International Journal of Cardiovascular ResearchISSN: 2324-8602

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Research Article, Int J Cardiovas Res Vol: 5 Issue: 4

The Impact Of Glucose Control On Carotid Arterial Wall Thickness In Asymptomatic Subjects For Cardiovascular Disease

Yong-Kyun Kim1, Keum Won Kim1, Wuon-Shik Kim2, Ki-Hong Kim1, Taek-Geun Kwon1, Duck-Jun Seo1, In-Geol Song1, Dong- Ju Yang1, Wan-Ho Kim1, Hwan-Hyi Cho1, Young-Hoon Seo1, Hyun-Woong Park1, Kee-Sik Kim3, Jeong Bae Park4, Jeong Taek Woo5 and Jang-Ho Bae1*
1Cardiology, Konyang University Hospital, Daejeon, Korea
2Korea Research Institute of Standards and Science, Daejeon, Korea
3Cardiology, Daegu Catholic University Medical Center, Daegu, Korea
4Cardiology, Cheil General Hospital, Dankook University, Seoul, Korea
5Endocrinology, Kyung Hee University Medical Center, Seoul, Korea
Corresponding author : Jang-Ho Bae, MD, PhD
Heart center, Konyang University Hospital 685 Gasuwon-Dong, Seo-Gu Daejeon city, South Korea 302-718, South korea
Tel: 82-42-600-9400
Fax: 82-42-600-9420
E-mail: [email protected]
Received: May 18, 2016 Accepted: July 01, 2016 Published: July 08, 2016
Citation: Kim Y, Kim KW, Kim W, Kim K, Kwon T, et al. (2016) The Impact of Glucose Control on Carotid Arterial Wall Thickness in Asymptomatic Subjects for Cardiovascular Disease. Int J Cardiovasc Res 5:4. doi:10.4172/2324-8602.1000273

Abstract

Objective: We evaluated the impact of diabetes mellitus (DM) and DM control status on each layers of carotid artery in asymptomatic population. Methods: This is an observational cohort study consisted of 1,479 patients. The carotid images were sent to the Korea Research Institute of Standards and Science for core laboratory analysis using specialized software which can measure intima and media thickness respectively. Results: DM patients (n=634, 42.9%) were likely to be older, higher prevalence of male, hypertension and dyslipidemia, and higher creatinine level than non-DM patients (n=845, 57.1%). There was no significant demographic difference according to DM control status in DM patients. DM patients showed higher carotid intima-media thickness (CIMT, 0.70 ± 0.15 mm vs. 0.66 ± 0.16 mm, p<0.001) and media thickness (CMT, 0.41 ± 0.12 mm vs. 0.36 ± 0.12 mm, p<0.001) than non-DM patients, whereas intima thickness (CIT) showed no significant difference (0.29 ± 0.07 mm vs. 0.30 ± 0.06 mm, p=0.067) between 2 groups. Well controlled DM patients (HbA1C<7.0%, n=232, 47.4%) showed higher CIT (0.30 ± 0.08 mm vs. 0.27 ± 0.06 mm, p=0.003) than poorly controlled DM (HbA1C ≥ 7.0%, n=257, 52.6%). Old age and LDL-cholesterol were the independent factors for CIMT, CIT and CMT in total asymptomatic adults as well as DM patients. DM control status was not significant independent factor for CIMT. Conclusions: The increased CIMT in DM patients was mainly due to the increased CMT. DM control status did not impact on carotid arterial wall thickness in this study. Lipid control rather than glucose control may be the most important factor to decrease atherosclerosis progression in subclinical adults.

Keywords: Carotid artery; Arterial intima; Arterial media; Diabetes mellitus; Ultrasonography

Keywords

Carotid artery; Arterial intima; Arterial media; Diabetes mellitus; Ultrasonography

Introduction

Patient with type 2 diabetes mellitus (DM) is associated with endothelial dysfunction and increased carotid artery intima-media thickness (CIMT) [1-9]. The endothelial dysfunction and increased CIMT are associated with increased risk of cardiovascular disease [1-9]. Early detection of atherosclerosis in patient with type 2 DM is important to reduce the cardiovascular disease, because DM accelerates atherosclerosis [10]. CIMT measured by carotid ultrasonography is significantly associated with future cardiovascular events and it is useful marker of atherosclerosis [11-15]. 2010 American College of Cardiology Foundation/American Heart Association guideline recommends CIMT evaluation for the assessment of cardiovascular risk in asymptomatic adults.
Many studies have already shown that conventional risk factors of atherosclerosis were associated with CIMT, but the relationship between CIMT and DM, especially DM control status, is poorly understood. It is still unknown which layer out of intima, media, and CIMT of carotid artery is thickened in DM patients [16-18]. And it is also unknown that DM control status effect on which layer (s) of carotid artery [16-18]. Our previous study revealed that each layer of carotid artery can be differently affected by each cardiovascular risk factor [19]. Therefore, we hypothesize DM control status as well as the presence of DM itself will affect differently on each layer (s) of carotid artery.
We evaluated the relationship between CIMT and DM control status as well as DM. The second purpose of this study was to see which layer out of intima, media and IMT is thickened in DM patients and the relationship between DM control status and each layers of carotid artery in asymptomatic adults.

