High Ankle–Brachial Index Indicates Cardiovascular and Peripheral Arterial Disease in Patients With Type 2 Diabetes

Angiology 1-7 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0003319715573657 ang.sagepub.com

Qing Li, MD1, Hui Zeng, BS1, Fang Liu, MD, PhD1, Jing Shen, MD1, Lianxi Li, MD, PhD1, Jungong Zhao, MD, PhD2, Jun Zhao, MD, PhD3, and Weiping Jia, MD, PhD1

Abstract We assessed the association between high ankle–brachial index (ABI) and cardiovascular disease (CVD) and peripheral arterial disease (PAD) in Chinese patients with type 2 diabetes mellitus (T2DM). The ABI was measured, and foot inspection was performed in 2080 outpatients with T2DM. The clinical characters in different ABI levels were analyzed, and the diagnostic value of high ABI to CVD and PAD was determined. Compared with the normal ABI group, the high ABI (>1.3) group had a higher prevalence of CVD and PAD but less than the low ABI (0.9) group. High ABI was an independent risk factor for the development of CVD and PAD. Receiver–operating characteristic curve analysis showed that the optimal cutoff of high ABI to predict CVD and PAD was 1.43 and 1.45, respectively. The odds ratio of high ABI for CVD and PAD was 2.25 and 6.97, respectively, after adjusting for other confounding risk factors. In conclusion, high ABI indicated the risk of CVD and PAD in Chinese populations with T2DM. Keywords ankle–brachial index, type 2 diabetes, cardiovascular disease, peripheral arterial disease

Introduction The ankle–brachial index (ABI) is the ratio of the systolic blood pressure (BP) in the lower extremities (posterior tibial artery or dorsalis pedis artery) to the BP in the arms.1 It is an accurate, simple, and noninvasive measurement for the screening of lower extremity arterial disease and is considered to be the most accurate noninvasive diagnostic method for peripheral arterial disease (PAD) and its assessment.2 More evidence indicated that PAD was associated with an increased incidence of coronary artery disease (CAD), which was independent of the presence of other cardiovascular risk factors. A low ABI (0.9) is a predictor of cardiovascular diseases (CVD),3,4 but an abnormally elevated ABI was also associated with increased CVD risk.5-10 In a study of 16 493 outpatients identified by noninvasive lower extremity arterial testing, 17% had poorly compressible lower extremity arteries, defined as an ABI 1.4 and/or an ankle systolic BP >255 mm Hg.11 Patients with high ABI had poor survival, worse than those with a normal ABI or low ABI.11 A high ABI is more prevalent than previously recognized and carries important prognostic implications. Patients with type 2 diabetes mellitus (T2DM) are at higher risk of macrovascular disease, particularly CAD, cerebrovascular disease, and PAD. A high ABI may have equally important clinical value in the diagnosis of CVD and PAD in diabetic patients. However, to date, there are limited studies on the

prevalence of CVD and PAD in diabetic patients with high ABI, especially for Chinese patients with T2DM. Therefore, we evaluated the clinical characteristics associated with high ABI and its diagnostic value for CVD and PAD in Chinese patients diagnosed with T2DM.

Patients and Methods Patients A total of 2188 outpatients with T2DM were recruited for this cross-sectional study (through random sampling of a natural population) consecutively from the population attending the 1

Department of Endocrinology & Metabolism, Shanghai Jiao-Tong University Affiliated Sixth People’s Hospital, Shanghai Clinical Medical Center of Diabetes, Shanghai Key Clinical Center of Metabolic Diseases, Shanghai Institute for Diabetes, Shanghai Key Laboratory of Diabetes, Shanghai, China 2 Department of Interventional Radiology, Shanghai Jiao-Tong University Affiliated Sixth People’s Hospital, Shanghai, China 3 Department of Vascular Surgery, Shanghai Jiao-Tong University Affiliated Sixth People’s Hospital, Shanghai, China Corresponding Authors: Fang Liu and Weiping Jia, Department of Endocrinology and Metabolism, Shanghai Jiao-Tong University Affiliated Sixth People’s Hospital, 600 Yishan Road, Shanghai 200233, China. Email: [email protected]; [email protected]

