夜间高血压研究进展
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夜间高血压研究进展. 哈医大第一临床医学院 心内科. 李 悦. 正常血压昼夜节律. BP follows a circadian rhythm (Dipping) , with 10–20% lower values during sleep than during wakefulness. 靶器官灌注需要最低血压. Nocturnal dip < 10% of daytime pressure – No ndipping ( 非杓型) - PowerPoint PPT PresentationTRANSCRIPT
The First Clinical College of Harbin Medical University
哈医大第一临床医学院 心内科
李 悦
The First Clinical College of Harbin Medical University
BP follows a circadian rhythm (Dipping), with 10–20%
lower values during sleep than during wakefulness.
靶器官灌注需要最低血压
正常血压昼夜节律
The First Clinical College of Harbin Medical University
Nocturnal dip
< 10% of daytime pressure – Nondipping ( 非杓型)
< significant increase – Reverse dipping ( 反杓型)
> 20% of daytime pressure – Extreme dipping ( 超杓型)
The First Clinical College of Harbin Medical University
夜间平均血压 > 120/ 70 mmHg (ABPM) 。
《中国高血
压防治指南》 2010
有学者建议用夜间睡眠血压替代夜间血压。
定 义
The First Clinical College of Harbin Medical University
原发性高血压和继发性高血压常见现象。流行病学
Can J Cardiol 2009;25(9):e312-e316
Friedman 等对白天血压正常组(未服用降压药 , 白天血压 < 13
5/85mmHg )可控制高血压组(服用≤ 3 种降压药 , 白天血压 < 135/85
mmHg )和难控制高血压组(服用≥3 种达最大剂量降压药 , 白天血压
>135/85mmHg )人群夜间血压模式进行研究。
The First Clinical College of Harbin Medical University
无论白天血压正常人群还是白天高血压人群 , 夜间高血压均有较高发生率 , 常与非杓型并存。
The First Clinical College of Harbin Medical University
2009;53;466-472 Hypertension
西班牙 500 个初级保健中心 42947 例高血压患者,未治疗 8384 例,已接受治疗 34563 例, ABPM 显示 ,
41% 未治疗患者及 52% 治疗患者呈非杓型曲线。
The First Clinical College of Harbin Medical University
许多研究证实,亚洲人和黑人夜间血压增高比
高加索人(白人)更常见。
J Hypertens. 2002;20:2183–2189
Am J Cardiol. 1995; 75:1239–1243
Am J Hypertens. 2000;13:884–891
Am J Hypertens. 2002;15:525–530
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2007 年 ,上海瑞金医院
观察浙江景宁畲族自治县 14 个村庄 2059 位受试者
The First Clinical College of Harbin Medical University
单纯夜间高血压( 22:00 - 4:00 平均血压≥ 120/70mmHg, 白天血压正常 )达 10.9% ;日夜高血压 38.4% ;单纯白天高血压 ( 从 8: 00 到 16: 00 平均血压 135/ 85 mm
Hg, 夜间血压正常 ) 为 4.9% 。
The First Clinical College of Harbin Medical University
夜间高血压危害 相比夜间血压正常者 , 夜间血压增高或下降迟缓病人伴发心、脑、肾等靶器官损害(左室肥厚、心衰、脑卒中、
微量蛋白尿等)以及心血管死亡风险明显增加。
Expert Rev. Cardiovasc. Ther. 7(6), 607–618 (2009)
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DM 患者中反杓型高血压患者较其他血压类型患者心血管不良事件增加 2.8 倍。
透析患者伴夜间收缩压增高者心血管死亡率增加 41
% 。
Diabetes Metab. 34(6 Pt 1), 560–567 (2008).
Kidney Int. 57(6), 2485–2491 (2000)
The First Clinical College of Harbin Medical University
Ohasama 研究证实,夜间血压下降每减少 5% ,
心血管死亡率增加 >20% 。
First study demonstrating that a diminished nocturnal decline in blood pressure is a risk factor for cardiovascular mortality
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一项爱尔兰研究显示:
夜间 SBP 每增加 10 mmHg ,心血管死亡率增加 2
1% ;
夜间 DBP 增加 5mmHg ,心血管死亡率增加 9% 。
JAMA. 2006 Jun 28;295(24):2859-66
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发生机制
The timing and amplitude of BP rhythm is affected by
Intrinsic factors, such as neurohormonal regulation (e.g., sympathetic nervous system and RAAS system) .
Extrinsic factors, such as sodium load, sleep quality physical activity, and behavioral and lifestyle factors (smoking and alcohol intake) .
