老年2型糖尿病患者下肢周圍動脈病變與心率變異率相關性分析

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圍動脈病變與心率變異率相關性分析

于 玲1，楊 磊2，宋彬彬3，王永慧1，李連霞1，高 珊1*

（首都醫科大學附屬北京朝陽醫院西區：1內分泌科，3心電圖室，北京 100045；2首都醫科大學附屬北京朝陽醫院神經內科，北京 100020）

探討老年2型糖尿病患者（≥60歲）下肢周圍動脈病變（PAD）與心率變異率（HRV）的關系。選擇2012年6月至2014年7月在首都醫科大學附屬北京朝陽醫院西區內分泌科住院的128例老年2型糖尿病患者，根據有無PAD（ABI＜0.9定義為PAD）分為兩組。測定體質量指數（BMI）、血壓、血脂、周圍神經病變、尿微量白蛋白（UAER）、雙下肢踝肱指數（ABI）和動態心電圖，由儀器自動分析計算出HRV各項時域及頻域指標。對兩組間各項指標進行統計學分析。共128例患者，其中90例無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及高血壓發生率均高于無PAD組（＜0.05）。PAD組患者HRV指標下降，包括大部分時域指標SDNN、SDNN-index、SDANN及頻域指標低頻功率、高頻功率。校正年齡、糖尿病病程、HbA1c、TG、UAER、高血壓后，HRV指標與PAD程度呈負相關。老年2型糖尿病合并PAD者具有更低的HRV，表明心臟自主神經系統調節能力下降。

糖尿病，2型；老年人；下肢周圍動脈病變；心率變異率

下肢周圍動脈病變（peripheral artery disease，PAD）是糖尿病的常見慢性并發癥之一，既是全身血管病變的一個局部反映，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，嚴重影響著患者生活和生存質量。踝肱指數（ankle brachial index，ABI）指踝動脈壓與肱動脈壓的比值，是篩查和診斷PAD的一種簡便、有效、無創的方法，ABI值的異常提示患者存在下肢閉塞性動脈粥樣硬化性疾病。心臟自主神經病變（cardiac autonomic neuropathy，CAN）也是糖尿病重要的慢性并發癥之一，當病變累及交感神經而表現為體位性低血壓時，臨床預后不良，可發生猝死[2]。糖尿病患者常存在多種代謝紊亂，高血糖、脂代謝紊亂、氧化應激反應增加等均為神經和血管并發癥發生的共同基礎。目前，關于老年2型糖尿?。╰ype 2 diabetes mellitus，T2DM）患者PAD與心率變異率（heart rate variability，HRV）的研究較少，為研究二者之間關系，我們通過分析合并或不合并PAD的T2DM患者的HRV指標，以及不同程度的HRV指標間PAD的發生率，探討兩者間的關系。

1 對象與方法

1.1 研究對象

選擇2012年6月至2014年7月在首都醫科大學附屬北京朝陽醫院西區內分泌科住院的老年T2DM患者128例，均符合1999年WHO糖尿病診斷標準，既往無冠心病史，伴或不伴有四肢肢端麻木、便秘等神經病變的臨床表現，排除嚴重的肝腎疾病、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個月。

1.2 檢測指標

檢測并記錄年齡、性別、糖尿病病程、身高、體質量、吸煙、血壓、糖尿病性周圍神經病變（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，FBG）、空腹胰島素（fasting insulin，FINS）。

DPN由MEDELEC肌電圖誘發電位系統（英國牛津）測定，診斷標準參照2010年《中國T2DM防治指南》中的規定：明確的糖尿病病史；在診斷糖尿病時或之后出現的神經病變；臨床癥狀和體征與DPN的表現相符；以下4項檢查中如果任1項異常則診斷為DPN：（1）踝反射異常（或踝反射正常、膝反射異常）；（2）針刺痛覺異常；（3）振動覺異常；（4）壓力覺異常。本研究中各患者均行雙下肢神經傳導速度檢測協助診斷[3]。

1.3 HRV測定

全部患者行24h動態心電圖檢查，記錄其24h心電變化，由儀器自動分析計算出HRV各項時域及頻域指標，時域指標包括：正常R-R間期標準差（standard deviation of the R-R intervals，SDNN），每5min R-R間期均值標準差（standard deviation of averages of R-R intervals calculated in 5-min segments，SDANN），每5min正常R-R間期均值標準差（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）。將各指標分別?。?3%為1st組，33%～67%為2nd組，＞67%為3rd組，觀察各組中PAD的發生率。

1.4 ABI的測定

用ES-1000 SPM多普勒血流探測儀測定。根據心血管和介入放射學協會（Society of Cardiovascular and Interventional Radiology，SCVIR）標準[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脈處獲取信號，測得雙側肱動脈收縮壓（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脈、足背動脈處獲取信號，測得踝動脈收縮壓（ankle systolic blood pressure，ASBP），取其高值，ASBP高值/BSBP高值即為ABI，相同方法測對側肢體。按2011年美國心臟病學會基金會（American College of Cardiology Foundation，ACCF）及美國心臟聯合會（American Heart Association，AHA）的標準[5]測定ABI，雙側脛后或足背動脈ABI有1項＜0.9，為PAD組，取4個ABI數值中最小的一個納入研究，雙側ABI中有1項＜0.9，即選入PAD組。ABI均≥0.9者選入非PAD組。

