于 玲，楊 磊，宋彬彬，王永慧，李連霞，高 珊*

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老年2型糖尿病患者下肢周?chē)鷦?dòng)脈病變與心率變異率相關(guān)性分析

于 玲1，楊 磊2，宋彬彬3，王永慧1，李連霞1，高 珊1*

（首都醫(yī)科大學(xué)附屬北京朝陽(yáng)醫(yī)院西區(qū)：1內(nèi)分泌科，3心電圖室，北京 100045；2首都醫(yī)科大學(xué)附屬北京朝陽(yáng)醫(yī)院神經(jīng)內(nèi)科，北京 100020）

探討老年2型糖尿病患者（≥60歲）下肢周?chē)鷦?dòng)脈病變（PAD）與心率變異率（HRV）的關(guān)系。選擇2012年6月至2014年7月在首都醫(yī)科大學(xué)附屬北京朝陽(yáng)醫(yī)院西區(qū)內(nèi)分泌科住院的128例老年2型糖尿病患者，根據(jù)有無(wú)PAD（ABI＜0.9定義為PAD）分為兩組。測(cè)定體質(zhì)量指數(shù)（BMI）、血壓、血脂、周?chē)窠?jīng)病變、尿微量白蛋白（UAER）、雙下肢踝肱指數(shù)（ABI）和動(dòng)態(tài)心電圖，由儀器自動(dòng)分析計(jì)算出HRV各項(xiàng)時(shí)域及頻域指標(biāo)。對(duì)兩組間各項(xiàng)指標(biāo)進(jìn)行統(tǒng)計(jì)學(xué)分析。共128例患者，其中90例無(wú)PAD、38例合并PAD。2型糖尿病合并PAD組年齡、糖尿病病程、糖化血紅蛋白（HbA1c）、甘油三酯（TG）、UAER及高血壓發(fā)生率均高于無(wú)PAD組（＜0.05）。PAD組患者HRV指標(biāo)下降，包括大部分時(shí)域指標(biāo)SDNN、SDNN-index、SDANN及頻域指標(biāo)低頻功率、高頻功率。校正年齡、糖尿病病程、HbA1c、TG、UAER、高血壓后，HRV指標(biāo)與PAD程度呈負(fù)相關(guān)。老年2型糖尿病合并PAD者具有更低的HRV，表明心臟自主神經(jīng)系統(tǒng)調(diào)節(jié)能力下降。

糖尿病，2型；老年人；下肢周?chē)鷦?dòng)脈病變；心率變異率

下肢周?chē)鷦?dòng)脈病變（peripheral artery disease，PAD）是糖尿病的常見(jiàn)慢性并發(fā)癥之一，既是全身血管病變的一個(gè)局部反映，又是造成糖尿病足潰瘍、壞疽乃至截肢的主要原因[1]，其病情重、致殘致死率高，嚴(yán)重影響著患者生活和生存質(zhì)量。踝肱指數(shù)（ankle brachial index，ABI）指踝動(dòng)脈壓與肱動(dòng)脈壓的比值，是篩查和診斷PAD的一種簡(jiǎn)便、有效、無(wú)創(chuàng)的方法，ABI值的異常提示患者存在下肢閉塞性動(dòng)脈粥樣硬化性疾病。心臟自主神經(jīng)病變（cardiac autonomic neuropathy，CAN）也是糖尿病重要的慢性并發(fā)癥之一，當(dāng)病變累及交感神經(jīng)而表現(xiàn)為體位性低血壓時(shí)，臨床預(yù)后不良，可發(fā)生猝死[2]。糖尿病患者常存在多種代謝紊亂，高血糖、脂代謝紊亂、氧化應(yīng)激反應(yīng)增加等均為神經(jīng)和血管并發(fā)癥發(fā)生的共同基礎(chǔ)。目前，關(guān)于老年2型糖尿病（type 2 diabetes mellitus，T2DM）患者PAD與心率變異率（heart rate variability，HRV）的研究較少，為研究二者之間關(guān)系，我們通過(guò)分析合并或不合并PAD的T2DM患者的HRV指標(biāo)，以及不同程度的HRV指標(biāo)間PAD的發(fā)生率，探討兩者間的關(guān)系。

1 對(duì)象與方法

1.1 研究對(duì)象

選擇2012年6月至2014年7月在首都醫(yī)科大學(xué)附屬北京朝陽(yáng)醫(yī)院西區(qū)內(nèi)分泌科住院的老年T2DM患者128例，均符合1999年WHO糖尿病診斷標(biāo)準(zhǔn)，既往無(wú)冠心病史，伴或不伴有四肢肢端麻木、便秘等神經(jīng)病變的臨床表現(xiàn)，排除嚴(yán)重的肝腎疾病、靜脈曲張、急性感染性疾病、酮癥等。其中，男69例，女59例，年齡63～83歲，病程6～348個(gè)月。