Demographic factors, such as age and race.
Am. J. Hypertens. 6(6 Pt 2), S166–S169 (1993).
Am. J. Hypertens. 6(6 Pt 2), S170–S173 (1993).
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2008;52;925-931 Hypertension
Grassi 等观察杓型、极度杓型、非杓型以及反杓型
原发性高血压患者肌肉交感神经活性。
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正常血压(17)
杓型高血压
(34)
非杓型高血压
(18)
超杓型高血压
(17)
反杓型高血压
(10)
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与血压正常者比 , 高血压患者肌肉交感神经系统异常兴奋 ,
反杓型者为甚,提示交感神经在夜间高血压发生发展中起重 要作用。
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研究发现:主动脉瓣膜病变患者夜间血压下降程度
与肾素、醛固酮活性呈负相关 , 提示肾素、醛固酮活性
增加是引起夜间高血压的主要原因之一。
J. Hypertens. 8(1) 85–95 (1990).
The First Clinical College of Harbin Medical University
常伴随疾病 CKD and end-stage kidney disease DM Sleep apnea Autonomic neuropathy and autonomic failure Primary aldosteronism Pheochromocytoma (嗜铬细胞瘤) Cushing’s syndrome Solid organ transplantation Pre-eclampsia and eclampsia (子痫和先兆子痫) CHF
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正常肾脏功能对于保证血压昼夜节律非常重要。 肾小球滤过率( GFR )与夜间 / 白天血压比值呈反比。 CKD 患者血压非杓型比率高达 70%-80% 。
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23% of patients (188 T1D ) with clinical normotension had
masked nocturnal hypertension.
Hypertensives with diabetic nephropathy have significantly
higher night-time SBP compared with patients with
nondiabetic glomerulopathy (142 versus 132 mmHg; p = 0.02) .
DM
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阻塞性睡眠呼吸暂停低通气综合征
(Obstructive sleep apnea-hyponea syndrome, OSAHS)
40岁以上人群中,美国患病率为 2%-4% ,澳大利亚
高达 6.5% ,我国香港地区 4.1% ,上海市 3.62% ,长春
市 4.81% ,男性多于女性,老年人、肥胖患病率更高 。
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约 50%OSAHS 患者伴高血压 ,
至少 30% 高血压患者伴有 OSAHS 。
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新近研究表明, OSAHS 患者 , 无论是否有高血压,睡眠时血压杓型变化的规律性减弱或消失 ,出现不同程度的血压升高或夜间高血压。
OSAHS 程度越重,平均血氧浓度及最低血氧浓度越低 , 非杓型血压发生率越高。
Hypertension Res, 2009, 32 (6) : 428 -432
Sleep, 2008, 31(6) : 795-800.
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有证据提示,夜间血压下降缓慢、夜间高血压者与高盐饮食及盐敏感关系密切。
Hypertension. 1996;28:139–142
Circulation. 1997;96:1859–1862
Am J Hypertens. 1999;12:35–39
Hypertension. 1997;30:163-167
Am J Hypertens. 1995;8:970–977
J Hypertens. 1998;16:1745–1748
盐与夜间高血压
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我国人群食盐摄入量严重超标
北方 : 每人每天约 12-18g
南方 :每人每天约 7-8g
WHO 组织建议每人每日食盐摄入量≤ 5g
2.Report of a WHO Forum and Technical meeting 5–7 October 2006,Paris, France
1. 《中国高血压指南 2005 》
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我国高血压患者盐敏感型为主
2.Journal of Hypertension 2008, 26:381–391
正常 盐抵抗 盐敏感
正常盐摄入
低盐摄入
血压 (mmHg)
钠摄入量
我国盐敏型高血压占高血压总人群的 50%-60%
1. 刘杰等,高血压杂志 1999 7(3):251-253
盐敏感: 盐敏感型高血压患者血压随钠的摄入量的增加 ( 或减少 )
有更显著的增加 ( 或减少 ) 。
3.Hypertension. 1996;27:481-490
*
*正常:血压正常的个体
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诊 断
与传统诊所血压相比 , 24 h 动态血压监测 (ABPM ) 对夜间高血压诊断、昼夜节律观察及临床结果预测方面更有价值。
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有研究显示 , ABPM 监测出的夜间高血压患 74 例在使用诊室血压监测时仅有 4 名被检测出患有高血压。
Hypertension. 2007;50:333-339
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AHA 夜间血压诊断标准:
