Comparing associations of different metabolic syndrome definitions with ischemic stroke in Chinese elderly population

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Original Article

Comparing associations of different metabolic syndrome definitions with ischemic stroke in Chinese elderly population Qian Liua, Yan-xun Lia, Zhi-hao Hua, Xiao-yan Jiangb, Shu-juan Lia,⁎,1, Xiao-feng Wangc,⁎⁎ a b c

Department of Neurology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China Department of Pathology and Pathophysiology, School of Medicine, Tongji University, Shanghai 200092,China College of Life Sciences, Fudan University, Shanghai 200433, China

A R T I C L E I N F O

A B S T R A C T

Keywords: Metabolic syndrome Hypertension Diabetes Obesity Ischemic stroke

Objectives: Studies have showed the associations between different definitions of metabolic syndrome (MetS) and risk of ischemic stroke were inconsistent. In this study, we compared associations of different MetS definitions with ischemic stroke in Chinese elderly population. Methods: A total of 1713 individuals aged 70–84 years from Rugao Longevity and Ageing Study were analyzed. The MetS was defined by four different criteria: Chinese Adult Dyslipidemia Prevention Guide, International Diabetes Federation (IDF), Updated ATPIII (Updated ATPIII) by American heart association/American heart, lung and blood institute (AHA/NHLBI), and Joint Interim Statement(JIS) recommended by IDF and the American heart association/American national institutes of health/American heart, lung and blood institute (AHA/NIH/NHLBI). Results: Prevalence of MetS in the whole population was 24.0% (Chinese guide), 32.5% (IDF), 38.8% (Updated ATPIII) and 24.0% (JIS) and in stroke population was 27.1% (Chinese guide), 41.1% (IDF), 48.8% (Updated ATPIII) and 27.1% (JIS), respectively. The agreement between definitions was highest in Updated ATPIII vs. IDF (kappa = 0.863). It showed that only definitions of IDF (OR 1.55, 95%CI 1.04–2.31, p = 0.031) and Updated ATPIII (OR 1.64, 95%CI 1.11–2.42, p = 0.013) were independently associated with risk of ischemic stroke in multivariable logistic regression analysis. The risk of ischemic stroke increased with the increasing of numbers of Mets components in Updated ATPIII (p < 0.05). Conclusion: In this population, Updated ATPIII criteria was a more suitable definition of Mets than definitions of Chinese guide, IDF and JIS for screening high-risk individuals of ischemic stroke, and the additive effects of Mets components might play a greater role than its composition alone in ischemic stroke.

In recent years, the prevalence of cardiovascular disease increased greatly all over the world with the development of economy and changes of lifestyle. And it was often found the risk factors of cardiovascular disease concentrated in an individual at one time, which gradually put forward a concept of metabolic syndrome (MetS) [1–2]. MetS refers to a pathological state that various vascular risk factors and metabolic abnormalities gathered and mutually connected, mainly including hyperglycemia, raised blood pressure, elevated triglycerides, low high-density lipoprotein cholesterol, and obesity (particularly central obesity) [3]. Epidemiological studies have shown an increased rate of Mets in the world, especially increased with the population ageing [4–5]. In addition, as an aggregation of risk factors, Mets is also

an important independent risk factor of cardiovascular disease, and closely related to the progression and poor prognosis of cardiovascular disease [6–7]. Brola's study showed the prevalence of Mets in acute ischemic stroke patient was significantly higher than in patients with other neurologic disorders (61.2% vs. 18.1%), which indicated Mets was strongly associated with ischemic stroke [8]. Moreover, studies have reported that individuals with MetS could have more than two fold increased the risk of ischemic stroke, and the risk for ischemic stroke also increased with the increasing of Mets components [9–10]. However, there were studies showing that the predicted risk for ischemic stroke was inconsistent in different definitions of Mets [11–13]. And previous study has shown that specific definition of the Mets

⁎

Correspondence to: S. Li, Department of Neurology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China. Correspondence to: X. Wang, Unit of Epidemiology, State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, 220 Handan Rd, Shanghai 200433, China. E-mail addresses: [email protected] (S.-j. Li), [email protected], [email protected] (X.-f. Wang). 1 Please contact Dr. Shujuan Li for the proofs and payment. ⁎⁎

http://dx.doi.org/10.1016/j.ejim.2017.10.010 Received 1 July 2017; Received in revised form 1 October 2017; Accepted 11 October 2017 0953-6205/ © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Liu, Q., European Journal of Internal Medicine (2017), http://dx.doi.org/10.1016/j.ejim.2017.10.010

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predicts cardio-cerebrovascular events in elderly population while other definition does not [14]. Therefore, this study was aimed to compare the associations of different definitions of Mets with ischemic stroke, which endeavored to identify a more favorable definition of Mets for Chinese ischemic stroke patient. The academic organizations and authorities in many countries have put forward and constantly updated their own diagnostic criteria of Mets according to their understanding about the Mets and their people's characteristics. Almost all those criteria include obesity, hyperglycemia, hypertension, dyslipidemia and insulin resistance as its evaluation contents, and the main disparities lie in the different thresholds for obesity and whether the abdominal obesity should be treat as a prerequisite [15]. The Mets definitions of international diabetes federation (IDF) [16] and the updated ATPIII criteria by American heart association/American heart, lung and blood institute (AHA/NHLBI) in 2005 [17] were the most widely recognized and used in the world nowadays [18–19]. The Joint Interim Statement(JIS) was jointly recommended by international diabetes federation (IDF) and the American heart association/American national institutes of health/American heart, lung and blood institute (AHA/NIH/NHLBI) in 2009, which remained the components of Updated ATPIII criteria but further put forward different cut points of waist circumference for different regions and ethnic groups [1,20–21]. The main difference between IDF and Updated ATPIII was whether the abdominal obesity should be a prerequisite for Mets [17], and between Updated ATPIII and JIS was different thresholds for abdominal obesity [1]. Our revised Chinese Adult Dyslipidemia Prevention Guide (Chinese guide) in 2016 was an update for Chinese Adult Dyslipidemia Prevention Guide 2007, whose cut points of waist circumference, high-density lipoprotein cholesterol and hyperglycemia differed from the IDF and JIS, and were considered more favorable for Chinese individuals [22]. In the ageing arm of the RuLAS, we explored the prevalence of four different Mets definitions (Chinese guide, IDF, updated ATPIII and JIS) and their association with ischemic stroke in the elderly, which aimed to determine a more favorable definition of Mets for Chinese ischemic stroke patient.