1.2 檢測(cè)指標(biāo)

檢測(cè)并記錄年齡、性別、糖尿病病程、身高、體質(zhì)量、吸煙、血壓、糖尿病性周?chē)窠?jīng)病變（diabetic peripheral neuropathy，DPN）、糖化血紅蛋白（glycosylated hemoglobin A1c，HbA1c）、血肌酐（serum creatinine，SCr）、血尿酸（serum uric acid，SUA）、總膽固醇（total cholesterol，TC）、甘油三酯（triglycerides，TG）、高密度脂蛋白膽固醇（high-density lipoprotein cholesterol，HDL-C）、低密度脂蛋白膽固醇（low-density lipoprotein cholesterol，LDL-C）、尿白蛋白排泄率（urinary albumin excretion rate，UAER）、空腹血糖（fasting blood glucose，F(xiàn)BG）、空腹胰島素（fasting insulin，F(xiàn)INS）。

DPN由MEDELEC肌電圖誘發(fā)電位系統(tǒng)（英國(guó)牛津）測(cè)定，診斷標(biāo)準(zhǔn)參照2010年《中國(guó)T2DM防治指南》中的規(guī)定：明確的糖尿病病史；在診斷糖尿病時(shí)或之后出現(xiàn)的神經(jīng)病變；臨床癥狀和體征與DPN的表現(xiàn)相符；以下4項(xiàng)檢查中如果任1項(xiàng)異常則診斷為DPN：（1）踝反射異常（或踝反射正常、膝反射異常）；（2）針刺痛覺(jué)異常；（3）振動(dòng)覺(jué)異常；（4）壓力覺(jué)異常。本研究中各患者均行雙下肢神經(jīng)傳導(dǎo)速度檢測(cè)協(xié)助診斷[3]。

1.3 HRV測(cè)定

全部患者行24h動(dòng)態(tài)心電圖檢查，記錄其24h心電變化，由儀器自動(dòng)分析計(jì)算出HRV各項(xiàng)時(shí)域及頻域指標(biāo)，時(shí)域指標(biāo)包括：正常R-R間期標(biāo)準(zhǔn)差（standard deviation of the R-R intervals，SDNN），每5min R-R間期均值標(biāo)準(zhǔn)差（standard deviation of averages of R-R intervals calculated in 5-min segments，SDANN），每5min正常R-R間期均值標(biāo)準(zhǔn)差（mean of the standard deviation of R-R intervals calculated in 5-min segments，SDNN-index），相鄰正常R-R間期差值均方根值（root mean square of successive differences of adjacent R-R intervals，RMSSD），相鄰正常R-R間期＞50ms百分比（percentage of differences between adjacent R-R intervals＞50ms，PNN50）。頻域指標(biāo)包括：低頻功率（0.04～0.15Hz，low frequency，LF）、高頻功率（0.15～0.40Hz，high frequency，HF）、低頻/高頻（LF/HF）。將各指標(biāo)分別?。?3%為1st組，33%～67%為2nd組，＞67%為3rd組，觀察各組中PAD的發(fā)生率。

1.4 ABI的測(cè)定

用ES-1000 SPM多普勒血流探測(cè)儀測(cè)定。根據(jù)心血管和介入放射學(xué)協(xié)會(huì)（Society of Cardiovascular and Interventional Radiology，SCVIR）標(biāo)準(zhǔn)[4]，檢查前，患者休息10～15min，室溫下，仰臥位，分別置袖帶于雙上臂，用多普勒探頭于肘部肱動(dòng)脈處獲取信號(hào)，測(cè)得雙側(cè)肱動(dòng)脈收縮壓（brachial systolic blood pressure，BSBP），取兩者中的高值，置相同的袖帶于踝部，用多普勒探頭于脛后動(dòng)脈、足背動(dòng)脈處獲取信號(hào)，測(cè)得踝動(dòng)脈收縮壓（ankle systolic blood pressure，ASBP），取其高值，ASBP高值/BSBP高值即為ABI，相同方法測(cè)對(duì)側(cè)肢體。按2011年美國(guó)心臟病學(xué)會(huì)基金會(huì)（American College of Cardiology Foundation，ACCF）及美國(guó)心臟聯(lián)合會(huì)（American Heart Association，AHA）的標(biāo)準(zhǔn)[5]測(cè)定ABI，雙側(cè)脛后或足背動(dòng)脈ABI有1項(xiàng)＜0.9，為PAD組，取4個(gè)ABI數(shù)值中最小的一個(gè)納入研究，雙側(cè)ABI中有1項(xiàng)＜0.9，即選入PAD組。ABI均≥0.9者選入非PAD組。

