MJ, et al. Improved prediction of fatal myocardial infarction using the ankle brachial index in addition to conventional risk factors: the Edinburgh Artery Study. Circulation. Nov 9 2004;110(19):3075-3080.
    4. Murabito JM, Evans JC, Larson MG, et al. The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Arch Intern Med. Sep 8 2003;163(16):1939-1942.
    5. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med. Feb 6 1992;326(6):381-386.
    6. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. Jama. Oct 3 2001;286(13):1599-1606.
    7. McDermott MM, Greenland P, Guralnik JM, et al. Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med. Jun 2003; 18(6) :461-467.
    8. McDermott MM, Liu K, Greenland P, et al. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. Jama. Jul 28 2004;292(4):453-461.
    9. Dormandy JA, Murray GD. The fate of the claudicant~a prospective study of 1969 claudicants. Eur J Vasc Surg. Apr 1991;5(2):131-133.
    10. Jelnes R, Gaardsting O, Hougaard Jensen K, et al. Fate in intermittent claudication: outcome and risk factors. Br Med J (Clin Res Ed). Nov 1 1986;293(6555):1137-1140.
    11. Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med. Apr 28 2003;163(8):884-892.
    12. Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med. Jan 2002;112(1):49-57.
    13. McDermott MM, Hahn EA, Greenland P, et al. Atherosclerotic risk factor reduction in peripheral arterial diseasea: results of a national physician survey. J Gen Intern Med. Dec 2002;17(12):895-904.
    14. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. Jama. Sep 19 2001;286(11):1317-1324.
    15. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. Jama. Jan 11 2006;295(2): 180-189.
    16. Hasimu B, Li J, Yu J, et al. Evaluation of medical treatment for peripheral arterial disease in Chinese high-risk patients. Circ J. Jan 2007;71(1):95-99.
    17. Newman AB, Tyrrell KS, Kuller LH. Mortality over four years in SHEP participants with a low ankle-arm index. J Am Geriatr Soc. Dec 1997;45( 12): 1472-1478.
    18. Myerburg RJ, Kessler KM, Castellanos A. Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med. Dec 15 1993;119(12):1187-1197.
    19. Ouriel K. Peripheral arterial disease. Lancet. Oct 13 2001;358(9289):1257-1264.
    20. Caruana MF, Bradbury AW, Adam DJ. The validity, reliability, reproducibility and extended utility of ankle to brachial pressure index in current vascular surgical practice. Eur J Vasc Endovasc Surg. May 2005;29(5):443-451.
    21. Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol. Jul 2005;25(7):1463-1469.
    22. Bots ML, de Jong PT, Hofman A, et al. Left, right, near or far wall common carotid intima-media thickness measurements: associations with cardiovascular disease and lower extremity arterial atherosclerosis. J Clin Epidemiol. Jul 1997;50(7):801-807.
    23. Sutton KC, Wolfson SK, Jr., Kuller LH. Carotid and lower extremity arterial disease in elderly adults with isolated systolic hypertension. Stroke. Sep-Oct 1987;18(5):817-822.
    24. Sing CF, Stengard JH, Kardia SL. Genes, environment, and cardiovascular disease. ArteriosclerThromb Vasc Biol. Jul 1 2003;23(7):1190-1196.
    25. Zerba KE, Ferrell RE, Sing CF. Genotype-environment interaction: apolipoprotein E (ApoE) gene effects and age as an index of time and spatial context in the human. Genetics. May 1996;143(1):463-478.
    26. Zerba KE, Ferrell RE, Sing CF. Complex adaptive systems and human health: the influence of common genotypes of the apolipoprotein E (ApoE) gene polymorphism and age on the relational order within a field of lipid metabolism traits. Hum Genet. Nov 2000; 107(5):466-475.
    27. O'Hare AM, Glidden DV, Fox CS, et al. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999-2000. Circulation. Jan 27 2004;109(3):320-323.
    28. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. Jama. May 16 2001;285(19):2481-2485.
    29. Staffers HE, Kester AD, Kaiser V, et al. Diagnostic value of signs and symptoms associated with peripheral arterial occlusive disease seen in general practice: a multivariable approach. Med Decis Making. Jan-Mar 1997;17(1):61-70.
    30. Kullo LT, Turner ST, Kardia SL, et al. A genome-wide linkage scan for ankle-brachial index in African American and non-Hispanic white subjects participating in the GENOA study. Atherosclerosis. Aug 2006;187(2):433-438.
    31. Boerwinkle E, Doris PA, Fornage M. Field of needs: the genetics of stroke. Circulation. Jan 26 1999;99(3):331-333.
    32. Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. Dec 8 1989;246(4935): 1306-1309.
    33. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. Feb 1997;18(1):4-25.
    34. Oku T, Tjuvajev JG, Miyagawa T, et al. Tumor growth modulation by sense and antisense vascular endothelial growth factor gene expression: effects on angiogenesis, vascular permeability, blood volume, blood flow, fluorodeoxyglucose uptake, and proliferation of human melanoma intracerebral xenografts. Cancer Res. Sep 15 1998;58(18):4185-4192.
    35. Koch AE, Harlow LA, Haines GK, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. Apr 15 1994;152(8):4149-4156.
    36. Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy. Diabetes Metab Rev. Mar 1997;13(1):37-50.
