- Email: [email protected]
Relationship between adipokines and coronary artery aneurysm in children with Kawasaki disease
Relationship between adipokines and coronary artery aneurysm in children with Kawasaki disease RUIXI LIU, BO HE, FANG GAO, QIAN LIU, and QIJIAN YI CHONGQING, P.R. CHINA
Body fat is an important source of adipokines not only in association with energy balance, but also with inflammatory and immune responses. This study investigated the relationship between serum levels of adipokines and coronary artery aneurysm in patients with Kawasaki disease (KD). Levels of leptin, adiponectin, and resistin were measured in 165 cases, including 4 groups: the control group (n 5 85), KD with normal coronary arteries (n 5 41), KD with dilatation and/or ectasia (n 5 31), and KD with coronary aneurysm (n 5 8). White blood cells counts (WBC), red blood cells counts (RBC), hemoglobin (HB), Hematocrit (Hct), platelet count, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were tested in children. Levels of adiponectin and resistin levels were significantly elevated; hemoglobin significantly decreased in the group of KD with coronary aneurysm compared with the controls or other KD subgroups. There were markedly positive relationships between levels of resistin and CRP, and negative relationships between levels of resistin and RBC in patients with KD. Levels of adiponectin, resistin, and hemoglobin were associated with the development of coronary aneurysm in children with KD. The up-regulation of resistin secreted from adipose tissue may be closely linked to up-regulation of systemic proinflammatory markers in acute KD. (Translational Research 2012;160:131–136) Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BSA ¼ body surface area; CALs ¼ coronary artery lesions; CRP ¼ C reactive protein; ESR ¼ erythrocyte sedimentation rate; HB ¼ hemoglobin; Hct ¼ Hematocrit; HMW ¼ high molecular weight; IL ¼ interleukin; IVIG ¼ intravenous immunoglobulin; KD ¼ Kawasaki disease; LMW ¼ low molecular weight; MCP ¼ monocyte chemoattractant protein; MMP ¼ matrix metalloproteinase; RBC ¼ red blood cells counts; TNF ¼ tumor necrosis factor; WBC ¼ white blood cells counts
awasaki disease (KD) is an acute febrile disorder with coronary and other systemic vasculitis that occurs predominantly in infancy and early childhood. This disease is of great concern to pediatricians, because approximately 15% to 25% of
K
the patients develop coronary aneurysms.1 Although the pathogenesis of KD has not been clearly identified, serum levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-a, are elevated during the acute phase of KD, suggesting
From the Department of Cardiovascular Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P.R. China; Key Laboratory of Pediatrics in Chongqing, Chongqing, P.R. China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, P.R. China.
Reprint requests: Qijian Yi, Department of Cardiovascular Medicine, Children’s Hospital of Chongqing Medical University, #136 Zhongshan Er Road, Yuzhong District, Chongqing 400014, P.R. China; e-mail: [email protected]. 1931-5244/$ - see front matter
Conflict of interest: None.
Crown Copyright Ó 2012 Published by Mosby, Inc. All rights reserved.
Submitted for publication October 19, 2011; revision submitted January 11, 2012; accepted for publication January 12, 2012.
doi:10.1016/j.trsl.2012.01.013
131
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AT A GLANCE COMMENTARY Liu R, et al. Background
Adipose tissue, besides its main function as an energy storage depot, is currently considered an endocrine organ that secretes several self-produced cytokines. The three best-studied adipokines are leptin, adiponectin, and resistin. All three adipokines exert significant effects on metabolism and lipogenesis as well as in regulation of human inflammatory responses. Moreover, they participate in the systemic inflammatory response with strong reciprocal influences on other cytokines like TNF-a, IL-6, and IL-10, regulating systemic inflammatory response, angiogenesis, and subclinical coronary atherosclerosis. Translational Significance
Up to now, there is little known about the relationship between adipokines and vasculitis and coronary artery lesions (CALs) in patients with KD. Thus, we examined serum concentrations of leptin, adiponectin, and resistin in KD patients to ascertain whether these adipokines are involved in the development of KD.