1.5 統(tǒng)計(jì)學(xué)處理

2 結(jié) 果

2.1 PAD組與非PAD組患者一般資料的比較

128例老年T2DM患者中ABI＜0.9者占38例，非PAD組90例。與非PAD組比較，PAD組年齡更大，病程更長(zhǎng)，TG、高血壓發(fā)生率、HbA1c及UAER更高，上述指標(biāo)差異均具有統(tǒng)計(jì)學(xué)意義（＜0.05；表1）。

表1 兩組T2DM患者臨床資料比較

T2DM: type 2 diabetes mellitus; PAD: peripheral artery disease; DM: diabetes mellitus; BMI: body mass index; ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; CCB: calcium channel blocker; DPN: diabetic peripheral neuropathy; HbA1c: glycosylated hemoglobin A1c; SCr: serum creatinine; SUA: serum uric acid; TC: total cholesterol; TG: triglycerides; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; UAER: urinary albumin excretion rate; FBG: fasting blood glucose; FINS: fasting insulin. Compared with without PAD group,*＜0.05,**＜0.01

2.2 兩組患者HRV各項(xiàng)指標(biāo)比較

兩組患者HRV時(shí)域指標(biāo)：SDNN、SDANN、SDNN-index差異均具有統(tǒng)計(jì)學(xué)意義（＜0.01）；PNN50、RMSSD差異無(wú)統(tǒng)計(jì)學(xué)意義（＞0.05）；兩組患者HRV頻域指標(biāo)：LF、HF差異均具有統(tǒng)計(jì)學(xué)意義（＜0.05），LF/HF差異無(wú)統(tǒng)計(jì)學(xué)意義（＞0.05；表2）。

圖1結(jié)果表明SDNN、SDANN、SDNN-index、LF中各自1st組PAD發(fā)生率＞3rd組，差異有統(tǒng)計(jì)學(xué)意義（＜0.05），即在HRV越低的組PAD的發(fā)生率相對(duì)更高。

表2 兩組糖尿病患者HRV各指標(biāo)比較

PAD: peripheral artery disease; HRV: heart rate variability; SDNN: standard deviation of the R-R intervals; SDNN-index: mean of the standard deviation of R-R intervals calculated in 5-min segments; SDANN: standard deviation of averages of R-R intervals calculated in 5-min segments; RMSSD: root mean square of successive differences of adjacent R-R intervals; PNN50: percentage of differences between adjacent R-R intervals＞50ms; LF: low frequency; HF: high frequency. Compared with without PAD group,*＜0.05,**＜0.01

圖1 SDNN、SDANN、SDNN-index、LF、HF各取三分位后PAD的發(fā)生率

Figure 1 The incidence of PAD categorized by tertiles of SDNN, SDANN, SDNN-index, LF, and HF

PAD: peripheral artery disease; SDNN: standard deviation of the R-R intervals; SDANN: standard deviation of the averages of R-R intervalscalculated in 5-min segments; SDNN-index: mean of the standard deviation of the R-R intervals calculated in 5-min segments; LF: low frequency; HF: high frequency. The 1st group:＜33%; the 2nd group: 33?67%; the 3rd group:＞67%. Compared with the 3rd group,*＜0.05

2.3 PAD與否與各指標(biāo)進(jìn)行多因素相關(guān)及回歸分析

Spearman相關(guān)分析顯示，校正年齡、性別、糖尿病病程、HbA1c、TG、UAER、高血壓后，所有患者大部分HRV各指標(biāo)與ABI呈負(fù)相關(guān)（＜0.05）。結(jié)果如下：SDNN（＝-0.347，＜0.01）、SDNN-index（＝-0.287，＜0.01）、SDANN（＝-0.370，＜0.01）、LF（＝-0.192，＜0.05），HF（＝-0.180，＜0.05）；上述各心率變異率指標(biāo)取三分位后分為3組行l(wèi)ogistic回歸，除HF1st與3rd組比較差異無(wú)統(tǒng)計(jì)學(xué)意義外，各指標(biāo)1st組與3rd組比較差異均有統(tǒng)計(jì)學(xué)意義（＜0.05），即SDNN、SDNN-index、SDANN、LF中各自1st組PAD發(fā)生率均＞3rd組，OR值分別為5.149、3.100、6.727、2.643（表3）。

