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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,Cholecalciferol(
2、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)bysex and race/ethnicity across age groups:Third National Health and Nutrition Examination Surve
3、y,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 Hemisphere(great
4、er 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 syndromes Older age(decreased a
5、bsorption 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 recommended daily allowance 200 I
6、U/day for ages 1-50 400 IU/day for ages 51-70 600 IU/day for those 70 years Maximum daily allowance 2000 IU/day2010 recommended daily allowance 600 IU/day for ages 1-70 800 IU/day for those 71 Maximum daily allowance 4000 IU/day2010 update:Blood levels 20 ng/ml are probably adequate,www.bio-,What ab
7、out 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 calcification,and death,Age-,Sex-,and Race
8、-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 prospective cohort study,Mean age 59 y,55%women,a
9、ll 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 season*Fully-Adjusted Model includes age,sex,race,sea
10、son,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 predicts risk of incident hypertension,Measured Plasma 25(OH)D and
11、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 from Health Professionals Follow-up Study and 1198 women from the Nur
12、ses 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 Sthdy,Giovanucci et al Arch Int Med 2008,www.bio-,Vitamin D and subcl
13、inical 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 medial thickness Targher G.Clin Endocrinol.2006 Reis JP.Michos ED et al.Ather
14、oscierosis 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 lower serum 25(OH)D levels:NHANES-linked mortality study,*adjusted for age,sex,race/et
15、hnicity 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 A Curr Opin Lipidol 2007 Feh;18(1):41-6,www.bio-,Vitamin D and calcium supplementation fo
16、r the prevention of CVD events:RCT Meta-analysis,*For Vitamin D supplements alone:trend for benefit,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
17、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。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-hydroxy
18、vitamin D levels,Low cellular calcitriol concentrations,Vascular smooth cell proliferation,MGPSynthesis,PTH,TNF-IL-6IL-10,RAS,VascularCalcification,Myocardialcalcification,Lnflammatoryprocesses,HypertensionStrokeHeart attack,LVH,CVD,Insulin,glucose,Activated vitamin D is a negative inhibitor of the
19、RAAS,Vitamin D receptor knock out-/-mice compared to wild type,1,25(OH)2Dtreatment in wild typemice suppressesrenin 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
20、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3425-4810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
21、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。,Martins,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！,
