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Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes
Accepted Manuscript Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes Yusuke Mineoka, Michiyo Ishii, Yoshitaka Hashimoto, Muhei Tanaka, Naoto Nakamura, Yasukazu Katsumi, Motohide Isono, Michiaki Fukui PII: DOI: Reference:
S0168-8227(16)31721-1 http://dx.doi.org/10.1016/j.diabres.2017.07.002 DIAB 7012
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
2 December 2016 9 June 2017 3 July 2017
Please cite this article as: Y. Mineoka, M. Ishii, Y. Hashimoto, M. Tanaka, N. Nakamura, Y. Katsumi, M. Isono, M. Fukui, Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes, Diabetes Research and Clinical Practice (2017), doi: http://dx.doi.org/10.1016/j.diabres.2017.07.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes Running head: Limited joint mobility of hand and atherosclerosis
Yusuke Mineoka, MD, PhD1; Michiyo Ishii, MD, PhD1;Yoshitaka Hashimoto, MD, PhD2; Muhei Tanaka, MD, PhD2; Naoto Nakamura, MD, PhD2,3; Yasukazu Katsumi, MD, PhD4; Motohide Isono, MD, PhD1; Michiaki Fukui, MD, PhD2*
1
Department of Internal Medicine, Otsu Municipal Hospital, Japan
2
Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine,
Graduate School of Medical Science, Japan 3
Department of Internal Medicine, Saiseikai Kyoto Hospital, Japan
4
Department of Orthopedics, Uji Takeda Hospital, Japan
*Corresponding author: Michiaki Fukui M.D. Ph.D. Department of Endocrinology and Metabolism Kyoto Prefectural University of Medicine, Graduate School of Medical Science 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Fax: +81-75-252-3721, Tel: +81-75-251-5505, E-mail: [email protected]
Word count; 2,440 words, Figure; 1, Table; 2.
Abstract Aim: Limited joint mobility (LJM) of hand, which is one of a complication of diabetic hand, has a close association with diabetic microangiopathy. However, it remains to be elucidated about the relationships between LJM of hand and subclinical atherosclerosis in patients with type 2 diabetes. Therefore, we conducted a cross-sectional study to evaluate the relationships between LJM of hand and carotid intima-media thickness (IMT) and plaque score in patients with type 2 diabetes. Methods: We evaluated the relationships between LJM of hand, and carotid IMT and plaque score, evaluated by carotid ultrasound examination, in 341 consecutive patients with type 2 diabetes. LJM of hand was diagnosed using a ‘prayer sign’ or ‘table test’. Results: LJM of hand was present in 72 patients. Carotid IMT and plaque score were higher in patients with LJM of hand than those in patients without (1.45 ± 0.66 vs. 1.14 ± 0.68 mm, P = 0.013 and 8.0 ± 5.3 vs. 5.4 ± 4.8 mm, P <0.001). Multivariate linear regression analysis revealed that LJM of hand was positively correlated with plaque score (β = 0.423, P = 0.043) after adjusted for age, sex, durations of diabetes, body mass index, hemoglobin A1c, creatinine, uric acid, smoking, hypertension and dyslipidemia. Conclusions: Our results demonstrate a relation between LJM of hand and subclinical atherosclerosis, especially plaque score, in patients with type 2 diabetes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes.
Keywords: Screening, Macrovascular disease, Other complications, Type 2 diabetes
Abbrebiations: CVD, Cardiovascular disease; CHD, Chronic heart disease; PAD, Peripheral arterial disease; FRS, Framingham Risk Score; LJM, Limited joint mobility; IMT, Intima-media thickness;
BMI, Body mass index; HbA1c, glycated hemoglobin; eGFR, Estimated glomerular filtration rate.
Introduction Cardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in patients with diabetes (1) and atherosclerosis is a major risk factor for CVD (2). Type 2 diabetes is known risk for atherosclerosis, leading to non-embolic ischemic stroke (3) and peripheral arterial disease (PAD) (4). To assess the risk for chronic heart disease (CHD) and CVD, traditional risk scores, such as Framingham Risk Score (FRS) and Framingham based risk score, have been widely used, however a previous report indicated that 175 of 1015 patients who classified low risk of FRS had subclinical atherosclerosis (5). Therefore, screening for subclinical atherosclerosis has a critical issue for improving the outcome of high risk patients, including patients with diabetes. ‘Diabetic hand’ is a complication of the upper extremity that manifests as conditions such as limited joint mobility (LJM), Dupuytren's contracture, and trigger finger (6-9). Diabetic hand tends to be ignored in clinical situation (10), in spite of several reports about positive relation between LJM of hand and microvascular complications (6-8,11,12). As for macroangiopathy, only few data was reported about the relation to LJM of hand previously (13,14). It has been reported that the prevalence of history of coronary heart disease and cerebrovascular disease is higher in type 2 diabetic patients with LJM of hand (13) and that there is a relationship between LJM of hand and early atherosclerosis in patients with type 1 diabetes (14). Moreover, little is known about the relationship between diabetic hand and subclinical atherosclerosis in patients with type 2 diabetes mellitus. Therefore, we investigated the relationship between LJM of hand, and carotid intima-media thickness (IMT) and carotid plaque in this cross-sectional study.