表3 多元logistic回歸：HRV取三分位后作為自變量，PAD與否為因變量

PAD: peripheral artery disease; HRV: heart rate variability; SDNN: standard deviation of the R-R intervals; SDNN-index: mean of the standard deviation of R-R intervals calculated in 5-min segments; SDANN: standard deviation of averages of R-R intervals calculated in 5-min segments; LF: low frequency; HF: high frequency. The odds ratio was adjusted for age, diabetic duration, hypertension, HbA1c, TG, and UAER in each model; upper index tertile (3rd) for each index was considered as the reference (OR＝1)

3 討 論

近年來(lái)，糖尿病發(fā)病率明顯增高，成為影響人類(lèi)健康的重要慢性疾病。糖尿病合并PAD是糖尿病患者下肢截肢致殘的主要原因。國(guó)內(nèi)有報(bào)道顯示,糖尿病患者下肢截肢率比正常人高5～15倍[6]。早期診斷和治療PAD可預(yù)防糖尿病足壞疽乃至截肢的發(fā)生[7]。應(yīng)用較廣的ABI測(cè)定，其操作方法簡(jiǎn)單、費(fèi)用低、無(wú)創(chuàng)傷。隨著研究的深入，我們進(jìn)一步發(fā)現(xiàn)，ABI除了能作為較為準(zhǔn)確的下肢動(dòng)脈硬化閉塞癥的篩選性檢查外，同時(shí)也是動(dòng)脈粥樣硬化所造成心血管事件率的新的危險(xiǎn)預(yù)測(cè)因子。以ABI＜0.9診斷為周?chē)鷦?dòng)脈疾病，其敏感度和特異度均為95%[8]。

糖尿病下肢動(dòng)脈硬化的發(fā)病原因涉及許多方面，發(fā)病機(jī)制比較復(fù)雜，是多種因素長(zhǎng)期綜合性作用引起的。在本文所觀察的病例中，合并PAD的老年糖尿病患者具有高齡、病程長(zhǎng)、血糖控制差、TG高、高血壓發(fā)生率高、UAER高等特點(diǎn)。大量研究證據(jù)支持餐后血糖持續(xù)升高與血管病變密切相關(guān)[9,10]。血脂異常、高血壓是公認(rèn)的動(dòng)脈硬化的危險(xiǎn)因素。UAER的升高也是導(dǎo)致動(dòng)脈硬化的危險(xiǎn)因素，在T2DM患者伴微量白蛋白尿的階段，已存在廣泛的內(nèi)皮細(xì)胞功能紊亂，血漿蛋白可通過(guò)受損的內(nèi)皮細(xì)胞滲透至血管內(nèi)膜下，促進(jìn)動(dòng)脈硬化的發(fā)生[11]。

糖尿病自主神經(jīng)病變是糖尿病最常見(jiàn)的并發(fā)癥之一，因診斷標(biāo)準(zhǔn)不盡相同，文獻(xiàn)報(bào)道其發(fā)生率為2.5%～40.0%[12]。糖尿病患者發(fā)生CAN，使惡性心律失常、心絞痛、無(wú)痛性心肌梗死、心力衰竭、心源性休克、卒中、運(yùn)動(dòng)耐力下降等發(fā)生率上升，猝死發(fā)生率明顯增加[12?16]。HRV有時(shí)域分析和頻域分析兩種指標(biāo)，臨床應(yīng)用較多的為時(shí)域指標(biāo)。一般認(rèn)為SDNN代表總體的心率變異程度，SDANN和SDNN-index代表心率緩慢變化的成分，反映了交感神經(jīng)的功能，RMSSD和PNN50代表心率速度變化的成分，反映了迷走神經(jīng)功能。頻域分析中高頻功率反映迷走神經(jīng)調(diào)節(jié)功能，低頻功率與壓力反射調(diào)節(jié)有關(guān)，它反映交感和副交感神經(jīng)系統(tǒng)對(duì)竇房結(jié)的復(fù)合調(diào)節(jié)作用[17,18]。通常認(rèn)為糖尿病患者發(fā)生CAN時(shí)早期表現(xiàn)為副交感神經(jīng)的損害，患者表現(xiàn)為靜息時(shí)心率增快，而體位性低血壓是晚期交感神經(jīng)病變的表現(xiàn)。

