高血压与维生素 D 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< 20μg/L 为缺乏； 20 ～30μg/L 为不足；≥ 30μg/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

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Vitamin D has long been known to be important for bVitamin D has long been known to be important for bone healthone health

Cholecalciferol(D3)Ergocalciferol(D2)

•

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Synthesis and Metabolism of Vitamin DSynthesis 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(Prevalence of insufficient 25(OH)D levels( ＜＜ 30ng/ml) by30ng/ml) bysex and race/ethnicity across age groups:sex and race/ethnicity across age groups:

Third National Health and Nutrition Examination SurveyThird National Health and Nutrition Examination 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 deficiencyRisk factors for Vitamin D deficiency

• Darker skin coloring (increased melanin blocks UVB synthesis of vit D)

• Living in Northern Hemisphere(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 syndromes

• Older age (decreased absorption from diet, decreased production from skin)

• Kidney disease (can't make activated form)

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CHD death rates are higer in countries of increased geographic CHD death rates are higer in countries of increased geographic latitudes where average serum vitamin D are lowestlatitudes where average serum vitamin D are lowest

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Institute of Medicine RecommendationsInstitute of Medicine Recommendations

• 1997 recommended 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 probably adequate

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What about toxicity?What about toxicity?• Rare, resulting mostly from acutehypercalcemi

a

• 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-Adjusted ORs of Select CVD Risk Factors Between the 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 froFirst and Fourth Quartiles of Serum 25(OH)D Levels (cross-sectional data from NHANES- )Ⅲm NHANES- )Ⅲ

Martins,D. et al. Arch Intern Med 2007;167:1159-1165

Risk Factor OR95%CI P value

BP≥140/90mmHg 1.30（ 1.13-1.49） .001

Fasting glucose 110-125mg/dl≥125mg/dl

2.15（ 1.69-2.74）1.98（ 1.57-2.51）

＜ 0.001＜ 0.001

History of diabetes mellitus 1.73（ 1.38-2.16） ＜ 0.001

Body mass index ≥30 kg/m2 2.29（ 1.99-2.63） ＜ 0.001

Triglycerides ≥150mg/dl 1.47（ 1.30-1.65） ＜ 0.001

Serum albumin ＜ 3.5 g/dl 2.90（ 1.89-4.46） ＜ 0.001

eGFR ＜ 60 ml/min per 1.73m2

1.08（ 1.87-1.35） 0.47

ACR≥200men/≥300 Women 2.54（ 1.65-3.48） ＜ 0.007

Vitamin D levels and risk of CVD events:Vitamin D levels and risk of CVD events:Framingham offspring prospective cohort studyFramingham offspring prospective cohort study

Mean age 59 y,55% women , all Caucasian

HR(95% CI) Adjusted for age/sex

+clinicalcovariates

+clinical covariages and CRP

25-OH D ≥15 ng/ml 1.00(Referent)

1.00(Referent)

1.00(Referent)

25-OH D ＜ 15 ng/ml

2.04(1.42-2.94)

1.62(1.11-2.36)

1.66(1.13-2.43)

P ＜ 0.001 0.01 0.01

CVD events included MI ， coronary insufficiency ， angina, stroke, TIA, caludication, or heart failure

Clinical covariates are age, sex, systolic blood pressure,antihypertensive treament, diabetes mellitus, serum creatinine, total-to-high-density lipoprotein cholesterol ratio,cigarette smoking,and body mass index.

Wang TJ et al. Circulation 2008;117:503-511.

Mortality Rate Ratios of All-Cause Mortality for 13,331 adults Mortality Rate Ratios of All-Cause Mortality for 13,331 adults ≥ 20≥ 20y followed for y followed for median 9 year by 25(OH)D Quartiles:NHANES-median 9 year by 25(OH)D Quartiles:NHANES-ⅢⅢ linked mortality files linked mortality files

RR:All-Cause Mortality

＞ 32.1ng/ml

24.4-32.1ng/ml 17.8-24.4ng/ml

＜ 17.8ng/ml

Unadjusted 1.0(Ref) 1.14(0.94-1.39) 1.49(1.24-1.78)

1.78(1.44-2.21)

Limited* 1.0(Ref) 0.92(0.78-1.08) 1.11(0.95-1.31)

1.52(1.31-1.77)

Full** 1.0(Ref) 0.93(0.79-1.10) 1.06(0.89-1.24)

1.26(1.08-1.46)

*Limited Model adjusted for age, sex, race, and season

**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 predicts risk of incident hypertension25(OH)D deficiency predicts risk of incident hypertension

Measured Plasma 25(OH)D,ng/ml

Statistic ≥30 15-29 ＜ 15

Men

Person-years 865 1295 122

No.of cases 22 33 6

Multivariable RR (95% CI) 1.0(reference)

1.12(0.51 to 2.48) 6.13(1.00 to 37.8)

women

Person-years 2207 2317 335

No.of cases 58 60 11

Multivariable RR (95% CI) 1.0(reference)

0.85(0.53 to 1.34) 2.67(1.05 to 6.79)

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 from Health Professionals' Follow-up Study and 1198 women from the Nurses' Health Study

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Meta-analysis of data on all-cause mortality in 18 randomized controlled trials (including WHI) with vitamin D Supplementation