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Shanghai medical center for diabetes between January 2011 and June 2012; 30 cases with type 1 diabetes, 4 with normal glucose tolerance, 29 with impaired glucose regulation, 5 with prior lower extremity arterial revascularization, and 40 with lumbar intervertebral disc protrusion or spinal stenosis were excluded. In total, 2080 patients with T2DM were included (mean age: 61.5 + 12.0 years; mean duration of diabetes 8.4 + 6.9 years; 1125 male, 960 female); they did not have acute complications of diabetes, liver dysfunction, cancer, thyroid disease, or recent major surgery. These patients were diagnosed with T2DM based on the 1999 World Health Organization criteria and American Diabetes Association standards.12 A questionnaire was designed to collect information regarding gender, age, height, weight, duration of T2DM, and smoking history. Body mass index (BMI) was calculated as body weight (kg) divided by the square of height (m). Possible risk factors and comorbidities including the history of medication, hypertension (HTN), CAD, arrhythmia, cerebral infarction (CI), diabetic retinopathy (DR), and diabetic nephropathy (DN) were included in the questionnaire. The clinical symptoms of lower limbs in all patients (such as cold, burning, cramping, lameness, soreness, fatigue, etc) were obtained by the questionnaire, and a through physical examination was performed.

Methods Physical examination. The clinical manifestations (such as drying, bruising, swelling, blister, ulcers, gangrene, arterial pulse, etc) of lower limbs were recorded by physical examination. The normal dorsal pedal pulse and posterior tibial pulse was recorded as 0, and a diminished or absent pulse as 1, by pulse palpation. All patients underwent ABI measurement. In all, 438 patients with abnormal ABI were submitted to carotid Doppler ultrasound in which 314 patients had lower extremity arterial ultrasound and 124 patients had a magnetic resonance angiography (MRA) examination. Laboratory tests. Venous blood samples were drawn both after an overnight fast and 2 hours after breakfast. The laboratory evaluation included (1) measurement of fasting and 2-hour postprandial plasma glucose, fasting insulin, glycated hemoglobin (HbA1c), and glycated serum albumin (GA); (2) routine laboratory tests for liver function including the measurement of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and g-glutamyl-transferase; (3) measurement of renal function including urinary albumin–creatinine ratio (UACR), blood urea nitrogen (BUN) and creatinine (Cr), serum uric acid (UA), and glomerular filtration rate (GFR); (4) level of fasting serum triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C); and (5) measurement of hemoglobin. Homeostasis model assessment insulin resistance and homeostasis model assessment b-cell function were estimated by homeostasis model assessment.13 Fasting plasma glucose and 2-hour postprandial blood glucose were measured by glucose oxidase method. Insulin levels were determined by

radioimmunoassay (DPC Inc., Los Angeles, CA, USA). Kidney and liver function were measured on an automatic analyzer (Hitachi 7180 biochemistry autoanalyzer, Japan). The HbA1c levels were estimated by high-pressure liquid chromatography using a Variant II machine (Bio-Rad Inc., Hercules, CA, USA). The GA was determined by liquid enzymatic method using the Glamour 2000 automatic biochemical analyzer (MD Inc., Silicon Valley, CA, USA). Urinary albumin (Alb) was detected by immunoturbidimetry, urine Cr was measured by enzymatic, and the UACR was calculated. The GFR was measured using a Technetium-99 isotope scan (Precedence SPECT/CT Imaging System, Eindhoven, Netherland) in the whole cohort. The total GFR was calculated as the sum of the left and right kidneys. Measurement of ABI. Ankle–brachial index was evaluated using the 2-way Doppler blood-flow detector (ES-1000SPM, Hadeco, Japan). The investigators were specifically trained to perform ABI measurement under standardized conditions. Examination was carried out after at least a 5-minute rest in the supine position, keeping the upper body as flat as possible. The ABI for each leg was calculated as a ratio of the higher systolic BP between the posterior tibial artery and dorsalis pedis artery, to the higher of the brachial BP in the arms. The lower ABI value was then used for analysis. The ABI levels were classified into the following groups: ABI 0.9, 0.9 < ABI  1.3, and ABI >1.3. Measurement of vibration perception threshold. Vibration perception threshold was measured by the same technician using a neurothesiometer (Bio-Medical Instrument Co, Newbury, Ohio). The operational approaches were based on the International Working Group on the Diabetic Foot of the International Diabetes Federation.14 In brief, the patients lay down, in a quiet and relaxed setting in the decubitus position with eyes closed. The vibration probe was applied on a bony part on the dorsal side of the distal phalanx of the first toe. The voltage (in V) was slowly increased in increments of 5 V, and the VPT, defined as the moment when the patient indicated he or she first felt the vibration, was recorded. The test was repeated 3 times, and the mean voltage was calculated and considered as the VPT result. The higher value of VPT in either limb was used for analysis. As a general criterion, VPT was stratified as abnormal (VPT >25 V), intermediate (VPT 16-25 V), and normal (VPT 1.3 groups (P < .05); the 0.9 group had the highest proportions (Figure 1A). Similarly, the 0.9 group had highest proportions of clinical manifestation (drying, bruising, swelling, blister, ulcer, gangrene,