Material and methods Study design and patients We included the patients who visited the outpatient clinic of Otsu Municipal Hospital from April
2012 to December 2014 and who were performed carotid ultrasound in this cross-sectional study. Patients were excluded if they had a history of articular rheumatism or surgery for spinal disease. Patients with a history of cardiovascular disease (myocardial infarction, coronary revascularization or stroke) were also excluded. In addition, we excluded the patients who could not be obtained complete results of carotid ultrasound examination. This study was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from all patients. The Ethics Committee of Otsu Municipal Hospital gave approval for this study. All patients provided details of their demographics, medical history and medication usage. Body mass index (BMI) was calculated as weight (kg) divided by height (m2) squared. We classified patients as current smokers or not according to self-administered questionnaire. Retinopathy was assessed by ophthalmologists who were unaware of the severity of other diabetic complications (15). If findings in the left and right fundi were discordant, the worse side was taken as representative of the patient. Neuropathy was defined using the diagnostic criteria for diabetic neuropathy proposed by the Diagnostic Neuropathy Study Group (16). Nephropathy was graded as normoalbuminuria, urine albumin excretion (UAE) <30 mg/g creatinine (Cr); microalbuminuria, 30-300 mg/g Cr; or macroalbuminuria, >300 mg/g Cr. Microalbuminuria and macroalbuminuria were considered to indicate nephropathy.
Measurement of carotid IMT, plaque score Carotid ultrasound examination was performed by a sonographer who was unaware of the participant’s clinical characteristics. Both the left and right common carotid artery, carotid bulb, and internal carotid arteries were scanned using high-resolution B-mode ultrasound scanners (Xario, Toshiba, Inc., Tokyo, Japan), equipped with a 7.5 MHz high-resolution linear array transducer according to recommendations of the American Society of Echocardiography Carotid Intima Media Thickness Task Force (17). Patients were all examined in the supine position with their necks
extended and chins facing the contra lateral side. Intima-media thickness (IMT) was measured in the posterior wall of the carotid artery and was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in plaque-free area and greater than 75 percentile (17). Significant variation was not revealed in repeated measurements of IMT which were randomly selected. Intra-operator coefficients of variation was 2.4%. Mean maximum IMT was defined as the average of three measurements of the maximum IMTs across the 12 carotid arterial segments: the near and far walls of the distal common, the bifurcation and the proximal internal left and right carotid artery (18). Plaque was defined as IMT of more than 1.2 mm and as a focal thickening of 50% thicker than the neighboring segment (19). Plaque score was defined as the sum of maximum carotid plaque thickness of all plaques (20). Plaque echogenicity was assessed with the criteria of the European Carotid Plaque Study Group (21). Echogenicity is rated on a three-category scale: strong (echo-rich), intermediate, or weak (low echogenicity or echolucency). As previously reported, we defined the weak and intermediate echogenic plaque as the vulnerable plaque and the strong echogenic plaque was considered as stable plaque (22).
Diagnosis of diabetic hand LJM of hand was diagnosed using a ‘prayer sign’ or ‘table test’ (11). Patients with LJM were unable to bring the palms together or place them on a table with full contact when they were asked to close their palms in a praying position with the fingers in contact with each other or to place the palms on a table with the wrists flexed maximally (7,8).
Data collection and measurements Blood samples were drawn in the morning after an overnight fast for measurement of glycated
hemoglobin (HbA1c), total cholesterol, triglycerides, creatinine and uric acid. Blood examinations were performed using a Bio Majesty JCA-BM 6050 (JEOL, Tokyo, Japan). Hypertension was defined as systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, and/or having received treatment for hypertension. Dyslipidemia was defined as a total cholesterol concentration >5.69 mmol/l, a triglycerides concentration >1.70 mmol/l, and/or having received treatment for dyslipidemia. The estimated glomerular filtration rate (eGFR) was used to estimate kidney function and was calculated as follows (23): Male: eGFR (ml·min–1·1.73m–2) = 0.741 × 175 × age–0.203 × (serum creatinine)–1.154. Female: eGFR = 0.741 × 175 × age–0.203 × (serum creatinine)–1.154 × 0.742.
Statistical analysis Statistical analyses were performed using JMP v. 9.0 (SAS Institute Inc., Cary, NC) and a P value <0.05 was considered statistically significant. Continuous variables were presented as the mean value ± 1 SD. Categorical variables were presented as a number (percentage). The significance of differences between groups were evaluated by unpaired Student t-test or Pearson χ2 test. Multivariate linear regression analyses were used to adjust factors of relationship between LJM of hand and markers of subclinical atherosclerosis. We selected covariates which were known interest for multivariate analysis; age, sex, duration of diabetes, BMI, HbA1c, creatinine, uric acid, current smoking, hypertension and dyslipidemia.