that they may be involved in the development of KD.2-4 Adipose tissue, besides its main function as an energy storage depot, is currently considered an endocrine organ that secretes several self-produced cytokines. The three best-studied adipokines are leptin, adiponectin and resistin.5 All three adipokines exert significant effects on metabolism and lipogenesis as well as in regulation of human inflammatory responses.6 Moreover, they participate in the systemic inflammatory response with strong reciprocal influences on other cytokines like TNF-a, IL-6, IL-10, regulating in this way systemic inflammatory response, angiogenesis, subclinical coronary atherosclerosis.7-11 Up to now, there is little known about the relationship between adipokines and vasculitis and coronary artery lesions (CALs) in patients with KD. Thus, we examined serum concentrations of leptin, adiponectin, and resistin in KD patients to ascertain whether these adipokines are involved in the development of KD. METHODS Subjects and data collection. We enrolled patients with KD from the Children’s Hospital of Chongqing
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Medicine University, Chongqing, China. Eighty patients (50 males and 30 females, 3.18 6 2.61 years old) involved in the study, all of whom met the criteria proposed by the Japanese Kawasaki Disease Research Committee.12 In addition, 85 sex-and age-matched healthy blood subjects were used as healthy controls. The study protocol was approved by the Ethics Committee of Chongqing Medicine University, and written informed consents were obtained from the parents of all subjects. Echocardiography was obtained within 2 weeks of the onset or before intravenous immunoglobulin administration. CALs were defined as coronary vessel internal diameter $2 SDs above the mean for age adjusted for body surface area (BSA).13 Patients were divided into 2 groups according to the presence of CAL: 39 patients with CAL and 41 patients without CALs. Among patients with CALs, dilatation and ectasia are descriptive terms used to characterize an internal vessel diameter $2 SDs but ,0.4 cm,14 diameter $0.4 cm is defined as an aneurysm. Patients with CALs were assigned to 2 groups depending on the extent of CALs, which were visualized by echocardiography or coronary arteriography, dilatation, and/or ectasia and aneurysms. White blood cells counts (WBC), red blood cells (RBC) counts, hemoglobin (HB), Hematocrit (Hct), platelet count, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were obtained in all subjects; blood samples were drawn before intravenous immunoglobulin therapy in KD patient. Measurement of serum leptin, adiponectin, and serum resistin levels. Serum concentrations of leptin, adiponec-
tin, and resistin were measured using a DuoSet ELISA Development Kit (R&D Systems, Minneapolis, Minn). Samples were prepared at the appropriate dilutions and paired samples were assayed together according to the instructions of the manufacturers. The intra- and interassay coefficients of variation for adiponectin were: ,4% and ,7%, ,8% and ,10%, ,5% and ,7%, respectively. Statistical analysis. All values in this study are described as mean 6 standard deviation (SD) or number and percent (n, %). Comparisons of the frequencies between groups were analyzed using c2 tests. Differences among groups were assessed using the unpaired 2tailed t test. Pearson’s correlation analysis was used to test for associations between sequential parameters. SPSS 12.0 K for Windows (SPSS Inc., Chicago, Ill) was used for all statistical analyses. All P values were 2-sided and a value of ,0.05 was considered as statistically significant.
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Table I. Comparison of laboratory characteristic in patients and control groups KD (n 5 80)
Age (y) Sex (male/female) Hemoglobin (g/dL) Platelet (103/uL) WBC (103/uL) RBC (106/mm3) Hematocrit (%) AST (U/L) ALT (U/L) CRP (mg/dL) ESR (mm/h) Adiponectin (mg/mL) Resistin (ng/mL) Leptin (ng/mL)
Controls (n 5 85)
3.18I2.61 2.57 6 2.01 50/30 55/30 103.38 6 10.47 123.02 6 15.94 418.76 6 183.66 255.87 6 43.49 13.38 6 6.37 7.35 6 1.40 3.98 6 0.53 4.43 6 0.29 32.32 6 3.16 37.02 6 2.38 54.82 6 80.51 17.60 6 6.49 80.49 6 101.56 27.6 6 6.80 47.64 6 52.26 4.39 6 1.30 50.69 6 28.44 7.89 6 3.30 4.79 6 3.38 3.41 6 1.99 22.23 6 15.82 8.24 6 7.88 87.19 6 37.13 109.47 6 75.89
Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between control and patients.
RESULTS General characteristics and levels of adipokines of study subjects. Clinical characteristics of enrolled KD pa-
tients and healthy controls are summarized in Table I. There were no statistically significant differences in age, gender, and leptin between the KD patients and normal controls. Compared with control subjects, a significantly decrease in HB (103.38 6 10.47 vs. 123.02 6 15.94 g/dL), RBC (3.98 6 0.53 vs. 4.43 6 0.29 106/mm3) and Hct (32.32 6 3.16 vs. 37.02 6 2.38 %) (all P , 0.001) and increase in WBC, platelet count, ALT, AST, CRP, ESR, serum adiponectin, and resistin levels were noted in children with KD (Table I). Differences in serum leptin, adiponectin, and resistin between KD with and without CALs. There were no signif-
icant differences between group of KD with CALs and group of KD without CALs in age, sex, ALT, AST, CRP, platelet count, WBC counts, ESR levels, leptin, adiponectin, and resistin but HB levels (99.89 6 9.60 g/dL vs. 106.68 6 9.26 g/dL, P 5 0.011) (Tables II and III). However, serum adiponectin and resistin levels in patients with coronary aneurysm were significantly higher than that of with dilatation and/or ectasia (8.33 6 3.33 vs. 3.84 6 2.89, P 5 0.005; 49.28 6 21.09 vs. 20.21 6 12.09, P , 0.001 respectively) (Figs 1 and 2, respectively). Correlations characteristics.
between
adipokines
and
Table II. Relation between clinical parameters in KD patients and development of CAL
P
0.421 0.657 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.020 ,0.001 0.157
patient
CPR and RBC levels were significantly correlated with resistin in patients with KD (r 5 0.283, P 5 0.045; r 5 –0.332, P 5 0.013, respectively) (Table IV). Moreover, age in KD patients were negatively associated with leptin and adiponectin (r 5 –0.314, P 5 0.01; r 5 –0.42, P 5 0.001, respectively) (Table IV).
