Hypoadiponectinemia Is Associated With Ischemic Cerebrovascular Disease
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动脉硬化血栓血管生物学 2005年第4期
From the Departments of Clinical Research (M.-P.C., J.C.-R.T., F.-M.C., Y.-J.L.), Neurology (S.-S.Y.), and Clinical Laboratory (L.-L.H.), Pingtung Christian Hospital, Taiwan; and the Graduate Institute of Medicine (S.-J.S.), Kaohsiung Medical University, Taiwan.
Correspondence to Dr Yau-Jiunn Lee, Department of Clinical Research, Pingtung Christian Hospital, No.60 Da-Lien Rd, Pingtung, 90000, Taiwan. E-mail t3275@ms25.hinet.net
Abstract
Objective— Adiponectin, an adipocyte-derived peptide with antiinflammatory and antiatherogenic effects, is known to protect against the initiation and progression of atherosclerosis. In this study, we investigate whether hypoadiponectinemia is present in patients with ischemic cerebrovascular disease (CVD).
Methods and Results— In this case-control study, plasma adiponectin concentration was measured by an enzyme-linked immunosorbent assay in type 2 diabetic and nondiabetic subjects with or without ischemic CVD. A total of 534 subjects were studied. The mean plasma level of adiponectin of the 228 patients with ischemic CVD was significantly lower than that of 306 subjects without CVD. When the analysis was stratified according to diabetes status, plasma levels of adiponectin in CVD subjects with or without type 2 diabetes were significantly lower than those of their counterparts. Decreasing concentrations of adiponectin were independently and significantly associated with a higher risk of CVD when concentrations were analyzed by quartile and as a continuous variable. When patients with CVD were subgrouped according to the comorbidity with or without type2 diabetes, the same trend of association between plasma adiponectin and risk of CVD was observed in each group.
Conclusion— These data show that there are significantly lower levels of plasma adiponectin in patients with ischemic CVD.
Adiponectin, an adipocyte-derived peptide with antiinflammatory and antiatherogenic effects, is known to protect against the initiation and progression of atherosclerosis. In this study, we investigate whether hypoadiponectinemia is present in patients with ischemic cerebrovascular disease (CVD). Our data show that there are significantly lower levels of plasma adiponectin in patients with ischemic CVD.
Key Words: adiponectin ? atherosclerosis ? cerebrovascular disease ? metabolic syndrome ? type 2 diabetes mellitus
Introduction
Adiponectin, also called GBP-28, apM1, AdipoQ, and Acrp30, an adipose tissue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, circulates at high levels in human plasma.1–4 It is one of the adipocyte-expressed proteins that contribute to the homeostatic control of glucose, lipid, energy metabolism, and antiinflammatory activity.5,6 According to several studies, dysregulation of adiponectin has been implicated in metabolic X syndrome and atherosclerosis disorders, including insulin resistance, obesity, type 2 diabetes, hypertension, and coronary artery disease (CAD).7–10 Decreased plasma adiponectin levels have been found to be independently associated with the presence of CAD after adjustment for other well-known CAD risk factors in men, with male patients with hypoadiponectinemia (<4.0 μg/mL) having a significant 2-fold increase in CAD prevalence.9 Adiponectin has a potential inhibitory effect on all molecular mechanisms of atherosclerosis,11 including the inhibition of monocyte adhesion to endothelial cells,12 the inhibition of oxidized low-density lipoprotein (LDL) uptake of macrophage through scavenger receptors,13 and inhibition of proliferation of migrated smooth muscle cells by the action of growth factors.14 Recently, Pischon et al, in a nested case-control study of 19 225 men who had been followed-up for >6 years, have associated high plasma adiponectin concentrations with lower risk of myocardial infarction in men.15 Although these findings indicate that adiponectin plays a crucial role in the development of atherosclerosis, to the best of our knowledge, there have been no studies of the association between plasma adiponectin and ischemic cerebrovascular disease (CVD). Because ischemic CVD is the second most common cause of death in Taiwan, more common than cardiovascular disease,16 and the second leading cause of mortality worldwide,17 a study of whether adiponectin is involved in CVD is important. This study measures the plasma adiponectin levels in ischemic CVD patients with and without type 2 diabetes.
Methods
From February 2001 to December 2003, we studied 228 patients with ischemic CVD who made consecutive visits to the Pingtung Christian Hospital diabetic or neurological clinics. Patients with ischemic stroke were all enrolled in an outpatient disease management program and all were clinically stable and had no manifestations of acute illness. Patients with CVD were studied at least 3 months after the onset of acute illness and could be regularly followed-up by the program manager. Ischemic CVD was defined as patients with an acute or sudden focal neurological defect lasting for >24 hours and positive brain image lesions by computed tomography, magnetic resonance imaging, or magnetic resonance angiography examination.
