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高血压与维生素 D

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. 研究背景. 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% 。.

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高血压与维生素 D

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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

  2. 研究背景 • 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%。

  3. Vitamin D has long been known to be important for bone health Cholecalciferol(D3) Ergocalciferol(D2) •

  4. 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。

  5. Prevalence of insufficient 25(OH)D levels(＜30ng/ml) bysex and race/ethnicity across age groups:Third 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

  6. 肥胖 纬度 年龄 摄入含维生 素D的食物 维生素D 季节 性别 防晒霜 种族

  7. Risk 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)

  8. CHD death rates are higer in countries of increased geographic latitudes where average serum vitamin D are lowest www.bio-rad.com

  9. Institute 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

  10. 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 calcification, and death

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

  12. Vitamin D levels and risk of CVD events:Framingham offspring prospective cohort study Mean age 59 y,55% women , all Caucasian Wang TJ et al. Circulation 2008;117:503-511.

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

  14. 25(OH)D deficiency predicts 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 from Health Professionals' Follow-up Study and 1198 women from the Nurses' Health Study

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

  16. 25-OH D Levels and Myocardial Infarction Health Professionals Followup Sthdy www.bio-rad.com Giovanucci et al Arch Int Med 2008

  17. Vitamin 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

  18. Increased risk of all-cause mortality for those at lower serum 25(OH)D levels: NHANES-Ⅲ linked mortality study *adjusted for age, sex, race/ethnicity and season Metamed ML. Michos ED, et al. Arch Intern Med 2008;158:1629-1637.

  19. 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-rad.com

  20. 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 0.77-1.05 www.bio-rad.com Wang L. et al. Ann Intern Med 2010;152:315-323

  21. Vitamin D and calcium supplementation for the prevention of CVD events:RCT Meta-analysis **For calcium alone or vit D + calcium: No Benefit www.bio-rad.com

  22. 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。

  23. 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。

  24. 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↑ ↓Insulin Vascular Calcification Myocardial calcification Lnflammatory processes↑ Hypertension Stroke Heart attack ↑glucose LVH CVD

  25. Activated vitamin D is a negative inhibitor of the RAAS Vitamin D receptor knock out -/- mice compared to wild type 1,25(OH)2D treatment in wild type mice suppresses renin secretion

  26. Activated vitamin D is a negative inhibitor of the RAAS 1,25(OH)2D treatment in wild type mice

  27. 研究背景 • 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。

  28. 对收缩压的敏感性分析

  29. 年龄大于60岁组与年龄小于60岁组之间收缩压的比较年龄大于60岁组与年龄小于60岁组之间收缩压的比较

  30. 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。

  31. 骨化三醇干预治疗 Martins,D. et al. Arch Intern Med 2007;167:1159-1165

  32. 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。

  33. 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。

  34. 谢 谢！

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