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KD with CAL (n 5 39)
KD without CAL (n 5 41)
Age (y) 3.03 6 2.93 3.35 6 2.42 Sex (male/female) 20/8 18/12 Hemoglobin (g/dL) 99.89 6 9.60 106.68 6 9.62 432.00 6 198.78 420.00 6 172.35 Platelet (103/uL) 14.35 6 6.91 13.12 6 6.55 WBC (103/uL) 3.92 6 0.53 4.02 6 0.51 RBC (106/mm3) Hematocrit (%) 31.4 6 2.99 33.01 6 3.06 AST (U/L) 59.11 6 90.99 47.12 6 68.55 ALT (U/L) 92.74 6 113.86 69.60 6 86.89 CRP (mg/dL) 53.6027.45 49.5329.26 ESR (mm/h) 99.89 6 9.60 106.59 6 9.80 Adiponectin (mg/mL) 4.62 6 3.37 4.33 6 2.51 Resistin (ng/mL) 25.69 6 17.58 20.84 6 13.74 Leptin (ng/mL) 84.56 6 22.56 89.26 6 48.96
P
0.651 0.326 0.011 0.815 0.490 0.501 0.510 0.601 0.417 0.612 0.130 0.714 0.255 0.646
Abbreviations: KD, Kawasaki disease; CAL, coronary artery lesion; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between patients without CAL and those with CAL.
DISCUSSION
Adipokines are an important group of inflammationrelated molecules that play roles in the immune system and inflammation.15 We were motivated to study the concentrations of adipocytokine leptin, resistin, and adiponectin in children with KD, and healthy controls to assess its role in the pathogenesis of KD. Our study demonstrated that (1) levels of resistin and adiponectin increased in patients with KD, compared with healthy subjects, and (2) serum levels of resistin and adiponectin increased, and levels of hemoglobin decreased in KD patients with aneurysms, compared with healthy subjects and with KD with normal coronary arteries and with dilatation and/or ectasia. Moreover, we found that (3) CPR and RBC levels were significantly correlated with resistin in patients with KD, and that (4) age in KD patients were negatively associated with leptin and adiponectin. Our study showed that serum leptin levels in patients with KD were lower than that of in healthy controls but not statistically significant. Published studies suggested that leptin participates in systemic inflammatory response,16 and increased concentrations of such is an independent risk factor for coronary heart disease.17 Our results do not support their direct involvement in KD inflammation or may only indicate their neutralization due to unknown interactions with other antiinflammatory cytokines. Finally, another possible explanation for our findings would be the lack of leptin participation in generalized inflammation of KD patients.
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Table III. Relation between clinical parameters in KD patients and development of coronary aneurysm Dilatation and/or ectasia (n 5 28)
Coronary aneurysm (n 5 11)
P
Age (y) 3.41 6 3.09 1.06 6 0.67 0.003 Hemoglobin 100.70 6 9.7 90.80 6 8.43 0.042 (g/dL) 0.106 Platelet (103/uL) 396.04 6 160.09 556.63 6 22.18 13.32 6 6.94 18.41 6 4.64 0.174 WBC (103/uL) 3.97 6 0.55 3.48 6 0.26 0.095 RBC (106/mm3) Hematocrit (%) 31.60 6 3.11 29.72 6 2.81 0.226 AST (U/L) 66.09 6 99.68 41.25 6 16.97 0.629 ALT (U/L) 95.34 6 120.31 41.25 6 21.53 0.386 CRP (mg/dL) 56.71 6 26.24 47.66 6 31.97 0.59 ESR (mm/h) 49.50 6 43.98 107.80 6 104.66 0.284 3.84 6 2.89 8.33 6 3.33 0.005 Adiponectin (mg/mL) Resistin (ng/mL) 20.21 6 12.09 49.28 6 21.09 ,0.001 Leptin (ng/mL) 83.19 6 15.64 96.09 6 45.78 0.266 Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between patients with dilatation and/or ectasia and these with coronary aneurysm.
Fig 1. Levels of adiponectin in the subgroups of patients with Kawasaki disease type 1(n 5 41): Patients without CALs; Type 2 (n 5 28): Dilatation and/or ectasia; Type 3 (n 5 11): Aneurysm. (Color version of figure is available online.)
On the other hand, serum resistin levels were significantly higher in patients with KD than that of in controls. This result is in line with a previous observation that patients with KD present of increased resistin levels in the acute phase.18 To our knowledge, this is the first study investigating the relationship between resistin and CALs in KD patients. In our study, serum resistin level in KD patients with coronary aneurysm were significantly higher than that in KD patients with dilatation and/or ectasia. Resistin is mainly produced by the stromovascular fraction of adipose tissue and peripheral blood monocytes.6 Resistin level that increased in KD patients with aneurysm suggested
Fig 2. Levels of resistin in the subgroups of patients with Kawasaki disease type 1 (n 5 41): Patients without CALs; Type 2 (n 5 28): Dilatation and/or ectasia; Type 3 (n 5 11): Aneurysm. (Color version of figure is available online.)