Results We included 399 consecutive patients with type 2 diabetes in this study. Among them, 47 were excluded because of history of cardiovascular events, 8 were excluded because of histories of articular rheumatism or surgery for spinal disease and 3 were excluded because of incomplete results of carotid ultrasound examination (Figure 1). The clinical characteristics of 341 patients (199 male and 142 female) with type 2 diabetes are shown in Table 1.
LJM of hand was present in 72 patients, and in univariate analysis, these patients had significantly older age, worse glycaemic control, a longer duration of diabetes and, worse renal function and microvascular complications. (Table 1). Carotid IMT in patients with LJM of hand was higher than that in patients without (1.45 ± 0.66 mm vs. 1.14 ± 0.68 mm, P = 0.013), and same result was obtained as to carotid plaque score (8.0 ± 5.3 mm vs. 5.4 ± 4.8 mm, P <0.001). The proportion of vulnerable plaque had tended to be higher in patients with LJM of hand, but significant difference was not found (74% vs. 58% P = 0.117) (Table 1). Multivariate linear regression analyses revealed that LJM of hand was positively correlated with carotid plaque score (β = 0.423, P = 0.043) (Table 2). In addition, LJM of hand was also tended to be correlated with mean maximum IMT (β = 0.129, P = 0.077), although it did not reach statistical significance.
Discussion In this study, we evaluated the relationships between LJM of hand and subclinical atherosclerosis, such as carotid IMT and plaque score in patients with type 2 diabetes and showed that LJM of hand correlated with subclinical atherosclerosis, especially carotid plaque score. LJM of hand is one of the complications of ‘Diabetic Hand’ which is tended to be overlooked recently (10). Relationship between diabetic hand, especially LJM of hand, and microvascular complications were reported previously (6-8,10-12). In contrast, only few study has been reported the relation between LJM of hand and macroangiopathy (13) or subclinical atherosclerosis (14). Carotid IMT and plaque score represent components of carotid atherosclerosis, and also the established marker for predicting CHD, atherosclerotic heart disease and stroke (24, 25), while the difference between IMT and plaque score has been mentioned. The result from meta-analysis revealed that carotid plaque was a typical phenotype of atherosclerosis and had higher accuracies for the prediction of future myocardial infarction and for the detection of coronary artery disease,
compared with carotid IMT (26). Carotid plaques indicate a later stage of atherogenesis which is related to inflammation, endothelial dysfunction, oxidative stress, and smooth muscle cell proliferation (27). In this study, both of carotid IMT and plaque score in patients with LJM of hand was higher than patients without LJM of hand, however multivariate linear regression analyses indicated that LJM of hand was positively correlated with carotid plaque score, whereas no significant relation was found between LJM of hand and IMT. Previous report indicated that IMT was influenced by genetic determinants, but plaque is determined by CHD risk factors such as age, hypertension, dyslipidemia and diabetes mellitus (28). Progression of plaque score is more affected with the duration of diabetes (29). In patients with dialysis, differential association was reported between traditional and non-traditional risk factors with carotid IMT and plaque formation (30). Taken together, our study suggested that LJM of hand reflects carotid plaque formation rather than thickening of intima-media layer. As to plaque echogenicity, vulnerable plaque, especially echolucent plaque, was reported to have predictive value for occurrence of stroke (20). In this study, no significant difference was found about the proportion of vulnerable plaques, however this might be because of relatively few cases of carotid stenosis and echolucent plaques. Macroangiopathy and LJM of hand have common background factors, including a long duration of diabetes, poor metabolic control, and microvascular complications (7,8,31). Though, the precise mechanism of LJM of hand was not fully understood, several mechanisms were proposed previously; genetic components (32), microvascular complications and an increase of advanced glycosylation end-products (AGEs) which lead to skin thickening and formation of nodules (33). Increased collagen deposition in the skin and musculoskeletal connective tissues of hand are thought to be results from overproduction of growth factors and cytokines such as transforming growth factor-beta (34). Those mechanisms might be also related to both LJM of hand and macrovascular complications
of diabetes (35,36). Overall, the differences between the result of mean max IMT and that of carotid plaque in our study suggested that LJM of hand might be a marker for advanced atheroma formation and atherosclerosis in patients with type 2 diabetes mellitus. This study has several limitations. First, the cross-sectional design only permits inference of the causal relationships between LJM of hand and subclinical atherosclerosis. Second, we did not investigate other “Diabetic hand”, such as Dupuytren’s contracture and carpal tunnel syndrome in this study. However, it is likely that these hand syndromes might be associated with subclinical atherosclerosis, because of the involvement of the same pathologies (36). Third, although we included all the patients who received ultrasonic examination of carotid artery, ultrasonic examination of carotid artery was part of the comprehensive care delivered to each patient with diabetes. Thus, there is a possibility of selection bias for the percentage of LJM of hand. However, the selection bias might be small because the percentage of LJM in this study was almost the same as the other studies (9,12). Finally the patients in this study were relatively small number and all Japanese, therefore, it is uncertain whether this finding can be applied more broadly to other populations. In addition, we only investigated the association between LJM of hand and carotid intima-media thickness (IMT) or carotid plaque. Thus, further studies would be needed for the association between LJM of hand and another parameter of early vascular changes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes. In a clinical situation, it is important to measure carotid IMT or plaque directly by noninvasive echography as an established surrogate marker for concomitant cardiovascular diseases or predictors. In conclusion, LJM of hand correlated with subclinical atherosclerosis, especially carotid plaque score.