    37. Veikkola T, Karkkainen M, Claesson-Welsh L, et al. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. Jan 15 2000;60(2):203-212.
    38. Waltenberger J, Claesson-Welsh L, Siegbahn A, et al. Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem. Oct 28 1994;269(43):26988-26995.
    39. Quinn TP, Peters KG, De Vries C, et al. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A. Aug 15 1993;90(16):7533-7537.
    40. Shalaby F, Rossant J, Yamaguchi TP, et al. Failure of blood-island formation and vasculogenesis in Flk-1 -deficient mice. Nature. Jul 6 1995;376(6535):62-66.
    41. Gerber HP, McMurtrey A, Kowalski J, et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3'-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. Nov 13 1998;273(46):30336-30343.
    42. Alon T, Hemo I, Itin A, et al. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. NatMed. Oct 1995;1(10):1024-1028.
    43. Fong TA, Shawver LK, Sun L, et al. SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types. Cancer Res. Jan 1 1999;59(1):99-106.
    44. Dvorak HF, Brown LF, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. May 1995; 146(5): 1029-1039.
    45. Ramos MA, Kuzuya M, Esaki T, et al. Induction of macrophage VEGF in response to oxidized LDL and VEGF accumulation in human atherosclerotic lesions. Arterioscler Thromb Vasc Biol. Jul 1998;18(7):1188-1196.
    46. Chen YX, Nakashima Y, Tanaka K, et al. Immunohistochemical expression of vascular endothelial growth factor/vascular permeability factor in atherosclerotic intimas of human coronary arteries. Arterioscler Thromb Vasc Biol. Jan 1999;19(1):131-139.
    47. Celletti FL, Waugh JM, Amabile PG, et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat Med. Apr 2001;7(4):425-429.
    48. Moulton KS, Heller E, Konerding MA, et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation. Apr 6 1999;99(13): 1726-1732.
    49. Lemstrom KB, Krebs R, Nykanen AI, et al. Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Circulation. May 28 2002;105(21):2524-2530.
    50. Awata T, Inoue K, Kurihara S, et al. A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. May 2002;51(5): 1635-1639.
    51. Howell WM, Bateman AC, Turner SJ, et al. Influence of vascular endothelial growth factor single nucleotide polymorphisms on tumour development in cutaneous malignant melanoma. Genes Immun. Jun 2002;3(4):229-232.
    52. Applegate RJ, Cheng CP, Little WC. Simultaneous conductance catheter and dimension assessment of left ventricle volume in the intact animal. Circulation. Feb 1990;81(2):638-648.
    53. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. Jul 15 2003;139(2):137-147.
    54. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. Feb 2002;39(2 Suppl 1):S 1-266.
    55. Resnick HE, Lindsay RS, McDermott MM, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation. Feb 17 2004;109(6):733-739.
    56. Wu Y, Liu X, Li X, et al. Estimation of 10-year risk of fatal and nonfatal ischemic cardiovascular diseases in Chinese adults. Circulation. Nov 21 2006;114(21):2217-2225.
    57. Li Y, Stamler J, Xiao Z, et al. Serum uric acid and its correlates in Chinese adult populations, urban and rural, of Beijing. The PRC-USA Collaborative Study in Cardiovascular and Cardiopulmonary Epidemiology. Int J Epidemiol. Apr 1997;26(2):288-296.
    58. Mohler ER, 3rd. Peripheral arterial disease: identification and implications. Arch Intern Med. Oct 27 2003;163(19):2306-2314.
    59. Shadman R, Criqui MH, Bundens WP, et al. Subclavian artery stenosis: prevalence, risk factors, and association with cardiovascular diseases. J Am Coll Cardiol. Aug 4 2004;44(3):618-623.
    60. Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol. Mar 1999;19(3):538-545.
    61. L W. National nutrition and health survey: report I. General Report: Beijing: People's Medical Publishing House; 2002.
    62. Cui R, Iso H, Yamagishi K, et al. Ankle-arm blood pressure index and cardiovascular risk factors in elderly Japanese men. Hypertens Res. May 2003;26(5):377-382.
    63. Kweon SS, Shin MH, Park KS, et al. Distribution of the ankle-brachial index and associated cardiovascular risk factors in a population of middle-aged and elderly koreans. J Korean Med Sci. Jun 2005;20(3):373-378.
    64. Li XY, Wang J, He Y, et al. [The relation between peripheral arterial occlusive disease and cardiovascular diseases in elderly population: a cross-section study in Wanshoulu area, Beijing]. Zhonghua Yi Xue Za Zhi. Nov 10 2003;83(21):1847-1851.
    65. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. Jama. Sep 27 1995;274( 12):975-980.
    66. Newman AB S-TK, Rutan GR, Locher JA, Kuller LH. Lower extremity arterial disease in elderly subjects with systolic hypertension. J Clin: Epidemiol. 1991;44:15-20.
    67. Curb JD, Masaki K, Rodriguez BL, et al. Peripheral artery disease and cardiovascular risk factors in the elderly. The Honolulu Heart Program. Arterioscler Thromb Vasc Biol. Dec 1996;16(12):1495-1500.
    68. Criqui MH, Vargas V, Denenberg JO, et al. Ethnicity and peripheral arterial disease: the San Diego Population Study. Circulation. Oct 25 2005;112(17):2703-2707.