that the adipose tissue was involved in the inflammatory process and coronary aneurysm in patients with KD. Elevated serum concentrations of resistin have been reported in patients with chronic inflammatory diseases like rheumatoid arthritis,19 inflammatory bowel disease,20 and asthma,21 but little data are available on the role of resistin in acute inflammatory diseases like KD.22-23 Our results showed that serum resistin levels were significantly elevated in the acute phase of KD, especially in those KD patients with aneurysm. Adiponectin has emerged most recently as an important adipocytokine that has been clearly demonstrated to have a variety of functions, including anti-atherogenic, anti-inflammatory, and insulin-sensitizing properties.24-26 Adiponectin has been reported to inhibit the expression and production of TNF-a and CRP, while it has been shown to be negatively regulated by TNFa and IL-6 in adipose tissue.27 On the other hand, increased production of proinflammatory molecules such as IL-6, IL-8, MCP-1, and matrix metalloproteinase (MMP)-1 after adiponectin stimulation has been described.28-29 The authors suggested that adiponectin could actively participate in the process of immune response, inflammation, and matrix degradation. This discrepancy may be explained by the fact that adiponectin circulates mainly as a low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer that induce isoform-specific responses. It has recently been discovered that only LMW adiponectin displays anti-inflammatory properties and HMW adiponectin may be responsible for proinflammatory effects.30 Therefore, analysis of specific adiponectin isoforms may be of great importance in determining these diverse effects. In previous studies, CRP, a widely used marker of infection, has been reported to positively correlate with resistin levels in several inflammatory conditions.31-33 Our study showed the same relationship between
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Table IV. Correlations of leptin, resistin, and adiponectin with clinical and laboratory variables in all KD patients Adiponectin
Age (y) Sex (Female) Hemoglobin (g/dL) Platelet (103/uL) WBC (103/uL) RBC (106/mm3) Hematocrit (%) AST (U/L) ALT (U/L) CRP (mg/dL) ESR (mm/h) Adiponectin (mg/mL) Resistin (ng/mL) Leptin (ng/mL)
Resistin
Leptin
r
P
r
P
r
P
20.420 20.250 0.015 0.034 0.092 20.040 0.105 0.040 20.060 20.254 20.156 0.046 0.225
0.001* 0.100 0.916 0.815 0.500 0.772 0.446 0.778 0.678 0.072 0.281 0.726 0.081
20.129 20.200 0.147 20.099 0.262 20.332 20.261 0.000 20.039 0.283 20.256 0.046 20.179
0.328 0.210 0.285 0.488 0.051 0.013* 0.054 0.998 0.786 0.045* 0.073 0.726 0.168
20.314 20.110 0.073 20.019 0.241 0.106 0.120 0.016 0.109 20.010 20.261 0.225 20.179 -
0.015* 0.500 0.595 0.893 0.074 0.442 0.383 0.912 0.445 0.96 0.067 0.081 0.168 -
Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. *P , 0.05.
resistin and CRP in patients with KD. We also observed that there was a relationship between levels of resistin and RBC in KD patients. Although the mechanism causing resistin elevation in slightly anemic patients is currently unknown, it may suggest that resistin might suppress the bone marrow function in vivo, and hemoglobin decrease may indicate a higher risk of CALs in patients with KD. Although the protective effects of hemoglobin has not be determined in KD, the present data suggest that circulating levels of hemoglobin are useful as a predictive marker for aneurysm development, and they may serve as a therapeutic target for prevention of CALs in future. In addition, adiponectin in KD patients was negatively associated with age. Younger patients with KD have higher level of adiponectin and higher risk of developing aneurysms. However, other studies failed to demonstrate the correlation of adiponectin levels with inflammatory markers such as ESR and CRP. Therefore, larger studies examining the relationship of adipokines with inflammatory markers will be necessary. Major shortcomings of this study are the relatively low small number of patients recruited and proinflammatory cytokine such as IL-1, IL-6 and TNF-a could not be measured in the same time. In conclusion, in children with KD and coronary aneurysm, serum levels of resistin and adiponectin elevated significantly and HB level decreased in the acute phase, compared with those without CALs. Their serum levels may serve as good predictors for the later phase of development of coronary aneurysm in children with KD. Further studies are needed to elucidate the role of
hyper-adiponectinemia and hyper-resistinemia in the pathogenesis of KD vasculitis.
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1. Kato H, Ichinose E, Yoshioka F, et al. Fate of coronary aneurysms in Kawasaki disease: serial coronary angiography and long-term follow-up study. Am J Cardiol 1982;49:1758–66. 2. Burns JC, Glode MP. Kawasaki syndrome. Lancet 2004;364: 533–44. 3. Matsubara T, Ichiyama T, Furukawa S. Immunological profile of peripheral blood lymphocytes and monocytes/macrophages in Kawasaki disease. Clin Exp Immunol 2005;141:381–7. 4. Furuno K, Yuge T, Kusuhara K, et al. CD251CD41 regulatory T cells in patients with Kawasaki disease. J Pediatr 2004;145:385–90. 5. Koerner A, Kratzsch J, Kiess W. Adipocytokines: leptin-the classical, resistin-the controversial, adiponectin-the promising, and more to come. Best Pract Res Clin Endocrinol Metab 2005;19:525–46. 6. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004;50: 511–25. 7. Steppan CM, Lazar MA. The current biology of resistin. J Intern Med 2004;255:439–47. 8. Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006;101:2629–40. 9. Lago F, Dieguez C, Gomez-Reino J, et al. The emerging role of adipokines as mediators of inflammation and immune responses. Cytokine Growth Factor Rev 2007;18:313–25. 10. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6: 772–83. 11. Martin SS, Qasim A, Reilly MP. Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease. J Am Coll Cardiol 2008;52:1201–10. 12. Research Committee on Kawasaki Disease 1984 Report of Subcommittee on Standardization of Diagnostic Criteria and
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24. Ouchi N, Kihara S, Arita Y. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999;100:2473–6. 25. Ouchi N, Kihara S, Arita Y, et al. Adiponectin, an adipocytederived plasma protein, inhibits endothelial NF-kB signaling through a cAMP-dependent pathway. Circulation 2000;102: 1296–301. 26. Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30 kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001;98:2005–10. 27. Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K. Obesity, adiponectin and vascular inflammatory disease. Curr Opin Lipidol 2003;14:561–6. 28. Ehling A, Schaffler A, Herfarth H, et al. The potential of adiponectin in driving arthritis. J Immunol 2006;176:4468–78. 29. Rovin BH, Song H, Hebert LA, et al. Plasma, urine, and renal expression of adiponectin in human systemic lupus erythematosus. Kidney Int 2005;68:1825–33. 30. Neumeier M, Weigert J, Schafflerer A, et al. Different effects of adiponectin isoforms in human monocytic cells. J Leukoc Biol 2006;79:803–8. 31. Bo S, Gambino R, Pagani A, et al. Relationships between human serum resistin, inflammatory markers and insulin resistance. Int J Obes (Lond) 2005;29:1315–20. 32. Shetty GK, Economides PA, Horton ES, Mantzoros CS, Veves A. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 2004;27: 2450–7. 33. Al-Daghri N, Chetty R, McTernan PG, et al. Serum resistin is associated with C-reactive protein and LDL cholesterol in type 2 diabetes, coronary artery disease in a Saudi population. Cardiovasc Diabetol 2005;4:10.
