血压变异性与脑白质病变的研究进展
Research Progress of Blood Pressure Variability and White Matter Lesions

作者: 张 艺 , 谈 跃 :昆明医科大学第二附属医院脑血管病科,云南 昆明;

关键词: 脑白质病变血压变异性研究进展White Matter Lesions Blood Pressure Variability The Research Progress

摘要: 脑白质病变是以神经纤维脱髓鞘为主要病理改变的一种亚临床脑血管疾病,是脑小血管病的典型表现之一。脑白质病变好发于老年人,目前研究认为,脑白质病变与卒中风险增加、血管性痴呆、认知功能障碍等密切相关。高血压是脑白质病变公认的危险因素,同时血压变异性也与脑白质病变的发生密切相关,二者相关的机制目前尚未完全明确。本文对血压变异性与脑白质病变的研究进展进行综述,旨在为脑白质病变的防治提供一定依据。

Abstract: White matter lesions is a kind of subclinical cerebrovascular disease with demyelination of nerve fibers as the main pathological change, which is one of the typical manifestations of cerebral small vessel disease. White matter lesions tend to occur in the elderly. Current studies believe that white matter lesions is closely related to the increased risk of storke, vascular dementia, cognitive dysfuntion and son on. Hypertension is a recognized risk factor for white matter lesions, and blood pressure variability is also closely related to the white matter lesions. The mechanism of the correlation between the blood pressure variability and white matter lesions is not fully understand. In this paper, the research progress of blood pressure variability and white matter lesions is reviewed in order to provide some basis for the prevention and treatment of white matter lesions.

1. 引言

脑白质病变(white matter lesions, WMLs)是由多种病因引起的一系列神经纤维传导脱髓鞘、轴突缺失和胶质增生等病理改变,是脑小血管病的典型表现之一,其在核磁共振T2WI和FLAIR上呈高信号,T1WI上呈等信号或低信号,病灶常双侧对称存在,好发于基底节区、放射冠及半卵圆中心 [1]。随着年龄的增长,WMLs的患病率逐渐升高,在65岁以上人群中WMLs的患病率为11%~21%,80岁以上人群中WMLs的患病率约为94% [2]。WMLs的存在与卒中、阿尔茨海默病、轻度抑郁和老年人认知功能障碍发生的风险增加密切相关 [3] [4] [5]。高血压是WMLs最重要的危险因素之一,长期高血压引起的一系列脑微血管结构的改变会增加白质低灌注的风险 [6]。此外,较高的血压变异性(blood pressure variability, BPV)也与WMLs发生的风险增加有关 [7],相关的机制目前尚未完全明确。现就BPV与WMLs的研究进展进行综述。

2. 血压变异性

2.1. 概念

血压是一个连续的变量,随着身体和精神活动、睡眠、体液和环境刺激的各种变化而不断波动,血压变异性则反映了一定时间内血压的波动程度,其不依赖于血压水平而独立存在 [8]。近年的研究表明,除了正常血压值之外,BPV的评估和量化也具有重要的意义,较高的BPV与高血压靶器官损害及心脑血管事件发生风险增加独立相关 [9] [10]。

2.2. 分类和评估

血压变异性是一个复杂的现象,根据其发生的时间范围分为短期BPV和长期BPV [11]。短期BPV又分为每次心搏间血压波动和一天(24小时)内发生的血压变化,前者通常在实验室通过动脉内记录进行评估,后者可通过24小时动态血压监测(ambulatory blood pressure monitoring, ABPM)或特殊的家庭血压监测(home blood pressure monitoring, HBPM)设备在睡眠时测量血压以评估短时BPV [12]。短期(24小时) BPV具有血压正常的昼夜节律变化的特征,包括夜间血压下降、早晨血压升高等 [11]。血压正常的患者夜间血压通常会下降10%~20%,而在高血压患者中夜间血压下降程度不完全一致,可根据夜间血压下降程度分为杓型(夜间血压下降在10%~20%)、非杓型(夜间血压下降<10%)、深杓型(夜间血压下降>20%)和反杓型(夜间血压升高)四种类型 [11]。早晨血压升高也是一个正常的生理过程,一部分高血压患者会出现极端的早晨高血压,即早晨与夜间血压差值大于35~55 mmHg [13]。目前临床最常用的评估短期BPV的指标包括整个24小时、白天和夜间测量的平均血压值的标准差(standard deviation, SD),为消除夜间血压下降的影响,也会采用加权标准差(weighted standard deviation, wSD)来评估24小时BPV [11]。SD具有一定的局限性,其仅反映偏离平均值差值的平均数,未将血压测量值的顺序考虑在内,同时对ABPM的低采样频率较为敏感 [14];因此,其他指标包括变异系数(coefficient of variation, CV)、平均真实变异性(average real variability, ARV)也常用于评估短期BPV。与SD相比,CV和ARV是更为可靠的评估指标,能更好的预测靶器官损伤和心血管疾病发生的风险 [15] [16]。