本研究中合并與未合并PAD的患者相比，HRV除RMSSD、PNN50外各指標(biāo)均低于無(wú)PAD者，差異均有統(tǒng)計(jì)學(xué)意義（＜0.05）。在校正年齡、性別、病程、HbA1c、TG、UREA后，HRV各指標(biāo)仍與PAD呈負(fù)相關(guān)。HRV取三分位后，除HF外，各1st組（即心率變異率越低組）PAD的發(fā)生率高于3rd組，差異有統(tǒng)計(jì)學(xué)意義（＜0.05）。文獻(xiàn)報(bào)道長(zhǎng)期血糖升高者血管活性因子產(chǎn)生減少，血液的高凝狀態(tài)以及糖、蛋白質(zhì)、脂肪代謝紊亂均造成動(dòng)脈粥樣硬化和微血管病變，神經(jīng)缺血及營(yíng)養(yǎng)障礙導(dǎo)致自主神經(jīng)功能損害[19]。國(guó)外文獻(xiàn)也指出，高血壓、胰島素抵抗、肥胖、高TG、吸煙、中心性肥胖等均與糖尿病患者HRV下降有關(guān)[20?22]。以PAD為因變量，各因素進(jìn)入logistic回歸方程后，SDNN、SDNN-index、SDANN、LF與其獨(dú)立相關(guān)，OR＞1。說(shuō)明HRV與PAD的發(fā)生獨(dú)立相關(guān)。目前國(guó)內(nèi)外有關(guān)下肢動(dòng)脈硬化與心率變異之間的相關(guān)性研究較少。在1型糖尿病患者中發(fā)現(xiàn)下肢動(dòng)脈硬化與自主神經(jīng)病變獨(dú)立相關(guān)[23]。Canani等[24]發(fā)現(xiàn)在T2DM患者中下肢動(dòng)脈硬化與自主神經(jīng)病變獨(dú)立相關(guān)，與本文觀察到的結(jié)果一致。

臨床上我們對(duì)老年糖尿病患者動(dòng)脈硬化的篩查更為關(guān)注，而自主神經(jīng)及心率變異檢測(cè)方面相對(duì)不足。在老年T2DM患者中，若出現(xiàn)下肢動(dòng)脈硬化者，應(yīng)加強(qiáng)對(duì)其HRV的監(jiān)測(cè)，及早干預(yù)，以防止心臟等不良事件的發(fā)生，減少糖尿病患者的死亡率。由于本研究樣本量較少，在今后的研究中，還需大樣本資料對(duì)二者的關(guān)系進(jìn)行進(jìn)一步研究。

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（編輯: 周宇紅）

Correlation of lower extremities peripheral arterial disease and heart rate variability in elderly patients with type 2 diabetes mellitus

YU Ling1, YANG Lei2, SONG Bin-Bin3, WANG Yong-Hui1, LI Lian-Xia1, GAO Shan1*

(1Department of Endocrinology,3Department of Electrocardiography, Jingxi Branch, Beijing Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100045, China;2Department of Neurology, Beijing Chaoyang Hospital, Capital University of Medical Sciences, Beijing 100020, China)

To investigate the correlation of lower extremities peripheral arterial disease (PAD) and heart rate variability (HRV) in the elderly patients (over 60 years) with type 2 diabetes mellitus (T2DM).A total of 128 T2DM patients admitted to our hospital from June 2012 to July 2014 were included in this study. All subjects were divided into 2 groups according to having PAD or not [ankle brachial index (ABI)＜0.9 defined as PAD]. Their body mass index (BMI), blood pressure, serum lipids, peripheral neuropathy, urinary albumin excretion rate (UAER), ABI and HRV were measured and analyzed.In the 128 T2DM patients, there were 90 patients having no PDA and 38 having. Those with PAD had older age, longer diabetes duration, higher UAER, higher incidence of hypertension, and higher levels of HbA1c and triglycerides (TG) than the patients without PAD (＜0.05). And they had lower HRV indices, including those in time domain, such as, the standard deviation of the R-R intervals (SDNN), mean of the standard deviation of the R-R intervals calculated in 5-min segments (SDNN-index) and the standard deviation of the averages of R-R intervals (SDANN), and those infrequency domain, high-frequency activity and low-frequency activity, for example. After adjustment for age, diabetes duration, UAER, levels of HbA1c and TG, and incidence of hypertension, HRV indices were negatively correlated with the severity of PAD.In the cohort of the elderly T2DM patients, those with PAD have lower HRV indices than those without, suggesting a dysfunction of cardiovascular autonomic regulation.

diabetes mellitus, type 2; elderly; peripheral artery disease, lower extremities; heart rate variability

R592; R587.1

A

10.11915/j.issn.1671?5403.2015.01.013

2014?09?29;

2014?11?15

高 珊, E-mail: gaoshanmw@163.com