Acknowledgments We thank all staff members of the diabetes team in Otsu Municipal Hospital for their assistance. Funding sources: None. Conflict of interest: Michiaki Fukui has received grants, honoraria and research supports from AstraZeneca plc., Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Company Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. The authors declare that although they are affiliated with a department that is supported financially by pharmaceutical company, the authors received no current funding for this study and this does not alter their adherence to all the journal policies on sharing data and materials. The other authors have nothing to disclose. Contributors: YM contributed to the conception and design, wrote the manuscript, and researched and analyzed data. MI contributed to acquisition of data, critical revision of the manuscript, and analysis and interpretation of data, and approved the final version of the manuscript. AT and YK contributed to acquisition of data. YH and MT contributed to critical revision of the manuscript, and to analysis and interpretation of data. NN and YK contributed to revision of the manuscript. MI contributed to acquisition of data and reviewed the manuscript. MF contributed to critical revision of the manuscript.
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Figure Legends Figure 1. Flow chart of patients in the study.
Highlights ·Limited joint mobility (LJM) of hand is one of a complication of diabetic hand. ·Carotid IMT and plaque score were higher in patients with LJM of hand. ·The presence of LJM of hand was independently associated with carotid plaque score. ·LJM of hand is a useful for assessment of subclinical atherosclerosis.
Table 1. Comparisons of variables in patients with and without LJM of hand No LJM
LJM
269
72
65.1 ± 12.7
72.8± 9.9
< 0.001
60.9
48.6
0.058
Duration of type 2 diabetes (year)
14.1 ± 11.0
17.8 ±12.0
0.017
BMI (kg/m2)
25.1 ± 4.7
23.9 ± 4.6
0.068
Hemoglobin A1c (%)
7.1 ± 1.1
7.5 ± 1.0
< 0.001
68.1 ± 22.3
59.9 ± 23.5
< 0.001
n Age (years) Male (%)
eGFR (ml/min/1.73m2) Creatinine (µmol/L)
75.5 ± 36.1
Uric acid (µmol/L)
324.8 ± 89.8
320.1 ± 95.1
0.699
Current smoking (%)
7.4
11.8
0.209
Hypertension (%)
60.3
77.3
0.006
Dyslipidemia (%)
64.9
72.4
0.211
Retinopathy (%)
32.7
56.5
< 0.001
Neuropathy (%)
38.2
78.9
< 0.001
Nephropathy (%)
44.1
74.7
< 0.001
1.14 ± 0.68
1.45 ± 0.66
0.013
5.4 ± 4.8
8.0 ± 5.3
< 0.001
58
74
0.117
Mean maximum IMT (mm) Plaque score (mm) Vulnerable plaque (%)
80.9 ± 40.0
P
0.272
Continuous variables are presented as the mean value ± 1 SD and skewed variables are presented as a median (interquartile range). Categorical variables are presented as a number (percentage). LJM, Limited joint mobility; BMI, body mass index; eGFR, estimated glomerular filtration rate; IMT, intima-media thickness.
Table 2. Multivariate-regression analysis between LJM of hand and marker of subclinical atherosclerosis. Mean max IMT
Plaque score
β
P
β
P
Age
0.010
0.137
0.040
0.030
Men
0.092
0.150
0.599
0.001
Duration of diabetes
0.001
0.933
0.001
0.944
BMI
0.018
0.326
0.016
0.761
Hemoglobin A1c
0.010
0.883
0.099
0.631
Creatine
0.271
0.134
0.506
0.317
Uric acid
0.039
0.413
0.205
0.136
Current smoking
0.066
0.587
0.210
0.540
Hypertension
0.233
0.001
0.338
0.096
Dyslipidemia
0.073
0.275
0.254
0.189
LJM of hand
0.129
0.077
0.423
0.043
IMT, intima-media thickness; BMI, body mass index; LJM, limited joint mobility.