长期BPV指数天、数周、数月或季节之间的血压变化,其反映了接受降压治疗的患者血压控制的稳定性 [11]。日常BPV (day-to-day BPV)常采用连续的ABPM (超过48小时)进行评估,家庭血压监测用于评估数周或数月内的血压变化,ABPM和诊室间血压监测则用于评估数周、数月或数年的随诊间BPV (vist-to-vist BPV) [12]。SD和CV是临床常用的评估长期BPV的指标,研究发现,随诊间收缩压SD较高的患者发生心血管疾病及缺血性卒中的风险明显增加(P < 0.05) [17]。目前BPV与心脑血管疾病发生风险增加的相关机制尚未完全明确,还需进一步研究探索。

2.3. 调控机制

血压变异性受神经、体液、个体行为变化和外界环境等多种因素影响,不同类型的BPV具有不同的影响因素。短期BPV,包括每次心搏间和24小时内的血压变化,主要受中枢神经因素(交感神经兴奋增强)、反射性自主调节(动脉和心肺反射减弱)、体液(血管紧张素II、内皮素-1、一氧化氮)、动脉弹性(动脉顺应性降低)、行为(体力活动和睡眠)和情绪(心理压力)等因素的影响 [18]。长期BPV主要反映了长期服用降压药物的患者血压控制的稳定性,因此容易受不恰当的降压治疗方案、患者的治疗依从性差以及血压测量误差的影响 [19]。此外,季节变化所带来的温度和日照时间的差异也会对长期BPV造成一定影响 [12]。既往研究 [20] 已证实,在接受降压治疗的老年高血压患者中,气温升高与夜间收缩压升高密切相关,表明在极端天气变化的情况下,需更严密监测老年高血压患者的降压治疗效果,以通过平稳降压来降低BPV对心脑血管的损害。

3. 脑白质病变

随着影像学技术的发展,脑白质病变的检出率日益增高。WMLs可能是正常衰老过程的一部分,构成白质髓鞘的蛋白随着会衰老逐渐减少,同时脑血管功能也会随着年龄的增长而下降,增加了WMLs的风险 [21]。WMLs根据解剖位置通常分为脑室旁白质病变(periventricular WMLs, PVWMLs)和深部白质病变(deep WMLs, DWMLs),前者与脑室相连,后者位于皮质下白质 [22]。脑室旁白质的血供来源于室管膜下动脉的脉络膜动脉和纹状体动脉的终末分支,侧支循环较少,因此容易受到血流动力学的影响 [23]。深部白质的供血主要来自于大脑中动脉的滋养动脉,更容易受脑血管危险因素影响 [24],因而PVWMLs和DWMLs由于血供不同受血管危险因素的影响存在差异。

大量研究表明,WMLs与认知功能障碍、抑郁、卒中风险增加及步态障碍等有关 [3] [5]。然而,WMLs的发病机制和相关危险因素目前尚未完全明确。血脑屏障破坏、脑血流调节功能障碍及长期低灌注被认为是WMLs的主要发病机制 [23]。许多血管危险因素,如高龄、高血压、糖尿病、高同型半胱氨酸血症及血脂异常等均与WMLs的发生和发展密切相关,高龄和高血压是最重要的危险因素 [6] [21] [23]。研究显示,与血压正常的患者相比,高血压患者WMLs的发生率和进展速度显著增加 [25]。高血压引起的一系列微血管结构改变,包括管壁增厚、管腔狭窄、微血管延长和弯曲,会导致脑血管自动调节紊乱,增加白质缺血的风险 [26]。因此,对WMLs的患者严格控制血压可能有利于减少WMLs的发生,控制阈值有待进一步研究探索。