participants who smoked at least 1 cigarette per day or used to smoke > 5 years. Drinking was defined as participants who drank > 3 drinks per week within 5 years. Blood pressure was measured twice at interval of 5 min in the right arm in a sitting position, and the mean value of the two measurements was taken as the final blood pressure recording. Body height and weight were measured with subjects not wearing shoes or outerwear. Waist circumference (WC) was measured by placing a soft tape horizontally midway between the lower border of the ribs and iliac crest on the mid-axillary line. Body mass index (BMI) was calculated using body weight (kilograms) divided by the square of body height (m2). According to the 2016 revised Chinese Adult Dyslipidemia Prevention Guide, cut-off points for general obesity were with BMI ≥ 28 kg/m2 for both genders, and cut-off points for central obesity was with WC ≥ 90 for male and ≥85 cm for female [22]. Also, according to the 2016 revised Chinese Adult Dyslipidemia Prevention Guide, the dyslipidemia were divided into two categories: serum total cholesterol (TC) ≥ 5.2 mmol/l was defined as high total cholesterol (HTC), high-density lipoproteins (HDL) < 1.0 mmol/l was defined as low high-density lipoproteins (L-HDL), low-density lipoproteins (LDL) ≥ 3.4 mmol/l was defined as high low-density lipoproteins (HLDL) and triglyceride (TG) ≥ 1.7 mmol/l was defined as high triglyceride (H-TG), while otherwise above were classified as normal [22].

1. Materials and methods

Descriptive statistics were given as percentages or mean ± standard deviation (SD). Independent numeric variables were compared using independent t-test. Chi-squared test was used for comparing categorical variables in groups. The Kappa analysis was used to identify the agreement between four Mets definitions. The Logistic regression analysis was used to analyze associations between different Mets definition and their components and ischemic stroke. The odds ratio (OR) values and its 95% confidence interval (95%CI) in Model 1 (original model) and Model 2 (adjusting for gender, age, smoking and alcohol consumption) were recorded. All statistical tests were two-sided. A p value of < 0.05 was considered statistically significant. All statistical tests were carried out using SPSS 19 (Statistical Package for the Social Sciences, Inc., Chicago, IL, USA).

1.3. Definition of metabolic syndrome and stroke In the present study, we defined MetS using the following four definitions: revised Chinese Adult Dyslipidemia Prevention Guide in 2016 [22], IDF in 2005 [16], Updated ATPIII in 2005 [17] and JIS in 2009 [1] (more details see Table 1). Ischemic stroke was diagnosed according to past ischemic stroke medical history with typical symptoms or brain imaging of computed tomography (CT) and magnetic resonance imaging (MRI). Those with a specific symptoms or infarction imaging were divided into stroke group, and otherwise were control group. 1.4. Statistical analysis

1.1. Study population and procedure We obtained the data from the ageing arm of the RuLAS, a population-based observational cohort study conducted in Rugao, a typical, medium-sized city of Jiangsu province, China, between November 13, 2014 and December 21, 2014. A total of 1788 elderly were randomly selected according to 5-year age and sex strata, among which 1713 participants who fulfilled the data of stoke history and Mets definitions were included in this study. During the field survey, detailed structured questionnaire and physical examinations were administered by trained physicians from the Rugao People's Hospital. More detailed information about the study was provided in our previous publication [23]. Written informed consent was obtained from participants. The Human Ethnics Committee of Fudan University School of Life Sciences approved the research.

2. Results 2.1. Demographic characteristics of participants Among 1713 individuals aged 70–84 years old, (129 cases in stroke group and 1584 cases in control group), prevalence of MetS was 27.1% (Chinese guide), 41.1% (IDF), 48.8% (Updated ATPIII) and 27.1% (JIS) in stroke group, respectively. The prevalence of Mets in stroke group were higher than control group in all four definitions, but the statistically significance only remained in the IDF and Updated ATPIII definitions (p < 0.05) (see Table 2).

1.2. Data collection A standard questionnaire was administered by trained staff to obtain information on demographic characteristics. The past medical history and drug using history were recorded. Height, weight and waist circumference were measured and a blood sample was collected for biochemical measurements. The blood specimens were drawn after overnight fasting, immediately subjected to centrifugation, and analyzed within 8 h for glucose (Glu), serum uric, C-reactive protein (CRP), serum total cholesterol (TC), high-density lipoproteins (HDL), lowdensity lipoproteins (LDL), triglyceride (TG). Smoking was defined as

2.2. The agreement between four definitions of Mets Among four definitions of Mets, the agreement was highest between 2

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≥5.6 mmol/l (100 mg/dl) or treat for previously diagnosed type 2 diabetes