One hundred forty-one nondiabetic subjects without clinical evidence of stroke were recruited from an unselected population who underwent routine health checkups and were used as the nondiabetic control group. Nondiabetic subjects were defined as those with a fasting plasma glucose level <126 mg/dL and no family history of type 2 diabetes (including parents, siblings, and children). One hundred sixty-five type 2 diabetic patients without CVD were also randomly selected from the patients enrolled in a diabetic clinic disease-management program. A medical history and history of drug use for all control subjects were taken by a physician. All study subjects underwent complete physical examinations and routine biochemical analyses of blood and urine, as well as an assessment of the presence and extent of macrovascular or microvascular complications. The diagnosis of type 2 diabetes was based on World Health Organization criteria.18
Patients with a history of >1 stroke were requested to give information about the most recent stroke only. The type of CVD was clinically categorized according to the Classification of Cerebrovascular Disease III revised by the National Institute of Neurological Disorders and Stroke.19 Patients with brain hemorrhage, transient ischemic attack, and cardiogenic brain infarction were excluded from the study. Also excluded were patients with ischemic CVD caused by less common causes such as drugs, metabolic disease, infection, vasculopathy, moyamoya disease, or venous thrombosis, which may have been discovered during history taking and laboratory work.
This is a case-control study that was approved by the human research ethics committee of our hospital, and informed consent was obtained from each patient. All study subjects were of Han Chinese origin, without any other known ethnic origin, and they all lived in the same region at the time of study.20,21 The anthropometric parameters required that the body mass index (BMI) and waist-to-hip ratio (WHR) be calculated. Seated blood pressure (BP) and plasma biochemical parameters were measured after overnight fasting. A trained nurse measured BP with a digital automatic BP monitor (model HEM-907; Omron, Japan) after these subjects had rested for 5 minutes. Plasma triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, uric acid, creatinine, and glucose were measured by a parallel-multichannel analyzer (Hitachi 7170A, Tokyo, Japan). Those who had stopped smoking >1 year before the examination were considered former/nonsmokers.
Plasma Adiponectin and Highly Sensitive C-Reactive Protein Measurements
All blood samples were drawn after an overnight fast. Plasma samples were kept at –80°C for subsequent assay. Plasma was diluted 5100-fold before assay. The concentration of plasma adiponectin was determined by a commercial solid phase enzyme-linked immunosorbent assay kit (B-Bridge International, Sunnyvale, Calif). The dilution curve was parallel to the standard curve. The inter-assay and intra-assay coefficients of variation of assay were 3.2% to 7.3% (n=3) and 3.1% to 6.2% (n=4), respectively. Plasma highly sensitive C-reactive protein (hsCRP) was measured using a Beckman Coulter IMMAGE Immunochemistry System (Brea, Calif). The detection limit of this hsCRP assay system was 0.2 mg/L.
Statistical Analysis
The data are shown as the mean±SD. All statistical analyses were performed using the Statistical Package for Social Science (SPSS for Windows, version 10.0; SPSS Inc, Chicago, Ill). The statistical differences in variables were compared using unpaired t test or the Mann-Whitney U test. The differences of plasma adiponectin in study groups were also compared after adjustment for age, sex, BMI, WHR, diabetes, and smoking status by General Linear Modeling function analysis. Because the distributions of plasma adiponectin, serum triglycerides, and hsCRP were skewed, logarithmically transformed values were used for statistical analysis. The study subjects were categorized by quartile based on the plasma adiponectin level of healthy controls. Correlation between ischemic CVD and all other parameters were analyzed first by simple logistic regression analysis and then by multivariate logistic regression analysis; variables included in the multivariate analysis were sex, age, systolic BP and diastolic BP, lipid profile, serum uric acid, plasma adiponectin and hsCRP levels, and smoking status. For stratified analysis, we also calculated the multivariable-adjusted odd ratio associated with a doubling in adiponectin levels. Multivariate adjusted odds ratios are presented with 95% confidence interval. Simple and multiple linear stepwise regression analysis were used to examine the associations and independence between plasma concentrations of adiponectin and the values of other parameters. Pearson correlation analysis was used to evaluate the bivariate relationship between individual variables with plasma adiponectin. P<0.05 was considered statistically significant.