    69. Meijer WT, Grobbee DE, Hunink MG, et al. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med. Oct 23 2000;160(19):2934-2938.
    70. Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis. 1981;34(6):261-269.
    71. Gallotta G, Iazzetta N, Milan G, et al. Prevalence of peripheral arterial disease in an elderly rural population of southern Italy. Gerontology. 1997;43(5):289-295.
    72. Vogt MT, Cauley JA, Kuller LH, et al. Prevalence and correlates of lower extremity arterial disease in elderly women. Am J Epidemiol. Mar 1 1993;137(5):559-568.
    73. Newman AB, Siscovick DS, Manolio TA, et al. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation. Sep 1993;88(3):837-845.
    74. Fowkes FG, Housley E, Riemersma RA, et al. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemiol. Feb 15 1992; 135(4):331-340.
    75. Palumbo PJ, O'Fallon WM, Osmundson PJ, et al. Progression of peripheral occlusive arterial disease in diabetes mellitus. What factors are predictive? Arch Intern Med. Apr 1991;151(4):717-721.
    76. Aquino R, Johnnides C, Makaroun M, et al. Natural history of claudication: long-term serial follow-up study of 1244 claudicants. J Vase Surg. Dec 2001;34(6):962-970.
    77. Smith FB, Lowe GD, Lee AJ, et al. Smoking, hemorheologic factors, and progression of peripheral arterial disease in patients with claudication. J Vase Surg. Jul 1998;28(1):129-135.
    78. Smith I, Franks PJ, Greenhalgh RM, et al. The influence of smoking cessation and hypertriglyceridaemia on the progression of peripheral arterial disease and the onset of critical ischaemia. Eur J Vasc Endovasc Surg. May 1996; 11 (4).402-408.
    79. Murabito JM, D'Agostino RB, Silbershatz H, et al. Intermittent claudication. A risk profile from The Framingham Heart Study. Circulation. Jul 1 1997;96(1):44-49.
    80. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC). J Vase Surg. Jan 2000;31(1 Pt 2):S1-S296.
    81. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis. Arch Intern Med. Feb 22 1999;159(4):337-345.
    82. Jonason T, Bergstrom R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand. 1987;221(3):253-260.
    83. Ingolfsson IO, Sigurdsson G, Sigvaldason H, et al. A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968-1986: a strong relationship to smoking and serum cholesterol~the Reykjavik Study. J Clin Epidemiol. Nov 1994;47(11): 1237-1243.
    84. Faulkner KW, House AK, Castleden WM. The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust.Msr 5 1983;1(5):217-219.
    85. Abbott RD, Rodriguez BL, Petrovitch H, et al. Ankle-brachial blood pressure in elderly men and the risk of stroke: the Honolulu Heart Program. J Clin Epidemiol. Oct 2001 ;54(10):973-978.
    86. Tsai AW, Folsom AR, Rosamond WD, et al. Ankle-brachial index and 7-year ischemic stroke incidence: the ARIC study. Stroke. Aug 2001;32(8):1721-1724.
    87. Langlois M, De Bacquer D, Duprez D, et al. Serum uric acid in hypertensive patients with and without peripheral arterial disease. Atherosclerosis. May 2003;168(1):163-168.
    88. Tapp RJ, Shaw JE, de Courten MP, et al. Foot complications in Type 2 diabetes: an Australian population-based study. Diabet Med. Feb 2003;20(2): 105-113.
    89. Tseng CH. Independent association of uric acid levels with peripheral arterial disease in Taiwanese patients with Type 2 diabetes. Diabet Med. Jul 2004;21(7):724-729.
    90. Fu CC, Chang CJ, Tseng CH, et al. Development of macrovascular diseases in NIDDM patients in northern Taiwan. A 4-yr follow-up study. Diabetes Care. Jan 1993;16(1):137-143.
    91. Tseng CH. Prevalence and risk factors of peripheral arterial obstructive disease in Taiwanese type 2 diabetic patients. Angiology. May-Jun 2003;54(3):331-338.
    92. Zimmerman BR, Palumbo PJ, O'Fallon WM, et al. A prospective study of peripheral occlusive arterial disease in diabetes. III. Initial lipid and lipoprotein findings. Mayo Clin Proc. Apr 1981;56(4):233-242.
    93. Kannel WB, Skinner JJ, Jr., Schwartz MJ, et al. Intermittent claudication. Incidence in the Framingham Study. Circulation. May 1970;41(5):875-883.
    94. Newman AB, Sutton-Tyrrell K, Vogt MT, et al. Morbidity and mortality in hypertensive adults with a low ankle/arm blood pressure index. Jama. Jul 28 1993;270(4):487-489.
    95. Newman AB, Sutton-Tyrrell K, Kuller LH. Lower-extremity arterial disease in older hypertensive adults. Arterioscler Thromb. Apr 1993;13(4):555-562.
    96. Shinozaki T, Hasegawa T, Yano E. Ankle-arm index as an indicator of atherosclerosis: its application as a screening method. J Clin Epidemiol. Dec 1998;51(12):1263-1269.