0.9

0.91-1.3

>1.3

Sex (M/F) 134/129 885/757 103/72 74.1 + 9.1a 59.3 + 11.3 62.7 + 9.8a,b Age, years1 BMI, kg/m21 22.9 + 6.8a 24.2 + 4.7 25.3 + 4.3a,b DM duration 13.2 + 8.5a 7.6 + 6.3 9.3 + 7.0a,b 1 (years) HbA1c, %1 8.2 + 1.7a 7.6 + 1.7 7.5 + 1.6b GA, %1 22.3 + 6.2a 20.0 + 6.1 19.2 + 5.5b FPG, mmol/L1 8.2 + 2.9 8.2 + 2.6 8.1 + 2.7 PPG, mmol/L1 12.6 + 4.3 12.2 + 4.6 12.0 + 4.3 ALT, U/L2 15 + 10 20 + 13 21 + 13 AST, U/L2 18 + 7 20 + 8 21 + 8 ALP, U/L1 77 + 27 72 + 30 74 + 23 g-GT, U/L1 38 + 38 36 + 33 37 + 35 TC, mmol/L1 4.8 + 1.1 5.1 + 1.0 5.1 + 0.9 TG, mmol/L1 1.6 + 1.1 2.2 + 10.6 1.8 + 1.1 HDL-C, 1.1 + 0.3 1.5 + 7.5 1.3 + 0.4 mmol/L1 2.7 + 1.3 3.7 + 1.1 3.1 + 1.0 LDL-C, mmol/ L2c 6.35 + 3.18 5.30 + 1.80 5.40 + 2.05 BUN, mmol/ L2c 76 + 34 64 + 20 66 + 24 Cr, mmol/L2c UA, mmol/L2c 328 + 144 305 + 106 316 + 110 UACR, mg/ 43.25 + 151.40 12.24 + 24.54 12.72 + 25.93 mg2c 70 + 15a 93 + 25 94 + 28b GFR, mL/min1 HOMA-IR1 24.46 + 95.83 4.51 + 8.08 3.98 + 2.79 HOMA-b1 126.87 + 308.73 60.92 + 144.45 88.22 + 167.79 VPT1 29.58 + 14.23a 17.59 + 8.86 19.61 + 9.84a,b Abbreviations: BMI, body mass index; DM duration, duration of diabetes; HbA1c, glycosylated hemoglobin; GA, glycosylated albumin; FPG, fasting plasma glucose; PPG, 2-hour postprandial blood glucose; Hb, hemoglobin; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; g-GT, g-glutamyl-transpeptidase; TC, total cholesterol; TG, triglyceride; HDLC, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BUN, blood urea nitrogen; Cr, serum creatinine; UA, uric acid; UACR, urine albumin:creatinine ratio; GFR, glomerular filtration rate; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-b, homeostasis model assessment-b; VPT, vibration perception threshold; ABI, ankle–brachial index; QR, quartile range; SD, standard deviation; M, male; F, female. a P < .05, comparing with group 0.91 to 1.3. b P < .05, comparing with group 0.9. c P < .05, comparing among 3 groups; 1, normal distribution variables and 2, nonnormal distribution variables.

deformity, and arterial pulse) of lower limbs (P < .05) except for fungal infection; the >1.3 group was second (Figure 1B data and Supplement Table 1).