Body fat is an important source of adipokines not only in association with energy balance, but also with inflammatory and immune responses. This study investigated the relationship between serum levels of adipokines and coronary artery aneurysm in patients with Kawasaki disease (KD). Levels of leptin, adiponectin, and resistin were measured in 165 cases, including 4 groups: the control group (n 5 85), KD with normal coronary arteries (n 5 41), KD with dilatation and/or ectasia (n 5 31), and KD with coronary aneurysm (n 5 8). White blood cells counts (WBC), red blood cells counts (RBC), hemoglobin (HB), Hematocrit (Hct), platelet count, C reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were tested in children. Levels of adiponectin and resistin levels were significantly elevated; hemoglobin significantly decreased in the group of KD with coronary aneurysm compared with the controls or other KD subgroups. There were markedly positive relationships between levels of resistin and CRP, and negative relationships between levels of resistin and RBC in patients with KD. Levels of adiponectin, resistin, and hemoglobin were associated with the development of coronary aneurysm in children with KD. The up-regulation of resistin secreted from adipose tissue may be closely linked to up-regulation of systemic proinflammatory markers in acute KD. (Translational Research 2012;160:131–136) Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase; BSA ¼ body surface area; CALs ¼ coronary artery lesions; CRP ¼ C reactive protein; ESR ¼ erythrocyte sedimentation rate; HB ¼ hemoglobin; Hct ¼ Hematocrit; HMW ¼ high molecular weight; IL ¼ interleukin; IVIG ¼ intravenous immunoglobulin; KD ¼ Kawasaki disease; LMW ¼ low molecular weight; MCP ¼ monocyte chemoattractant protein; MMP ¼ matrix metalloproteinase; RBC ¼ red blood cells counts; TNF ¼ tumor necrosis factor; WBC ¼ white blood cells counts
awasaki disease (KD) is an acute febrile disorder with coronary and other systemic vasculitis that occurs predominantly in infancy and early childhood. This disease is of great concern to pediatricians, because approximately 15% to 25% of
K
the patients develop coronary aneurysms.1 Although the pathogenesis of KD has not been clearly identified, serum levels of proinflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-a, are elevated during the acute phase of KD, suggesting
From the Department of Cardiovascular Medicine, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Chongqing, P.R. China; Key Laboratory of Pediatrics in Chongqing, Chongqing, P.R. China; Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, P.R. China.
Reprint requests: Qijian Yi, Department of Cardiovascular Medicine, Children’s Hospital of Chongqing Medical University, #136 Zhongshan Er Road, Yuzhong District, Chongqing 400014, P.R. China; e-mail: [email protected]. 1931-5244/$ - see front matter
Conflict of interest: None.
Crown Copyright Ó 2012 Published by Mosby, Inc. All rights reserved.
Submitted for publication October 19, 2011; revision submitted January 11, 2012; accepted for publication January 12, 2012.
doi:10.1016/j.trsl.2012.01.013
131
132
Liu et al
AT A GLANCE COMMENTARY Liu R, et al. Background
Adipose tissue, besides its main function as an energy storage depot, is currently considered an endocrine organ that secretes several self-produced cytokines. The three best-studied adipokines are leptin, adiponectin, and resistin. All three adipokines exert significant effects on metabolism and lipogenesis as well as in regulation of human inflammatory responses. Moreover, they participate in the systemic inflammatory response with strong reciprocal influences on other cytokines like TNF-a, IL-6, and IL-10, regulating systemic inflammatory response, angiogenesis, and subclinical coronary atherosclerosis. Translational Significance
Up to now, there is little known about the relationship between adipokines and vasculitis and coronary artery lesions (CALs) in patients with KD. Thus, we examined serum concentrations of leptin, adiponectin, and resistin in KD patients to ascertain whether these adipokines are involved in the development of KD.
