心率變異性(HRV)是評(píng)價(jià)心臟自主神經(jīng)活動(dòng)獨(dú)立性較好的無(wú)創(chuàng)手段,目前常被用作判斷心臟自主神經(jīng)病變,廣泛用于身心疾病、情緒障礙、心理障礙等各個(gè)領(lǐng)域的研究中。HRV降低不僅是心血管事件的重要危險(xiǎn)因素,也是重要的死亡預(yù)測(cè)因素。一般來(lái)說(shuō)HRV越高,自主神經(jīng)調(diào)節(jié)能力越強(qiáng),副交感神經(jīng)張力越大,心臟電活動(dòng)越穩(wěn)定;HRV降低則提示自主神經(jīng)穩(wěn)態(tài)被破環(huán),迷走神經(jīng)張力降低,或是交感神經(jīng)活性增強(qiáng),高血壓、糖尿病、心血管事件等發(fā)生率增加[1-2]。影響HRV的因素有很多,本文主要綜述廣泛性焦慮障礙(GAD)對(duì)于HRV的影響。

1 定義

GAD又稱(chēng)為慢性焦慮障礙,是一類(lèi)缺乏明確對(duì)象和具體內(nèi)容、難以控制的過(guò)度擔(dān)憂、提心吊膽、緊張不安的焦慮障礙,伴有一系列顯著的自主神經(jīng)系統(tǒng)癥狀如臉部潮紅、心悸、多汗、發(fā)抖、肌肉緊張、運(yùn)動(dòng)性不安等[3]。其主要特征為慢性持續(xù)彌散的焦慮狀態(tài),伴自主神經(jīng)癥狀。病人因難以忍受的擔(dān)心和緊張卻又無(wú)法解脫而感到痛苦,病情嚴(yán)重者可造成精神殘疾,嚴(yán)重影響其社會(huì)功能和生活質(zhì)量。

HRV是指瞬時(shí)心率或瞬時(shí)心動(dòng)周期的微小變化。HRV中時(shí)域和頻域的各參數(shù),均由竇性心搏NN間期的變化計(jì)算而來(lái)。常用時(shí)域指標(biāo)有24 h內(nèi)全部R-R 間期的標(biāo)準(zhǔn)差(SDNN)，一般認(rèn)為其體現(xiàn)整體心率變異程度;24 h每5 min R-R 間期平均值標(biāo)準(zhǔn)差(SDANN)，主要反映交感神經(jīng)功能;全程每?jī)蓚€(gè)相鄰的R-R 間期差值的均方根值(RMSSD)和24 h R-R 間期標(biāo)準(zhǔn)差>50 ms的數(shù)量占總心搏數(shù)的百分比(PNN50),后兩者主要反映迷走神經(jīng)張力,其中RMSSD最能代表副交感神經(jīng)活性。頻域指標(biāo)常用參數(shù):總功率(TP,頻段小于0.04 Hz,單位:ms)，反映心率變異性大小;高頻功率(HF,頻段0.15～0.4 Hz) 反映迷走神經(jīng)功能水平,與RMSSD和PNN50有關(guān),最常見(jiàn)于焦慮相關(guān)文獻(xiàn)中[4]; 低頻功率(LF,頻段0.04～0.15 Hz)反映自主神經(jīng)平衡性,與SDNN指數(shù)相關(guān);LF/HF因準(zhǔn)確性不高,臨床不常用[5]。

2 病理生理機(jī)制

2.1 解剖學(xué) HRV與GAD存在共同的解剖學(xué)基礎(chǔ)。焦慮障礙的起源與應(yīng)激反應(yīng)有關(guān)的網(wǎng)狀激活系統(tǒng)相關(guān)[4],而此部位同時(shí)也是心血管中樞、呼吸中樞,控制心血管呼吸活動(dòng)、全身激動(dòng)等,使得機(jī)體能夠?qū)ν饨绛h(huán)境變化迅速做出相應(yīng)反應(yīng)。

