新 評 議 員 要 旨 25 129 135 2014 キーワード : 1.はじめに 1960 1970 1970 2000 1 2. 生 活 習 慣 病 と 動 脈 硬 化 113-8421 2-1-1 TEL: 03-3813-3111 FAX : 03-5800-0547 E-mail: kazuo-y@juntendo.ac.jp 2 TIA 1A 3 4 1B 3 5 3. 脂 質 異 常 症 と 脳 動 脈 における 血 管 内 皮 機 能 障 害 6 129
25 2 図 1. A B 図 2.ApoE ACh ApoE A SPER-NO NO ApoE B 7 nitric oxide: NO 8 NO endothelial NO synthase: enos 9 NO 10 NO 11 ApoE 12, 13 ApoE 14 ApoE C57BL/6J ACh 2A SPER-NO NO 2B 130
図 3.ApoE -1 ET-1 A ApoE ET-1 enos L-NAME B 図 4.Western blot ApoE enos enos ApoE enos A enos B ApoE -1 ET-1 3A ACh ET-1 ApoE 15, 16 enos ET-1 17 enos enos 18 19 NO 20 enos enos NO 21, 22 ApoE enos enos 4A B NO NOx 5 enos enos NO ApoE 3 ACh 2A ET-1 enos L-NAME 131
25 2 図 5.ApoE NO nitrite nitrate NOx A ApoE NOx 3B enos 4A NOx 5 2 cyclic AMP/protein kinase A enos 23 enos NO enos 24 enos 4. 内 臓 脂 肪 と 脳 小 血 管 病 変 1998 American Heart Association 25 1980 6.4 2008 12 26 27~30 31~34 35 55 CT MRI 36 100 cm 2 2 37 100 cm 2 1 body mass index BMI 38 39 BMI 40 5.おわりに enos 132
表 1. WMLs SLI Model 1 Model 2 OR (95%CI) P value OR (95%CI) P value WMLs Age 60 years 2.34 (1.51 3.63) 0.0001 2.42 (1.57 3.74) <0.0001 VFA 100 cm 2 1.82 (1.08 3.05) 0.03 1.95 (1.10 3.47) 0.02 Large WC a 1.26 (0.69 2.28) 0.44 Large WC b 1.41 (0.83 2.41) 0.21 BMI 30 kg/m 2 1.05 (0.39 2.72) 0.92 BMI 25 kg/m 2 0.75 (0.43 1.29) 0.3 Hypertension 1.26 (0.80 1.97) 0.32 1.21 (0.76 1.91) 0.42 SLI Age 60 years 2.17 (1.47 3.20) <0.0001 2.33 (1.59 3.44) <0.0001 VFA 100 cm 2 1.70 (1.06 2.75) 0.03 1.69 (1.01 2.85) 0.04 Large WC a 1.61 (0.93 2.82) 0.09 Large WC b 1.73 (1.09 2.74) 0.02 BMI 30 kg/m 2 0.82 (0.32 2.07) 0.68 BMI 25 kg/m 2 0.71 (0.44 1.15) 0.17 Hypertension 1.43 (0.96 2.14) 0.08 1.33 (0.88 1.99) 0.18 OR, odds ratio; CI, confidence interval; VFA, visceral fat area; WC, waist circumference; BMI, body mass index; WMLs, white matter lesions; SLI, silent lacunar infarction. a 88 cm in women and 102 cm in men. b 90 cm in women and 85 cm in men VFA 100 cm 2 41 文 献 1 Hata J, Ninomiya T, Hirakawa Y, Nagata M, Mukai N, Gotoh S, Fukuhara M, Ikeda F, Shikata K, Yoshida D, Yonemoto K, Kamouchi M, Kitazono T, Kiyohara Y: Secular trends in cardiovascular disease and its risk factors in Japanese: half-century data from the Hisayama Study (1961 2009). Circulation 128: 1198 1205, 2013 2 Mannami T, Baba S, Ogata J: Strong and significant relationships between aggregation of major coronary risk factors and the acceleration of carotid atherosclerosis in the general population of a Japanese city: the Suita Study. Arch Intern Med 160: 2297 2303, 2000 3 Yamashiro K, Watanabe T, Tanaka R, Komine-Kobayashi M, Mizuno Y, Urabe T: Clustering of risk factors increases the incidence of echolucent carotid plaque in stroke patients. Cerebrovasc Dis 22: 432 438, 2006 4 Wolverson MK, Bashiti HM, Peterson GJ: Ultrasonic tissue characterization of atheromatous plaques using a high resolution real time scanner. Ultrasound Med Biol 9: 599 609, 1983 5 Ross R: Atherosclerosis an inflammatory disease. N Engl J Med 340: 115 126, 1999 6 Amarenco P, Labreuche J: Lipid management in