广泛性焦虑障碍与心率变异性的相关性研究

心率变异性(HRV)是评价心脏自主神经活动独立性较好的无创手段,目前常被用作判断心脏自主神经病变,广泛用于身心疾病、情绪障碍、心理障碍等各个领域的研究中。HRV降低不仅是心血管事件的重要危险因素,也是重要的死亡预测因素。一般来说HRV越高,自主神经调节能力越强,副交感神经张力越大,心脏电活动越稳定;HRV降低则提示自主神经稳态被破环,迷走神经张力降低,或是交感神经活性增强,高血压、糖尿病、心血管事件等发生率增加[1-2]。影响HRV的因素有很多,本文主要综述广泛性焦虑障碍(GAD)对于HRV的影响。

1 定义

GAD又称为慢性焦虑障碍,是一类缺乏明确对象和具体内容、难以控制的过度担忧、提心吊胆、紧张不安的焦虑障碍,伴有一系列显著的自主神经系统症状如脸部潮红、心悸、多汗、发抖、肌肉紧张、运动性不安等[3]。其主要特征为慢性持续弥散的焦虑状态,伴自主神经症状。病人因难以忍受的担心和紧张却又无法解脱而感到痛苦,病情严重者可造成精神残疾,严重影响其社会功能和生活质量。

HRV是指瞬时心率或瞬时心动周期的微小变化。HRV中时域和频域的各参数,均由窦性心搏NN间期的变化计算而来。常用时域指标有24 h内全部R-R 间期的标准差(SDNN)，一般认为其体现整体心率变异程度;24 h每5 min R-R 间期平均值标准差(SDANN)，主要反映交感神经功能;全程每两个相邻的R-R 间期差值的均方根值(RMSSD)和24 h R-R 间期标准差>50 ms的数量占总心搏数的百分比(PNN50),后两者主要反映迷走神经张力,其中RMSSD最能代表副交感神经活性。频域指标常用参数:总功率(TP,频段小于0.04 Hz,单位:ms)，反映心率变异性大小;高频功率(HF,频段0.15～0.4 Hz) 反映迷走神经功能水平,与RMSSD和PNN50有关,最常见于焦虑相关文献中[4]; 低频功率(LF,频段0.04～0.15 Hz)反映自主神经平衡性,与SDNN指数相关;LF/HF因准确性不高,临床不常用[5]。

2 病理生理机制

2.1 解剖学 HRV与GAD存在共同的解剖学基础。焦虑障碍的起源与应激反应有关的网状激活系统相关[4],而此部位同时也是心血管中枢、呼吸中枢,控制心血管呼吸活动、全身激动等,使得机体能够对外界环境变化迅速做出相应反应。

2.3 神经内分泌 持续焦虑状态下,下丘脑-垂体-肾上腺轴过度激活[7],促肾上腺皮质激素释放因子、皮质醇增加,诱发体质量增加、高血压、糖尿病、引起自主神经稳定性下降等。

3 研究现状

目前关于HRV 研究参考最多的是频域指标HRV-HF,其主要反映副交感神经张力水平。大部分研究中GAD病人平静状态下常有HRV-HF下降[4,8],但未发现GAD严重程度与HRV-HF存在线性关系[9]。少数研究中GAD患病初期可出现HRV-HF暂时升高[10],但该研究样本量很少,可信度需进一步验证。亦有研究认为平静状态下,GAD与HRV并无相关性[11-12],只在紧张状态时(人为设置的紧张场景或是病人本身紧张焦虑时)方存在负相关[13-14],这样的差异不仅与样本量有关,入组样本的GAD病情、病程、并发症、用药情况等均会对研究结果造成影响。

HRV下降并不是GAD所特有,在其他心理疾病如惊恐障碍、社交恐惧症、创伤后应激障碍、抑郁症等都会出现。如GAD合并抑郁症时,HRV下降较单纯GAD下降更明显[4]。抑郁症与心血管疾病(CVD)密切相关,其可增加冠心病(CHD)病人的致命性心血管事件的发生率,同时约20%～40%的CVD病人伴有抑郁倾向[1,12],即便控制体质量指数(BMI)、运动量、高血压、高血脂等高危因素,合并抑郁症的CHD病人的死亡率亦高于单纯CHD的死亡率。研究表明抑郁症可引起心脏自主神经功能紊乱,迷走神经控制减弱,HRV下降[15],因此往往认为GAD若合并抑郁症则易形成叠加效应,使得HRV下降更为明显。同时GAD与抑郁症很难彻底区别,据报道有近60%的GAD可出现抑郁倾向[16],抑郁症又可出现焦虑症状,两者在病程的某一阶段甚至可以相互转化[12],因此研究对象是否伴有其他心理并发症明显影响研究结果。

有研究认为试验对象是否经药物治疗明显影响研究结果。GAD伴抑郁者,HRV高于单纯GAD,究其原因可能是入组对象有抗抑郁治疗史[17]。甚至有研究认为GAD并不能引起HRV下降,而是药物直接作用的结果[18]。三环类抗抑郁药物(TCA)、5-羟色胺再摄取抑制剂(SSRIs)[19]等均可降低迷走神经活性,使得心率加快,传导减慢等,从而增加CVD发生率与死亡率[20]。苯二氮类可通过与γ-氨基丁酸A受体氯离子通道复合体相互作用而影响心脏自主神经调节功能,抑制中枢迷走神经活性,降低HRV[21]。在一些试验中，焦虑病人服用氯硝西泮后SDANN、SDNN、LF、HF均较对照组降低[22]。虽然也有研究认为未经药物治疗的GAD病人HRV亦下降,以此来说明HRV不受药物影响,但是细读此类文献,我们可发现其研究对象包括暂停药物7 d以上人群[23]，而抗焦虑药物对心功能的影响是长期的、多方面的,如TCA可引起体质量增加、降低HRV、延长QT间期、增加高血压的风险等,总之药物对HRV影响的值得重视[24]。

此外,尼古丁可刺激儿茶酚胺释放,激活交感神经系统[25],吸烟包括二手烟[26]皆降低HRV,即便戒烟,这种效应仍能继续存在。种族、性别、肥胖、运动等均会影响HRV,1周锻炼3次以上可改善自主神经系统稳定性,增加副交感神经系统活性,降低HRV,使心血管系统获益[27]。甚至有研究发现，GAD病人经药物治疗、认知行为疗法(CBT)治疗后,HRV可出现反转[4],从而推测焦虑病人可从改善生活方式、饮食控制、运动、药物治疗中获益。

4 结语

GAD是一种慢性持续弥散的焦虑状态,常伴一系列自主神经症状;HRV是判断心脏迷走神经张力的敏感指标。GAD与HRV具有共同的病理生理基础,目前的研究表明，GAD病人往往存在不同程度的HRV下降,且HRV下降的程度并不受GAD严重程度的影响。但样本量、试验条件、病人情绪状态、GAD严重程度、并发症、药物作用等因素控制并不理想,因此GAD对HRV的影响仍需进一步研究。

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