2.3. The associations between four Mets definitions and ischemic stroke As showed in Table 4, we only found significant association between Mets definitions diagnosed by IDF and Updated ATPIII and ischemic stroke (p < 0.05). In addition, the estimated risk was higher and more significant in Updated ATPIII than IDF (OR 1.64, 95%CI 1.11–2.42, p = 0.013 vs. OR 1.55, 95%CI 1.04–2.31, p = 0.031), which indicated that the Updated ATPIII might be a more favorable definition of Mets for Chinese ischemic stroke patients combining with a higher agreement with Chinese guide (see Table 4). 2.4. The association between components of Mets defined by IDF and ischemic stroke The logistic regression analysis showed that the risk of ischemic stroke increased with the number of Mets components increased in definition of IDF (p < 0.05). However, the abdominal obesity or gradually plus other components did not show significantly increasing the risk of ischemic stroke (p > 0.05) (see Table 5). 2.5. The association between components of Mets defined by Updated ATPIII and ischemic stroke The logistic regression analysis showed that the risk of ischemic stroke increased with the number of Mets components increased in definition of Updated ATPIII, and it was statistically significant when there were three or more Mets components (p < 0.05). However, it only found reduced HDL significantly increased the risk of ischemic stroke when all the Mets components (hypertension, hyperglycemia, low HDL, high triglycerides and abdominal obesity) were in the logistic regression analysis (p < 0.05). In addition, we compared continuous values of the components of the Mets, but there were no significant difference as well. The results above suggested that the superposition of components of Mets play greater role in ischemic stroke than its single component (see Table 6).

MetS: metabolic syndrome; TG: triglycerides; HDL-C: high-density lipid cholesterol; SBP: systolic blood pressure; DBP: diastolic blood pressure.

Fasting glucose

Blood pressure

Women

SBP ≥ 130 or DBP ≥ 85 mm Hg, or treatment of previously diagnosed hypertension ≥ 6.1 mmol/l (110 mg/dl) or previously diagnosed type 2 diabetes

< 1.03 mmol/l (40 mg/dl) in men or drug treatment for reduced HDL-C < 1.30 mmol/l (50 mg/dl) in women or drug treatment for reduced HDL-C SBP ≥ 130 or DBP ≥ 85 mm Hg or treatment of previously diagnosed hypertension ≥ 5.6 mmol/l (100 mg/dl) or treat for previously diagnosed type 2 diabetes < 1.03 mmol/l (40 mg/dl) in males or specific treatment for this lipid abnormality < 1.30 mmol/l (50 mg/dl) in women, or specific treatment for this lipid abnormality SBP ≥ 130 or DBP ≥ 85 mm Hg, or treatment of previously diagnosed hypertension ≥ 5.6 mmol/l (100 mg/dl), or previously diagnosed type 2 diabetes < 1.0 mmol/l (40 mg/dl) HDL-C Men

< 1.0 mmol/l (40 mg/dl)

≥ 90 cm for Asian men ≥ 80 cm for Asian women ≥ 1.70 mmol/l (150 mg/dl) or drug treatment for elevated TG ≥ 90 cm for Chinese men ≥ 80 cm for Chinese women ≥ 1.70 mmol/l (150 mg/dl) mg/dl or specific treatment for this lipid abnormality ≥ 90 cm ≥ 85 cm ≥ 1.70 mmol/l (150 mg/dl) Waist circumference Men Women TG

< 1.03 mmol/l (40 mg/dl) in men or drug treatment for reduced HDL-C < 1.30 mmol/l (50 mg/dl) in women or drug treatment for reduced HDL-C SBP ≥ 130 or DBP ≥ 85 mm Hg or treatment

Any three or more of the following five components Central obesity plus any two other factors Any three or more of the following five components To be identified as Mets

≥85 cm for Chinese men ≥80 cm for Chinese women ≥1.70 mmol/l (150 mg/dl) or drug treatment for elevated TG

Updated ATPIII IDF criteria Chinese guide

Any three or more of the following five components

Updated ATPIII and IDF (kappa = 0.863). However, it was lowest between Chinese guide and JIS (kappa = 0.451) (see Table 3).

MetS component

Table 1 Diagnosis criteria of metabolic syndrome used in the current study.

JIS criteria

Q. Liu et al.

3. Discussion In this population-based cross-sectional study from ageing arm of the RuLAS, we explored the associations of different definitions of Mets (Chinese guide, IDF, updated ATPIII and JIS) and ischemic stroke in the elderly. And our study showed the prevalence of Mets was obvious different in different Mets definitions (24.0% in Chinese guide, 32.5% in IDF, 38.8% in Updated ATPIII and 44.7% in JIS, respectively). The prevalence of Mets in Chinese guide was the lowest among four Mets definitions due to the higher cut-off values of abnormal components in Mets. Prevalence was higher in definition of Updated ATPIII and JIS than IDF because central obesity was not a necessary requirement in Updated ATPIII and JIS. And it was highest in definition of JIS as a result of lower threshold of central obesity than Updated ATPIII. Additionally, the prevalence of Mets in stroke group was higher than control group, which was consist with previous researches [9–10,24–26] and indicated a closely association between Mets and ischemic stroke. And the same prevalence of Mets in definitions of Updated ATPIII and JIS in stroke group might prompt that Updated ATPIII definition was more sensitive to identify ischemic stroke than JIS definition in this population. Since the first formalized definition of the MetS in 1998 by the World Health Organization (WHO) [27], it has experienced constantly updated after discussing and investigating over and over again [28–29]. The first revision of the Mets definition was in 1999 by the European Group for the Study of Insulin Resistance (EGIR), which renamed the syndrome with “insulin resistance syndrome” (IRS) [30]. And then it 3

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Table 2 Characteristics of the population in the study.