Methods

Study subjects
The study subjects were prospectively enrolled from May 2010 to August 2013 from 12 university hospitals in the Republic of Korea. The study subjects were enrolled in this study if they had no subjective symptoms related with cardiovascular disease and provided informed consent. A total of 2,340 subjects were enrolled and underwent carotid ultrasound examination and the images were stored for core laboratory analysis. We excluded 861 subjects from this study; 1 for peripheral arterial occlusion disease, 44 for stable angina, 56 for acute coronary syndrome, 28 for stroke, 2 for hemodialysis and 730 for incomplete data. Finally, 1,479 subjects were enrolled for this study. Patient laboratory data including lipid profile, blood glucose and high-sensitivity C-reactive protein (Hs-CRP) measured within 2 weeks of enrollment were collected from medical records.
Baseline evaluation included a complete history and physical examination regarding following information: hypertension (blood pressure ≥ 140/90 mmHg based on the average of 3 times-repeated readings or patients on antihypertensive drugs), DM (controlled with diet, oral hypoglycemic agents, or insulin; or fasting glucose level ≥ 126 mg/dL or 2 hr oral glucose tolerance test ≥ 200 mg/dL), smoking habits (current smoker or not), and dyslipidemia (total cholesterol ≥ 240 mg/dL or low density lipoprotein (LDL) cholesterol ≥ 160 mg/ dL or high density lipoprotein (HDL) cholesterol ≤ 40 mg/dL in male and ≤ 50 mg/dL in female or patients on lipid lowering therapy)
This study was approved by the ethics committee of Konyang University Hospital and conducted in accordance with the Declaration of Helsinki.
Carotid artery scanning
Carotid artery scanning was performed using a high-resolution ultra-sonographic unit (HP Sonos-5500, Phillips, USA) with a linear array transducer (set to 11 MHz) in each hospital. The subjects were assessed in a supine position with mild head extension. The far wall of the right and left common carotid artery (CCA) was scanned in each subject. The depth control was fixed at 4 cm to optimize the image quality. The gain control was adjusted according to the carotid artery image to obtain a clear delineation of the intima, media, and adventitial layers of the CCA far wall. After obtaining a clear carotid artery image, the images were digitally captured and sent to the Cardio-Cerebrovascular Data Center in the Korea Research Institute of Standards and Science for off-line core laboratory analysis.
Measurement of CIMT, Carotid intima thickness (CIT) and Carotid media thickness (CMT)
We measured CIMT, CIT and CMT of both left and right CCA using specialized software (KCIMT, Cardio Cerebrovascular Data Center, Daejeon, South Korea) developed to measure intima and media wall also. This method was reported and the accuracy was validated in our previous study [19]. Briefly, the carotid artery consists of intima, media, and adventitia. The far wall image of the CCA consists of 3 main echoes. The first echo is generated between lumen and intima, the second is generated between intima and media, and the third is generated between media and adventitia. The first and the second echoes are superposed because the axial resolution of diagnostic ultrasound is larger than the intima thickness. Therefore, we can measure only the first echogenic line, i.e., the leading edge of superposed echoes, and the second echogenic line, i.e., the leading edge of the third echo. The CIMT was defined as the distance between the first echogenic line and the second one [20,21]. The CIT was assessed by measuring the echo width of the superposed echoes, because it is almost proportional to the intima thickness incase in the region consists of relatively uniform materials for intima and media, respectively [19]. The CMT was assessed by measuring the distance between the trailing edge of the superposed echoes and the leading edge of the third echo, i.e., the hypoechoic space in CIMT [19].
First, the CCA image was loaded, and the size per pixel was determined with electronic caliper, which was previously calibrated at 4-cm depth in axial direction of a multipurpose phantom (Model 539, ATS Laboratories). Next, a region of interest (ROI) for each CCA image was selected at least 1 cm length at far wall of the CCA and at 1 cm proximal to the carotid bulb. The ROI was manually moved to more proximal or distal to avoid any plaque or calcification in this region, if present. The quality of the ROI image was evaluated, and the noise was removed with a filtering algorithm. The 3 layers (intima, media, and adventitia) were identified (Figure 1) after acquiring the edge images using the Canny edge-detection algorithm [22]. However, if the border between each layer was not clear enough to be identified with the Canny algorithm, we differentiated each layer by its autocorrelation based on statistical signal processing [23]. To measure the thickness of each layer, the number of pixels corresponding to the thickness of each layer was calculated. Finally, the CIT, CMT, and CIMT were determined by multiplying the calibration factor (millimeters per pixel) by the number of pixels for each of the 3 layers. We defined the image quality index (QI) as the ratio of the pixels detected for thickness measurement to the pixels selected for the ROI.
Figure 1: This figure represents typical example of carotid intima thickness (CIT), media thickness (MT) and intima-media thickness (IMT) which was automatically measured by the described algorithm in the method section.
Statistical analysis
All data were analyzed using SPSS version 12.0 (SPSS Inc., Chicago, IL, USA). Values are expressed as mean ± standard deviation, frequencies and percentages. The value of CIMT, CIT and CMT were compared according to the presence of DM and also glucose control status in DM group. Comparison of data between each group was performed with chi-square test and/or the independent t test. Multivariate analysis was performed with linear regression analysis to see the independent factors for CIMT, CIT and CMT in DM group as well as in total subjects. All tests were 2-tailed with a significance level of 0.05.