Hypertension. 2006 Jul;48(1):e3
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根据欧洲高血压学会( ESH )指南
白天平均值 < 135/ 85 mm Hg
夜间平均值 < 125/ 70 mm Hg
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中国 ABPM 正常标准:
24 h 平均值 < 130/ 80 mm Hg
白天平均值 < 135/ 85 mm Hg
夜间平均值 < 125/ 75 mm Hg
(<120/70mmHg , 2010 中国,台湾)
《中国高血压防治指南》 2005
《中国高血压防治指南》 2010
J Formos Med Assoc. 2010. 109(10): 740-73
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ABPM局限性 患者佩戴 ABPM
觉醒期间运动明显减少,坐位时间平均增加 27分钟 ( P=0.002 )。
夜间睡眠时间减少 98分钟( P< 0.0001 ),睡眠效率由 8
2%
降至 77% ( P=0.02 )。
日间血压值相对降低、夜间血压相对升高,倾向非杓型。 J Am Soc Nephrol. 2010. 5(2): 281-5
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对准确性低血压数值进行舍弃,其标准为:
收缩期 ABP> 260mmHg 或< 70mmHg ;
舒张期 ABP> 150mmHg 或< 40mmHg ;
ABP 脉压> 150mmHg 或< 20mmHg ;
被舍弃血压读数约占全部读数的 10~15% 。
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夜间高血压治疗 降压同时重视纠正血压昼夜节律 ,
包括非杓型血压、血压晨峰现象。
临床治疗涉及生活方式干预、 药物治疗的时间学 和相关疾病的治疗。
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生活方式干预 盐敏感者应首先限制钠摄入,补充钾盐。 Uzu 等证实:盐敏感性高血压患者限盐程度 与夜间血压下降幅度呈正相关。
盐敏感性高血压患者限盐后血压可由非杓型恢复为杓型。
Circulation. 1997 Sep 16;96(6):1859-62
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荟萃分析显示( 33 项随机对照研究, 2609 ):
补钾治疗能够明显降低收缩压和舒张压。 ( 3.1 / 1.9mmHg)
高钠盐摄入者血压降低更明显。
JAMA. 1997 May 28;277(20):1624-32.
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年轻非高血压黑人高钾摄入( 80mg/d) 使所有非杓型血压状态恢复为杓型血压状态,但白天血压无明显变化。
Blood press monit. 1996 Dec;1(6):447-455 补钾可减轻高盐对靶器官损害, 可能与其抗氧化作用有关。
Hypertension, 2008, 51: 2252-2231
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美国全国高血压教育项目协调委员会( NHBPEP )
推荐的钾与钠摄入比为 2 : 1 。
陕西农民调查,摄取钾约为 35 mmol/ d ,
而钠摄入为 230 mmol/ d , 钾与钠摄入比仅 0.15 。
补钾最可通过多食用含钾丰富的水果、蔬菜等或
添加钾盐。
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戒烟、戒酒
吸烟是重要的心血管危险因素,但戒烟对 24小时
血压控制影响不明显,尚无证据显示戒烟能够降低夜
间血压。
Arq. Bras. Cardiol. 87(4), 504–511 (2006).
Am. J. Hypertens. 14(9 Pt 1), 942–949 (2001).
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过量饮酒增加睡眠时交感神经活性,加重血压晨峰效应。
Hypertension 53(1), 13–19 (2009).
研究证实,戒酒能够降低 24小时血压,但不影响血压模式。
Hypertension 33(2), 653–657 (1999).
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保证良好睡眠。
睡眠障碍者非杓型高血压发生率增加 3 倍。
Blood Press. 2007;16(2):101-5
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对严重自主神经病变导致仰卧位高血压者 ,
睡眠时头部抬高有助于降低仰卧位血压 。
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药物治疗 Blockers of the RAAS
肾素活性夜间增加,到凌晨达高峰 .
Evening dosing consistently results in better nocturnal
BP reduction and increased dipping than with morning
dosing.
Pharmaco. Ther. 111(3), 629–651 (2006).
J. Hypertens. 23(10), 1913–1922 (2005).
Hypertension 50(4), 715–722 (2007).
Chronobiol. Int. 26(1), 61–79 (2009).
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CCB
180 patients (50% nondippers) receiving nifedipine GIT
S in a prospective, open-label, parallel-group design comp
aring morning and bedtime administration.
Bedtime dosing resulted in greater sleep-BP lowering
(9.6% vs 6% fall; p = 0.004), also accompanied by better 24-h
SBP control (9% vs 6.5% fall; p = 0.035) and a decrease in the
number of nondippers from 51% to 35%.
