Arterial Stiffness and Carotid Intima-Media Thickness in Diabetic Peripheral Neuropathy

Background

Type 2 diabetes mellitus (T2DM) is a worldwide epidemic, particularly in developed and developing countries [1]. Peripheral neuropathy, which unfavorably influences patient quality of life quite, is an early and common complication of T2DM. Although reported prevalence rates have differed across studies due to differences in study populations and diagnostic criteria, peripheral neuropathy is involved in 30–50% of patients with T2DM [1,2]. Chronic sensorimotor distal symmetric polyneuropathy is the most common form of diabetic peripheral neuropathy [1]. Hyperglycemia is a primary risk factor associated with diabetic peripheral neuropathy, and other independent predictors include T2DM duration, smoking, alcohol consumption, hypertension, hypertriglyceridemia, and increased body mass index [2,3].

Cardiovascular diseases are the leading causes of death in patients with diabetes, and T2DM is considered as a coronary artery disease equivalent [4]. Vascular changes due to microvascular disease and subclinical atherosclerosis are associated with the development of T2DM-related complications such as nephropathy, retinopathy, and autonomic neuropathy [5–7]. Recent studies have demonstrated the relationship between peripheral neuropathy, which is a frequent complication of T2DM, and atherosclerotic vascular changes [8,9]. These studies consistently demonstrated the relationship between functional parameters of arterial stiffness and peripheral neuropathy. However, results regarding the relationship between carotid intima-media thickness (CIMT) and peripheral neuropathy are contradictory [8,9].

T2DM is a major risk factors for carotid atherosclerosis [10]. The relationship between carotid atherosclerosis and cerebrovascular and coronary artery diseases has been demonstrated in many studies [11,12]. It has been reported that increased CIMT, which is measured by B-mode ultrasonography, is correlated with increased aortic intima-media thickness, which is measured by echocardiography, and is a marker of systemic atherosclerosis [10,12].

The present study investigated the relationship between peripheral neuropathy and functional parameters of arterial stiffness, which were measured by 24-h blood pressure monitoring, and CIMT, which was measured by B-mode ultrasonography, in patients with T2DM.

Material and Methods

PATIENTS:

The study population included 161 patients (81 males, mean age 52.60±8.26 years) with T2DM, who were examined using ambulatory blood pressure monitoring, carotid ultrasonography, transthoracic echocardiography, and electromyography between April 2013 and January 2014 at Selcuk University. The diagnosis of T2DM was made based on the criteria of the American Diabetes Association. Medical history was obtained and physical examination was performed in all patients. Individuals with clinically proven coronary heart disease, cerebrovascular disease, peripheral vascular disease, congestive heart failure, valvular heart disease, chronic kidney disease, and neuropathy due to other reasons (e.g., alcoholic neuropathy, carpal tunnel syndrome, and cerebrovascular disease sequel) were excluded from the study. Patients were divided into 2 groups: those with (n=69) and without (n=92) peripheral neuropathy. Venous blood samples for biochemical analyses and hematologic parameters were drawn after 12-h fasting before the patients received any medication. Fasting blood glucose, serum creatinine, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, white blood cell (WBC), hemoglobin (Hb), and glycated hemoglobin (HbA1c) levels were recorded. Glomerular filtration rate (GFR) was estimated by MDRD method. The study protocol was approved by the local ethics committee, and all patients gave their written informed consent to participate in the study.

24-H BLOOD PRESSURE MONITORING:

24-h noninvasive ambulatory blood pressure monitoring was performed in each subject using a Mobile O Graph 24h PWA (I.E.M. GmbH Stolberg Germany), which yields a simultaneous measure of brachial BP, PWV, and augmentation index. The device is supported with an expert software package, Hospital Management System (Hypertension Management System Client Server Company, IEM, GmbH Germany), for analysis of all registered measurements. In addition, the device is able to measure central BP and Alx@75 by an integrated pulse-wave analysis device. Waveforms were recorded with a regular oscillatory brachial cuff suitable for ambulatory measurement the using Austrian Research Centers (ARC) Solver method (Austrian Institute of Technology, Vienna, Austria). The ARC Solver method is a novel method for the determination of aortic systolic BP and Aix based on oscillometric blood pressure measurement with a common cuff. The method uses the pulse-waves assessed at the brachial artery [13,14]. Blood pressure was measured every 15 min during the day and evening (from 6:00 to 22:00) and every 30 min at night (from 22:00 to 06:00). Presence of at least 50 acceptable measurements was considered as an acceptable 24-h blood pressure monitoring recording for our study. The mean systolic blood pressure, diastolic blood pressure, mean arterial pressure, pulse-wave velocity (PWV), and Alx@75 were calculated for 24 h. The distribution of PWV with age and BP category is described and reference values for PWV are established. The mean PWV found was 6.84 m/s±1.65 [15].

ECHOCARDIOGRAPHIC ASSESSMENT:

All patients underwent transthoracic echocardiographic examination using the Vivid E9 system with a 1.5–4.6 MHz probe (GE-Vingmed Ultrasound AS, Horten, Norway). Left ventricular (LV) dimensions and wall thickness were obtained from the parasternal long axis view with the M-mode cursor positioned just below the mitral leaflet tips, perpendicular to the long axis of the LV. LV ejection fraction was measured in accordance with Simpson’s method. LV mass (LVM) was measured using the formula defined by Devereux. LVM index was calculated by dividing LVM by the body surface area. All standard conventional echocardiographic assessments were performed according to the published criteria of the American Society of Echocardiography.