Results
The clinical characteristics of our subjects are shown in Table 1. Of the 228 patients with ischemic CVD, 174 had lacunar infarct, and the other 54 had large artery infarctions (35 middle cerebral artery, 9 posterior cerebral artery, 4 anterior cerebral artery, and 6 basilar artery infarcts). Patients with ischemic CVD were older, had higher serum creatinine levels and smoking rates, and lower HDL cholesterol concentrations and BMI values than those without ischemic stoke. However, no significant difference was found in the 2 groups’ WHR, fasting plasma glucose, HbA1C, systolic BP and diastolic BP, serum total cholesterol, triglyceride, LDL cholesterol, and serum uric acid levels. The mean plasma level of adiponectin was significantly lower in patients with ischemic CVD than that of subjects without CVD (4.2±3.7 μg/mL versus 12.7±12.3 μg/mL; P<0.001). The plasma adiponectin levels remained significantly lower after adjustment for age, sex, BMI, WHR, diabetes, and smoking status. The mean plasma adiponectin levels in patients with small artery infarctions were not different from those with large artery infarctions (3.9±3.4 μg/mL versus 4.6±3.5 μg/mL; P=not significant). In contrast, patients with ischemic CVD had significantly higher mean plasma hsCRP levels than those without (11.2±23.9 mg/L versus 2.5±6.3 mg/L; P<0.001).
TABLE 1. Clinical Characteristics of Subjects Studied
One previous report revealed that plasma adiponectin levels were decreased in patients with type 2 diabetes,7 so we further stratified our patients according to comorbidity with type 2 diabetes. Plasma levels of adiponectin in ischemic CVD subjects with or without type 2 diabetes were significantly lower than their counterparts. The mean plasma adiponectin level of men (8.9±10.8 μg/L) was not different from that of women (9.2±10.2 μg/L; P=not significant), whereas the levels in males with ischemic CVD were significantly lower than in females (3.2±2.7 μg/mL versus 5.1±4.2 μg/mL; P<0.001). This difference remained even when grouped by the presence or absence of type 2 diabetes (males and females=2.7±2.7 μg/mL versus 4.4±3.0 μg/mL, P=0.003 in diabetic subjects; 3.6±2.7 μg/mL versus 6.0±5.3 μg/mL, P=0.003 in nondiabetic subjects). As expected, the plasma adiponectin levels of patients with type 2 diabetes were found to be significantly lower than those of nondiabetic subjects (4.5±3.8 μg/mL versus 14.2±13.1 μg/mL, P<0.001). Simple logistic regression analysis found that age, BMI, serum HDL cholesterol and creatinine levels, smoking status, and plasma adiponectin and hsCRP levels to be predictors of ischemic CVD (Table 2). Multiple logistic regression analysis revealed that age, BMI, serum HDL cholesterol and creatinine levels, smoking status, and plasma adiponectin concentration to be independently correlated with ischemic CVD. Decreasing concentrations of adiponectin were independently and significantly associated with a higher risk of CVD when concentrations were analyzed by quartile and by a continuous variable (Tables 2 and 3 ). There was a linear trend among the risk of CVD and the plasma adiponectin levels. This model was adjusted for other known risk factors such as age, BMI, WHR, serum HDL cholesterol, creatinine, and plasma hsCRP levels, and diabetes status. Similar statistic patterns were observed when we subgrouped the study subjects by comorbidity with or without type 2 diabetes (Table 3 and Figure 1).
TABLE 2. Logistic Regression Analyses With Ischemic Cerebrovascular Disease
TABLE 3. Univariate and Multivariate Analysis of the Impact of Plasma Adiponectin Level on Cerebrovascular Disease
Figure 1. Odds ratios for ischemic CVD according to the quartiles of plasma adiponectin levels of healthy controls. The highest quartile was set for reference (Q1). This model was adjusted for age, BMI, WHR, systolic BP and diastolic BP, lipid profile, creatinine, hsCRP levels, and smoking status. Vertical bars indicate 95% confidence interval.
Plasma adiponectin level was positively correlated with HDL cholesterol and LDL cholesterol levels (Table 4 and Figure 2). In contrast, plasma adiponectin concentration was inversely correlated to male gender, WHR, smoking status, diastolic BP, fasting plasma glucose, serum triglyceride, and plasma hsCRP levels. Multiple linear regression analysis confirmed WHR, diastolic BP, fasting plasma glucose, serum triglyceride, HDL cholesterol, LDL cholesterol, and hsCRP levels were independently associated with plasma adiponectin levels.
TABLE 4. Linear Regression Analysis of Variables Associated With Plasma Adiponectin Levels in Subjects Studied
Figure 2. Relationship between log-transformed plasma adiponectin levels and HDL cholesterol (A), LDL cholesterol (B), WHR (C), diastolic BP (D), fasting plasma glucose (E), serum triglyceride (F), and plasma CRP (G) levels in type 2 diabetes (white circle) and nondiabetic subjects (black circle) as determined by Pearson correlation analysis.