19
S0168-8227(16)31721-1 http://dx.doi.org/10.1016/j.diabres.2017.07.002 DIAB 7012
To appear in:
Diabetes Research and Clinical Practice
Received Date: Revised Date: Accepted Date:
2 December 2016 9 June 2017 3 July 2017
Please cite this article as: Y. Mineoka, M. Ishii, Y. Hashimoto, M. Tanaka, N. Nakamura, Y. Katsumi, M. Isono, M. Fukui, Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes, Diabetes Research and Clinical Practice (2017), doi: http://dx.doi.org/10.1016/j.diabres.2017.07.002
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Relationship between limited joint mobility of hand and carotid atherosclerosis in patients with type 2 diabetes Running head: Limited joint mobility of hand and atherosclerosis
Yusuke Mineoka, MD, PhD1; Michiyo Ishii, MD, PhD1;Yoshitaka Hashimoto, MD, PhD2; Muhei Tanaka, MD, PhD2; Naoto Nakamura, MD, PhD2,3; Yasukazu Katsumi, MD, PhD4; Motohide Isono, MD, PhD1; Michiaki Fukui, MD, PhD2*
1
Department of Internal Medicine, Otsu Municipal Hospital, Japan
2
Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine,
Graduate School of Medical Science, Japan 3
Department of Internal Medicine, Saiseikai Kyoto Hospital, Japan
4
Department of Orthopedics, Uji Takeda Hospital, Japan
*Corresponding author: Michiaki Fukui M.D. Ph.D. Department of Endocrinology and Metabolism Kyoto Prefectural University of Medicine, Graduate School of Medical Science 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Fax: +81-75-252-3721, Tel: +81-75-251-5505, E-mail: [email protected]
Word count; 2,440 words, Figure; 1, Table; 2.
Abstract Aim: Limited joint mobility (LJM) of hand, which is one of a complication of diabetic hand, has a close association with diabetic microangiopathy. However, it remains to be elucidated about the relationships between LJM of hand and subclinical atherosclerosis in patients with type 2 diabetes. Therefore, we conducted a cross-sectional study to evaluate the relationships between LJM of hand and carotid intima-media thickness (IMT) and plaque score in patients with type 2 diabetes. Methods: We evaluated the relationships between LJM of hand, and carotid IMT and plaque score, evaluated by carotid ultrasound examination, in 341 consecutive patients with type 2 diabetes. LJM of hand was diagnosed using a ‘prayer sign’ or ‘table test’. Results: LJM of hand was present in 72 patients. Carotid IMT and plaque score were higher in patients with LJM of hand than those in patients without (1.45 ± 0.66 vs. 1.14 ± 0.68 mm, P = 0.013 and 8.0 ± 5.3 vs. 5.4 ± 4.8 mm, P <0.001). Multivariate linear regression analysis revealed that LJM of hand was positively correlated with plaque score (β = 0.423, P = 0.043) after adjusted for age, sex, durations of diabetes, body mass index, hemoglobin A1c, creatinine, uric acid, smoking, hypertension and dyslipidemia. Conclusions: Our results demonstrate a relation between LJM of hand and subclinical atherosclerosis, especially plaque score, in patients with type 2 diabetes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes.
Keywords: Screening, Macrovascular disease, Other complications, Type 2 diabetes
Abbrebiations: CVD, Cardiovascular disease; CHD, Chronic heart disease; PAD, Peripheral arterial disease; FRS, Framingham Risk Score; LJM, Limited joint mobility; IMT, Intima-media thickness;
BMI, Body mass index; HbA1c, glycated hemoglobin; eGFR, Estimated glomerular filtration rate.
Introduction Cardiovascular disease (CVD) is the most prevalent cause of morbidity and mortality in patients with diabetes (1) and atherosclerosis is a major risk factor for CVD (2). Type 2 diabetes is known risk for atherosclerosis, leading to non-embolic ischemic stroke (3) and peripheral arterial disease (PAD) (4). To assess the risk for chronic heart disease (CHD) and CVD, traditional risk scores, such as Framingham Risk Score (FRS) and Framingham based risk score, have been widely used, however a previous report indicated that 175 of 1015 patients who classified low risk of FRS had subclinical atherosclerosis (5). Therefore, screening for subclinical atherosclerosis has a critical issue for improving the outcome of high risk patients, including patients with diabetes. ‘Diabetic hand’ is a complication of the upper extremity that manifests as conditions such as limited joint mobility (LJM), Dupuytren's contracture, and trigger finger (6-9). Diabetic hand tends to be ignored in clinical situation (10), in spite of several reports about positive relation between LJM of hand and microvascular complications (6-8,11,12). As for macroangiopathy, only few data was reported about the relation to LJM of hand previously (13,14). It has been reported that the prevalence of history of coronary heart disease and cerebrovascular disease is higher in type 2 diabetic patients with LJM of hand (13) and that there is a relationship between LJM of hand and early atherosclerosis in patients with type 1 diabetes (14). Moreover, little is known about the relationship between diabetic hand and subclinical atherosclerosis in patients with type 2 diabetes mellitus. Therefore, we investigated the relationship between LJM of hand, and carotid intima-media thickness (IMT) and carotid plaque in this cross-sectional study.