that they may be involved in the development of KD.2-4 Adipose tissue, besides its main function as an energy storage depot, is currently considered an endocrine organ that secretes several self-produced cytokines. The three best-studied adipokines are leptin, adiponectin and resistin.5 All three adipokines exert significant effects on metabolism and lipogenesis as well as in regulation of human inflammatory responses.6 Moreover, they participate in the systemic inflammatory response with strong reciprocal influences on other cytokines like TNF-a, IL-6, IL-10, regulating in this way systemic inflammatory response, angiogenesis, subclinical coronary atherosclerosis.7-11 Up to now, there is little known about the relationship between adipokines and vasculitis and coronary artery lesions (CALs) in patients with KD. Thus, we examined serum concentrations of leptin, adiponectin, and resistin in KD patients to ascertain whether these adipokines are involved in the development of KD. METHODS Subjects and data collection. We enrolled patients with KD from the Children’s Hospital of Chongqing
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Medicine University, Chongqing, China. Eighty patients (50 males and 30 females, 3.18 6 2.61 years old) involved in the study, all of whom met the criteria proposed by the Japanese Kawasaki Disease Research Committee.12 In addition, 85 sex-and age-matched healthy blood subjects were used as healthy controls. The study protocol was approved by the Ethics Committee of Chongqing Medicine University, and written informed consents were obtained from the parents of all subjects. Echocardiography was obtained within 2 weeks of the onset or before intravenous immunoglobulin administration. CALs were defined as coronary vessel internal diameter $2 SDs above the mean for age adjusted for body surface area (BSA).13 Patients were divided into 2 groups according to the presence of CAL: 39 patients with CAL and 41 patients without CALs. Among patients with CALs, dilatation and ectasia are descriptive terms used to characterize an internal vessel diameter $2 SDs but ,0.4 cm,14 diameter $0.4 cm is defined as an aneurysm. Patients with CALs were assigned to 2 groups depending on the extent of CALs, which were visualized by echocardiography or coronary arteriography, dilatation, and/or ectasia and aneurysms. White blood cells counts (WBC), red blood cells (RBC) counts, hemoglobin (HB), Hematocrit (Hct), platelet count, alanine aminotransferase (ALT) level, aspartate aminotransferase (AST) level, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were obtained in all subjects; blood samples were drawn before intravenous immunoglobulin therapy in KD patient. Measurement of serum leptin, adiponectin, and serum resistin levels. Serum concentrations of leptin, adiponec-
tin, and resistin were measured using a DuoSet ELISA Development Kit (R&D Systems, Minneapolis, Minn). Samples were prepared at the appropriate dilutions and paired samples were assayed together according to the instructions of the manufacturers. The intra- and interassay coefficients of variation for adiponectin were: ,4% and ,7%, ,8% and ,10%, ,5% and ,7%, respectively. Statistical analysis. All values in this study are described as mean 6 standard deviation (SD) or number and percent (n, %). Comparisons of the frequencies between groups were analyzed using c2 tests. Differences among groups were assessed using the unpaired 2tailed t test. Pearson’s correlation analysis was used to test for associations between sequential parameters. SPSS 12.0 K for Windows (SPSS Inc., Chicago, Ill) was used for all statistical analyses. All P values were 2-sided and a value of ,0.05 was considered as statistically significant.
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Table I. Comparison of laboratory characteristic in patients and control groups KD (n 5 80)
Age (y) Sex (male/female) Hemoglobin (g/dL) Platelet (103/uL) WBC (103/uL) RBC (106/mm3) Hematocrit (%) AST (U/L) ALT (U/L) CRP (mg/dL) ESR (mm/h) Adiponectin (mg/mL) Resistin (ng/mL) Leptin (ng/mL)
Controls (n 5 85)
3.18I2.61 2.57 6 2.01 50/30 55/30 103.38 6 10.47 123.02 6 15.94 418.76 6 183.66 255.87 6 43.49 13.38 6 6.37 7.35 6 1.40 3.98 6 0.53 4.43 6 0.29 32.32 6 3.16 37.02 6 2.38 54.82 6 80.51 17.60 6 6.49 80.49 6 101.56 27.6 6 6.80 47.64 6 52.26 4.39 6 1.30 50.69 6 28.44 7.89 6 3.30 4.79 6 3.38 3.41 6 1.99 22.23 6 15.82 8.24 6 7.88 87.19 6 37.13 109.47 6 75.89
Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between control and patients.
RESULTS General characteristics and levels of adipokines of study subjects. Clinical characteristics of enrolled KD pa-
tients and healthy controls are summarized in Table I. There were no statistically significant differences in age, gender, and leptin between the KD patients and normal controls. Compared with control subjects, a significantly decrease in HB (103.38 6 10.47 vs. 123.02 6 15.94 g/dL), RBC (3.98 6 0.53 vs. 4.43 6 0.29 106/mm3) and Hct (32.32 6 3.16 vs. 37.02 6 2.38 %) (all P , 0.001) and increase in WBC, platelet count, ALT, AST, CRP, ESR, serum adiponectin, and resistin levels were noted in children with KD (Table I). Differences in serum leptin, adiponectin, and resistin between KD with and without CALs. There were no signif-
icant differences between group of KD with CALs and group of KD without CALs in age, sex, ALT, AST, CRP, platelet count, WBC counts, ESR levels, leptin, adiponectin, and resistin but HB levels (99.89 6 9.60 g/dL vs. 106.68 6 9.26 g/dL, P 5 0.011) (Tables II and III). However, serum adiponectin and resistin levels in patients with coronary aneurysm were significantly higher than that of with dilatation and/or ectasia (8.33 6 3.33 vs. 3.84 6 2.89, P 5 0.005; 49.28 6 21.09 vs. 20.21 6 12.09, P , 0.001 respectively) (Figs 1 and 2, respectively). Correlations characteristics.