the prevention of stroke: review and updated meta-analysis of statins for stroke prevention. Lancet Neurol 8: 453 463, 2009 7 Wolfrum S, Jensen KS, Liao JK: Endothelium-dependent effects of statins. Arterioscler Thromb Vasc Biol 23: 729 736, 2003 8 Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA: The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 88: 2541 2547, 1993 9 Napoli C, de Nigris F, Williams-Ignarro S, Pignalosa O, Sica V, Ignarro LJ: Nitric oxide and atherosclerosis: an update. Nitric Oxide 15: 265 279, 2006 10 Maeda H, Matsumoto M, Handa N, Hougaku H, Ogawa S, Itoh T, Tsukamoto Y, Kamada T: Reactivity of cerebral blood flow to carbon dioxide in various types of ischemic cerebrovascular disease: evaluation by the transcranial 133
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Metabolic syndrome is associated with silent ischemic brain lesions. Stroke 39: 1607 1609, 2008 35 Fantuzzi G, Mazzone T: Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 27: 996 1003, 2007 36 Examination Committee of Criteria for Obesity Disease in Japan; Japan Society for the Study of Obesity: New criteria for obesity disease in Japan. Circ J 66: 987 992, 2002 37 Yamashiro K, Tanaka R, Tanaka Y, Miyamoto N, Shimada Y, Ueno Y, Urabe T, Hattori N: Visceral fat accumulation is associated with cerebral small vessel disease. Eur J Neurol 21: 667 673, 2014 38 Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S: Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol 288: H2031 2041, 2005 39 94: 188 203, 2005 40 Park YW, Allison DB, Heymsfield SB, Gallagher D: Larger amounts of visceral adipose tissue in Asian Americans. Obes Res 9: 381 387, 2001 41 Kaufman FR: Type 2 diabetes mellitus in children and youth: a new epidemic. J Pediatr Endocrinol Metab 15 Suppl 2: 737 744, 2002 Abstract Lifestyle-related risk factors and cerebrovascular disease Kazuo Yamashiro Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan Recent changes in dietary habits and insufficient physical activity are associated with the increase of lifestyle-related risk factors such as dyslipidemia and obesity. Hypercholesterolemia is associated with endothelial dysfunction and reduced endothelial nitric oxide synthase phosphorylation in cerebral arteries. Furthermore, visceral fat accumulation is independently associates with the presence of cerebral small vessel disease. Visceral fat releases several bioactive mediators, such as adiponectin and inflammatory cytokines, that influence inflammation and coagulation, resulting in endothelial dysfunction and atherosclerosis. Because the prevalence of obesity in children and youth has increased, the role of lifestyle-related risk factors in cerebrovascular disease is expected to be more important in the future. Improvement of endothelial dysfunction caused by lifestyle-related risk factors could be one of the effective treatments for the prevention of cerebrovascular disease. Key words: lifestyle-related risk factors, nitric oxide, endothelial nitric oxide synthase, endothelial dysfunction 135