Material and methods Study design and patients We included the patients who visited the outpatient clinic of Otsu Municipal Hospital from April
2012 to December 2014 and who were performed carotid ultrasound in this cross-sectional study. Patients were excluded if they had a history of articular rheumatism or surgery for spinal disease. Patients with a history of cardiovascular disease (myocardial infarction, coronary revascularization or stroke) were also excluded. In addition, we excluded the patients who could not be obtained complete results of carotid ultrasound examination. This study was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from all patients. The Ethics Committee of Otsu Municipal Hospital gave approval for this study. All patients provided details of their demographics, medical history and medication usage. Body mass index (BMI) was calculated as weight (kg) divided by height (m2) squared. We classified patients as current smokers or not according to self-administered questionnaire. Retinopathy was assessed by ophthalmologists who were unaware of the severity of other diabetic complications (15). If findings in the left and right fundi were discordant, the worse side was taken as representative of the patient. Neuropathy was defined using the diagnostic criteria for diabetic neuropathy proposed by the Diagnostic Neuropathy Study Group (16). Nephropathy was graded as normoalbuminuria, urine albumin excretion (UAE) <30 mg/g creatinine (Cr); microalbuminuria, 30-300 mg/g Cr; or macroalbuminuria, >300 mg/g Cr. Microalbuminuria and macroalbuminuria were considered to indicate nephropathy.
Measurement of carotid IMT, plaque score Carotid ultrasound examination was performed by a sonographer who was unaware of the participant’s clinical characteristics. Both the left and right common carotid artery, carotid bulb, and internal carotid arteries were scanned using high-resolution B-mode ultrasound scanners (Xario, Toshiba, Inc., Tokyo, Japan), equipped with a 7.5 MHz high-resolution linear array transducer according to recommendations of the American Society of Echocardiography Carotid Intima Media Thickness Task Force (17). Patients were all examined in the supine position with their necks
extended and chins facing the contra lateral side. Intima-media thickness (IMT) was measured in the posterior wall of the carotid artery and was defined as the distance between the leading edge of the lumen-intima echo and the leading edge of the media-adventitia echo in plaque-free area and greater than 75 percentile (17). Significant variation was not revealed in repeated measurements of IMT which were randomly selected. Intra-operator coefficients of variation was 2.4%. Mean maximum IMT was defined as the average of three measurements of the maximum IMTs across the 12 carotid arterial segments: the near and far walls of the distal common, the bifurcation and the proximal internal left and right carotid artery (18). Plaque was defined as IMT of more than 1.2 mm and as a focal thickening of 50% thicker than the neighboring segment (19). Plaque score was defined as the sum of maximum carotid plaque thickness of all plaques (20). Plaque echogenicity was assessed with the criteria of the European Carotid Plaque Study Group (21). Echogenicity is rated on a three-category scale: strong (echo-rich), intermediate, or weak (low echogenicity or echolucency). As previously reported, we defined the weak and intermediate echogenic plaque as the vulnerable plaque and the strong echogenic plaque was considered as stable plaque (22).
Diagnosis of diabetic hand LJM of hand was diagnosed using a ‘prayer sign’ or ‘table test’ (11). Patients with LJM were unable to bring the palms together or place them on a table with full contact when they were asked to close their palms in a praying position with the fingers in contact with each other or to place the palms on a table with the wrists flexed maximally (7,8).
Data collection and measurements Blood samples were drawn in the morning after an overnight fast for measurement of glycated
hemoglobin (HbA1c), total cholesterol, triglycerides, creatinine and uric acid. Blood examinations were performed using a Bio Majesty JCA-BM 6050 (JEOL, Tokyo, Japan). Hypertension was defined as systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg, and/or having received treatment for hypertension. Dyslipidemia was defined as a total cholesterol concentration >5.69 mmol/l, a triglycerides concentration >1.70 mmol/l, and/or having received treatment for dyslipidemia. The estimated glomerular filtration rate (eGFR) was used to estimate kidney function and was calculated as follows (23): Male: eGFR (ml·min–1·1.73m–2) = 0.741 × 175 × age–0.203 × (serum creatinine)–1.154. Female: eGFR = 0.741 × 175 × age–0.203 × (serum creatinine)–1.154 × 0.742.
Statistical analysis Statistical analyses were performed using JMP v. 9.0 (SAS Institute Inc., Cary, NC) and a P value <0.05 was considered statistically significant. Continuous variables were presented as the mean value ± 1 SD. Categorical variables were presented as a number (percentage). The significance of differences between groups were evaluated by unpaired Student t-test or Pearson χ2 test. Multivariate linear regression analyses were used to adjust factors of relationship between LJM of hand and markers of subclinical atherosclerosis. We selected covariates which were known interest for multivariate analysis; age, sex, duration of diabetes, BMI, HbA1c, creatinine, uric acid, current smoking, hypertension and dyslipidemia.