2.3 神經(jīng)內(nèi)分泌 持續(xù)焦慮狀態(tài)下,下丘腦-垂體-腎上腺軸過(guò)度激活[7],促腎上腺皮質(zhì)激素釋放因子、皮質(zhì)醇增加,誘發(fā)體質(zhì)量增加、高血壓、糖尿病、引起自主神經(jīng)穩(wěn)定性下降等。

3 研究現(xiàn)狀

目前關(guān)于HRV 研究參考最多的是頻域指標(biāo)HRV-HF,其主要反映副交感神經(jīng)張力水平。大部分研究中GAD病人平靜狀態(tài)下常有HRV-HF下降[4,8],但未發(fā)現(xiàn)GAD嚴(yán)重程度與HRV-HF存在線性關(guān)系[9]。少數(shù)研究中GAD患病初期可出現(xiàn)HRV-HF暫時(shí)升高[10],但該研究樣本量很少,可信度需進(jìn)一步驗(yàn)證。亦有研究認(rèn)為平靜狀態(tài)下,GAD與HRV并無(wú)相關(guān)性[11-12],只在緊張狀態(tài)時(shí)(人為設(shè)置的緊張場(chǎng)景或是病人本身緊張焦慮時(shí))方存在負(fù)相關(guān)[13-14],這樣的差異不僅與樣本量有關(guān),入組樣本的GAD病情、病程、并發(fā)癥、用藥情況等均會(huì)對(duì)研究結(jié)果造成影響。

HRV下降并不是GAD所特有,在其他心理疾病如驚恐障礙、社交恐懼癥、創(chuàng)傷后應(yīng)激障礙、抑郁癥等都會(huì)出現(xiàn)。如GAD合并抑郁癥時(shí),HRV下降較單純GAD下降更明顯[4]。抑郁癥與心血管疾病(CVD)密切相關(guān),其可增加冠心病(CHD)病人的致命性心血管事件的發(fā)生率,同時(shí)約20%～40%的CVD病人伴有抑郁傾向[1,12],即便控制體質(zhì)量指數(shù)(BMI)、運(yùn)動(dòng)量、高血壓、高血脂等高危因素,合并抑郁癥的CHD病人的死亡率亦高于單純CHD的死亡率。研究表明抑郁癥可引起心臟自主神經(jīng)功能紊亂,迷走神經(jīng)控制減弱,HRV下降[15],因此往往認(rèn)為GAD若合并抑郁癥則易形成疊加效應(yīng),使得HRV下降更為明顯。同時(shí)GAD與抑郁癥很難徹底區(qū)別,據(jù)報(bào)道有近60%的GAD可出現(xiàn)抑郁傾向[16],抑郁癥又可出現(xiàn)焦慮癥狀,兩者在病程的某一階段甚至可以相互轉(zhuǎn)化[12],因此研究對(duì)象是否伴有其他心理并發(fā)癥明顯影響研究結(jié)果。

有研究認(rèn)為試驗(yàn)對(duì)象是否經(jīng)藥物治療明顯影響研究結(jié)果。GAD伴抑郁者,HRV高于單純GAD,究其原因可能是入組對(duì)象有抗抑郁治療史[17]。甚至有研究認(rèn)為GAD并不能引起HRV下降,而是藥物直接作用的結(jié)果[18]。三環(huán)類(lèi)抗抑郁藥物(TCA)、5-羥色胺再攝取抑制劑(SSRIs)[19]等均可降低迷走神經(jīng)活性,使得心率加快,傳導(dǎo)減慢等,從而增加CVD發(fā)生率與死亡率[20]。苯二氮類(lèi)可通過(guò)與γ-氨基丁酸A受體氯離子通道復(fù)合體相互作用而影響心臟自主神經(jīng)調(diào)節(jié)功能,抑制中樞迷走神經(jīng)活性,降低HRV[21]。在一些試驗(yàn)中，焦慮病人服用氯硝西泮后SDANN、SDNN、LF、HF均較對(duì)照組降低[22]。雖然也有研究認(rèn)為未經(jīng)藥物治療的GAD病人HRV亦下降,以此來(lái)說(shuō)明HRV不受藥物影響,但是細(xì)讀此類(lèi)文獻(xiàn),我們可發(fā)現(xiàn)其研究對(duì)象包括暫停藥物7 d以上人群[23]，而抗焦慮藥物對(duì)心功能的影響是長(zhǎng)期的、多方面的,如TCA可引起體質(zhì)量增加、降低HRV、延長(zhǎng)QT間期、增加高血壓的風(fēng)險(xiǎn)等,總之藥物對(duì)HRV影響的值得重視[24]。