Am J Hypertens 2008, 21(8):948-54
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利尿剂
利尿剂对血压昼夜模式无明显影响(盐敏感高血压除外) ,
仍有待大规模临床研究证实。
Circulation 100(15), 1635–1638 (1999)
Chronobiol. Int. 25(6), 950–970 (2008)
Hypertension 47(3), 352–358 (2006).
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β 受体阻滞剂
The BP-lowering effects are more pronounced
during wakefulness(失眠 ) and OSAHS.
β-blockers have not been well studied to date.
Curr.Opin.Nephrol. Hypertens. 14(5), 453–459 (2005).
Pharmaco. Ther. 111(3), 629–651 (2006).
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其他药物褪黑素
由松果体腺分泌,能够改善内皮功能,增加 NO合成,
导致血管扩张和降压效应。
高血压病人夜间褪黑素分泌明显降低。
对夜间高血压治疗作用仍有待大规模临床研究证实。
Am. J. Med. 119(10), 898–902 (2006).
Am. J. Hypertens. 18(12 Pt 1), 1614–1618 (2005)
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阿司匹林
A potent antioxidative agent that reduces vascular produc
tion of superoxide, prevents angiotensin II–induced hyperte
nsion, and induces NO release.
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257 patients with mild hypertension randomly assigned
to receive 100 mg per day of aspirin either on awakening or
at bedtime.
A highly significant blood pressure reduction was
observed in patients who received aspirin at bedtime
(7.2/4.9 mmHg; P<0.001) .
The reduction in nocturnal BP was double in non-dippers
(11.0/7.1 mm Hg) compared with dippers (5.5/3.3 mm Hg;
P<0.001).
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The First Clinical College of Harbin Medical University
噻唑烷二酮类 (格列酮类 ) 增强机体组织对胰岛素的敏感性,
改善胰岛 β细胞功能。
Insulin resistance plays a role in elevation of BP by
various mechanisms.
Have a favorable effect on nocturnal hypertension.J. Hypertens. 24(10), 2047–2055 (2006).
Minerva Endocrinol. 29(1), 11–17 (2004).
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药物时间治疗学
根据不同药物的药代学特点 , 使用不同药物剂型、控制药物释放时间 , 以改变异常的血压昼夜节律 , 称为药物时间治疗学。
长效制剂
有利于夜间高血压控制,
有助于血压晨峰控制。
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调整服药时间 Minutolo 等发现( 32 例 CKD 伴夜间血压增高)将不同降压药物服用时间从早改到晚 , 结果显示:
Am J Kidney Dis. 2007 Dec;50(6):908-17
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After the shift, dipping increased in 94% of patients, with normal circadian rhythm restored in 88% .
Nocturnal SBP was significantly decreased (114±11 to
107±12 mmHg; p< 0.001).
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In resistant hypertension ( 578 ) , receiving at leas
t one of their medications in the evening had signiicantl
y lower nocturnal BP, lower prevalence of nondipping
(57 vs 82%; p < 0.001) and lower urinary albumin excretio
n (31 vs 47 mg/24h; p = 0.005) when compared with patient
s who were receiving all medications in the morning.
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A cross-sectional study was performed in 1,794 patients with resistant hypertension
There was no significant difference between the two groups in terms of daytime BP, but nocturnal BP was significantly lower when the drug regimen included an evening dose of at least 1 antihypertensive agent.
Am J Hypertens 2010, 23:432–439
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睡眠呼吸暂停综合征
一般治疗:减肥、侧卧睡眠、戒烟酒
器械治疗: CPAP 、口腔矫治器
外科治疗: 鼻腔手术、咽腭区手术、联合手术
伴随疾病治疗
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药物治疗 不宜选择具镇静作用降压药
以免加重呼吸暂停,如利血平、可乐定等。
OSAHS 患者存在 RAAS亢进, RAAS拮抗剂能够明显
降低 24 h 血压,且具改善呼吸暂停及睡眠结构作用。
有病例报道, ACEI使气道充血,加重呼吸暂停。
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有报道,非选择性 β 受体阻滞剂(普奈洛尔)
增加气道阻力和呼吸暂停次数,应避免使用。
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Carlberg等 2004 年对阿替洛尔与安慰剂或其它降压药物比较的荟萃分析证实:
阿替洛尔降压同时,不能减少心血管事件发生、卒中和病死率,指出阿替洛尔不应再作为抗高血压研究参照药物。
“老鼠屎”
Lancet 2004;364:1684-89
The First Clinical College of Harbin Medical UniversityAtenolol vs. placebo
All cause mortality
Cardiovascular mortality
MI
Stroke
The First Clinical College of Harbin Medical UniversityAtenolol vs. Other antihypertensive drug
All cause mortality
Cardiovascular mortality
MI
Stroke
Favour other drug
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阿替洛尔疗效欠佳原因
阿替洛尔为中度 β1 受体选择性, 100mg时阻断 80%β1 受体和 25%β2 受体,比索洛尔在 5 ~ 10mg时不与β2 受体结合。
阿替洛尔血浆半衰期为 6~ 7h, T/P 为 31% ,而比索洛尔半衰期为 10 ~ 12h, T/P 为 78% 。
水溶性。
细胞毒性 ?