Results We included 399 consecutive patients with type 2 diabetes in this study. Among them, 47 were excluded because of history of cardiovascular events, 8 were excluded because of histories of articular rheumatism or surgery for spinal disease and 3 were excluded because of incomplete results of carotid ultrasound examination (Figure 1). The clinical characteristics of 341 patients (199 male and 142 female) with type 2 diabetes are shown in Table 1.
LJM of hand was present in 72 patients, and in univariate analysis, these patients had significantly older age, worse glycaemic control, a longer duration of diabetes and, worse renal function and microvascular complications. (Table 1). Carotid IMT in patients with LJM of hand was higher than that in patients without (1.45 ± 0.66 mm vs. 1.14 ± 0.68 mm, P = 0.013), and same result was obtained as to carotid plaque score (8.0 ± 5.3 mm vs. 5.4 ± 4.8 mm, P <0.001). The proportion of vulnerable plaque had tended to be higher in patients with LJM of hand, but significant difference was not found (74% vs. 58% P = 0.117) (Table 1). Multivariate linear regression analyses revealed that LJM of hand was positively correlated with carotid plaque score (β = 0.423, P = 0.043) (Table 2). In addition, LJM of hand was also tended to be correlated with mean maximum IMT (β = 0.129, P = 0.077), although it did not reach statistical significance.
Discussion In this study, we evaluated the relationships between LJM of hand and subclinical atherosclerosis, such as carotid IMT and plaque score in patients with type 2 diabetes and showed that LJM of hand correlated with subclinical atherosclerosis, especially carotid plaque score. LJM of hand is one of the complications of ‘Diabetic Hand’ which is tended to be overlooked recently (10). Relationship between diabetic hand, especially LJM of hand, and microvascular complications were reported previously (6-8,10-12). In contrast, only few study has been reported the relation between LJM of hand and macroangiopathy (13) or subclinical atherosclerosis (14). Carotid IMT and plaque score represent components of carotid atherosclerosis, and also the established marker for predicting CHD, atherosclerotic heart disease and stroke (24, 25), while the difference between IMT and plaque score has been mentioned. The result from meta-analysis revealed that carotid plaque was a typical phenotype of atherosclerosis and had higher accuracies for the prediction of future myocardial infarction and for the detection of coronary artery disease,
compared with carotid IMT (26). Carotid plaques indicate a later stage of atherogenesis which is related to inflammation, endothelial dysfunction, oxidative stress, and smooth muscle cell proliferation (27). In this study, both of carotid IMT and plaque score in patients with LJM of hand was higher than patients without LJM of hand, however multivariate linear regression analyses indicated that LJM of hand was positively correlated with carotid plaque score, whereas no significant relation was found between LJM of hand and IMT. Previous report indicated that IMT was influenced by genetic determinants, but plaque is determined by CHD risk factors such as age, hypertension, dyslipidemia and diabetes mellitus (28). Progression of plaque score is more affected with the duration of diabetes (29). In patients with dialysis, differential association was reported between traditional and non-traditional risk factors with carotid IMT and plaque formation (30). Taken together, our study suggested that LJM of hand reflects carotid plaque formation rather than thickening of intima-media layer. As to plaque echogenicity, vulnerable plaque, especially echolucent plaque, was reported to have predictive value for occurrence of stroke (20). In this study, no significant difference was found about the proportion of vulnerable plaques, however this might be because of relatively few cases of carotid stenosis and echolucent plaques. Macroangiopathy and LJM of hand have common background factors, including a long duration of diabetes, poor metabolic control, and microvascular complications (7,8,31). Though, the precise mechanism of LJM of hand was not fully understood, several mechanisms were proposed previously; genetic components (32), microvascular complications and an increase of advanced glycosylation end-products (AGEs) which lead to skin thickening and formation of nodules (33). Increased collagen deposition in the skin and musculoskeletal connective tissues of hand are thought to be results from overproduction of growth factors and cytokines such as transforming growth factor-beta (34). Those mechanisms might be also related to both LJM of hand and macrovascular complications
of diabetes (35,36). Overall, the differences between the result of mean max IMT and that of carotid plaque in our study suggested that LJM of hand might be a marker for advanced atheroma formation and atherosclerosis in patients with type 2 diabetes mellitus. This study has several limitations. First, the cross-sectional design only permits inference of the causal relationships between LJM of hand and subclinical atherosclerosis. Second, we did not investigate other “Diabetic hand”, such as Dupuytren’s contracture and carpal tunnel syndrome in this study. However, it is likely that these hand syndromes might be associated with subclinical atherosclerosis, because of the involvement of the same pathologies (36). Third, although we included all the patients who received ultrasonic examination of carotid artery, ultrasonic examination of carotid artery was part of the comprehensive care delivered to each patient with diabetes. Thus, there is a possibility of selection bias for the percentage of LJM of hand. However, the selection bias might be small because the percentage of LJM in this study was almost the same as the other studies (9,12). Finally the patients in this study were relatively small number and all Japanese, therefore, it is uncertain whether this finding can be applied more broadly to other populations. In addition, we only investigated the association between LJM of hand and carotid intima-media thickness (IMT) or carotid plaque. Thus, further studies would be needed for the association between LJM of hand and another parameter of early vascular changes. Diagnosis of diabetic hand is simple and non-invasive, and thus is a useful method for assessment of subclinical atherosclerosis in patients with type 2 diabetes. In a clinical situation, it is important to measure carotid IMT or plaque directly by noninvasive echography as an established surrogate marker for concomitant cardiovascular diseases or predictors. In conclusion, LJM of hand correlated with subclinical atherosclerosis, especially carotid plaque score.