1.5 統計學處理

2 結 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，TG、高血壓發生率、HbA1c及UAER更高，上述指標差異均具有統計學意義（＜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各項指標比較

兩組患者HRV時域指標：SDNN、SDANN、SDNN-index差異均具有統計學意義（＜0.01）；PNN50、RMSSD差異無統計學意義（＞0.05）；兩組患者HRV頻域指標：LF、HF差異均具有統計學意義（＜0.05），LF/HF差異無統計學意義（＞0.05；表2）。

圖1結果表明SDNN、SDANN、SDNN-index、LF中各自1st組PAD發生率＞3rd組，差異有統計學意義（＜0.05），即在HRV越低的組PAD的發生率相對更高。

表2 兩組糖尿病患者HRV各指標比較

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與否與各指標進行多因素相關及回歸分析

Spearman相關分析顯示，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各指標與ABI呈負相關（＜0.05）。結果如下：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取三分位后分為3組行logistic回歸，除HF1st與3rd組比較差異無統計學意義外，各指標1st組與3rd組比較差異均有統計學意義（＜0.05），即SDNN、SDNN-index、SDANN、LF中各自1st組PAD發生率均＞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，糖尿病發病率明顯增高，成為影響人類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。國內有報道顯示,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可預防糖尿病足壞疽乃至截肢的發生[7]。應用較廣的ABI測定，其操作方法簡單、費用低、無創傷。隨著研究的深入，我們進一步發現，ABI除了能作為較為準確的下肢動脈硬化閉塞癥的篩選性檢查外，同時也是動脈粥樣硬化所造成心血管事件率的新的危險預測因子。以ABI＜0.9診斷為周圍動脈疾病，其敏感度和特異度均為95%[8]。

糖尿病下肢動脈硬化的發病原因涉及許多方面，發病機制比較復雜，是多種因素長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、血糖控制差、TG高、高血壓發生率高、UAER高等特點。大量研究證據支持餐后血糖持續升高與血管病變密切相關[9,10]。血脂異常、高血壓是公認的動脈硬化的危險因素。UAER的升高也是導致動脈硬化的危險因素，在T2DM患者伴微量白蛋白尿的階段，已存在廣泛的內皮細胞功能紊亂，血漿蛋白可通過受損的內皮細胞滲透至血管內膜下，促進動脈硬化的發生[11]。

糖尿病自主神經病變是糖尿病最常見的并發癥之一，因診斷標準不盡相同，文獻報道其發生率為2.5%～40.0%[12]。糖尿病患者發生CAN，使惡性心律失常、心絞痛、無痛性心肌梗死、心力衰竭、心源性休克、卒中、運動耐力下降等發生率上升，猝死發生率明顯增加[12?16]。HRV有時域分析和頻域分析兩種指標，臨床應用較多的為時域指標。一般認為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，反映了交感神經的功能，RMSSD和PNN50代表心率速度變化的成分，反映了迷走神經功能。頻域分析中高頻功率反映迷走神經調節功能，低頻功率與壓力反射調節有關，它反映交感和副交感神經系統對竇房結的復合調節作用[17,18]。通常認為糖尿病患者發生CAN時早期表現為副交感神經的損害，患者表現為靜息時心率增快，而體位性低血壓是晚期交感神經病變的表現。

本研究中合并與未合并PAD的患者相比，HRV除RMSSD、PNN50外各指標均低于無PAD者，差異均有統計學意義（＜0.05）。在校正年齡、性別、病程、HbA1c、TG、UREA后，HRV各指標仍與PAD呈負相關。HRV取三分位后，除HF外，各1st組（即心率變異率越低組）PAD的發生率高于3rd組，差異有統計學意義（＜0.05）。文獻報道長期血糖升高者血管活性因子產生減少，血液的高凝狀態以及糖、蛋白質、脂肪代謝紊亂均造成動脈粥樣硬化和微血管病變，神經缺血及營養障礙導致自主神經功能損害[19]。國外文獻也指出，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[20?22]。以PAD為因變量，各因素進入logistic回歸方程后，SDNN、SDNN-index、SDANN、LF與其獨立相關，OR＞1。說明HRV與PAD的發生獨立相關。目前國內外有關下肢動脈硬化與心率變異之間的相關性研究較少。在1型糖尿病患者中發現下肢動脈硬化與自主神經病變獨立相關[23]。Canani等[24]發現在T2DM患者中下肢動脈硬化與自主神經病變獨立相關，與本文觀察到的結果一致。

臨床上我們對老年糖尿病患者動脈硬化的篩查更為關注，而自主神經及心率變異檢測方面相對不足。在老年T2DM患者中，若出現下肢動脈硬化者，應加強對其HRV的監測，及早干預，以防止心臟等不良事件的發生，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，還需大樣本資料對二者的關系進行進一步研究。

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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