Discussion
The present study shows that plasma adiponectin concentration was significantly lower in subjects with ischemic CVD than in controls after adjustment for age, sex, BMI, WHR, diabetes, and smoking status. Furthermore, our study also showed that plasma adiponectin level was significantly associated with all components of metabolic syndrome, which are well-known risk factors for development of atherosclerosis such as WHR, BP, plasma glucose, serum triglyceride, HDL cholesterol, and hsCRP levels. This is the first report to our knowledge to show that hypoadiponectinemia is present in patients with ischemic CVD. The pathophysiologic links between adiponectin and atherosclerosis has been investigated extensively.5,6,10–13 This evidence suggests that adiponectin plays a crucial role in the inflammatory process and the development of atherosclerosis. Patients with hypoadiponectinemia may, therefore, have less antiinflammatory ability and be more vulnerable to the development of ischemic vascular disease.
Our results show that plasma adiponectin levels are correlated with all components of metabolic syndrome. Adiponectin was initially believed to regulate adipocyte differentiation and energy homeostasis by increasing fatty acid oxidation,22 and later plasma adiponectin level has been found to be associated with anthropometric characters, insulin sensitivity, BP, and lipid profiles.6,11,23,24 Mechanisms explaining the relationship between adiponectin and metabolic syndrome or insulin-resistance syndrome remain obscure. It has been shown that adiponectin and tumor necrosis factor (TNF)- inhibit each other’s expression and production in adipocyte and actions in target organs.10,25 Sonnenberg et al26 have proposed that plasma adiponectin is closely negatively related to the visceral adiposity, which may result in increased TNF- secreted from the visceral adipose tissue. Hypoadiponectinemia may cause patients with central obesity may to lose the antiinflammatory capability needed to antagonize the action of TNF- that could stimulate nuclear transcription factor-kappa B activation. Adiponectin plays a protective role against the atherosclerotic vascular change, and loss of effects enhances endothelial dysfunction, as in CVD patients.27
Our study has also shown that plasma adiponectin concentrations are negatively associated with plasma hsCRP levels. Recently, a negative correlation between plasma adiponectin levels and CRP levels has been reported in patients with CAD.28,29 CRP is generally produced in the liver, under regulation by cytokines, such as IL-1?, IL-6, and TNF-,30 and is believed to be directly or indirectly involved in vascular inflammation. The association of plasma adiponectin and hs-CRP levels gives evidence that suggests plasma adiponectin has some role in inflammation and atherosclerosis. The present study shows that hypoadiponectinemia is closely related to metabolic syndrome and inflammatory marker (Table 4). Recent reports suggest that adiponectin modulates the inflammatory response.11–14 Taken together, these pieces of evidence demonstrate that hypoadiponectinemia contributes to the pathogenesis of ischemic stroke.
How adiponectin levels relate to lipid profiles remains unclear. Positive association between plasma adiponectin with HDL cholesterol and negative association with serum triglyceride levels have been reported.31,32 Decreased postheparin lipoprotein lipase activity in hypoadiponectinemia was found by Eynatten et al.33 This fact suggests that adiponectin may regulate plasma HDL and triglyceride levels via modulation of lipoprotein lipase activity. However, whether hypoadiponectinemia aggravates both insulin resistance and lipid profile, or whether low insulin resistance and/or a good lipid profile increase the plasma adiponectin levels is unknown. The finding of plasma adiponectin level positively correlated with LDL cholesterol is not expected and is in contrast to the study results of Yamamoto et al in a Japanese population,31 but it is similar to those of Schulze et al in 741 type 2 diabetic men.32 However, the role of adiponectin in regulating lipid metabolism needs to be clarified by further studies.
Limitations of our study include its cross-sectional design, and the time that the blood drawn from patients with cerebrovascular disease was at least 3 months after acute illness, which limit our ability to infer a causal relationship between decreased plasma adiponectin level and ischemic cerebrovascular disease. It would be interesting to measure the serial changes of plasma adiponectin level in acute and chronic stable stages to further clarify the role of adiponectin in cerebrovascular disease. The cases studied in the present study are only survivors from CVD and cases with more severe forms are not included. The plasma adiponectin level in patients with severe form of ischemic stroke may be different from that with survivors. In addition, although we controlled for other major cerebrovascular risk factors, the existence of unrecognized confounding variables is always possible. Our analyses are based on single measurements of blood adiponectin, which may not reflect the relationship over time.
In conclusion, the present report shows that plasma adiponectin concentration is low in patients with ischemic CVD and it finds a possible close relationship between adiponectin- metabolic syndrome-inflammation and the development of atherosclerosis. However, a large-scale prospective cohort study is necessary to resolve the potential causal relationship between adiponectin and CVD.
Acknowledgments
We are grateful to the staff of the diabetes and cerebrovascular disease care team for their assistance in various measurements and other organizational aspects of this study. This work was supported by a grant from National Science Council of Taiwan (93-2314-B-475-002).