CAROTID ULTRASONOGRAPHY:

CIMT was measured recording ultrasonographic images of both the left and right common carotid arteries with a 4.5–12 MHz linear array transducer (Vivid E9 system; GE Medical Systems, Horten, Norway). A region 1 cm proximal to the carotid bifurcation was identified. The intima-media thickness was measured using automated edge detection software as the distance between the lumen-intima interface and the media-adventitia interface. All examinations were performed by a single experienced examiner, who was blind to the clinical and biochemical data.

NEUROLOGICAL EXAMINATION:

All patients were examined by a neurologist for the presence of peripheral neuropathy. Neuropathic pain was defined as pain in the limbs in the absence of history of trauma or any other external cause. Bilateral spontaneous pain, hypoesthesia including decreased sensation to pinprick and temperature (cold tuning fork), or paresthesia of the legs were considered as the symptoms of polyneuropathy. Response of the Achilles tendon reflex was investigated in the knee-standing position, ie, with reinforcement, with a standard reflex hammer. Results were considered abnormal when no reflex was seen in 1 or both extremities. Vibration perception was measured on the medial malleolus in the lower extremities. Nerve conduction velocity was measured using a Nihonkohden electromyography system (Nihonkohden MEB-9002K VMA EP/EMG Measuring System 2005, USA). Patients with 2 or more of the following 4 components were diagnosed with neuropathy: presence of symptoms, absence of ankle tendon reflexes, abnormal scores of vibration perception, and abnormal nerve conduction velocity.

STATISTICAL ANALYSIS:

SPSS 17.0 for Windows was used for statistical analyses (SPSS, Chicago, IL, USA). Continuous variables are presented as median or mean ±SD; categorical variables are presented as percentage. Differences in the continuous variables between groups were determined by t test or the Mann-Whitney U test, for variables with or without normal distribution, respectively. To test the normal distribution, the Kolmogorov-Smirnov test was used. Categorical variables are summarized as percentages and compared with the χ² test. The Pearson correlation coefficient was computed to determine the association between 2 continuous variables. Logistic regression analysis with enter method was performed including independent variables being significantly different between patients with T2DM having a possible causative role for neuropathy (+). All tests of significance were 2-tailed. Statistical significance was defined as a p value of less than 0.05.

Results

In the present study, data of a total of 161 patients (80 females and 81 males) were evaluated. Patients with peripheral neuropathy were older (54.68±8.35 years vs. 51.04±7.89 years; p=0.005) and had T2DM for longer time (month) (60 months vs. 36 months; p=0.004). Likewise, elevated HbA1c value, which indicates poorly controlled T2DM, was higher in the peripheral neuropathy group (8.55±1.85 mg/dL vs. 7.30±1.51 mg/dL; p<0.001). Body mass index, serum lipid concentrations, hematological parameters, and serum thyroid stimulating hormone levels were similar in both groups. Prevalence of hypertension and type of antihypertensive drugs received were similar in both groups. GFR was lower in the peripheral neuropathy group, but the difference was not statistically significant (Table 1).

With regard to the results of 24-h blood pressure monitoring, PWV, which is the parameter of arterial stiffness, was statistically increased in the group with peripheral neuropathy as compared to the group without peripheral neuropathy (7.74±1.14 m/s vs. 7.15±1.10 m/s; p=0.001) (Figure 1). Pulse pressure, which is another important parameter of arterial stiffness, was higher in the peripheral neuropathy group, but the difference was not statistically significant. Other results of 24-h blood pressure monitoring were similar in both groups (Table 2).

Echocardiographic evaluation was performed in both groups. LVM index was significantly increased in the group with peripheral neuropathy (98.68±26.28 g/m2vs. 89.71±19.70 g/m2; p=0.02). Other echocardiographic parameters were found to be similar in both groups (Table 2).

CIMT was measured in the patients. Anterior measurement (0.74±0.15 mm vs. 0.67±0.13 mm; p=0.01) and posterior measurement (0.65±0.10 mm vs. 0.60±0.10 mm; p=0.006) were statistically significantly increased in the group with peripheral neuropathy (Table 2, Figure 1).

Bivariate correlation analysis revealed a significant correlation between PWV with CIMT and LVM index (Figures 2 and 3).

Retrospective stepwise analysis was performed in multivariate analysis to detect the predictors of peripheral neuropathy. Parameters that were considered to be associated with peripheral neuropathy (sex, age, PWV, CIMT, smoking, hypertension, diabetes duration, and HbA1c and LVM index) were evaluated. As the result of analysis, duration of diabetes, HbA1c, and LVM index were determined to be the predictors of peripheral neuropathy (Table 3).

Discussion

LIMITATIONS:

The main limitation of the present study arises from its cross-sectional design. It was not possible to establish a cause-and-effect relationship between peripheral neuropathy, CIMT, and arterial stiffness. Moreover, we did not determine predictors of peripheral neuropathy, since neither the patient number nor study design used were suitable for this.

Conclusions

The study determined a significant relationship of peripheral neuropathy with increased PWV and CIMT in patients with T2DM. The duration of diabetes, increased HbA1C, and increased LVM index were predictors of diabetic peripheral neuropathy.