European Journal of Neurology 2014, 21: 667–673
doi:10.1111/ene.12374
Visceral fat accumulation is associated with cerebral small vessel disease K. Yamashiroa, R. Tanakaa, Y. Tanakab, N. Miyamotoc, Y. Shimadaa, Y. Uenoc, T. Urabec and N. Hattoria a
Department of Neurology, Juntendo University School of Medicine, Tokyo; bDepartment of Neurology, Tokyo Rinkai Hospital, Tokyo; and cDepartment of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
Keywords:
cerebral small vessel disease, lacunar infarct, obesity Received 28 August 2013 Accepted 27 December 2013
Background and purpose: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. Methods: This study comprised 506 Japanese subjects 35–74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm2. Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). Results: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm2 than those with VFA < 100 cm2. A VFA ≥ 100 cm2 was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. Conclusions: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.
Introduction The prevalence of obesity has increased globally since 1980 and the increase has accelerated. The global age-standardized prevalence of obesity nearly doubled from 6.4% in 1980 to 12.0% in 2008 and half of this rise occurred in the 8 years between 2000 and 2008. In absolute numbers, 508 million people worldwide were obese in 2008 [1]. Obesity is an important risk factor for cardiovascular disease [2]. Abdominal obesity, measured by the waist-to-hip ratio, waist-to-height ratio or waist circumference (WC), is more strongly associated with the risk of Correspondence: R. Tanaka, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan (tel.: +81 3 3813 3111; fax: +81 3 5800 0547; email: [email protected]).
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
coronary artery disease [3] and stroke [4–6] than the body mass index (BMI), a marker of general obesity. Furthermore, this association is independent of other vascular risk factors. It is considered that visceral fat plays a significant role in the atherogenic effects of obesity [7]. Visceral fat accumulation, as measured by computed tomography (CT), has been shown to be independently associated with coronary artery disease [8,9]. The presence of cerebral small vessel disease (SVD), such as white matter lesions (WMLs) and silent lacunar infarction (SLI), is a risk factor for cognitive decline, stroke and death [10–12]. Although one previous study has demonstrated an association between a large WC and SLI [13], other studies found no independent association of the presence of WMLs with a large WC [14,15] or increased BMI [16]. To date, little
667
668
K. Yamashiro et al.
is known about the association of visceral fat accumulation with the presence of WMLs and SLI. Our aim in the present study was to investigate whether visceral fat accumulation, as measured by CT, was an independent risk factor for the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.
Methods Subjects A total of 1068 consecutive subjects working at information technology companies and their families underwent health screening tests including abdominal CT and carotid echography at the TJK Health Center, Tokyo, Japan, between April 2002 and January 2007. Of these, 522 subjects also underwent brain magnetic resonance imaging (MRI). After excluding 16 subjects with a history of symptomatic cerebrovascular disease, 506 subjects 35–74 years of age (mean 55.3 years) were examined in the present study. The study was approved by the local ethics committee. Risk factors
Hypertension was defined as having a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or taking antihypertensive treatment. Diabetes mellitus was defined as having a fasting blood glucose level ≥126 mg/dl and/or an HbA1c level ≥6.5% and/or using insulin or oral hypoglycemics. Dyslipidemia was defined as having a total cholesterol level ≥220 mg/dl and/or a triglyceride level ≥150 mg/dl and/or using lipid-lowering medication. The subjects were considered current smokers if they had at least one cigarette a day within the previous year. The WC was measured at the umbilicus. A large WC was defined as ≥88 cm in females and ≥102 cm in males as proposed in the NCEP-ATP III report [17]. A specific value for large WC (≥90 cm in females and ≥85 cm in males) proposed by the Japanese Society for the Study of Obesity was also used [18]. The BMI was calculated from height and weight measurements. In addition to a BMI of ≥30 kg/m2, a BMI of ≥25 kg/m2 was also used to define obesity according to the criteria for the diagnosis of ‘obesity disease’ in Japan [18]. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by CT (Aquilion, Toshiba, Japan) at the level of the umbilicus, as reported previously [19]. The subjects were divided into those with VFA ≥ 100 cm2 and those with VFA < 100 cm2 according to the criteria for obesity disease in Japan [18] to examine the effects of visceral fat accumulation. The subjects were
also stratified according to the median value of SFA and the total volume of VFA and SFA in order to examine the effects of subcutaneous fat accumulation and the combination of visceral fat and subcutaneous fat accumulation. Carotid echography