M/F (rate) Age ± SD (range) WC ± SD (range) BMI ± SD (range) Glu ± SD (range) TC ± SD (range) HDL ± SD (range) LDL ± SD (range) TG ± SD (range) CRP ± SD (range) UA ± SD (range) SBP ± SD (range) DBP ± SD (range) TC Normal H-TC HDL Normal L-HDL LDL Normal H-LDL TG Normal H-TG BMI Normal Obesity WC Normal Central obesity Diabetes Yes No Hypertension Yes No Smoking Yes No Drinking Yes No Hypertension medication use Yes No Diabetes medication use Yes No Lipid-lowering medicine use Yes No Different definition of Metabolic syndrome Chinese guide Yes No IDF2005 Yes No Updated ATPIII Yes No JIS Yes No

All subjects (n = 1713)

Stroke group (n = 129)

Control group (n = 1584)

p

789/924 (46.1%/53.9%) 75.31 ± 3.90 (70–84) 83.03 ± 10.35 (51–140) 24.10 ± 3.55 (15.81–42.53) 5.86 ± 1.68 (1.9–30.1) 5.12 ± 0.95 (2.36–15.49) 1.47 ± 0.33 (0.69–3.19) 2.79 ± 0.72 (0.74–11.27) 1.41 ± 1.00 (0.32–13.75) 3.65 ± 7.14 (0.5–107.4) 330.3 ± 87.4 (115–771) 155.6 ± 22.3 (77.5–237.0) 81.8 ± 11.6 (45.0–148.5)

57/72 (44.2%/55.8%) 75.74 ± 3.95 84.73 ± 9.88 25.14 ± 3.74 5.99 ± 1.54 4.95 ± 0.96 1.40 ± 0.29 2.70 ± 0.73 1.49 ± 0.95 3.94 ± 5.90 333.8 ± 87.5 159.1 ± 22.4 83.5 ± 11.9

732/852 (46.2%/53.8%) 75.27 ± 3.89 82.89 ± 10.37 24.01 ± 3.52 5.85 ± 1.69 5.14 ± 0.95 1.47 ± 0.33 2.80 ± 0.72 1.40 ± 1.01 3.63 ± 7.24 330.0 ± 87.5 155.3 ± 22.3 81.7 ± 11.5

0.657 0.194 0.052 0.001 0.358 0.031 0.015 0.117 0.321 0.636 0.632 0.061 0.090

981 (57.3%) 732 (42.7%)

77 (59.7%) 52 (40.3%)

904 (57.1%) 680 (42.9%)

0.563

1585 (92.5%) 128 (7.5%)

116 (89.9%) 13 (10.1%)

1469 (92.7%) 115 (7.3%)

0.242

1705 (99.5%) 8 (0.5%)

129 (100.0%) 0 (0.0%)

1576 (99.5%) 8 (0.5%)

0.418

1695 (98.9%) 18 (1.1%)

128 (99.2%) 1 (0.8%)

1567 (98.9%) 17 (1.1%)

0.750

1497 (87.4%) 216 (12.6%)

106 (82.2%) 23 (17.8%)

1391 (87.8%) 193 (12.2%)

0.063

1117 (65.2%) 596 (34.8%)

77 (59.7%) 52 (40.3%)

1040 (65.7%) 544 (34.3%)

0.171

247 (14.4%) 1466 (85.6%)

23 (17.8%) 106 (82.2%)

224 (14.1%) 1360 (85.9%)

0.252

1381 (80.6%) 332 (19.4%)

113 (87.6%) 16 (12.4%)

1268 (80.1%) 316 (19.9%)

0.037

397 (23.2%) 1316 (76.8%)

25 (19.4%) 104 (80.6%)

372 (23.5%) 1212 (76.5%)

0.288

507 (29.6%) 1206 (70.4%)

31 (24.0%) 98 (76.0%)

476 (30.1%) 1108 (69.9%)

0.150

549 (32.0%) 1164 (68.0%)

72 (55.8%) 57 (44.2%)

477 (30.1%) 1107 (69.9%)

< 0.001

85 (5.0%) 1628 (95.0%)

11 (8.5%) 118 (91.5%)

74 (4.7%) 1510 (95.3%)

0.052

2 (0.1%) 1711 (99.9%)

1 (0.8%) 128 (99.2%)

1 (0.1%) 1583 (99.9%)

0.145

411 (24.0%) 1302 (76.0%)

35 (27.1%) 94 (72.9%)

376 (23.7%) 1208 (76.3%)

0.385

556 (32.5%) 1157 (67.5%)

53 (41.1%) 76 (58.9%)

503 (31.8%) 1081 (68.2%)

0.030

664 (38.8%) 1049 (61.2%)

63 (48.8%) 66 (51.2%)

601 (37.9%) 983 (62.1%)

0.015

765 (44.7%) 948 (55.3%)

63 (48.8%) 66 (51.2%)

702 (44.3%) 882 (55.7%)

0.321

SD: standard deviation; M/F: male/female; BMI: body mass index; WC: waist circumference; Glu: glucose; TC: total cholesterol; HDL: high-density lipoproteins; LDL: low-density lipoproteins; TG: triglyceride; CRP: C-reactive protein; UA: uric acid; SBP: systolic blood pressure; DBP: diastolic blood pressure; H-TC: high total cholesterol; L-HDL: low high-density lipoproteins; H-LDL: high low-density lipoproteins; H-TG: high triglyceride.

by Chinese Diabetes Society (CDS) [33], in 2005 by the international diabetes federation (IDF) [16], in 2005 by the American heart association/American heart, lung and blood institute (AHA/NHLBI) updating ATPIII criteria [17] and in 2009 a Joint Interim Statement(JIS)

experienced continuously updating by various organizations and constitutions, such as in 2001 by The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) [31], in 2003 by American Association of Clinical Endocrinologists (AACE) [32], in 2004 4