此外,尼古丁可刺激兒茶酚胺釋放,激活交感神經(jīng)系統(tǒng)[25],吸煙包括二手煙[26]皆降低HRV,即便戒煙,這種效應(yīng)仍能繼續(xù)存在。種族、性別、肥胖、運(yùn)動(dòng)等均會(huì)影響HRV,1周鍛煉3次以上可改善自主神經(jīng)系統(tǒng)穩(wěn)定性,增加副交感神經(jīng)系統(tǒng)活性,降低HRV,使心血管系統(tǒng)獲益[27]。甚至有研究發(fā)現(xiàn)，GAD病人經(jīng)藥物治療、認(rèn)知行為療法(CBT)治療后,HRV可出現(xiàn)反轉(zhuǎn)[4],從而推測(cè)焦慮病人可從改善生活方式、飲食控制、運(yùn)動(dòng)、藥物治療中獲益。

4 結(jié)語(yǔ)

GAD是一種慢性持續(xù)彌散的焦慮狀態(tài),常伴一系列自主神經(jīng)癥狀;HRV是判斷心臟迷走神經(jīng)張力的敏感指標(biāo)。GAD與HRV具有共同的病理生理基礎(chǔ),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嚴(yán)重程度的影響。但樣本量、試驗(yàn)條件、病人情緒狀態(tài)、GAD嚴(yán)重程度、并發(fā)癥、藥物作用等因素控制并不理想,因此GAD對(duì)HRV的影響仍需進(jìn)一步研究。

[參考文獻(xiàn)]

[1] Kemp AH, Quintana DS, Gray MA, et al.Impact of depression and antidepressant treatment on heart rate variability: a review and meta-analysis[J].Biol Psychiatry,2010,67(11):1067-1074.

[2] Wulsin LR, Horn PS, Perry JL, et al.Autonomic imbalance as a predictor of metabolic risks, cardiovascular disease, diabetes, and mortality[J].J Clin Endocrinol Metab,2015,100(6):2443-2448.

[3] Makovac E, Meeten F, Watson DR, et al.Neurostructural abnormalities associated with axes of emotion dysregulation in generalized anxiety[J].Neuroimage Clin,2016,10(6):172-181.

[4] Chalmers JA, Quintana DS, Abbott MJ, et al.Anxiety disorders are associated with reduced heart rate variability: a meta-analysis[J].Front Psychiatry,2014,(5):80.

[5] Zhong Y, Jan KM, Ju KH, et al.Quantifying cardiac sympathetic and parasympathetic nervous activities using principal dynamic modes analysis of heart rate variability[J].Am J Physiol Heart Circ Physiol,2006,291(3):H1475-H1483.

[6] Trivedi MH, Desaiah D, Ossanna MJ, et al.Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine[J].Int Clin Psychopharmacol,2008,23(3):161-9.

[7] Bandelow B, Baldwin D, Abelli M, et al.Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition[J].World J Biol Psychiatry,2017,18(3):162-214.

[8] Pittig A, Arch JJ, Lam CW, et al.Heart rate and heart rate variability in panic, social anxiety, obsessive-compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation[J].Int J Psychophysiol,2013,87(1):19-27.

[9] Kim K, Lee S, Kim JH. Diminished autonomic neurocardiac function in patients with generalized anxiety disorder[J].Neuropsychiatr Dis Treat,2016,12:3111-3118.