High-resolution B-mode ultrasonography of both carotid arteries was performed using an ultrasound scanner (Aplio 80, Toshiba, Tokyo, Japan) equipped with a linear 7.5 MHz transducer. The plaque score was measured by the methods proposed by Handa et al. [20]. The carotid arteries were scanned bilaterally at four segments (S1, the region of the internal carotid artery 1.0 mm. The plaque score was computed by adding the maximum thickness of the intima-media complex measured in millimeters on the near and far wall at each of four segments on both sides of the carotid arteries. Brain MRI
Brain MRI was performed using a 1.5 T MR system (Avanto, Siemens, Erlangen, Germany) and the whole brain was scanned at a slice thickness of 8 mm and an interslice gap of 1.5 mm, obtaining 15 axial images. The imaging protocol consisted of T1weighted (TR/TE = 2000/7.9 ms), T2-weighted (TR/ TE = 3070/102 ms) and fluid-attenuated inversion recovery (FLAIR) (TR/TE = 7000/104 ms, inversion time 2300 ms). SLI was defined as a small (3–15 mm in diameter) lesion with high signal intensity on T2weighted images and low signal intensity on T1weighted and FLAIR images. WMLs were graded according to the Atherosclerosis Risk in Communities (ARIC) Study [21] as follows: no white matter signal abnormalities (grade 0); discontinuous periventricular rim or minimal ‘dots’ of subcortical white matter (grade 1); thin continuous periventricular rim or a few patches of subcortical WMLs (grade 2); thicker continuous periventricular rim with scattered patches of subcortical WMLs (grade 3); thicker, shaggier periventricular rim with mild subcortical WMLs may have minimal confluent periventricular lesions (grade 4); © 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Visceral fat and cerebral small vessel disease
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mild periventricular confluence surrounding the frontal and occipital horns (grade 5); moderate periventricular confluence surrounding the frontal and occipital horns (grade 6); periventricular confluence with moderate involvement of the centrum semiovale (grade 7); periventricular confluence involving most of the centrum semiovale (grade 8); and all white matter involved (grade 9).
sion analyses, two regression models were used. In model 1, a large WC (defined as ≥88 cm in females and ≥102 cm in males) and a BMI ≥ 30 kg/m2 were entered. In model 2, a large WC (defined as ≥90 cm in females and ≥85 cm in males) and a BMI ≥ 25 kg/m2 were entered. The JMP Version 9.0 software program (SAS Inc., Cary, NC, USA) was used for the data analysis.
Statistical analysis
Results
Continuous variables are presented as the mean SD. Categorical variables are presented as the absolute numbers and percentages. The v2 test was used to compare the frequency distributions of categorical variables between the two groups. Continuous variables were compared using Student’s t test or the Mann– Whitney U test, as appropriate, after normality distribution testing. A logistic regression analysis was used to assess the association between the presence of WMLs and SLI and the VFA, SFA, WC, BMI and cardiovascular risk factors. In the multivariate regres-
The subject characteristics are listed in Table 1. Cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking, were significantly higher in subjects with VFA ≥ 100 cm2 than in those with VFA < 100 cm2. In addition, the blood pressure, fasting glucose, HbA1c, high-density lipoprotein cholesterol and triglyceride levels but not those of total cholesterol and low-density lipoprotein cholesterol were significantly different between the groups. Table 2 shows comparisons of cerebral SVD and carotid atherosclerosis between the subjects with VFA ≥
Table 1 Characteristics of the study subjects Age, years Male, n (%) VFA, cm2 SFA, cm2 BMI, kg/m2 WC, cm Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Current smokers, n (%) SBP, mmHg DBP, mmHg Fasting glucose, mg/dl HbA1c,% Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglyceride, mg/dl Medications Antihypertensive agents, n (%) Hypoglycemic agents, n (%) Lipid-lowering agents, n (%)
All subjects n = 506
VFA ≥ 100 cm2 n = 117
VFA < 100 cm2 n = 389
P value
55.3 8.8 361 (71) 69.9 43.2 136.6 101.7 24.1 3.2 88.0 8.4 168 (33) 51 (10) 304 (60) 71 (14) 121.2 17.7 75.1 11.1 104.0 27.6
57.2 8.3 100 (85) 132.6 29.6 167.6 79.9 27.3 3.0 96.8 7.0 61 (52) 28 (24) 89 (76) 24 (21) 127.4 14.6 79.4 10.0 114.7 29.6
54.7 8.9 261 (67) 51.0 24.9 127.3 105.7 23.1 2.6 85.4 6.9 107 (28) 23 (6) 215 (55) 47 (12) 119.3 18.1 73.8 11.1 100.7 26.2
0.008 0.0001
doi:10.1111/ene.12374
Visceral fat accumulation is associated with cerebral small vessel disease K. Yamashiroa, R. Tanakaa, Y. Tanakab, N. Miyamotoc, Y. Shimadaa, Y. Uenoc, T. Urabec and N. Hattoria a
Department of Neurology, Juntendo University School of Medicine, Tokyo; bDepartment of Neurology, Tokyo Rinkai Hospital, Tokyo; and cDepartment of Neurology, Juntendo University Urayasu Hospital, Chiba, Japan
Keywords:
cerebral small vessel disease, lacunar infarct, obesity Received 28 August 2013 Accepted 27 December 2013
Background and purpose: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. Methods: This study comprised 506 Japanese subjects 35–74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA ≥ 100 cm2. Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). Results: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA ≥ 100 cm2 than those with VFA < 100 cm2. A VFA ≥ 100 cm2 was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. Conclusions: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.