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by international diabetes federation (IDF) and the American heart association/American national institutes of health/American heart, lung and blood institute (AHA/NIH/NHLBI) [1]. The Mets definition of Chinese Adult Dyslipidemia Prevention Guide in 2016 was also a latest proposed definition in china [22], which was based on CDS and deemed to a suitable definition for Chinese people, but its association with ischemic stroke was paucity. Moreover, the IDF and Updated ATPIII are the most widely used definition of Mets worldwide [18–19,34], and JIS is the latest worldwide unified definition of Mets that also been widely recognized [21,28,35]. However, although there were good agreements between Chinese guide, IDF, Updated ATPIII and JIS in this study, their association with ischemic stroke was inconsistent. The IDF and Updated ATPIII were independent risk factor for ischemic stroke, while Chinese guide and JIS showed worse association with ischemic stroke. It indicated the IDF and Updated ATPIII were more favorable definitions of Mets for Chinese ischemic stroke people. Considering the main distinction between Updated ATP III and JIS was the different thresholds for abdominal obesity, perhaps we should adopted the cut-off value of waist circumstance in Updated ATPIII for Asian but not in JIS proposing for Chinese when screening risk factor for Chinese ischemic stroke patient. Besides, giving the main distinction between Chinese guide and the other three definitions of Mets was the different thresholds at components of Mets, there might need more discussing and further investigations to re-determine the precise cut-off points of various risk factors in Mets especially for Chinese ischemic stroke patients. However, although the risk of ischemic stroke increased as the number of Mets components increased in IDF criteria, the necessary abdominal obesity in definition of IDF did not significant associate with increasing risk of ischemic stroke in this study. In addition, besides the highest prevalence of Mets in stroke group and with relative higher agreements with other Mets definitions, Mets defined by Updated ATPIII also showed a highest and more significant OR for ischemic stroke. Therefore, we prompted the Updated ATPIII definition of Mets had a better association with ischemic stroke than IDF and other definitions. IDF definition of Mets might emphasize more on the pathophysiological mechanism of insulin resistance that regards abdominal obesity as a prerequisite, while the Updated ATP III and those ATP III derived definitions underline a state of risk factors clustering for cardiocerebrovascular disease that view abdominal obesity as one of the Mets components [1,16–17,36–37]. Therefore, the ATPIII might be a more appropriate Mets definition than IDF for ischemic stroke and other cardiovascular disease. Meanwhile, previous studies also showed that adding abdominal obesity to the Mets definition had limited benefit for predicting the risk of ischemic stroke [38–39]. Furthermore, there were some studies reported Updated ATPIII was a better definition of Mets to predict risk of cardio-cerebrovascular disease than other definitions

Table 3 Agreement between different definitions of metabolic syndrome. Different definition of metabolic syndrome

χ2

p-Value

Kappa

Chinese guide vs. IDF 2005 Chinese guide vs. updated ATP III Chinese guide vs. JIS IDF 2005 vs. updated ATP III IDF 2005 vs. JIS Updated ATP III vs. JIS

723.5 854.3 431.2 1300.5 704.5 839.6

< 0.001 < 0.001 < 0.001 < 0.001 < 0.001 < 0.001

0.636 0.666 0.451 0.863 0.620 0.695

Table 4 The associations between four Mets definitions and ischemic stroke. Definition of metabolic syndrome

Model 1

Model 2

OR (95% CI)

p-Value

OR (95% CI)

p-Value

Chinese guide

1.20(0.80–1.79)

0.386

0.403

IDF2005

1.50(1.04–2.16)

0.030

Updated ATPIII

1.59 (1.09–2.24)

0.015

JIS

1.20 (0.84–1.72)

0.321

1.19 (0.79–1.81) 1.55 (1.04–2.31) 1.64 (1.11–2.42) 1.19 (0.82–1.73)

0.031 0.013 0.363

Model 1: unadjusted model; Model 2: Adjusted for age, gender, smoking and alcohol consumption. Table 5 The association between components of Mets defined by IDF and ischemic stroke. Variables

Score of Mets Number of components 0a 1b 2c 3c 4c 5c

Model 1

Model 2

OR (95% CI)

p-Value

OR (95% CI)

p-Value

1.12(1.02–1.24)

0.024

1.13(1.02–1.26)

0.023

1.00 (reference) 0.00(0.00–) 1.19(0.66–2.14) 1.47(0.88–2.41) 1.49(0.86–2.58) 1.80(0.91–3.55)

– 0.999 0.565 0.126 0.155 0.089

1.00 (reference) 0.00(0.00–) 1.23(0.68–2.28) 1.54(0.91–2.60) 1.58(0.89–2.81) 1.88(0.93–3.83)

– 0.999 0.500 0.106 0.121 0.080

Model 1: unadjusted model; Model 2: Adjusted for age, gender, smoking and alcohol consumption. a Population not meet the metabolic syndrome definition of IDF criteria and without abdominal obesity. b Population with abdominal obesity. c Population with abdominal obesity plus 1 to 4 other components of Mets.

Table 6 The association between components of Mets defined by Updated ATPIII and risks of ischemic stroke. Variables

4 Number of metabolic syndrome components ≤1 2 3 4 5 Components of metabolic syndrome Abdominal obesity Low HDL Hypertriglyceridemia High blood pressure High glucose level

Model 1

Model 2

OR (95% CI)

p-Value

OR (95% CI)

p-Value

1.24 (1.08–1.43)

0.002

1.27 (1.09–1.48)

0.002

1.00 1.53 1.73 2.21 2.33

(reference) (0.92–2.55) (1.00–2.99) (1.23–3.97) (1.11–4.88)

– 0.102 0.050 0.008 0.025

1.00 1.54 1.85 2.41 2.52

(reference) (0.92–2.58) (1.04–3.30) (1.30–4.47) (1.16–5.47)

– 0.100 0.035 0.005 0.020

1.17 1.81 1.05 1.98 0.97

(0.79–1.73) (1.16–2.81) (0.68–1.63) (0.90–4.33) (0.67–1.41)

0.427 0.008 0.818 0.089 0.873

1.25 1.88 1.07 1.93 0.97

(0. 83–1.89) (1.19–2.98) (0.69–1.67) (0.88–4.23) (0.67–1.41)

0.284 0.007 0.749 0.103 0.889

Model 1: unadjusted model; Model 2: Adjusted for age, gender, smoking and alcohol consumption.