[10] Shinba T. Major depressive disorder and generalized anxiety disorder show different autonomic dysregulations revealed by heart-rate variability analysis in first-onset drug-naive patients without comorbidity[J].Psychiatry Clin Neurosci,2017,71(2):135-145.

[11] Hammel JC, Smitherman TA, McGlynn FD, et al.Vagal influence during worry and cognitive challenge[J].Anxiety Stress Coping,2011,24(2):121-136.

[12] Fisher AJ, Newman MG, Heart rate and autonomic response to stress after experimental induction of worry versus relaxation in healthy, high-worry, and generalized anxiety disorder individuals[J].Biol Psychol,2013,93(1):65-74.

[13] Levine JC, Fleming R, Piedmont JI, et al.Heart rate variability and generalized anxiety disorder during laboratory-induced worry and aversive imagery[J].J Affect Disord,2016, 205:207-215.

[14] Seeley SH, Mennin DS, Aldao A, et al.Impact of comorbid depressive disorders on subjective and physiological responses to emotion in generalized anxiety disorder[J].Cognit Ther Res,2016,40(30):290-303.

[15] Chang HA, Chang CC, Chen CL, et al.Major depression is associated with cardiac autonomic dysregulation[J].Acta Neuropsychiatr,2012,24(6):318-327.

[16] Kessler RC, Du Pont RL, Berglund P, et al.Impairment in pure and comorbid generalized anxiety disorder and major depression at 12 months in two national surveys[J].Am J Psychiatry,1999,156(12):1915-1923.

[17] Hofmann SG, Schulz SM, Heering S, et al.Psychophysiological correlates of generalized anxiety disorder with or without comorbid depression[J].Int J Psychophysiol,2010,78(1):35-41.

[18] Kemp AH, Fraguas R, Brunoni AR, et al.Differential associations of specific selective serotonin reuptake inhibitors with resting-state heart rate and heart rate variability: Implications for Health and Well-Being[J].Psychosom Med,2016,78(7):810-818.

[19] Licht CM, de Geus EJ, van Dyck R, et al.Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability[J].Biol Psychiatry,2010,68(9):861-868.

[20] Kemp AH, Brunoni AR, Santos IS, et al.Effects of depression, anxiety, comorbidity, and antidepressants on resting-state heart rate and its variability: an ELSA-Brasil cohort baseline study[J].Am J Psychiatry,2014,171(12):1328-1334.

[21] Agelink MW, Majewski TB, Andrich J, et al.Short-term effects of intravenous benzodiazepines on autonomic neurocardiac regulation in humans: a comparison between midazolam, diazepam, and lorazepam[J].Crit Care Med,2002,30(5):997-1006.

[22] Prasko J, Latalova K, Diveky T, et al.Panic disorder, autonomic nervous system and dissociation-changes during therapy[J].Neuro Endocrinol Lett,2011,32(5):641-651.

[23] Chang HA, Chang CC, Tzeng NS, et al.Generalized anxiety disorder, comorbid major depression and heart rate variability: a case-control study in taiwan[J].Psychiatry Investig,2013,10(4):326-335.

[24] Hamer M, Batty GD, Seldenrijk A, et al.Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey[J].Eur Heart J,2011,32(4):437-342.

[25] Middlekauff HR, Park J, Moheimani RS. Adverse effects of cigarette and noncigarette smoke exposure on the autonomic nervous system: mechanisms and implications for cardiovascular risk[J].J Am Coll Cardiol,2014,64(16):1740-1750.

[26] Probst-Hensch NM, Imboden M, Felber Dietrich D, et al.Glutathione S-transferase polymorphisms, passive smoking, obesity, and heart rate variability in nonsmokers[J].Environ Health Perspect,2008,116(11):1494-1499.

[27] Kim CS, Kim MK, Jung HY, et al.Effects of exercise training intensity on cardiac autonomic regulation in habitual smokers[J].Ann Noninvasive Electrocardiol,2017,22(5). doi: 10.1111/anec.12434.