References
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Arita Y, Kihara S, Ouchi N, Maeda K, Kuriyama H, Okamoto Y, Kumada M, Hotta K, Nishida M, Takahashi M, Nakamura T, Shimomura I, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. Circulation. 2002; 105: 2893–2898.
Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004; 291: 1730–1737.
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Correspondence to Dr Yau-Jiunn Lee, Department of Clinical Research, Pingtung Christian Hospital, No.60 Da-Lien Rd, Pingtung, 90000, Taiwan. E-mail t3275@ms25.hinet.net
Abstract
Objective— Adiponectin, an adipocyte-derived peptide with antiinflammatory and antiatherogenic effects, is known to protect against the initiation and progression of atherosclerosis. In this study, we investigate whether hypoadiponectinemia is present in patients with ischemic cerebrovascular disease (CVD).
Methods and Results— In this case-control study, plasma adiponectin concentration was measured by an enzyme-linked immunosorbent assay in type 2 diabetic and nondiabetic subjects with or without ischemic CVD. A total of 534 subjects were studied. The mean plasma level of adiponectin of the 228 patients with ischemic CVD was significantly lower than that of 306 subjects without CVD. When the analysis was stratified according to diabetes status, plasma levels of adiponectin in CVD subjects with or without type 2 diabetes were significantly lower than those of their counterparts. Decreasing concentrations of adiponectin were independently and significantly associated with a higher risk of CVD when concentrations were analyzed by quartile and as a continuous variable. When patients with CVD were subgrouped according to the comorbidity with or without type2 diabetes, the same trend of association between plasma adiponectin and risk of CVD was observed in each group.
Conclusion— These data show that there are significantly lower levels of plasma adiponectin in patients with ischemic CVD.
Adiponectin, an adipocyte-derived peptide with antiinflammatory and antiatherogenic effects, is known to protect against the initiation and progression of atherosclerosis. In this study, we investigate whether hypoadiponectinemia is present in patients with ischemic cerebrovascular disease (CVD). Our data show that there are significantly lower levels of plasma adiponectin in patients with ischemic CVD.
Key Words: adiponectin ? atherosclerosis ? cerebrovascular disease ? metabolic syndrome ? type 2 diabetes mellitus
Introduction
Adiponectin, also called GBP-28, apM1, AdipoQ, and Acrp30, an adipose tissue-specific protein that has structural homology to collagen VIII and X and complement factor C1q, circulates at high levels in human plasma.1–4 It is one of the adipocyte-expressed proteins that contribute to the homeostatic control of glucose, lipid, energy metabolism, and antiinflammatory activity.5,6 According to several studies, dysregulation of adiponectin has been implicated in metabolic X syndrome and atherosclerosis disorders, including insulin resistance, obesity, type 2 diabetes, hypertension, and coronary artery disease (CAD).7–10 Decreased plasma adiponectin levels have been found to be independently associated with the presence of CAD after adjustment for other well-known CAD risk factors in men, with male patients with hypoadiponectinemia (<4.0 μg/mL) having a significant 2-fold increase in CAD prevalence.9 Adiponectin has a potential inhibitory effect on all molecular mechanisms of atherosclerosis,11 including the inhibition of monocyte adhesion to endothelial cells,12 the inhibition of oxidized low-density lipoprotein (LDL) uptake of macrophage through scavenger receptors,13 and inhibition of proliferation of migrated smooth muscle cells by the action of growth factors.14 Recently, Pischon et al, in a nested case-control study of 19 225 men who had been followed-up for >6 years, have associated high plasma adiponectin concentrations with lower risk of myocardial infarction in men.15 Although these findings indicate that adiponectin plays a crucial role in the development of atherosclerosis, to the best of our knowledge, there have been no studies of the association between plasma adiponectin and ischemic cerebrovascular disease (CVD). Because ischemic CVD is the second most common cause of death in Taiwan, more common than cardiovascular disease,16 and the second leading cause of mortality worldwide,17 a study of whether adiponectin is involved in CVD is important. This study measures the plasma adiponectin levels in ischemic CVD patients with and without type 2 diabetes.
Methods
From February 2001 to December 2003, we studied 228 patients with ischemic CVD who made consecutive visits to the Pingtung Christian Hospital diabetic or neurological clinics. Patients with ischemic stroke were all enrolled in an outpatient disease management program and all were clinically stable and had no manifestations of acute illness. Patients with CVD were studied at least 3 months after the onset of acute illness and could be regularly followed-up by the program manager. Ischemic CVD was defined as patients with an acute or sudden focal neurological defect lasting for >24 hours and positive brain image lesions by computed tomography, magnetic resonance imaging, or magnetic resonance angiography examination.