Acknowledgments We thank all staff members of the diabetes team in Otsu Municipal Hospital for their assistance. Funding sources: None. Conflict of interest: Michiaki Fukui has received grants, honoraria and research supports from AstraZeneca plc., Astellas Pharma Inc., Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Ltd., Eli Lilly Japan K.K., Kyowa Hakko Kirin Company Ltd., Kissei Pharmaceutical Co., Ltd., MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Sanwa Kagaku Kenkyusho Co., Ltd., Sanofi K.K., Ono Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. The sponsors were not involved in the study design; in the collection, analysis, interpretation of data; in the writing of this manuscript; or in the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article. The authors declare that although they are affiliated with a department that is supported financially by pharmaceutical company, the authors received no current funding for this study and this does not alter their adherence to all the journal policies on sharing data and materials. The other authors have nothing to disclose. Contributors: YM contributed to the conception and design, wrote the manuscript, and researched and analyzed data. MI contributed to acquisition of data, critical revision of the manuscript, and analysis and interpretation of data, and approved the final version of the manuscript. AT and YK contributed to acquisition of data. YH and MT contributed to critical revision of the manuscript, and to analysis and interpretation of data. NN and YK contributed to revision of the manuscript. MI contributed to acquisition of data and reviewed the manuscript. MF contributed to critical revision of the manuscript.
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Figure Legends Figure 1. Flow chart of patients in the study.
Highlights ·Limited joint mobility (LJM) of hand is one of a complication of diabetic hand. ·Carotid IMT and plaque score were higher in patients with LJM of hand. ·The presence of LJM of hand was independently associated with carotid plaque score. ·LJM of hand is a useful for assessment of subclinical atherosclerosis.
Table 1. Comparisons of variables in patients with and without LJM of hand No LJM
LJM
269
72
65.1 ± 12.7
72.8± 9.9
< 0.001
60.9
48.6
0.058
Duration of type 2 diabetes (year)
14.1 ± 11.0
17.8 ±12.0
0.017
BMI (kg/m2)
25.1 ± 4.7
23.9 ± 4.6
0.068
Hemoglobin A1c (%)
7.1 ± 1.1
7.5 ± 1.0
< 0.001
68.1 ± 22.3
59.9 ± 23.5
< 0.001
n Age (years) Male (%)
eGFR (ml/min/1.73m2) Creatinine (µmol/L)
75.5 ± 36.1
Uric acid (µmol/L)
324.8 ± 89.8
320.1 ± 95.1
0.699
Current smoking (%)
7.4
11.8
0.209
Hypertension (%)
60.3
77.3
0.006
Dyslipidemia (%)
64.9
72.4
0.211
Retinopathy (%)
32.7
56.5
< 0.001
Neuropathy (%)
38.2
78.9
< 0.001
Nephropathy (%)
44.1
74.7
< 0.001
1.14 ± 0.68
1.45 ± 0.66
0.013
5.4 ± 4.8
8.0 ± 5.3
< 0.001
58
74
0.117
Mean maximum IMT (mm) Plaque score (mm) Vulnerable plaque (%)
80.9 ± 40.0
P
0.272
Continuous variables are presented as the mean value ± 1 SD and skewed variables are presented as a median (interquartile range). Categorical variables are presented as a number (percentage). LJM, Limited joint mobility; BMI, body mass index; eGFR, estimated glomerular filtration rate; IMT, intima-media thickness.
Table 2. Multivariate-regression analysis between LJM of hand and marker of subclinical atherosclerosis. Mean max IMT
Plaque score
β
P
β
P
Age
0.010
0.137
0.040
0.030
Men
0.092
0.150
0.599
0.001
Duration of diabetes
0.001
0.933
0.001
0.944
BMI
0.018
0.326
0.016
0.761
Hemoglobin A1c
0.010
0.883
0.099
0.631
Creatine
0.271
0.134
0.506
0.317
Uric acid
0.039
0.413
0.205
0.136
Current smoking
0.066
0.587
0.210
0.540
Hypertension
0.233
0.001
0.338
0.096
Dyslipidemia
0.073
0.275
0.254
0.189
LJM of hand
0.129
0.077
0.423
0.043
IMT, intima-media thickness; BMI, body mass index; LJM, limited joint mobility.
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