    97. Adler AI, Stevens RJ, Neil A, et al. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. May 2002;25(5):894-899.
    98. Rhee SY, Guan H, Liu ZM, et al. Multi-country study on the prevalence and clinical features of peripheral arterial disease in asian type 2 diabetes patients at high risk of atherosclerosis. Diabetes Res Clin Pract. Apr 2007;76(1):82-92.
    99. Criqui MH, Denenberg JO, Langer RD, et al. The epidemiology of peripheral arterial disease: importance of identifying the population at risk. Vasc Med. 1997;2(3):221-226.
    100. Aronow WS, Ahn C. Prevalence of coexistence of coronary artery disease, peripheral arterial disease, and atherothrombotic brain infarction in men and women > or = 62 years of age. Am J Cardiol. Jul 1 1994;74(1):64-65.
    101. Bird CE, Criqui MH, Fronek A, et al. Quantitative and qualitative progression of peripheral arterial disease by non-invasive testing. Vasc Med. 1999;4(1): 15-21.
    102. Brand FN, Abbott RD, Kannel WB. Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study. Diabetes. Apr 1989;38(4):504-509.
    103. Kallio M, Forsblom C, Groop PH, et al. Development of new peripheral arterial occlusive disease in patients with type 2 diabetes during a mean follow-up of 11 years. Diabetes Care. Apr 2003;26(4):1241-1245.
    104. Norman PE, Davis WA, Bruce DG, et al. Peripheral arterial disease and risk of cardiac death in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. Mar 2006;29(3):575-580.
    105. Emanuele MA, Buchanan BJ, Abraira C. Elevated leg systolic pressures and arterial calcification in diabetic occlusive vascular disease. Diabetes Care. Mar-Apr 1981;4(2):289-292.
    106. Lepantalo M, Kangas T, Pietila J, et al. Non-invasive characterisation of angiopathy in the diabetic foot. Eur J Vasc Surg. Feb 1988;2(1):41-45.
    107. Ubbink DT, Tulevski, II, den Hartog D, et al. The value of non-invasive techniques for the assessment of critical limb ischaemia. Eur J Vasc Endovasc Surg. Mar 1997;13(3):296-300.
    108. Aboyans V, Criqui MH, Denenberg JO, et al. Risk factors for progression of peripheral arterial disease in large and small vessels. Circulation. Jun 6 2006;113(22):2623-2629.
    109. Joint National Committee on Prevention D, Evaluation, and Treatment of High Blood Pression. The sixth report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997; 157:2413-2446.
    110. Smith SC, Jr., Greenland P, Grundy SM. AHA Conference Proceedings. Prevention conference V: Beyond secondary prevention: Identifying the high-risk patient for primary prevention: executive summary. American Heart Association. Circulation. Jan 4-11 2000;101(1):111-116.
    111. O'Leary DH, Polak JF, Kronmal RA, et al. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke. Feb 1996;27(2):224-231.
    112. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama. May 16 2001;285(19):2486-2497.
    113. Smith SC, Jr., Blair SN, Criqui MH, et al. Preventing heart attack and death in patients with coronary disease. Circulation. Jul 1 1995;92(1):2-4.
    114. Ostergren J, Sleight P, Dagenais G, et al. Impact of ramipril in patients with evidence of clinical or subclinical peripheral arterial disease. Eur Heart J. Jan 2004;25(1):17-24.
    115. McDermott MM, Liu K, Criqui MH, et al. Ankle-brachial index and subclinical cardiac and carotid disease: the multi-ethnic study of atherosclerosis. Am J Epidemiol. Jul 1 2005;162(1):33-41.
    116. Allan PL, Mowbray PI, Lee AJ, et al. Relationship between carotid intima-media thickness and symptomatic and asymptomatic peripheral arterial disease. The Edinburgh Artery Study. Stroke. Feb 1997;28(2):348-353.
    117. Oei HH, Vliegenthart R, Hak AE, et al. The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study. J Am Coll Cardiol. Jun 5 2002;39( 11): 1745-1751.
    118. Cui R, Kitamura A, Yamagishi K, et al. Ankle-arm blood pressure index as a correlate of preclinical carotid atherosclerosis in elderly Japanese men. Atherosclerosis. Feb 2006;184(2):420-424.
    119. Grobbee DE, Bots ML. Carotid artery intima-media thickness as an indicator of generalized atherosclerosis. J Intern Med. Nov 1994;236(5):567-573.
    120. Mitsuhashi N, Onuma T, Kubo S, et al. Coronary artery disease and carotid artery intima-media thickness in Japanese type 2 diabetic patients. Diabetes Care. Aug 2002;25(8):1308-1312.
    121. Schulthess G, Maly FE, Meniconi A, et al. Hyperhomocysteinemia is linked with C. pneumoniae IgG seropositivity in coronary artery disease and peripheral arterial occlusive disease. Atherosclerosis. Feb 2003;166(2):409.
    122. O'Leary DH, Polak JF, Kronmal RA, et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. Jan 7 1999;340(1):14-22.
    123. Yamasaki Y, Kodama M, Nishizawa H, et al. Carotid intima-media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease. Diabetes Care. Sep 2000;23(9):1310-1315.
    124. Leys D, Woimant F, Ferrieres J, et al. Detection and management of associated atherothrombotic locations in patients with a recent atherothrombotic ischemic stroke: results of the DETECT survey. Cerebrovasc Dis. 2006;21(1-2):60-66.