One hundred forty-one nondiabetic subjects without clinical evidence of stroke were recruited from an unselected population who underwent routine health checkups and were used as the nondiabetic control group. Nondiabetic subjects were defined as those with a fasting plasma glucose level <126 mg/dL and no family history of type 2 diabetes (including parents, siblings, and children). One hundred sixty-five type 2 diabetic patients without CVD were also randomly selected from the patients enrolled in a diabetic clinic disease-management program. A medical history and history of drug use for all control subjects were taken by a physician. All study subjects underwent complete physical examinations and routine biochemical analyses of blood and urine, as well as an assessment of the presence and extent of macrovascular or microvascular complications. The diagnosis of type 2 diabetes was based on World Health Organization criteria.18
Patients with a history of >1 stroke were requested to give information about the most recent stroke only. The type of CVD was clinically categorized according to the Classification of Cerebrovascular Disease III revised by the National Institute of Neurological Disorders and Stroke.19 Patients with brain hemorrhage, transient ischemic attack, and cardiogenic brain infarction were excluded from the study. Also excluded were patients with ischemic CVD caused by less common causes such as drugs, metabolic disease, infection, vasculopathy, moyamoya disease, or venous thrombosis, which may have been discovered during history taking and laboratory work.
This is a case-control study that was approved by the human research ethics committee of our hospital, and informed consent was obtained from each patient. All study subjects were of Han Chinese origin, without any other known ethnic origin, and they all lived in the same region at the time of study.20,21 The anthropometric parameters required that the body mass index (BMI) and waist-to-hip ratio (WHR) be calculated. Seated blood pressure (BP) and plasma biochemical parameters were measured after overnight fasting. A trained nurse measured BP with a digital automatic BP monitor (model HEM-907; Omron, Japan) after these subjects had rested for 5 minutes. Plasma triglycerides, total cholesterol, LDL cholesterol, high-density lipoprotein (HDL) cholesterol, uric acid, creatinine, and glucose were measured by a parallel-multichannel analyzer (Hitachi 7170A, Tokyo, Japan). Those who had stopped smoking >1 year before the examination were considered former/nonsmokers.
Plasma Adiponectin and Highly Sensitive C-Reactive Protein Measurements
All blood samples were drawn after an overnight fast. Plasma samples were kept at –80°C for subsequent assay. Plasma was diluted 5100-fold before assay. The concentration of plasma adiponectin was determined by a commercial solid phase enzyme-linked immunosorbent assay kit (B-Bridge International, Sunnyvale, Calif). The dilution curve was parallel to the standard curve. The inter-assay and intra-assay coefficients of variation of assay were 3.2% to 7.3% (n=3) and 3.1% to 6.2% (n=4), respectively. Plasma highly sensitive C-reactive protein (hsCRP) was measured using a Beckman Coulter IMMAGE Immunochemistry System (Brea, Calif). The detection limit of this hsCRP assay system was 0.2 mg/L.
Statistical Analysis
The data are shown as the mean±SD. All statistical analyses were performed using the Statistical Package for Social Science (SPSS for Windows, version 10.0; SPSS Inc, Chicago, Ill). The statistical differences in variables were compared using unpaired t test or the Mann-Whitney U test. The differences of plasma adiponectin in study groups were also compared after adjustment for age, sex, BMI, WHR, diabetes, and smoking status by General Linear Modeling function analysis. Because the distributions of plasma adiponectin, serum triglycerides, and hsCRP were skewed, logarithmically transformed values were used for statistical analysis. The study subjects were categorized by quartile based on the plasma adiponectin level of healthy controls. Correlation between ischemic CVD and all other parameters were analyzed first by simple logistic regression analysis and then by multivariate logistic regression analysis; variables included in the multivariate analysis were sex, age, systolic BP and diastolic BP, lipid profile, serum uric acid, plasma adiponectin and hsCRP levels, and smoking status. For stratified analysis, we also calculated the multivariable-adjusted odd ratio associated with a doubling in adiponectin levels. Multivariate adjusted odds ratios are presented with 95% confidence interval. Simple and multiple linear stepwise regression analysis were used to examine the associations and independence between plasma concentrations of adiponectin and the values of other parameters. Pearson correlation analysis was used to evaluate the bivariate relationship between individual variables with plasma adiponectin. P<0.05 was considered statistically significant.