5

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References

[40–41]. We could consequently conclude that Updated ATPIII is a suitable definition of Mets for ischemic stroke patient, and we could adopt its threshold of waist circumstance to define central obesity for Chinese ischemic stroke population. Therefore, we further analyzed relationship between components of Mets in Updated ATPIII definition and ischemic stroke. And we found that only the lower high density lipoprotein is independently associated with ischemic stroke in this study, although we have recognized that all of the major components of Mets like hypertension, dyslipidemia and hyperglycemia were risk factors of ischemic stroke [17,42]. It was consistent with previous studies indicated that the lower HDL was an independent risk factor for ischemic stroke [43–44]. Besides, there might be other risk factors related with Mets like elevated plasma homocysteine associated with ischemic stroke but we failed to detect them in this study [45]. In addition, this study showed the risk of ischemic stroke increased as the numbers of Mets components increased, which suggested that the additive effects of Mets components play a greater role in ischemic stroke. Scholz and his colleagues reported that the interactions between metabolic disorders played important role on cardiovascular disease [46]. Angelo et al. have reported the Mets played an important role in arterial ageing in both gender, and especially components of Mets interact to synergistically impact vascular thickness and stiffness, which result in ischemic stroke finally [47–48]. And Mets was closely related to inflammation, which contributes to arterial stiffness and ischemic stroke consequently [49–51]. Furthermore, the interaction among the metabolic compositions could damage vasomotor function, promote the formation, progression and rupture of atherosclerotic plaque that lead to incidence of ischemic stroke [52]. The metabolic disorders could also produce a hypercoagulable state and reduce the fibrinolytic activity in the body [53], together with damage of cerebrovascular regulation function and microcirculation [54–55], made individuals be susceptible to ischemic stroke eventually. There are several limitations in this study. Firstly, we didn't exclude the non-vascular source ischemic stroke. Secondly, we failed to detect and analyze association between other abnormal compositions of Mets and ischemic stroke that made it insufficient for us to explore the specific mechanism. Last but not least, as a longevity town, the lifestyle and dietary patterns in population of Rugao may be different from other areas of china, and the sample size in this study was not only relative small but also localized, it still need the further large-scale and prospective studies to confirm and represent for all the Chinese elderly.

[1] Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Association for the Study of Obesity. Circulation 2009;120(16):1640–5. http://dx.doi.org/10.1161/CIRCULATIONAHA.109. 192644. [2] Moreira GC, Cipullo JP, Ciorlia LA, Cesarino CB, Vilela-Martin JF. Prevalence of metabolic syndrome: association with risk factors and cardiovascular complications in an urban population. PLoS One 2014;9(9):e105056http://dx.doi.org/10.1371/ journal.pone.0105056. [3] Srikanthan K, Feyh A, Visweshwar H, Shapiro JI, Sodhi K. Systematic review of metabolic syndrome biomarkers: a panel for early detection, management, and risk stratification in the West Virginian population. Int J Med Sci 2016;13(1):25–38. http://dx.doi.org/10.7150/ijms.13800. [4] Khosravi-Boroujeni H, Sarrafzadegan N, Sadeghi M, Roohafza H, Talaei M, Ng SK, et al. Secular trend of metabolic syndrome and its components in a cohort of Iranian adults from 2001 to 2013. Metab Syndr Relat Disord 2017;15(3):137–44. http://dx. doi.org/10.1089/met.2016.0073. [5] Roos V, Elmståhl S, Ingelsson E, Sundström J, Ärnlöv J, Lind L. Metabolic syndrome development during aging with special reference to obesity without the metabolic syndrome. Metab Syndr Relat Disord 2017;15(1):36–43. http://dx.doi.org/10. 1089/met.2016.0082. [6] Georgiopoulos G, Tsioufis C, Tsiachris D, Dimitriadis K, Kasiakogias A, Lagiou F, et al. Metabolic syndrome, independent of its components, affects adversely cardiovascular morbidity in essential hypertensives. Atherosclerosis 2016;244:66–72. http://dx.doi.org/10.1016/j.atherosclerosis.2015.10.099. [7] Sun DL, Wang JH, Jiang B, Li LS, Li LS, Wu L, et al. Metabolic syndrome vs. its components for prediction of cardiovascular mortality: a cohort study in Chinese elderly adults. J Geriatr Cardiol 2012;9(2):123–9. http://dx.doi.org/10.3724/SP.J. 1263.2012.01172. [8] Brola W, Sobolewski P, Fudala M, Goral A, Kasprzyk M, Szczuchniak W, et al. Metabolic syndrome in Polish ischemic stroke patients. J Stroke Cerebrovasc Dis 2015;24(9):2167–72. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2015.06. 003. [9] Kazlauskienė Butnorienė, Norkus A. Metabolic syndrome related to cardiovascular events in a 10-year prospective study. Diabetol Metab Syndr 2015;7(102). http:// dx.doi.org/10.1186/s13098-015-0096-2. [10] Maruyama K, Uchiyama S, Iwata M. Metabolic syndrome and its components as risk factors for first-ever acute ischemic noncardioembolic stroke. J Stroke Cerebrovasc Dis 2009;18(3):173–7. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2008.03. 008. [11] Younis A, Younis A, Tzur B, Peled Y, Shlomo N, Goldenberg I, et al. Metabolic syndrome is independently associated with increased 20-year mortality in patients with stable coronary artery disease. Cardiovasc Diabetol 2016;15(1):149. http://dx. doi.org/10.1186/s12933-016-0466-6. [12] Wen J, Yang J, Shi Y, Liang Y, Wang F, Duan X, et al. Comparisons of different metabolic syndrome definitions and associations with coronary heart disease, stroke, and peripheral arterial disease in a rural Chinese population. PLoS One 2015;10(5):e0126832http://dx.doi.org/10.1371/journal.pone.0126832. [13] Benetos A, Thomas F, Pannier B, Bean K, Jégo B, Guize L. All-cause and cardiovascular mortality using the different definitions of metabolic syndrome. Am J Cardiol 2008;102(2):188–91. http://dx.doi.org/10.1016/j.amjcard.2008.03.037. [14] Scuteri A, Najjar SS, Morrell CH, Lakatta EG, Cardiovascular Health Study. The metabolic syndrome in older individuals: prevalence and prediction of cardiovascular events: the Cardiovascular Health Study. Diabetes Care 2005;28:882–7. [15] O'Neill S, O'Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 2015;16(1):1–12. http://dx.doi.org/10. 1111/obr.12229. [16] Alberti KG, Zimmet P, Shaw J, IDF Epidemiology Task Force Consensus Group. The metabolic syndrome—a new worldwide definition. Lancet 2005;366(9491):1059–62. http://dx.doi.org/10.1016/S0140-6736(05)67402-8. [17] Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation 2005;112:2735–52. http://dx.doi.org/10.1161/CIRCULATIONAHA. 105.169404. [18] Hosseinpanah F, Asghari G, Barzin M, Golkashani HA, Azizi F. Prognostic impact of different definitions of metabolic syndrome in predicting cardiovascular events in a cohort of non-diabetic Tehranian adults. Int J Cardiol 2013;168(1):369–74. http:// dx.doi.org/10.1016/j.ijcard.2012.09.037. [19] Song P, Yu J, Chang X, Wang M, An L. Prevalence and correlates of metabolic syndrome in Chinese children: the China Health and Nutrition Survey. Nutrients 2017;9(1). http://dx.doi.org/10.3390/nu9010079. [pii: E79]. [20] Ford ES, Li C, Zhao G. Prevalence and correlates of metabolic syndrome based on a harmonious definition among adults in the US. J Diabetes 2010;2(3):180–93. http://dx.doi.org/10.1111/j.1753-0407.2010.00078.x. [21] Ramli AS, Daher AM, Nor-Ashikin MN, Mat-Nasir N, Ng KK, Miskan M, et al. JIS definition identified more Malaysian adults with metabolic syndrome compared to the NCEP-ATP III and IDF criteria. Biomed Res Int 2013;2013:760963. http://dx. doi.org/10.1155/2013/760963. [22] Chinese adult dyslipidemia prevention guide revised joint committee. Chinese Adult Dyslipidemia Prevention Guide (revised in 2016). Chinese Journal of