    125. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. Feb 15 1998;128(4):262-269.
    126. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. Jama. May 27 1998;279(20):1615-1622.
    127. Zachry WM, Shepherd MD, Wilson JR Inpatient utilization of medical services associated with peripheral arterial disease-related inpatient procedures in the Department of Defense. Vasc Med. 2001 ;6(2):71-76.
    128. Goldhaber SZ, Manson JE, Stampfer MJ, et al. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study. Lancet. Jul 18 1992;340(8812): 143-145.
    129. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. Jan 20 2000;342(3):145-153.
    130. Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circulation. Mar 1 1995;91(5):1472-1479.
    131. Mannami T, Baba S, Ogata J. Potential of carotid enlargement as a useful indicator affected by high blood pressure in a large general population of a Japanese city: the Suita study. Stroke. Dec 2000;31(12):2958-2965.
    132. Mackinnon AD, Jerrard-Dunne P, Sitzer M, et al. Rates and determinants of site-specific progression of carotid artery intima-media thickness: the carotid atherosclerosis progression study. Stroke. Sep 2004;35(9):2150-2154.
    133. Vos LE, Oren A, Uiterwaal C, et al. Adolescent blood pressure and blood pressure tracking into young adulthood are related to subclinical atherosclerosis: the Atherosclerosis Risk in Young Adults (ARYA) study. Am J Hypertens. Jul 2003;16(7):549-555.
    134. Lovett JK, Howard SC, Rothwell PM. Pulse pressure is independently associated with carotid plaque ulceration. J Hypertens. Sep 2003;21(9):1669-1676.
    135. Miller SA, Dykes DD, Polesky HE A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. Feb 11 1988; 16(3): 1215.
    136. Terman BI, Dougher-Vermazen M, Carrion ME, et al. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. Sep 30 1992;187(3):1579-1586.
    137. Gudmundsson G, Matthiasson SE, Arason H, et al. Localization of a gene for peripheral arterial occlusive disease to chromosome 1p31. Am J Hum Genet. Mar 2002;70(3):586-592.
    138. Carmelli D, Fabsitz RR, Swan GE, et al. Contribution of genetic and environmental influences to ankle-brachial blood pressure index in the NHLBI Twin Study. National Heart, Lung, and Blood Institute. Am J Epidemiol. Mar 1 2000;151(5):452-458.
    139. Reny JL, Alhenc-Gelas M, Fontana P, et al. The factor II G20210A gene polymorphism, but not factor V Arg506Gln, is associated with peripheral arterial disease: results of a case-control study. J Thromb Haemost. Aug 2004;2(8): 1334-1340.
    140. Flex A, Gaetani E, Pola R, et al. The -174 G/C polymorphism of the interleukin-6 gene promoter is associated with peripheral artery occlusive disease. Eur J Vase Endovasc Surg. Sep 2002;24(3):264-268.
    141. Whiteman MC, Deary IJ, Fowkes FG Personality and social predictors of atherosclerotic progression: Edinburgh Artery Study. Psychosom Med. Sep-Oct 2000;62(5):703-714.
    142. Gugl A, Renner W, Seinost G, et al. Two polymorphisms in the fracalkine receptor CX3CR1 are not associated with peripheral arterial disease. Atherosclerosis. Feb 2003;166(2):339-343.
    143. Karagiannis A, Balaska K, Tziomalos K, et al. Lack of an association between angiotensin converting enzyme gene polymorphism and peripheral arterial occlusive disease. Vasc Med. May 2004;9(3): 189-192.
    144. Renner W, Pabst E, Paulweber B, et al. The angiotensin-converting-enzyme insertion/deletion polymorphism is not a risk factor for peripheral arterial disease. Atherosclerosis. Nov 2002; 165(1): 175-178.
    145. Renner W, Schallmoser K, Gallippi P, et al. C242T polymorphism of the p22 phox gene is not associated with peripheral arterial occlusive disease. Atherosclerosis. Sep 2000; 152(1): 175-179.
    146. Losordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of ph VEGF 165 as sole therapy for myocardial ischemia. Circulation. Dec 22-29 1998;98(25):2800-2804.
    1. McDermott MM, Greenland P, Liu K, et al. Leg symptoms in peripheral arterial disease: associated clinical characteristics and functional impairment. Jama. Oct 3 2001;286(13):1599-1606.
    2. McDermott MM, Greenland P, Guralnik JM, et al. Depressive symptoms and lower extremity functioning in men and women with peripheral arterial disease. J Gen Intern Med. Jun 2003;18(6):461-467.
    3. McDermott MM, Liu K, Greenland P, et al. Functional decline in peripheral arterial disease: associations with the ankle brachial index and leg symptoms. Jama. Jul 28 2004;292(4):453-461.
    4. Dormandy JA, Murray GD. The fate of the claudicant-a prospective study of 1969 claudicants. Eur J Vasc Surg. Apr 1991;5(2):131-133.
    5. Jelnes R, Gaardsting O, Hougaard Jensen K, et al. Fate in intermittent claudication: outcome and risk factors. Br Med J (Clin Res Ed). Nov 1 1986;293(6555):1137-1140.