Results

Demographics of the study subjects
DM patients (n=634, 42.9%) were likely to be older (62.6 years old vs. 53.6 years old, p<0.001), and had higher prevalence of hypertension and dyslipidemia, higher total cholesterol, higher triglyceride, higher HDL cholesterol and higher LDL level than non-DM patients (n=845, 57.1%). Medications such as beta-blocker (27.7% vs. 13.5%), calcium channel blocker (29.0% vs. 16.7%), angiotensin receptor blocker or angiotensin converting enzyme-inhibitor (48.9% vs. 19.7%) and statin (52.7% vs 15.3%) were significantly more used in DM patients than non-DM patients (p<0.001) (Table 1).
Table 1: Demographics of the study population.
In DM patients, there was no significant difference in demographics between well controlled DM patients (HbA1C<7.0%, n=232, 47.4%) and poorly controlled DM patients (HbA1C ≥ 7.0%, n=257, 52.6%) except for use of oral hypoglycemic agent or insulin (OHA: n=126, 24.9% vs n=143, 61.4%, Insulin; n=11, 2.2% vs n=51, 21.9%, P<0.001). Mean HbA1C was 5.9 ± 0.5% (glucose 114 ± 31 mg/dL) and 8.3 ± 1.3% (glucose 167 63 mg/ dL) in well controlled DM patients and poorly controlled DM patients, respectively, (P<0.001) (Table 2).
Table 2: Demographics of the study population in diabetes mellitus patients according to the status of diabetes mellitus control.
Carotid ultrasound findings
DM patients showed significantly higher CIMT (0.70 ± 0.15 mm vs. 0.66 ± 0.16 mm, p<0.001) and CMT (0.41 ± 0.12 mm vs. 0.36 ± 0.12 mm, p<0.001) than non-DM patients, whereas CIT showed no significant difference (0.29 ± 0.07 mm vs. 0.30 ± 0.06 mm, p=0.067) between 2 groups (Table 3).
Table 3: Mean carotid arterial wall thickness in each group.
Linear regression analysis showed that LDL-cholesterol, old age (male >55 years old, female >65 years old) and, hypertension were associated with increased CIMT, CIT and, CMT in total subjects. DM was not an independent factor for any carotid arterial wall thickness in multivariate analysis.
In subgroup analysis of DM patients, well controlled DM patients (HbA1c<7.0, n=232, 47.4%) showed higher CIT (0.30 ± 0.08 mm vs. 0.27 ± 0.06 mm, p=0.003) than poorly controlled DM patients (HbA1c ≥ 7.0, n=257, 52.6%) (Table 3). However, there was no significant difference in CIMT and CMT between both groups.
Multivariate analysis in DM patients to see the independent factors with carotid artery wall thickness according to the status of DM control demonstrated that LDL-cholesterol (β=0.184, 95% confidence interval=0.000~0.001, p=0.001) and old age (β=0.253, 95% confidence interval=0.045~0.116, p=0.000) were the important independent factors for CIMT. Also, LDL-cholesterol and old age were the important independent factors for both CIT and CMT.
Hypertension (β=0.123, 95% confidence interval=0.002~0.035, p=0.030) and DM control status (β=-0.170, 95% confidence interval=0.038~0.008, p=0.003) were also associated with CIT in DM patients (Table 4). So, DM control status was associated with only CIT, not with CIMT and CMT, in DM patients.
Table 4: Independent factors for carotid arterial wall thickness.