between
adipokines
and
Table II. Relation between clinical parameters in KD patients and development of CAL
P
0.421 0.657 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.020 ,0.001 0.157
patient
CPR and RBC levels were significantly correlated with resistin in patients with KD (r 5 0.283, P 5 0.045; r 5 –0.332, P 5 0.013, respectively) (Table IV). Moreover, age in KD patients were negatively associated with leptin and adiponectin (r 5 –0.314, P 5 0.01; r 5 –0.42, P 5 0.001, respectively) (Table IV).
133
KD with CAL (n 5 39)
KD without CAL (n 5 41)
Age (y) 3.03 6 2.93 3.35 6 2.42 Sex (male/female) 20/8 18/12 Hemoglobin (g/dL) 99.89 6 9.60 106.68 6 9.62 432.00 6 198.78 420.00 6 172.35 Platelet (103/uL) 14.35 6 6.91 13.12 6 6.55 WBC (103/uL) 3.92 6 0.53 4.02 6 0.51 RBC (106/mm3) Hematocrit (%) 31.4 6 2.99 33.01 6 3.06 AST (U/L) 59.11 6 90.99 47.12 6 68.55 ALT (U/L) 92.74 6 113.86 69.60 6 86.89 CRP (mg/dL) 53.6027.45 49.5329.26 ESR (mm/h) 99.89 6 9.60 106.59 6 9.80 Adiponectin (mg/mL) 4.62 6 3.37 4.33 6 2.51 Resistin (ng/mL) 25.69 6 17.58 20.84 6 13.74 Leptin (ng/mL) 84.56 6 22.56 89.26 6 48.96
P
0.651 0.326 0.011 0.815 0.490 0.501 0.510 0.601 0.417 0.612 0.130 0.714 0.255 0.646
Abbreviations: KD, Kawasaki disease; CAL, coronary artery lesion; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between patients without CAL and those with CAL.
DISCUSSION
Adipokines are an important group of inflammationrelated molecules that play roles in the immune system and inflammation.15 We were motivated to study the concentrations of adipocytokine leptin, resistin, and adiponectin in children with KD, and healthy controls to assess its role in the pathogenesis of KD. Our study demonstrated that (1) levels of resistin and adiponectin increased in patients with KD, compared with healthy subjects, and (2) serum levels of resistin and adiponectin increased, and levels of hemoglobin decreased in KD patients with aneurysms, compared with healthy subjects and with KD with normal coronary arteries and with dilatation and/or ectasia. Moreover, we found that (3) CPR and RBC levels were significantly correlated with resistin in patients with KD, and that (4) age in KD patients were negatively associated with leptin and adiponectin. Our study showed that serum leptin levels in patients with KD were lower than that of in healthy controls but not statistically significant. Published studies suggested that leptin participates in systemic inflammatory response,16 and increased concentrations of such is an independent risk factor for coronary heart disease.17 Our results do not support their direct involvement in KD inflammation or may only indicate their neutralization due to unknown interactions with other antiinflammatory cytokines. Finally, another possible explanation for our findings would be the lack of leptin participation in generalized inflammation of KD patients.
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Table III. Relation between clinical parameters in KD patients and development of coronary aneurysm Dilatation and/or ectasia (n 5 28)
Coronary aneurysm (n 5 11)
P
Age (y) 3.41 6 3.09 1.06 6 0.67 0.003 Hemoglobin 100.70 6 9.7 90.80 6 8.43 0.042 (g/dL) 0.106 Platelet (103/uL) 396.04 6 160.09 556.63 6 22.18 13.32 6 6.94 18.41 6 4.64 0.174 WBC (103/uL) 3.97 6 0.55 3.48 6 0.26 0.095 RBC (106/mm3) Hematocrit (%) 31.60 6 3.11 29.72 6 2.81 0.226 AST (U/L) 66.09 6 99.68 41.25 6 16.97 0.629 ALT (U/L) 95.34 6 120.31 41.25 6 21.53 0.386 CRP (mg/dL) 56.71 6 26.24 47.66 6 31.97 0.59 ESR (mm/h) 49.50 6 43.98 107.80 6 104.66 0.284 3.84 6 2.89 8.33 6 3.33 0.005 Adiponectin (mg/mL) Resistin (ng/mL) 20.21 6 12.09 49.28 6 21.09 ,0.001 Leptin (ng/mL) 83.19 6 15.64 96.09 6 45.78 0.266 Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. P value is for comparison between patients with dilatation and/or ectasia and these with coronary aneurysm.
Fig 1. Levels of adiponectin in the subgroups of patients with Kawasaki disease type 1(n 5 41): Patients without CALs; Type 2 (n 5 28): Dilatation and/or ectasia; Type 3 (n 5 11): Aneurysm. (Color version of figure is available online.)