    6. Belch JJ, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med. Apr 28 2003;163(8):884-892.
    7. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N EnglJ Med. Feb 6 1992;326(6):381-386.
    8. Regensteiner JG, Hiatt WR. Current medical therapies for patients with peripheral arterial disease: a critical review. Am J Med. Jan 2002;112(1):49-57.
    9. McDermott MM, Hahn EA, Greenland P, et al. Atherosclerotic risk factor reduction in peripheral arterial diseasea: results of a national physician survey. J Gen Intern Med. Dec 2002;17(12):895-904.
    10. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. Jama. Sep 19 2001;286(11):1317-1324.
    11. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. Jama. Jan 11 2006;295(2):180-189.
    12. Hasimu B, Li J, Yu J, et al. Evaluation of medical treatment for peripheral arterial disease in Chinese high-risk patients. Circ J. Jan 2007;71(1):95-99.
    13. Meijer WT, Hoes AW, Rutgers D, et al. Peripheral arterial disease in the elderly: The Rotterdam Study. Arterioscler Thromb Vasc Biol. Feb 1998; 18(2): 185-192.
    14. Fowkes FG, Housley E, Cawood EH, et al. Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population. Int j Epidemiol. Jun 1991;20(2):384-392.
    15. Cui R, Iso H, Yamagishi K, et al. Ankle-arm blood pressure index and cardiovascular risk factors in elderly Japanese men. Hypertens Res. May 2003;26(5):377-382.
    16. Kweon SS, Shin MH, Park KS, et al. Distribution of the ankle-brachial index and associated cardiovascular risk factors in a population of middle-aged and elderly koreans. J Korean Med Sci. Jun 2005;20(3):373-378.
    17. Li XY, Wang J, He Y, et al. [The relation between peripheral arterial occlusive disease and cardiovascular diseases in elderly population: a cross-section study in Wanshoulu area, Beijing]. Zhonghua Yi Xue Za Zhi. Nov 10 2003;83(21):1847-1851.
    18. Curb JD, Masaki K, Rodriguez BL, et al. Peripheral artery disease and cardiovascular risk factors in the elderly. The Honolulu Heart Program. Arterioscler Thromb Vasc Biol. Dec 1996;16(12):1495-1500.
    19. Criqui MH, Vargas V, Denenberg JO, et al. Ethnicity and peripheral arterial disease: the San Diego Population Study. Circulation. Oct 25 2005;112(17):2703-2707.
    20. Newman AB, Shemanski L, Manolio TA, et al. Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. Arterioscler Thromb Vasc Biol. Mar 1999;19(3):538-545.
    21. Meijer WT, Grobbee DE, Hunink MG, et al. Determinants of peripheral arterial disease in the elderly: the Rotterdam study. Arch Intern Med. Oct 23 2000;160(19):2934-2938.
    22. Staffers HE, Rinkens PE, Kester AD, et al. The prevalence of asymptomatic and unrecognized peripheral arterial occlusive disease. Int J Epidemiol. Apr 1996;25(2):282-290.
    23. Stoffers HERP, Keater AD, et al. prevelence in general practice. In: Fowkes FGR, ed. Epidemiolgy of peripheral vascular disease, london: Springer-Verlag. 1991:109-115.
    24. O'Hare AM, Glidden DV, Fox CS, et al. High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999-2000. Circulation. Jan 27 2004; 109(3): 320-323.
    25. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. Jama. May 16 2001;285(19):2481-2485.
    26. Stoffers HE, Kester AD, Kaiser V, et al. Diagnostic value of signs and symptoms associated with peripheral arterial occlusive disease seen in general practice: a multivariable approach. Med Decis Making. Jan-Mar 1997;17(1):61-70.
    27. Kannel WB, McGee DL. Update on some epidemiologic features of intermittent claudication: the Framingham Study. J Am Geriatr Soc. Jan 1985;33(1): 13-18.
    28. Bainton D, Sweetnam P, Baker I, et al. Peripheral vascular disease: consequence for survival and association with risk factors in the Speedwell prospective heart disease study. Br Heart J. Aug 1994;72(2): 128-132.
    29. Ingolfsson IO, Sigurdsson G, Sigvaldason H, et al. A marked decline in the prevalence and incidence of intermittent claudication in Icelandic men 1968-1986: a strong relationship to smoking and serum cholesterol~the Reykjavik Study. J Clin Epidemiol. Nov 1994;47( 11): 1237-1243.
    30. Fowkes FG, Housley E, Riemersma RA, et al. Smoking, lipids, glucose intolerance, and blood pressure as risk factors for peripheral atherosclerosis compared with ischemic heart disease in the Edinburgh Artery Study. Am J Epidemiol. Feb 15 1992; 135(4):331-340.
    31. Newman AB, Siscovick DS, Manolio TA, et al. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Cardiovascular Heart Study (CHS) Collaborative Research Group. Circulation. Sep 1993;88(3):837-845.
    32. Zimmerman BR, Palumbo PJ, O'Fallon WM, et al. A prospective study of peripheral occlusive arterial disease in diabetes. III. Initial lipid and lipoprotein findings. Mayo Clin Proc. Apr 1981;56(4):233-242.
    33. Kannel WB, Skinner JJ, Jr., Schwartz MJ, et al. Intermittent claudication. Incidence in the Framingham Study. Circulation. May 1970;41(5):875-883.