Introduction The prevalence of obesity has increased globally since 1980 and the increase has accelerated. The global age-standardized prevalence of obesity nearly doubled from 6.4% in 1980 to 12.0% in 2008 and half of this rise occurred in the 8 years between 2000 and 2008. In absolute numbers, 508 million people worldwide were obese in 2008 [1]. Obesity is an important risk factor for cardiovascular disease [2]. Abdominal obesity, measured by the waist-to-hip ratio, waist-to-height ratio or waist circumference (WC), is more strongly associated with the risk of Correspondence: R. Tanaka, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan (tel.: +81 3 3813 3111; fax: +81 3 5800 0547; email: [email protected]).
© 2014 The Author(s) European Journal of Neurology © 2014 EFNS
coronary artery disease [3] and stroke [4–6] than the body mass index (BMI), a marker of general obesity. Furthermore, this association is independent of other vascular risk factors. It is considered that visceral fat plays a significant role in the atherogenic effects of obesity [7]. Visceral fat accumulation, as measured by computed tomography (CT), has been shown to be independently associated with coronary artery disease [8,9]. The presence of cerebral small vessel disease (SVD), such as white matter lesions (WMLs) and silent lacunar infarction (SLI), is a risk factor for cognitive decline, stroke and death [10–12]. Although one previous study has demonstrated an association between a large WC and SLI [13], other studies found no independent association of the presence of WMLs with a large WC [14,15] or increased BMI [16]. To date, little
667
668
K. Yamashiro et al.
is known about the association of visceral fat accumulation with the presence of WMLs and SLI. Our aim in the present study was to investigate whether visceral fat accumulation, as measured by CT, was an independent risk factor for the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease.
Methods Subjects A total of 1068 consecutive subjects working at information technology companies and their families underwent health screening tests including abdominal CT and carotid echography at the TJK Health Center, Tokyo, Japan, between April 2002 and January 2007. Of these, 522 subjects also underwent brain magnetic resonance imaging (MRI). After excluding 16 subjects with a history of symptomatic cerebrovascular disease, 506 subjects 35–74 years of age (mean 55.3 years) were examined in the present study. The study was approved by the local ethics committee. Risk factors
Hypertension was defined as having a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg and/or taking antihypertensive treatment. Diabetes mellitus was defined as having a fasting blood glucose level ≥126 mg/dl and/or an HbA1c level ≥6.5% and/or using insulin or oral hypoglycemics. Dyslipidemia was defined as having a total cholesterol level ≥220 mg/dl and/or a triglyceride level ≥150 mg/dl and/or using lipid-lowering medication. The subjects were considered current smokers if they had at least one cigarette a day within the previous year. The WC was measured at the umbilicus. A large WC was defined as ≥88 cm in females and ≥102 cm in males as proposed in the NCEP-ATP III report [17]. A specific value for large WC (≥90 cm in females and ≥85 cm in males) proposed by the Japanese Society for the Study of Obesity was also used [18]. The BMI was calculated from height and weight measurements. In addition to a BMI of ≥30 kg/m2, a BMI of ≥25 kg/m2 was also used to define obesity according to the criteria for the diagnosis of ‘obesity disease’ in Japan [18]. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by CT (Aquilion, Toshiba, Japan) at the level of the umbilicus, as reported previously [19]. The subjects were divided into those with VFA ≥ 100 cm2 and those with VFA < 100 cm2 according to the criteria for obesity disease in Japan [18] to examine the effects of visceral fat accumulation. The subjects were
also stratified according to the median value of SFA and the total volume of VFA and SFA in order to examine the effects of subcutaneous fat accumulation and the combination of visceral fat and subcutaneous fat accumulation. Carotid echography