Results
The clinical characteristics of our subjects are shown in Table 1. Of the 228 patients with ischemic CVD, 174 had lacunar infarct, and the other 54 had large artery infarctions (35 middle cerebral artery, 9 posterior cerebral artery, 4 anterior cerebral artery, and 6 basilar artery infarcts). Patients with ischemic CVD were older, had higher serum creatinine levels and smoking rates, and lower HDL cholesterol concentrations and BMI values than those without ischemic stoke. However, no significant difference was found in the 2 groups’ WHR, fasting plasma glucose, HbA1C, systolic BP and diastolic BP, serum total cholesterol, triglyceride, LDL cholesterol, and serum uric acid levels. The mean plasma level of adiponectin was significantly lower in patients with ischemic CVD than that of subjects without CVD (4.2±3.7 μg/mL versus 12.7±12.3 μg/mL; P<0.001). The plasma adiponectin levels remained significantly lower after adjustment for age, sex, BMI, WHR, diabetes, and smoking status. The mean plasma adiponectin levels in patients with small artery infarctions were not different from those with large artery infarctions (3.9±3.4 μg/mL versus 4.6±3.5 μg/mL; P=not significant). In contrast, patients with ischemic CVD had significantly higher mean plasma hsCRP levels than those without (11.2±23.9 mg/L versus 2.5±6.3 mg/L; P<0.001).
TABLE 1. Clinical Characteristics of Subjects Studied
One previous report revealed that plasma adiponectin levels were decreased in patients with type 2 diabetes,7 so we further stratified our patients according to comorbidity with type 2 diabetes. Plasma levels of adiponectin in ischemic CVD subjects with or without type 2 diabetes were significantly lower than their counterparts. The mean plasma adiponectin level of men (8.9±10.8 μg/L) was not different from that of women (9.2±10.2 μg/L; P=not significant), whereas the levels in males with ischemic CVD were significantly lower than in females (3.2±2.7 μg/mL versus 5.1±4.2 μg/mL; P<0.001). This difference remained even when grouped by the presence or absence of type 2 diabetes (males and females=2.7±2.7 μg/mL versus 4.4±3.0 μg/mL, P=0.003 in diabetic subjects; 3.6±2.7 μg/mL versus 6.0±5.3 μg/mL, P=0.003 in nondiabetic subjects). As expected, the plasma adiponectin levels of patients with type 2 diabetes were found to be significantly lower than those of nondiabetic subjects (4.5±3.8 μg/mL versus 14.2±13.1 μg/mL, P<0.001). Simple logistic regression analysis found that age, BMI, serum HDL cholesterol and creatinine levels, smoking status, and plasma adiponectin and hsCRP levels to be predictors of ischemic CVD (Table 2). Multiple logistic regression analysis revealed that age, BMI, serum HDL cholesterol and creatinine levels, smoking status, and plasma adiponectin concentration to be independently correlated with ischemic CVD. Decreasing concentrations of adiponectin were independently and significantly associated with a higher risk of CVD when concentrations were analyzed by quartile and by a continuous variable (Tables 2 and 3 ). There was a linear trend among the risk of CVD and the plasma adiponectin levels. This model was adjusted for other known risk factors such as age, BMI, WHR, serum HDL cholesterol, creatinine, and plasma hsCRP levels, and diabetes status. Similar statistic patterns were observed when we subgrouped the study subjects by comorbidity with or without type 2 diabetes (Table 3 and Figure 1).
TABLE 2. Logistic Regression Analyses With Ischemic Cerebrovascular Disease
TABLE 3. Univariate and Multivariate Analysis of the Impact of Plasma Adiponectin Level on Cerebrovascular Disease
Figure 1. Odds ratios for ischemic CVD according to the quartiles of plasma adiponectin levels of healthy controls. The highest quartile was set for reference (Q1). This model was adjusted for age, BMI, WHR, systolic BP and diastolic BP, lipid profile, creatinine, hsCRP levels, and smoking status. Vertical bars indicate 95% confidence interval.
Plasma adiponectin level was positively correlated with HDL cholesterol and LDL cholesterol levels (Table 4 and Figure 2). In contrast, plasma adiponectin concentration was inversely correlated to male gender, WHR, smoking status, diastolic BP, fasting plasma glucose, serum triglyceride, and plasma hsCRP levels. Multiple linear regression analysis confirmed WHR, diastolic BP, fasting plasma glucose, serum triglyceride, HDL cholesterol, LDL cholesterol, and hsCRP levels were independently associated with plasma adiponectin levels.
TABLE 4. Linear Regression Analysis of Variables Associated With Plasma Adiponectin Levels in Subjects Studied
Figure 2. Relationship between log-transformed plasma adiponectin levels and HDL cholesterol (A), LDL cholesterol (B), WHR (C), diastolic BP (D), fasting plasma glucose (E), serum triglyceride (F), and plasma CRP (G) levels in type 2 diabetes (white circle) and nondiabetic subjects (black circle) as determined by Pearson correlation analysis.