    34. Smith I, Franks PJ, Greenhalgh RM, et al. The influence of smoking cessation and hypertriglyceridaemia on the progression of peripheral arterial disease and the onset of critical ischaemia. EurJ Vasc Endovasc Surg. May 1996;11(4):402-408.
    35. Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med. Apr 25 1991 ;324( 17): 1149-1155.
    36. Da Silva A, Widmer LK, Ziegler HW, et al. The Basle longitudinal study: report on the relation of initial glucose level to baseline ECG abnormalities, peripheral artery disease, and subsequent mortality. J Chronic Dis. 1979;32(11-12):797-803.
    37. KM B. Natural history of arteriosclerosis of the lower extremities,. Ann R Coll Surg Engl. 1961;28:36-51.
    38. Cinsensus(TASC) TI-S. Management of peripheral artery disease, j Vasc Surg. 2000; 1(suppl): 1-296.
    39. The ICAI Group (gruppo di studio dell ischemia cronic critica degliarte inferior) Long-term mortality and its predictiors in patients with critical leg ischemia. Euro J Vasc Endovasc Surg. 1997; 14:91 -95.
    40. Juergens JL, Barker NW, Hines EA, Jr. Arteriosclerosis obliterans: review of 520 cases with special reference to pathogenic and prognostic factors. Circulation. Feb 1960;21:188-195.
    41. McDermott MM, Greenland P, Liu K, et al. The ankle brachial index is associated with leg function and physical activity: the Walking and Leg Circulation Study. Ann Intern Med. Jun 18 2002;136(12):873-883.
    42. Leng GC, Lee AJ, Fowkes FG, et al. Incidence, natural history and cardiovascular events in symptomatic and asymptomatic peripheral arterial disease in the general population. Int J Epidemiol. Dec 1996;25(6): 1172-1181.
    43. Vogt MT, Cauley JA, Newman AB, et al. Decreased ankle/arm blood pressure index and mortality in elderly women. Jama. Jul 28 1993;270(4):465-469.
    44. Kornitzer M, Dramaix M, Sobolski J, et al. Ankle/arm pressure index in asymptomatic middle-aged males: an independent predictor of ten-year coronary heart disease mortality. Angiology. Mar 1995;46(3):211-219.
    45. Newman AB, Tyrrell KS, Kuller LH. Mortality over four years in SHEP participants with a low ankle-arm index. J Am Geriatr Soc. Dec 1997;45(12):1472-1478.
    46. Hooi JD, Kester AD, Stoffers HE, et al. Asymptomatic peripheral arterial occlusive disease predicted cardiovascular morbidity and mortality in a 7-year follow-up study. J Clin Epidemiol. Mar 2004;57(3):294-300.
    47. Murabito JM, Evans JC, Larson MG et al. The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Arch Intern Med. Sep 8 2003;163(16): 1939-1942.
    48. McGee SR, Boyko EJ. Physical examination and chronic lower-extremity ischemia: a critical review. Arch Intern Med. Jun 22 1998;158(12):1357-1364.
    49. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. Thrombolysis or Peripheral Arterial Surgery (TOPAS) Investigators. N Engl J Med. Apr 16 1998;338(16):1105-1111.
    50. Oruriel K ZC. Doppler ankle pressure: an evaluation of three methods of express. Arch Surg. 1982; 117:1297-1300.
    51. Resnick HE, Lindsay RS, McDermott MM, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation. Feb 17 2004;109(6):733-739.
    52. Ubbink DT, Tulevski, II, den Hartog D, et al. The value of non-invasive techniques for the assessment of critical limb ischaemia. Eur J Vasc Endovasc Surg. Mar 1997;13(3):296-300.
    53. Visser K, Hunink MG Peripheral arterial disease: gadolinium-enhanced MR angiography versus color-guided duplex US-a meta-analysis. Radiology. Jul 2000;216(1):67-77.
    54. Geerts WH HJ, Clagett GP, etal. Prevention of venous thromboembolism. Chest. 2001;119(suppll):132-175.
    55. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Bmj. Jan 12 2002;324(7329):71-86.
    56. Patrono C, Garcia Rodriguez LA, Landolfi R, et al. Low-dose aspirin for the prevention of atherothrombosis. .N Engl J Med Dec 1 2005;353(22):2373-2383.
    57. Bergqvist D, Almgren B, Dickinson JP. Reduction of requirement for leg vascular surgery during long-term treatment of claudicant patients with ticlopidine: results from the Swedish Ticlopidine Multicentre Study (STIMS). Eur J Vase Endovasc Surg. Jul 1995;10(1):69-76.
    58. Goldhaber SZ, Manson JE, Stampfer MJ, et al. Low-dose aspirin and subsequent peripheral arterial surgery in the Physicians' Health Study. Lancet. Jul 18 1992;340(8812):143-145.
    59. Hess H, Mietaschk A, Deichsel G. Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. A prospective double-blind arteriographically controlled trial. Lancet. Feb 23 1985;1(8426):415-419.
    60. Boissel JP, Peyrieux JC, Destors JM. Is it possible to reduce the risk of cardiovascular events in subjects suffering from intermittent claudication of the lower limbs? Thromb Haemost. Sep 29 1989;62(2):681-685.