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25-OH D Levels and Myocardial Infarction25-OH D Levels and Myocardial Infarction

Health Professionals Followup Sthdy

Giovanucci et al Arch Int Med 2008

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Vitamin D and subclinical atherosclerosisVitamin D and subclinical atherosclerosis

• Low 25(OH)D levels have been shown to be associated with:

-Peripheral arterial disease (ABI＜ 0.9) 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. 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 lower serum 25(OH)D levels: NHANES-Increased risk of all-cause mortality for those at lower serum 25(OH)D levels: NHANES-ⅢⅢ linked mortality studylinked mortality study

*adjusted for age, sex, race/ethnicity and season

Metamed ML. Michos ED, et al. Arch Intern Med 2008;158:1629-1637.

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Biphasic response-suggests an optimal range where both Biphasic response-suggests an optimal range where both deficiency and excess cause CVD harmdeficiency and excess cause CVD harm

Optimal D statusZittermann A Curr Opin Lipidol 2007 Feh;18(1):41-6

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Vitamin D and calcium supplementation for the prevention of CVD Vitamin D and calcium supplementation for the prevention of CVD events:RCT Meta-analysisevents: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 0.77-1.05

Wang L. et al. Ann Intern Med 2010;152:315-323

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Vitamin D and calcium supplementation for the prevention of CVD events:RCT Vitamin D and calcium supplementation for the prevention of CVD events:RCT Meta-analysisMeta-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。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α与 IL-6、 IL-

1 、 IL-8的水平。

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Inadequate UVB exposure and low dietary vitamin D intake

Low circulating 25-hydroxyvitamin D levels

Low cellular calcitriol concentrations

Vascular smooth cell proliferation

MGP

Synthesis↓ PTH↑TNF-α↑IL-6↑IL-10↑

RAS↑

VascularCalcification

Myocardialcalcification

Lnflammatoryprocesses↑

HypertensionStrokeHeart attack

LVH

CVD

↓Insulin

↑glucose

Activated vitamin D is a negative inhibitor of the RAASActivated vitamin D is a negative inhibitor of the RAASVitamin 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 RAASActivated 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 34°25′-48°10′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

0

20

40

60

80

100

维族 汉族 合计

%（） 缺乏

不足充足

表 维吾尔族和汉族原发性高血压病患者1，25-二羟维生素D3浓度的分布

1，25（OH）2D3 血清浓度

族别 缺乏 不足 充足

维族(%) 82．00(82/100) 16.00(16/100) 2.00(2/100)

汉族(%) 78.46(204/260) 20.00(52/260) 1.54(4/260)

合计(%) 79.44（286/360） 18.89（68/360） 1.67（6/360）

对收缩压的敏感性分析

Study or Subgroup6.1.1 old people

Pan 1993Scragg 1995Pfeifer 2001Subtotal (95% CI)

Heterogeneity: Tau² = 10.81; Chi² = 3.98, df = 2 (P = 0.14); I² = 50%Test for overall effect: Z = 1.09 (P = 0.28)

6.1.2 young people

Lind 1989Zittermann 2009Nagpal 2009Jorde 2010Subtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 2.72, df = 3 (P = 0.44); I² = 0%Test for overall effect: Z = 2.07 (P = 0.04)

Total (95% CI)

Heterogeneity: Tau² = 6.43; Chi² = 12.00, df = 6 (P = 0.06); I² = 50%Test for overall effect: Z = 0.30 (P = 0.76)Test for subgroup differences: Chi² = 3.18, df = 1 (P = 0.07), I² = 68.5%

Mean

-2.64-5

-13.1

1-4

0.61.2

SD

17.7613

18.89

14.5216

9.8211.4

Total

149573

182

188235

114249

431

Mean

-1.07-5

-5.7

-4-3

-3.35-1.1

SD

15.0816

17.88

15.5216

7.2112.8

Total

159472

181

218336

112252

433

Weight

4.6%18.5%12.8%35.9%

6.8%16.0%19.0%22.4%64.1%

100.0%

IV, Random, 95% CI

-1.57 [-13.60, 10.46]0.00 [-4.16, 4.16]

-7.40 [-13.39, -1.41]-2.95 [-8.27, 2.37]

5.00 [-4.44, 14.44]-1.00 [-5.88, 3.88]3.95 [-0.07, 7.97]2.30 [-0.86, 5.46]2.27 [0.12, 4.43]

0.43 [-2.36, 3.21]

Year

199319952001

1989200920092010

vitamin D Control Mean Difference Mean DifferenceIV, Random, 95% CI

-20 -10 0 10 20Favours experimental Favours control

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。

Martins,D. et al. Arch Intern Med 2007;167:1159-1165

用药前 用药后25(OH)D 14.19±4.87 18.46±2.80 *

SBP 141.1±9.2 137.5±15 .3*

DBP 86.0±9.7 82.7±8.0 *

Ca 2.67±0.85 2.05±0.22 *

Glu 6.39±0.92 5.10±0.87*

CHOL 4.11±0.78 4.36±0.84

LDL-CHOL 3.25±0.53 2.63±0.59 *

Cr 93.81±18.49 60.79±21.04 *

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！