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1、高血压与维生素 D,新疆医科大学第一附属医院心脏中心高血压科 徐新娟,大量的流行病学研究发现，维生素D不足现象普遍存在。多数专家认为血清25(OH)D 20g/L为缺乏；2030g/L为不足；30g/L为充足。 据估计维生素D缺乏或不足可影响世界范围内约50%人口，全球有近10亿人维生素D缺乏或不足。 国内研究发现我国中老年人群维生素D 缺乏和不足发生率分别为69.2%和24.4%, 而维生素D充足的个体仅占6.4%。,研究背景,www.bio-,Vitamin D has long been known to be important for bone health,Cholecalcife
2、rol(D3) Ergocalciferol(D2),www.bio-,Synthesis and Metabolism of Vitamin D,1,25二羟维生素D3与其维生素D受体结合形成激素-受体复合物，再与细胞核的维生素D反应元件相结合，激活或抑制含有维生素D反应元件的基因约200，从而发挥其生物学作用。,Prevalence of insufficient 25(OH)D levels(30ng/ml) by sex and race/ethnicity across age groups: Third National Health and Nutrition Examinati
3、on Survey,41% of men and 53% of women in US have insufficient levels. Prevalence of insuficient vitamin D levels increase with age,维生素D,年龄,纬度,季节,肥胖,性别,摄入含维生 素D的食物,防晒霜,种族,Risk factors for Vitamin D deficiency, Darker skin coloring (increased melanin blocks UVB synthesis of vit D) Living in Northern H
4、emisphere(greater distance from equator) - for those living above 35 degrees latitude, little or no vitamin D can be produced from November to February Lower altitude, more cloud covering, sunscreen, covered manner of dress Winter season Obesity (fat cells sequester vitamin D) Malabsorption syndrome
5、s Older age (decreased absorption from diet, decreased production from skin) Kidney disease (cant make activated form),www.bio-,CHD death rates are higer in countries of increased geographic latitudes where average serum vitamin D are lowest,www.bio-,Institute of Medicine Recommendations, 1997 recom
6、mended daily allowance 200 IU/day for ages 1-50 400 IU/day for ages 51-70 600 IU/day for those 70 years Maximum daily allowance 2000 IU/day 2010 recommended daily allowance 600 IU/day for ages 1-70 800 IU/day for those 71 Maximum daily allowance 4000 IU/day 2010 update: Blood levels 20 ng/ml are pro
7、bably adequate,www.bio-,What about toxicity?, Rare, resulting mostly from acutehypercalcemia Typically from doses 10,000 IU per day with associated 25(OH)D levels 150 ng/ml Observational data suggests 25(OH)D levels 60 ng/ml were associated with increased risk of pancreatic cancer, vascular calcific
8、ation, and death,Age-, Sex-,and Race-Adjusted ORs of Select CVD Risk Factors Between the First and Fourth Quartiles of Serum 25(OH)D Levels (cross-sectional data from NHANES-),Martins,D. et al. Arch Intern Med 2007;167:1159-1165,Vitamin D levels and risk of CVD events: Framingham offspring prospecti
9、ve cohort study,Mean age 59 y,55% women , all Caucasian,Wang TJ et al. Circulation 2008;117:503-511.,Mortality Rate Ratios of All-Cause Mortality for 13,331 adults 20y followed for median 9 year by 25(OH)D Quartiles:NHANES- linked mortality files,*Limited Model adjusted for age, sex, race, and seaso
10、n *Fully-Adjusted Model includes age, sex, race, season, HTN, history of prior CVD, Diabetes mellitus, smoking, HDL cholesterol,total cholesterol medications, eGFR, albumin, log(albumin-creatinine ratio),log(CRP), BMI, physical activity, vitamin D supplementation and low SES.,25(OH)D deficiency pred
11、icts risk of incident hypertension,Measured Plasma 25(OH)D and 4-Year Multivariable Adjusted Relative Risk of Incident Hypertension in Men and Women,Multivariable models adjusted for age ,BMI,physical activity(all as continuous variables),as well as race, and(in women) menopausal status.,613 Men fro
12、m Health Professionals Follow-up Study and 1198 women from the Nurses Health Study,www.bio-,Meta-analysis of data on all-cause mortality in 18 randomized controlled trials (including WHI) with vitamin D Supplementation,www.bio-,25-OH D Levels and Myocardial Infarction,Health Professionals Followup S
13、thdy,Giovanucci et al Arch Int Med 2008,www.bio-,Vitamin D and subclinical atherosclerosis, Low 25(OH)D levels have been shown to be associated with: -Peripheral arterial disease (ABI0.9) Melamed ML. Michos ED et al. ATVB 2008 Teis JP, Michos ED et al. Am J Clin Nutr 2008 -Increased carotid intimal
14、medial thickness Targher G. Clin Endocrinol. 2006 Reis JP .Michos ED et al. Atheroscierosis 2009 -Incident coronary artery calcification de Boer IH.Michos ED et al. J Ain Soc Nephrol 2009 Findings are indeperndent of traditional CVD risk factors,Increased risk of all-cause mortality for those at low
15、er serum 25(OH)D levels: NHANES- linked mortality study,*adjusted for age, sex, race/ethnicity and season,Metamed ML. Michos ED, et al. Arch Intern Med 2008;158:1629-1637.,www.bio-,Biphasic response-suggests an optimal range where both deficiency and excess cause CVD harm,Optimal D status,Zittermann
16、 A Curr Opin Lipidol 2007 Feh;18(1):41-6,www.bio-,Vitamin D and calcium supplementation for the prevention of CVD events:RCT Meta-analysis,*For Vitamin D supplements alone: trend for benefit,Slight (non-significant) reduction in CVD risk with moderate doses(1000 IU/d) -Pooled RR 0.90, 95% CI 0.77-1.