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β 受体阻滞剂(阿替洛尔)比其他降压药(阿米洛 利、依那普利、氢氯噻嗪、氯沙坦)更能降低睡眠 呼吸暂停综合征患者的 24 h 和夜间血压。
Hypertension. 2000 Mar;35(3):787-94
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Curr Med Res Opin. 2010 Aug;26(8):1925-32 CONCLUSION:
Nebivolol (奈比洛尔) has a significant BP reduction effect in patients with OSA that is similar to valsartan and reduces heart rate to a greater extent which may prove beneficial in selected patients
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BPV
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2010
OSAHS
高 BPV ?
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Lancet 2010; 375: 906–15
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Compared with other drugs, interindividual variation in SBP wa
s reduced by CCB (VR 0·81, 95% CI 0·76–0·86, p<0·0001) and non-l
oop diuretic drugs (0·87, 0·79–0·96, p=0·007) , and increased by A
CEI (1·08, 1·02–1·15, p=0·008) , ARB (1·16, 1·07–1·25, p=0·0002) , an
d β blockers (1·17, 1·07–1·28, p=0·0007) .
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However, most studies included involved elderly people.
The pathophysiology of systolic hypertension in older
people (ie, ageing of vasculature) difers from that of
diastolic hypertension in younger people (which is linked to
obesity).
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容量依赖性 肾素依赖性
年轻人高血压
舒张期高血压
老年人高血压
收缩期高血压
黑人高血压
肥胖人群高血压
糖尿病人群高血压
CCB 、利尿剂 ACEI 、 ARB 、 β 受体阻滞剂
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Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlo¨ f B, Poulter NR, Sever PS, for the ASCOT-BPLA and MRC Trial Investigators. Effects of β-blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9:469–480.
Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta analysis. Lancet. 2010;375:906–915.
Assignment to β-adrenergic blockade–based treatment was associated with increased intervisit variability and worse outcome.
BPV Measurement imprecision related to bradycardia
Ben-Dov
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Determination of BP relies on detection of Korotkoff s
ounds (by auscultation) or the pulse wave oscillations (by o
scillatory devices) .
Bradycardia can decrease the precision of these dete
rminations
Increase the scatter around the true level of BP
Measurement imprecision related to bradycardia.
The First Clinical College of Harbin Medical UniversityHypertens Res. 2009;32:488–495
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Measurement imprecision related to bradycardia.
Bradycardia induced by β-blockers mediates lack of
diagnostic precision, which might have impact on
outcome rather than true increase in BPV.
The differential effects of ACEI/ARB and CCB on
HR might follow the same rationale.
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CCBs increase HF !
Marcelo 等
8 个数据库 44篇报道 5326篇参考文献,最终 19 个实验
156,766 病例, 5049 个事件
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二氢吡啶和非二氢吡啶 CCB都较对照组心衰发生率明显增高。
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J Hypertens. 2011 Jun;29(6):1236-41
( 186 hypertensive patients with OSA )
Use of CCB was associated with significant reduction in total sl
eep time (-41 min, P = 0.005) and 8% lower sleep efficiency (P
= 0.004).
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?
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总 结 夜间血压增高在原发和继发性高血压患者中普遍存在。
夜间高血压对心、脑和肾脏等靶器官损害更严重。
对于盐敏感性高血压患者,
限钠盐、补钾盐和利尿剂能有效降低夜间血压。
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睡前给予降压药物能够有效降低夜间血压,
恢复血压杓型状态。
睡眠呼吸暂停患者常伴夜间血压增高,
CPAP 是最有效治疗方法之一。
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ABPM 有助于高危病人筛查并指导治疗,
避免夜间血压过度降低。
夜间血压过度降低可能导致脑血管损伤,
并可能加重晨峰效应。
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