High-resolution B-mode ultrasonography of both carotid arteries was performed using an ultrasound scanner (Aplio 80, Toshiba, Tokyo, Japan) equipped with a linear 7.5 MHz transducer. The plaque score was measured by the methods proposed by Handa et al. [20]. The carotid arteries were scanned bilaterally at four segments (S1, the region of the internal carotid artery 1.0 mm. The plaque score was computed by adding the maximum thickness of the intima-media complex measured in millimeters on the near and far wall at each of four segments on both sides of the carotid arteries. Brain MRI
Brain MRI was performed using a 1.5 T MR system (Avanto, Siemens, Erlangen, Germany) and the whole brain was scanned at a slice thickness of 8 mm and an interslice gap of 1.5 mm, obtaining 15 axial images. The imaging protocol consisted of T1weighted (TR/TE = 2000/7.9 ms), T2-weighted (TR/ TE = 3070/102 ms) and fluid-attenuated inversion recovery (FLAIR) (TR/TE = 7000/104 ms, inversion time 2300 ms). SLI was defined as a small (3–15 mm in diameter) lesion with high signal intensity on T2weighted images and low signal intensity on T1weighted and FLAIR images. WMLs were graded according to the Atherosclerosis Risk in Communities (ARIC) Study [21] as follows: no white matter signal abnormalities (grade 0); discontinuous periventricular rim or minimal ‘dots’ of subcortical white matter (grade 1); thin continuous periventricular rim or a few patches of subcortical WMLs (grade 2); thicker continuous periventricular rim with scattered patches of subcortical WMLs (grade 3); thicker, shaggier periventricular rim with mild subcortical WMLs may have minimal confluent periventricular lesions (grade 4); © 2014 The Author(s) European Journal of Neurology © 2014 EFNS
Visceral fat and cerebral small vessel disease
669
mild periventricular confluence surrounding the frontal and occipital horns (grade 5); moderate periventricular confluence surrounding the frontal and occipital horns (grade 6); periventricular confluence with moderate involvement of the centrum semiovale (grade 7); periventricular confluence involving most of the centrum semiovale (grade 8); and all white matter involved (grade 9).
sion analyses, two regression models were used. In model 1, a large WC (defined as ≥88 cm in females and ≥102 cm in males) and a BMI ≥ 30 kg/m2 were entered. In model 2, a large WC (defined as ≥90 cm in females and ≥85 cm in males) and a BMI ≥ 25 kg/m2 were entered. The JMP Version 9.0 software program (SAS Inc., Cary, NC, USA) was used for the data analysis.
Statistical analysis
Results
Continuous variables are presented as the mean SD. Categorical variables are presented as the absolute numbers and percentages. The v2 test was used to compare the frequency distributions of categorical variables between the two groups. Continuous variables were compared using Student’s t test or the Mann– Whitney U test, as appropriate, after normality distribution testing. A logistic regression analysis was used to assess the association between the presence of WMLs and SLI and the VFA, SFA, WC, BMI and cardiovascular risk factors. In the multivariate regres-
The subject characteristics are listed in Table 1. Cardiovascular risk factors, such as hypertension, diabetes mellitus, dyslipidemia and smoking, were significantly higher in subjects with VFA ≥ 100 cm2 than in those with VFA < 100 cm2. In addition, the blood pressure, fasting glucose, HbA1c, high-density lipoprotein cholesterol and triglyceride levels but not those of total cholesterol and low-density lipoprotein cholesterol were significantly different between the groups. Table 2 shows comparisons of cerebral SVD and carotid atherosclerosis between the subjects with VFA ≥
Table 1 Characteristics of the study subjects Age, years Male, n (%) VFA, cm2 SFA, cm2 BMI, kg/m2 WC, cm Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Current smokers, n (%) SBP, mmHg DBP, mmHg Fasting glucose, mg/dl HbA1c,% Total cholesterol, mg/dl LDL cholesterol, mg/dl HDL cholesterol, mg/dl Triglyceride, mg/dl Medications Antihypertensive agents, n (%) Hypoglycemic agents, n (%) Lipid-lowering agents, n (%)
All subjects n = 506
VFA ≥ 100 cm2 n = 117
VFA < 100 cm2 n = 389
P value
55.3 8.8 361 (71) 69.9 43.2 136.6 101.7 24.1 3.2 88.0 8.4 168 (33) 51 (10) 304 (60) 71 (14) 121.2 17.7 75.1 11.1 104.0 27.6
57.2 8.3 100 (85) 132.6 29.6 167.6 79.9 27.3 3.0 96.8 7.0 61 (52) 28 (24) 89 (76) 24 (21) 127.4 14.6 79.4 10.0 114.7 29.6
54.7 8.9 261 (67) 51.0 24.9 127.3 105.7 23.1 2.6 85.4 6.9 107 (28) 23 (6) 215 (55) 47 (12) 119.3 18.1 73.8 11.1 100.7 26.2
0.008 0.0001