3.1. 短期血压变异性与脑白质病变

高血压是WMLs主要的危险因素,近年来,越来越多的研究开始关注BPV与WMLs发生发展的关联。在一项大型的临床流行病学研究中,研究者对487例高血压患者进行了头颅核磁共振检查和24小时ABPM后发现,收缩压的平均真实变异性(SBP-ARV)与PVWMLs和DWMLs的严重程度均密切相关(P < 0.001, P = 0.026) [27]。William [28] 等在老年人群中进行的一项横断面研究显示,与杓型血压的患者相比,非杓型血压的患者WMLs体积显著增加(p < 0.01)。另一项meta分析 [10] 表明,反杓型血压模式和非杓型血压模式均与WMLs的患病率升高有关,说明异常昼夜血压节律会增加WMLs发生的风险。异常昼夜血压模式与WMLs相关的病理机制目前尚不清楚,可能与非杓型和反杓型血压模式导致24小时平均血压水平升高,从而对血管产生更大的压力负荷,进而加速动脉粥样硬化性疾病的形成有关 [29]。但也有研究得出了相反的结论,该项研究发现夜间的收缩压水平,而不是非杓型血压模式,是无卒中史的普通人群发生WMLs的独立预测因素 [30]。关于短期BPV与WMLs的研究出现了相互矛盾的结果,有待进一步的研究深入探索二者的因果关系。

3.2. 长期血压变异性与脑白质病变

目前众多研究表明,除了短期BPV之外,长期BPV也与WMLs密切相关。Liu [31] 等对248名80岁以上高龄的老年人进行为期2年的随访后发现,收缩期血压CV较高的受试者在随访期间WMLs增加的百分比均大于CV较低和中等组的受试者(分别为18%;11%;15%,P < 0.05),表明由HBPM评估的收缩期血压CV是高龄老年人群WMLs体积增加的独立危险因素,收缩期过度的血压波动会加剧WMLs的进展。在一项基于社区的随访研究中,研究者对122例高血压患者进行了3年和6年的随访后发现,较高的随诊间收缩压BPV(CV)与WMLs进展具有显著相关性(β = 0.027 mL/y, 95% CI: 0.01~0.054, P = 0.043),舒张压BPV与WMLs进展没有关联。此外,他们还发现在首次进行核磁共振扫描时WMLs体积较低的患者中,随诊间BPV和WMLs进展的关联性最强,说明BPV可能主要影响新发的WMLs的进展,而不是已经存在的WMLs的进展 [32]。另一项基于普通人群的队列研究 [33] 也得出了一致的结论,即较高的收缩压BPV与WMLs的进展显著相关(P = 0.023),表明收缩压BPV可作为WMLs进展的独立预测因素。长期BPV,尤其是收缩压BPV在WMLs的进展中起着重要作用,相关的机制目前尚未完全明确,可能是由于长期较高的BPV会引起低血压频繁发作,导致大脑白质灌注不足,进而加速WMLs的形成 [25]。因此,在高血压人群的日常血压管理中,应注意监测BPV,以期通过平稳降压来减少过度的血压波动引发的脑血管损害。

4. 降压治疗

高血压是WMLs重要的可干预危险因素,已有研究证实有效的降压治疗可延缓WMLs的进展 [34]。国外开展的一项多中心随机临床试验显示,在为期3.4年的干预随访后,强化降压治疗组的患者WMLs体积平均增加了0.92 cm3,而标准降压治疗组的患者WMLs体积平均增加了1.45 cm3,表明强化血压控制会使患者从中获益更大 [35]。较高的短期和长期BPV均是WMLs发生发展的重要影响因素,对WMLs的患者,降压治疗不仅要控制平均血压值,还要重视长期平稳降压,以降低BPV带来的大脑结构的破坏。尽管有研究 [36] 表明在接受两联或三联降压药物治疗的患者中,尤其是包括血管紧张素II受体拮抗剂(angiotensin II receptor blocker, ARB)、钙通道阻滞剂(calcium-channel blockers, CCB)或利尿剂的联合治疗,BPV能被有效的降低,但目前无法明确是否WMLs患者采用降低BPV的降压药物联合治疗或单药治疗时,能有效的延缓WMLs的发展,还需进一步在大规模、多中心的研究中进行分析探索,以为WMLs患者选择更优的降压治疗方案提供指导依据。

5. 小结与展望

综上所述,长期BPV可作为WMLs发展的独立预测因素,在临床实践中监测BPV可能有助于实施早期干预措施,达到持续平稳降压的目标,减少WMLs的发生。短期BPV与WMLs的关联目前尚存争议,有待进一步研究证实。BPV与WMLs相关的机制目前也尚未完全明确,未来的研究应深入探索相关的病理生理机制,同时将降低BPV作为可干预的靶点,探索最有效的降压治疗方案,减少WMLs的发生。

基金项目

昆明医科大学2020年研究生创新基金(项目编号:2020S190)。

NOTES

*通讯作者。

文章引用: 张 艺 , 谈 跃 (2021) 血压变异性与脑白质病变的研究进展。 临床医学进展, 11, 2048-2054. doi: 10.12677/ACM.2021.115293

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