4. Conclusion This study indicated that Updated ATPIII criteria was a more suitable definition of Mets than definitions of Chinese guide, IDF and JIS for screening high-risk individuals of ischemic stroke, and the additive effects of Mets components might play a greater role than its composition alone on ischemic stroke. Our results suggest the Updated ATPIII definition of Mets should be used for screening those with high risk of ischemic stroke for clinicians, and we should reduce the abnormal metabolic components as possible as we can to decrease the risk of ischemic stroke in patients with Mets.

Conflict of interest statement We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled “Comparing associations of different metabolic syndrome definitions with ischemic stroke in Chinese elderly population”. 6

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[23]

[24]

[25]

[26]

[27]

[28] [29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40] Noda H, Iso H, Saito I, Konishi M, Inoue M, Tsugane S, et al. The impact of the metabolic syndrome and its components on the incidence of ischemic heart disease and stroke: the Japan public health center-based study. Hypertens Res 2009;32(4):289–98. http://dx.doi.org/10.1038/hr.2009.14. [41] Khosravi-Boroujeni H, Ahmed F, Sadeghi M, Roohafza H, Talaei M, Dianatkhah M, et al. Does the impact of metabolic syndrome on cardiovascular events vary by using different definitions? BMC Public Health 2015;15:1313. http://dx.doi.org/10. 1186/s12889-015-2623-3. [42] Tsai CF, Anderson N, Thomas B, Sudlow CL. Risk factors for ischemic stroke and its subtypes in Chinese vs. Caucasians: systematic review and meta-analysis. Int J Stroke 2015;10(4):485–93. http://dx.doi.org/10.1111/ijs.12508. [43] Kuwashiro T, Sugimori H, Kamouchi M, Ago T, Kitazono T, Iida M. Lower levels of high-density lipoprotein cholesterol on admission and a recurrence of ischemic stroke: a 12-month follow-up of the Fukuoka Stroke Registry. J Stroke Cerebrovasc Dis 2012;21(7):561–8. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2010.12. 011. [44] Zhang Y, Tuomilehto J, Jousilahti P, Wang Y, Antikainen R, Hu G. Total and highdensity lipoprotein cholesterol and stroke risk. Stroke 2012;43:1768–74. http://dx. doi.org/10.1161/STROKEAHA.111.646778. [45] Catena C, Colussi G, Nait F, Capobianco F, Sechi LA. Elevated homocysteine levels are associated with the metabolic syndrome and cardiovascular events in hypertensive patients. Am J Hypertens 2015;28(7):943–50. http://dx.doi.org/10. 1093/ajh/hpu248. [46] Scholz GH, Hanefeld M. Metabolic vascular syndrome: new insights into a multidimensional network of risk factors and diseases. Visc Med 2016;32(5):319–26. http://dx.doi.org/10.1159/000450866. [47] Scuteri A, Cunha PG, Rosei EA, Badariere J, Bekaert S, Cockcroft JR, et al. Arterial stiffness and influences of the metabolic syndrome: a cross-countries study. Atherosclerosis 2014;233:654–60. http://dx.doi.org/10.1016/j.atherosclerosis. 2014.01.041. [48] Scuteri A, Najjar SS, Muller DC, Andres R, Hougaku H, Metter EJ, et al. Metabolic syndrome amplifies the age-associated increases in vascular thickness and stiffness. J Am Coll Cardiol 2004;43:1388–95. http://dx.doi.org/10.1016/j.jacc.2003.10. 061. [49] Tuttolomondo A, Di Raimondo D, Di Sciacca R, Pecoraro R, Arnao V, Buttà C, et al. Arterial stiffness and ischemic stroke in subjects with and without metabolic syndrome. Atherosclerosis 2012;225(1):216–9. http://dx.doi.org/10.1016/j. atherosclerosis.2012.08.027. [50] Tuttolomondo A, Pecoraro R, Casuccio A, Di Raimondo D, Buttà C, Clemente G, et al. Peripheral frequency of CD4+ CD28 − cells in acute ischemic stroke: relationship with stroke subtype and severity markers. Medicine (Baltimore) 2015;94:e813http://dx.doi.org/10.1097/MD.0000000000000813. [51] Scuteri A, Orru M, Morrell C, Piras MG, Taub D, Schlessinger D, et al. Independent and additive effects of cytokine patterns and the metabolic syndrome on arterial aging in the SardiNIA Study. Atherosclerosis 2011;215(2):459–64. http://dx.doi. org/10.1016/j.atherosclerosis.2010.12.023. [52] Rask-Madsen C, Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 2012;32:2052–9. http:// dx.doi.org/10.1161/ATVBAHA.111.241919. [53] Kodaman N, Aldrich MC, Sobota R, Asselbergs FW, Brown NJ, Moore JH, et al. Plasminogen activator inhibitor-1 and diagnosis of the metabolic syndrome in a West African population. J Am Heart Assoc 2016;5(10). http://dx.doi.org/10.1161/ JAHA.116.003867. [pii: e003867]. [54] Zhang Z, Xiao M, Ye Z, et al. Noncardiogenic stroke patients with metabolic syndrome have more border-zone infarction and intracranial artery stenosis. J Stroke Cerebrovasc Dis 2015;24:629–34. http://dx.doi.org/10.1016/j. jstrokecerebrovasdis.2014.10.011. [55] Nazzaro P, Schirosi G, Mezzapesa D, et al. Effect of clustering of metabolic syndrome factors on capillary and cerebrovascular impairment. Eur J Intern Med 2013;24:183–8. http://dx.doi.org/10.1016/j.ejim.2012.08.017.