On the other hand, serum resistin levels were significantly higher in patients with KD than that of in controls. This result is in line with a previous observation that patients with KD present of increased resistin levels in the acute phase.18 To our knowledge, this is the first study investigating the relationship between resistin and CALs in KD patients. In our study, serum resistin level in KD patients with coronary aneurysm were significantly higher than that in KD patients with dilatation and/or ectasia. Resistin is mainly produced by the stromovascular fraction of adipose tissue and peripheral blood monocytes.6 Resistin level that increased in KD patients with aneurysm suggested
Fig 2. Levels of resistin in the subgroups of patients with Kawasaki disease type 1 (n 5 41): Patients without CALs; Type 2 (n 5 28): Dilatation and/or ectasia; Type 3 (n 5 11): Aneurysm. (Color version of figure is available online.)
that the adipose tissue was involved in the inflammatory process and coronary aneurysm in patients with KD. Elevated serum concentrations of resistin have been reported in patients with chronic inflammatory diseases like rheumatoid arthritis,19 inflammatory bowel disease,20 and asthma,21 but little data are available on the role of resistin in acute inflammatory diseases like KD.22-23 Our results showed that serum resistin levels were significantly elevated in the acute phase of KD, especially in those KD patients with aneurysm. Adiponectin has emerged most recently as an important adipocytokine that has been clearly demonstrated to have a variety of functions, including anti-atherogenic, anti-inflammatory, and insulin-sensitizing properties.24-26 Adiponectin has been reported to inhibit the expression and production of TNF-a and CRP, while it has been shown to be negatively regulated by TNFa and IL-6 in adipose tissue.27 On the other hand, increased production of proinflammatory molecules such as IL-6, IL-8, MCP-1, and matrix metalloproteinase (MMP)-1 after adiponectin stimulation has been described.28-29 The authors suggested that adiponectin could actively participate in the process of immune response, inflammation, and matrix degradation. This discrepancy may be explained by the fact that adiponectin circulates mainly as a low molecular weight (LMW) hexamer and a high molecular weight (HMW) multimer that induce isoform-specific responses. It has recently been discovered that only LMW adiponectin displays anti-inflammatory properties and HMW adiponectin may be responsible for proinflammatory effects.30 Therefore, analysis of specific adiponectin isoforms may be of great importance in determining these diverse effects. In previous studies, CRP, a widely used marker of infection, has been reported to positively correlate with resistin levels in several inflammatory conditions.31-33 Our study showed the same relationship between
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Table IV. Correlations of leptin, resistin, and adiponectin with clinical and laboratory variables in all KD patients Adiponectin
Age (y) Sex (Female) Hemoglobin (g/dL) Platelet (103/uL) WBC (103/uL) RBC (106/mm3) Hematocrit (%) AST (U/L) ALT (U/L) CRP (mg/dL) ESR (mm/h) Adiponectin (mg/mL) Resistin (ng/mL) Leptin (ng/mL)
Resistin
Leptin
r
P
r
P
r
P
20.420 20.250 0.015 0.034 0.092 20.040 0.105 0.040 20.060 20.254 20.156 0.046 0.225
0.001* 0.100 0.916 0.815 0.500 0.772 0.446 0.778 0.678 0.072 0.281 0.726 0.081
20.129 20.200 0.147 20.099 0.262 20.332 20.261 0.000 20.039 0.283 20.256 0.046 20.179
0.328 0.210 0.285 0.488 0.051 0.013* 0.054 0.998 0.786 0.045* 0.073 0.726 0.168
20.314 20.110 0.073 20.019 0.241 0.106 0.120 0.016 0.109 20.010 20.261 0.225 20.179 -
0.015* 0.500 0.595 0.893 0.074 0.442 0.383 0.912 0.445 0.96 0.067 0.081 0.168 -
Abbreviations: KD, Kawasaki disease; y, year; WBC, white blood cells counts; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RBC, red blood cells counts; ALT, alanine aminotransferase; AST, aspartate aminotransferase. *P , 0.05.
resistin and CRP in patients with KD. We also observed that there was a relationship between levels of resistin and RBC in KD patients. Although the mechanism causing resistin elevation in slightly anemic patients is currently unknown, it may suggest that resistin might suppress the bone marrow function in vivo, and hemoglobin decrease may indicate a higher risk of CALs in patients with KD. Although the protective effects of hemoglobin has not be determined in KD, the present data suggest that circulating levels of hemoglobin are useful as a predictive marker for aneurysm development, and they may serve as a therapeutic target for prevention of CALs in future. In addition, adiponectin in KD patients was negatively associated with age. Younger patients with KD have higher level of adiponectin and higher risk of developing aneurysms. However, other studies failed to demonstrate the correlation of adiponectin levels with inflammatory markers such as ESR and CRP. Therefore, larger studies examining the relationship of adipokines with inflammatory markers will be necessary. Major shortcomings of this study are the relatively low small number of patients recruited and proinflammatory cytokine such as IL-1, IL-6 and TNF-a could not be measured in the same time. In conclusion, in children with KD and coronary aneurysm, serum levels of resistin and adiponectin elevated significantly and HB level decreased in the acute phase, compared with those without CALs. Their serum levels may serve as good predictors for the later phase of development of coronary aneurysm in children with KD. Further studies are needed to elucidate the role of
hyper-adiponectinemia and hyper-resistinemia in the pathogenesis of KD vasculitis.
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