Discussion

The main findings of this study in asymptomatic adults were as follows; at first, DM patients had significantly higher CIMT and CMT than non-DM patients and CIT showed no significant difference in 2 groups, although these differences were not anymore significant in multivariate analysis,. Secondly, old age, LDL-cholesterol and hypertension (not DM) were the independent factors for all carotid arterial wall thickness in total asymptomatic adults. At third, well controlled DM patients had unexpectedly higher CIT than poorly controlled DM patients. Finally, old age and LDL-cholesterol were the independent factors for all carotid arterial wall thickness in DM patients.
DM is one of the leading causes of coronary artery disease and also related to comorbidities, such as hypertension and dyslipidemia, which are also the risk factors of atherosclerosis [2-4]. The increased CIMT in DM patients was already reported in many studies [11,14,15] and the present study also showed similar results to the previous results. In univariate analysis, we found that CMT and CIMT were higher in asymptomatic DM patients than non-DM patients. Therefore, the increased CIMT in DM patients might be resulted from increased CMT, because our study in asymptomatic adults showed that there was no significant difference in CIT between DM patients and non-DM patients. This result suggested that DM in asymptomatic adults may affect only CMT, rather than CIT. However, multivariate analysis showed that DM was not an independent factor for carotid arterial wall thickness in this asymptomatic population, but old age, hypertension and LDL-cholesterol level were the independent factors. So, old age, hypertension and LDL-cholesterol are more important in carotid arterial wall thickness than DM itself in this asymptomatic population, although DM has high chance of increased carotid arterial wall thickness.
We have previously reported that DM control status was important in coronary plaque composition in patients with coronary artery disease [24]. The poorly controlled DM patients had higher necrotic core and dense calcium in coronary plaque than well controlled DM patients. So we did this study to see the impact of DM control status on each carotid artery wall thickness, especially in asymptomatic adults. However, our study showed that the poorly controlled DM patients did not have worse findings with carotid artery wall thickness. Furthermore, the poorly controlled DM patients had thinner CIT than well controlled DM patients. We thought that this result might derived from relatively thicker CMT in poorly controlled DM patients, or DM control status was not an important factor in carotid artery wall thickness, especially in preclinical asymptomatic adults. We cannot rule out the possibility of unmeasured confounding variables that could have affected the results, so this finding should be studied in future.
DM control status was not an important factor for carotid artery wall thickness in asymptomatic DM patients, although asymptomatic DM patients had higher CIMT and CMT than non-DM patients. However, we found that old age and LDL-cholesterol were still significant independent factors for CIMT, CIT and CMT in total subjects and DM patients. This result suggests that LDL-cholesterol out of traditional atherosclerosis risk factors is an important factor for carotid artery wall thickness, which is an important atherosclerosis surrogate, even in asymptomatic subclinical subjects and DM patients. Therefore, lipid control may be the most important factor in order to decrease atherosclerosis progression in subclinical adults.
This result showing the importance of lipid control rather than glucose control in determining carotid arterial wall thickness is coincident with the previous study [25,26]. The future cardiovascular event was not associated with HbA1c level but lipid level in DM patients with cardiovascular disease and without cardiovascular disease [25] and asymptomatic adults [26]. Elevated LDL-cholesterol level was associated with an increased CIMT in patients with chronic kidney disease which suggest that the association between dyslipidemia and atherosclerosis [27]. Furthermore, aggressive lipid lowering agents such as high dose statin induced regression of CIMT in patients with familial hypercholesterolemia, cardiovascular disease and subclinical atherosclerosis [28-30]. The above studies [26-30] suggest that dysregulated lipid metabolism is associated with an increased CIMT and lipid lowering agents can reduce CIMT in various study populations including those with and without cardiovascular disease.

Conclusion

The increased CIMT in asymptomatic DM patients compared to non-DM patients was mainly due to the increased CMT, (not CIT). LDL-cholesterol, age and hypertension were independent factors in carotid artery wall thickness in asymptomatic total subjects. DM control status was not an important factor for carotid artery wall thickness by multivariate analysis in asymptomatic DM patients. LDL-cholesterol and age were also independent factors in carotid artery wall thickness in asymptomatic DM patients.
Therefore, lipid control, rather than glucose control, may be important for carotid artery wall thickness in asymptomatic DM patients as well as asymptomatic total population.

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