17、05,Wang L. et al. Ann Intern Med 2010;152:315-323,www.bio-,Vitamin D and calcium supplementation for the prevention of CVD events:RCT Meta-analysis,*For calcium alone or vit D + calcium: No Benefit,高血压是遗传和环境因素相互作用的结果，随着流行病学和分子生物学技术的深入研究，目前认识到高血压与机体的代谢因素密切相关。,研究显示血维生素D3浓度和血压呈负相关，其可能原因是维生素D抑制肾素释放及肾素活性
18、。维生素D可能是肾素-血管紧张素系统的负性内分泌调节剂。 研究证实1,25-(OH)2D3通过维生素D受体抑制肾素转录。维生素D可直接抑制血管平滑肌细胞增殖。维生素D有抗炎作用, 降低肿瘤坏死因子与IL-6、IL-1、IL-8的水平。,www.bio-,Inadequate UVB exposure and low dietary vitamin D intake,Low circulating 25-hydroxyvitamin D levels,Low cellular calcitriol concentrations,Vascular smooth cell proliferation
19、,MGP Synthesis,PTH,TNF- IL-6 IL-10,RAS,Vascular Calcification,Myocardial calcification,Lnflammatory processes,Hypertension Stroke Heart attack,LVH,CVD,Insulin,glucose,Activated vitamin D is a negative inhibitor of the RAAS,Vitamin D receptor knock out -/- mice compared to wild type,1,25(OH)2D treatm
20、ent in wild type mice suppresses renin secretion,Activated vitamin D is a negative inhibitor of the RAAS,1,25(OH)2D treatment in wild type mice,作为人类VitD的主要来源是阳光中UVB ,纬度越高,离赤道越远的地区,居民每年接受阳光UVB越少，血液中VitD水平与纬度的高低呈高度负相关 国内研究报道我国北纬 35以北的西北、华北、东北生活的人群Vit D营养状况不理想 , VitD缺乏58.7%为,不足36.9% ,充足者仅占4.4% 新疆北纬3425
21、-4810之间，大部分地区纬度超过北纬35，初步研究发现新疆乌鲁木齐高血压患者血清25(OH)D水平大部分偏低，而迄今尚无维生素D与乌鲁木齐地区高血压人群的相关性研究。,研究背景,对收缩压的敏感性分析,年龄大于60岁组与年龄小于60岁组之间收缩压的比较,干预治疗,从乌鲁木齐地区低25（OH）D水平伴高血压患者中随机选取50人(65岁年龄80岁)进行维生素D口服干预治疗（骨化三醇0.25ug/d）， 患者均为未合并其他疾病的原发性高血压， 降压药物仅口服钙离子拮抗剂， 现已定期跟踪随访调查3个月， 监测血压、心率， 干预治疗后第3个月复查一次血25（OH）D、电解质及肾功等生化指标。,Marti
22、ns,D. et al. Arch Intern Med 2007;167:1159-1165,骨化三醇干预治疗,问题和展望,研究对象的年龄，尽量涉及各个年龄阶段并对其对比分析，以准确的评估年龄是否为补充维生素D对血压产生作用的影响因素 研究对象所处纬度应在同一纬度，或者可以对不同纬度之间进行对比，以进一步确定纬度是否为补充维生素D对血压影响的因素 应注意描述研究进行时的季节，尽量减少研究对象的异质性。,问题和展望,有关维生素D对高血压的干预治疗 维生素D水平在什么范围时适宜补充 补充维生素D的剂量控制在什么范围，以及给药间隔、疗程、是否加补钙 影响维生素D和高血压间相关作用机制的因素，如血清钙、甲状旁腺激素、肾素-血管紧张素-醛固酮等都是今后在研究中应严格观察的主要因素 希望通过不同层次的研究为维生素D能否作为高血压的辅助治疗提供更多的依据。,谢 谢！,