Clinical Characteristics in the Different ABI Groups In the >1.3 group, age, duration of diabetes, HbA1c, and VPT were higher than in the 0.91 to 1.3 group (P < .05; Table 1) and significantly lower than in the 0.9 group (P < .05; Table 1). The BMI was highest in the >1.3 group. Compared with the 0.9 group, GFR in the >1.3 group was higher. The ALT, AST, ALP, LDL-C, BUN, Cr, UA, and UACR were nonnormal

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Angiology Table 2. The Prevalence of Cardiovascular Disease (CVD) and Peripheral Arterial Disease (PAD) Among 3 Ankle–Brachial Index (ABI) Groups in Different Gender, Age, and Glycosylated Hemoglobin (HbA1c) Level. ABI 0.9

0.91-1.3

>1.3

134 79 (59.0) 78 (58.2) 129 71 (55.0) 52 (40.3) 2 1 (50.0) 0 (0.0) 21 5 (23.8) 10 (47.6) 51 25 (49.0) 26 (51.0) 189 119 (63.0) 94 (49.7) 24 13 (54.2) 10 (41.7) 54 34 (63.0) 28 (51.9) 111 68 (61.3) 56 (50.5)

886 143 (16.1) 24 (2.7) 756 172 (22.7) 12 (1.6) 293 5 (1.7) 3 (1.0) 520 63 (12.1) 8 (1.5) 535 120 (22.4) 9 (1.7) 294 124 (42.2) 15 (5.1) 373 60 (16.1) 7 (1.9) 410 88 (21.5) 7 (1.7) 579 111 (19.2) 12 (2.1)

103 35 (34.0) 16 (15.5) 72 26 (36.1) 6 (8.3) 18 1 (5.5) 1 (5.5) 46 8 (17.4) 5 (10.9) 74 36 (48.6) 13 (17.6) 37 17 (45.9) 4 (10.8) 41 8 (19.5) 3 (7.3) 47 17 (36.2) 9 (19.1) 57 16 (28.1) 4 (7.0)

Group

Figure 2. Comparison of prevalence of macro- and microvascular complications among different ankle brachial index (ABI) groups. **, P < .01, comparing among 3 groups. LAU indicates lower limb artery ultrasound; CAU, carotid artery ultrasound; CAD, coronary artery disease; CI, cerebral infarction; DR, diabetic retinopathy; DN, diabetic nephropathy.

distributed continuous variables. Independent-samples MannWhitney U test indicated that there were significant differences in LDL-C, BUN, Cr, UA, and UACR among these groups (P < .05; Table 1), with the lowest values in the 0.91 to 1.3 group except for LDL-C.

Prevalence of Vascular Complications Among Different ABI Groups As shown in Figure 2, the prevalence of vascular complications, including lower limb arterial stenosis/obstruction assessed by lower extremity arterial ultrasound (LAU), carotid arterial stenosis/occlusion assessed by carotid arterial ultrasound (CAU), CAD, CI, DR, and DN, was obviously different among 3 ABI groups (P < .05). The prevalence of carotid arterial stenosis/occlusion, CAD, and CI in 0.9 group was the highest followed by the >1.3 group. The prevalence of CVD and PAD was compared among 3 ABI groups in different genders, age (1.3; Wald ¼ 5.437)

Male CVD (%) PAD (%) Female CVD (%) PAD (%) Age

High Ankle-Brachial Index Indicates Cardiovascular and Peripheral Arterial Disease in Patients With Type 2 Diabetes.

We assessed the association between high ankle-brachial index (ABI) and cardiovascular disease (CVD) and peripheral arterial disease (PAD) in Chinese ...
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