    61. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. Nov 16 1996;348(9038): 1329-1339.
    62. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). Jama. May 16 2001;285(19):2486-2497.
    63. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. Jul 6 2002;360(9326):7-22.
    64. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. Oct 8 2005;366(9493):1267-1278.
    65. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):837-853.
    66. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. Sep 12 1998;352(9131):854-865.
    67. Adler AI, Stevens RJ, Neil A, et al. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. May 2002;25(5):894-899.
    68. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med. Jun 5 2003;348(23):2294-2303.
    69. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. Nov 8 2003;362(9395):1527-1535.
    70. Lawes CM BD, Feigin VL, Rodgers A. Blood pressure and stroke: a overview of published reviews. Stroke. 2004;35:1024-1033.
    71. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. Jan 22 2000;355(9200):253-259.
    72. Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. Jan 20 2000;342(3):145-153.
    73. Mehler PS, Coll JR, Estacio R, et al. Intensive blood pressure control reduces the risk of cardiovascular events in patients with peripheral arterial disease and type 2 diabetes. Circulation. Feb 11 2003;107(5):753-756.
    74. Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet. Oct 29-Nov 4 2005;366(9496): 1545-1553.
    75. Harris T, Cook EF, Garrison R, et al. Body mass index and mortality among nonsmoking older persons. The Framingham Heart Study. Jama. Mar 11 1988;259(10):1520-1524.
    76. Yusuf S, Hawken S, Ounpuu S, et al. Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet. Nov 5 2005;366(9497): 1640-1649.
    77. Willigendael EM, Teijink JA, Bartelink ML, et al. Influence of smoking on incidence and prevalence of peripheral arterial disease. J Vasc Surg. Dec 2004;40(6):1158-1165.
    78. Girolami B, Bernardi E, Prins MH, et al. Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis. Arch Intern Med. Feb 22 1999;159(4):337-345.
    79. Jonason T, Bergstrom R. Cessation of smoking in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Acta Med Scand. 1987;221(3):253-260.
    80. Faulkner KW, House AK, Castleden WM. The effect of cessation of smoking on the accumulative survival rates of patients with symptomatic peripheral vascular disease. Med J Aust. Mar 5 1983;1(5):217-219.
    81. Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med. Oct 23 1997;337( 17): 1195-1202.
    82. Gardner AW, Poehlman ET. Exercise rehabilitation programs for the treatment of claudication pain. A meta-analysis. Jama. Sep 27 1995;274(12):975-980.
    83. Stewart KJ, Hiatt WR, Regensteiner JG, et al. Exercise training for claudication. N Engl J Med. Dec 12 2002;347(24):1941-1951.
    84. Thompson PD, Zimet R, Forbes WP, et al. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol. Dec 15 2002;90( 12): 1314-1319.
    85. Horsch S, Walther C. Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD)-a review based on randomized, controlled studies. Int J Clin Pharmacol Ther. Feb 2004;42(2):63-72.
    86. Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med. Mar 2000;108(4):276-281.
    87. Lederman RJ, Mendelsohn FO, Anderson RD, et al. Therapeutic angiogenesis with recombinant fibroblast growth factor-2 for intermittent claudication (the TRAFFIC study): a randomised trial. Lancet. Jun 15 2002;359(9323):2053-2058.
    88. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. Aug 10 2002;360(9331):427-435.
    89. Dotter CT, Judkins MR Transluminal Treatment of Arteriosclerotic Obstruction. Description of a New Technic and a Preliminary Report of Its Application. Circulation. Nov 1964;30:654-670.
    90. Henry M, Amor M, Ethevenot G, et al. Palmaz stent placement in iliac and femoropopliteal arteries: primary and secondary patency in 310 patients with 2-4-year follow-up. Radiology. Oct 1995; 197(1): 167-174.
    91. Matsi PJ, Manninen HI, Vanninen RL, et al. Femoropopliteal angioplasty in patients with claudication: primary and secondary patency in 140 limbs with 1-3-year follow-up. Radiology. Jun 1994;191(3):727-733.
    92. Murphy TP, Webb MS, Lambiase RE, et al. Percutaneous revascularization of complex iliac artery stenoses and occlusions with use of Wallstents: three-year experience. J Vasc Interv Radiol. Jan-Feb 1996;7(1):21-27.
    93. Caruana MF, Bradbury AW, Adam DJ. The validity, reliability, reproducibility and extended utility of ankle to brachial pressure index in current vascular surgical practice. Eur J Vasc Endovasc Surg. May 2005;29(5):443-451.
    94. Doobay AV, Anand SS. Sensitivity and specificity of the ankle-brachial index to predict future cardiovascular outcomes: a systematic review. Arterioscler Thromb Vasc Biol. Jul 2005;25(7): 1463-1469.
    95. Smith SC, Jr., Greenland P, Grundy SM. AHA Conference Proceedings. Prevention conference V: Beyond secondary prevention: Identifying the high-risk patient for primary prevention: executive summary. American Heart Association. Circulation. Jan 4-11 2000;101(1):111-116.
NGLC 2004-2010.National Geological Library of China All Rights Reserved.
Add:29 Xueyuan Rd,Haidian District,Beijing,PRC. Mail Add: 8324 mailbox 100083
For exchange or info please contact us via email.