Cardiology 2016;44(10):833–53. http://dx.doi.org/10.3760/cma.j.issn.0253-3758. 2016.10.005. Liu Z, Wang Y, Zhang Y, Chu X, Wang Z, Qian D, et al. Cohort profile: the Rugao Longevity and Ageing Study (RuLAS). Int J Epidemiol 2016;45(4):1064–73. http:// dx.doi.org/10.1093/ije/dyv101. Lucke-Wold BP, DiPasquale K, Logsdon AF, Nguyen L, Lucke-Wold AN, Turner RC, et al. Metabolic syndrome and its profound effect on prevalence of ischemic stroke. Am Med Stud Res J 2014;1(1):29–38. http://dx.doi.org/10.15422/amsrj.2014.05. 004. Wang GS, Tong DM, Chen XD, Yang TH, Zhou YT, Ma XB. Metabolic syndrome is a strong risk factor for minor ischemic stroke and subsequent vascular events. PLoS One 2016;11(8):e0156243http://dx.doi.org/10.1371/journal.pone.0156243. Sarrafzadegan N, Gharipour M, Sadeghi M, Nezafati P, Talaie M, Oveisgharan S, et al. Metabolic syndrome and the risk of ischemic stroke. J Stroke Cerebrovasc Dis 2017;26(2):286–94. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.09. 019. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539–53. http://dx. doi.org/10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S. Kassi E, Pervanidou P, Kaltsas G, Chrousos G. Metabolic syndrome: definitions and controversies. BMC Med 2011;9:48. http://dx.doi.org/10.1186/1741-7015-9-48. Lam DW, LeRoith D. Metabolic syndrome. [Updated 2015 May 19]. In: De Groot LJ, Chrousos G, Dungan K, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000 Available from: https://www.ncbi.nlm.nih.gov/books/ NBK278936/. Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR). Diabet Med 1999;16:442–3. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, et al. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 2003;9:237–52. Metabolic Syndrome Study Cooperation Group of Chinese Diabetes Society. Suggestions about metabolic syndrome of Chinese Diabetes Society (in Chinese). Chin J Diabetes 2004;12:156–61. Prasad H, Ryan DA, Celzo MF, Stapleton D. Metabolic syndrome: definition and therapeutic implications. Postgrad Med 2012;124(1):21–30. http://dx.doi.org/10. 3810/pgm.2012.01.2514. Hanefeld M, Pistrosch F, Bornstein SR, Birkenfeld AL. The metabolic vascular syndrome - guide to an individualized treatment. Rev Endocr Metab Disord 2016;17(1):5–17. http://dx.doi.org/10.1007/s11154-016-9345-4. Bhowmik B, Afsana F, Siddiquee T, Munir SB, Sheikh F, Wright E, et al. Comparison of the prevalence of metabolic syndrome and its association with diabetes and cardiovascular disease in the rural population of Bangladesh using the modified National Cholesterol Education Program Expert Panel Adult Treatment Panel III and International Diabetes Federation definitions. J Diabetes Investig 2015;6(3):280–8. http://dx.doi.org/10.1111/jdi.12268. Athyros VG, Ganotakis ES, Elisaf MS, Liberopoulos EN, Goudevenos IA, Karagiannis A, et al. Prevalence of vascular disease in metabolic syndrome using three proposed definitions. Int J Cardiol 2007;117(2):204–10. http://dx.doi.org/10.1016/j.ijcard. 2006.04.078. Chen HJ, Bai CH, Yeh WT, Chiu HC, Pan WH. Influence of metabolic syndrome and general obesity on the risk of ischemic stroke. Stroke 2006;37(4):1060–4. http://dx. doi.org/10.1161/01.STR.0000206458.58142.f3. Sánchez-Iñigo L, Navarro-González D, Fernández-Montero A, Pastrana-Delgado J, Martínez JA. Risk of incident ischemic stroke according to the metabolic health and obesity states in the Vascular-Metabolic CUN cohort. Int J Stroke 2017;12(2):187–91. http://dx.doi.org/10.1177/1747493016672083.

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