Discussion
The present study shows that plasma adiponectin concentration was significantly lower in subjects with ischemic CVD than in controls after adjustment for age, sex, BMI, WHR, diabetes, and smoking status. Furthermore, our study also showed that plasma adiponectin level was significantly associated with all components of metabolic syndrome, which are well-known risk factors for development of atherosclerosis such as WHR, BP, plasma glucose, serum triglyceride, HDL cholesterol, and hsCRP levels. This is the first report to our knowledge to show that hypoadiponectinemia is present in patients with ischemic CVD. The pathophysiologic links between adiponectin and atherosclerosis has been investigated extensively.5,6,10–13 This evidence suggests that adiponectin plays a crucial role in the inflammatory process and the development of atherosclerosis. Patients with hypoadiponectinemia may, therefore, have less antiinflammatory ability and be more vulnerable to the development of ischemic vascular disease.
Our results show that plasma adiponectin levels are correlated with all components of metabolic syndrome. Adiponectin was initially believed to regulate adipocyte differentiation and energy homeostasis by increasing fatty acid oxidation,22 and later plasma adiponectin level has been found to be associated with anthropometric characters, insulin sensitivity, BP, and lipid profiles.6,11,23,24 Mechanisms explaining the relationship between adiponectin and metabolic syndrome or insulin-resistance syndrome remain obscure. It has been shown that adiponectin and tumor necrosis factor (TNF)- inhibit each other’s expression and production in adipocyte and actions in target organs.10,25 Sonnenberg et al26 have proposed that plasma adiponectin is closely negatively related to the visceral adiposity, which may result in increased TNF- secreted from the visceral adipose tissue. Hypoadiponectinemia may cause patients with central obesity may to lose the antiinflammatory capability needed to antagonize the action of TNF- that could stimulate nuclear transcription factor-kappa B activation. Adiponectin plays a protective role against the atherosclerotic vascular change, and loss of effects enhances endothelial dysfunction, as in CVD patients.27
Our study has also shown that plasma adiponectin concentrations are negatively associated with plasma hsCRP levels. Recently, a negative correlation between plasma adiponectin levels and CRP levels has been reported in patients with CAD.28,29 CRP is generally produced in the liver, under regulation by cytokines, such as IL-1?, IL-6, and TNF-,30 and is believed to be directly or indirectly involved in vascular inflammation. The association of plasma adiponectin and hs-CRP levels gives evidence that suggests plasma adiponectin has some role in inflammation and atherosclerosis. The present study shows that hypoadiponectinemia is closely related to metabolic syndrome and inflammatory marker (Table 4). Recent reports suggest that adiponectin modulates the inflammatory response.11–14 Taken together, these pieces of evidence demonstrate that hypoadiponectinemia contributes to the pathogenesis of ischemic stroke.
How adiponectin levels relate to lipid profiles remains unclear. Positive association between plasma adiponectin with HDL cholesterol and negative association with serum triglyceride levels have been reported.31,32 Decreased postheparin lipoprotein lipase activity in hypoadiponectinemia was found by Eynatten et al.33 This fact suggests that adiponectin may regulate plasma HDL and triglyceride levels via modulation of lipoprotein lipase activity. However, whether hypoadiponectinemia aggravates both insulin resistance and lipid profile, or whether low insulin resistance and/or a good lipid profile increase the plasma adiponectin levels is unknown. The finding of plasma adiponectin level positively correlated with LDL cholesterol is not expected and is in contrast to the study results of Yamamoto et al in a Japanese population,31 but it is similar to those of Schulze et al in 741 type 2 diabetic men.32 However, the role of adiponectin in regulating lipid metabolism needs to be clarified by further studies.
Limitations of our study include its cross-sectional design, and the time that the blood drawn from patients with cerebrovascular disease was at least 3 months after acute illness, which limit our ability to infer a causal relationship between decreased plasma adiponectin level and ischemic cerebrovascular disease. It would be interesting to measure the serial changes of plasma adiponectin level in acute and chronic stable stages to further clarify the role of adiponectin in cerebrovascular disease. The cases studied in the present study are only survivors from CVD and cases with more severe forms are not included. The plasma adiponectin level in patients with severe form of ischemic stroke may be different from that with survivors. In addition, although we controlled for other major cerebrovascular risk factors, the existence of unrecognized confounding variables is always possible. Our analyses are based on single measurements of blood adiponectin, which may not reflect the relationship over time.
In conclusion, the present report shows that plasma adiponectin concentration is low in patients with ischemic CVD and it finds a possible close relationship between adiponectin- metabolic syndrome-inflammation and the development of atherosclerosis. However, a large-scale prospective cohort study is necessary to resolve the potential causal relationship between adiponectin and CVD.
Acknowledgments
We are grateful to the staff of the diabetes and cerebrovascular disease care team for their assistance in various measurements and other organizational aspects of this study. This work was supported by a grant from National Science Council of Taiwan (93-2314-B-475-002).
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