Original Cardiovascular

Increased Content of Resistin in Epicardial Adipose Tissue of Patients with Advanced Coronary Atherosclerosis and History of Myocardial Infarction Maciej Rachwalik1

Dorota Zyśko2

Dorota Diakowska3

1 Department of Cardiac Surgery, Wrocław Medical University,

Wrocław, Poland 2 Teaching Department for Emergency Medical Services, Wrocław Medical University, Wrocław Poland 3 Department and Clinic of Gastrointestinal and General Surgery, Wrocław Medical University, Wrocław, Poland

Wojciech Kustrzycki1

Address for correspondence Maciej Rachwalik, MD, PhD, Department of Cardiac Surgery, Wrocław Medical University, Borowska 213, 50-556 Wrocław, Poland (e-mail: [email protected]).

Thorac Cardiovasc Surg 2014;62:554–560.

Abstract

Keywords

► coronary artery disease ► adipokines ► coronary artery bypass graft ► epicardial adipose tissue

Objectives The aim of the study was to assess whether the plasma level and content of adipokines, in adipose tissue, is associated with a medical history of myocardial infarction. Patients and Methods The study group consisted of 33 consecutive patients (12 females, 21 males, aged 68.6  6.8 years) who underwent cardiac bypass surgery. Patients were divided into groups; group 1 presented with a history of myocardial infarction and group 2 presented without a history of myocardial infarction. During cardiac surgery, samples of epicardial adipose tissue, adipose tissue located at internal mammary artery, subcutaneous adipose tissue, and blood samples were taken for further assessment. Significantly higher levels of resistin in adipose tissue from the epicardial tissue were found in group 1 than in group 2: median and interquartile range, respectively, 37.2 (8.9–121.5) ng/g versus 15.0 (7.1–24.1) ng/g; p < 0.049. Multivariate analysis found that previous myocardial infarction was associated with male gender, older age, and higher content of resistin in epicardial adipose tissue. Conclusion The resistin content in epicardial adipose tissue in patients with advanced coronary atherosclerosis seems higher in those with a history myocardial infarction. Increased resistin epicardial content seems related to the previous myocardial infarction independent of the other established risk factors such as age and male gender. The importance of paracrine function of adipose pericardial tissue in the occurrence of complications of atherosclerosis merits further investigations.

Introduction The most common mechanism of acute coronary syndrome (ACS) is occlusion of the artery by a clot that forms on a

received December 17, 2013 accepted after revision April 2, 2014 published online May 29, 2014

ruptured plaque.1 This process is dependent on several environmental and genetic factors. Currently, the issue as to why advanced atherosclerosis is complicated in some patients by the occurrence of ACSs and not in others is yet

© 2014 Georg Thieme Verlag KG Stuttgart · New York

DOI http://dx.doi.org/ 10.1055/s-0034-1376403. ISSN 0171-6425.

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to be resolved. A factor of particular importance may be the pericardial adipose tissue, which may interact locally with the myocardium through paracrine or vasocrine secretion of proinflammatory adipokines. Adipokines have proinflammatory properties that could contribute to the ACS.2–4 Higher plasma concentrations of adipokines in patients with ACS were reported by some authors.5–9 The aim of the study was to assess whether the plasma level and content of adipokines in adipose tissue is associated with a medical history of myocardial infarction in patients with advanced coronary artery atherosclerosis, referred for coronary artery bypass grafting (CABG).

Materials and Methods The study group consisted of 33 consecutive patients who underwent CABG. Patients were divided into 2 groups: group 1 had a history of myocardial infarction and group 2 did not have a history of myocardial infarction. The criteria for inclusion in the study groups were willingness to participate in the study, age < 80 years, preserved left ventricular function with ejection fraction > 40%, the presence of advanced coronary artery disease (with involvement of main stem of left artery or two to three large arteries), and the absence of valvular pathology. Surgery was performed in a typical fashion, with the use of cardiopulmonary bypass. Cardio protection was achieved by warm blood cardioplegia according to the local protocols. Each patient had pedicled internal thoracic artery and saphenous vein harvested. During surgery, on average 2.7 grafts were performed (range, 2–3). The mean time of cardiopulmonary bypass was 105 minutes (range, 60–125 minutes), and the time of cross clamp of the aorta was on average 55 minutes (range, 40–75 minutes). During cardiac surgery, samples of epicardial adipose tissue, adipose tissue located at internal mammary artery, and subcutaneous adipose tissue were taken and immediately frozen, with avoidance of electrocoagulation in the separating process. In addition, blood samples were taken the morning before surgery after a minimum of 12 hours of fasting. The blood samples were collected in sterile test tubes, clotted (15 minutes, room temperature), and centrifuged (15 minutes, 900  g). The samples were stored at –45°C until assayed. The levels of adiponectin, apelin, and resistin were measured by enzyme-linked immunosorbent assay, using commercial kits supplied by RnDSystems (Abingdon, United Kingdom). The study was approved by the Commission of Bioethics at Wroclaw Medical University (No. 635/2009). All the patients provided their informed written consent to participate in this study.

Statistical Analysis The continuous variables were presented as mean and standard deviation or median and interquartile range, depending on their distribution. The studied variables were assessed for

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the distribution, and in the case that the variable did not have a normal distribution, it was converted by log transformation. Afterward, the distribution of transformed variable was checked for normality. The comparisons were performed with Student t-test or Mann–Whitney U-test according to the variable distribution. The categorical variables were presented as numbers and percentages. Comparisons were performed with chi-square test with Yates correction, when appropriate. The adipokines levels were analyzed as raw data and dichotomized according to the cutoff points, which were found with the receiver operating characteristics (ROC) curve analysis. ROC curve analysis is a statistical method designated to find cutoff points for a studied parameter which allow the distinguishing of two groups of studied subjects with the highest sensitivity and specificity. The ROC curve is a graph of sensitivity (y-axis) versus specificity (x-axis) for each assessed cutoff point to find the point which will best distinguish subgroups in the studied population: in that case those with and without history of previous myocardial infarction. This test is commonly used in medicine to determine the cutoff value for a clinical test. Multivariate analysis was performed by the means of logistic regression analysis and classification and regression trees (CART) analysis.10,11 The following variables were evaluated: gender, age, diabetes, smoking, hypertension, and adipokine levels. CART is a nonparametric method of identifying predictor variables by using binary partitioning. The possible cutoff point of each variable is assessed to identify the cutoff point that resulted in the maximum discrimination between subgroups of patients with respect to the probability of an assessed outcome. CART generates a classification rule which can be visualized as a “classification tree.”10,11 The results of the CART analysis are presented in the form of a graph. The graph consists of rectangles (called “nodes”) connected with lines. The rectangles are numbered. A number distinctive for each rectangle is positioned in the left upper corner. The first node is called the “root node.” The rectangle which is split into two rectangles is also called the “parent node,” whereas two rectangles growing up from the parent node are called the “child nodes.” The nodes which are not split into another two nodes and are marked by a red edge are called “leaves” (the graph represents a tree turned upside down). If a rectangle is split, two lines from its bottom are drawn and they are joined to other rectangles. The text below the node describes the split. The numbers above the lines represent the number of cases directed into the child nodes. The bars in each rectangle represent cases. The legend identifying what bars in the node histograms correspond to the assessed outcome is usually located in the top-right corner of the graph.12 CART was performed to identify factors associated with previous myocardial infarction such as age, gender, smoking status, diabetes, hypertension, and adipokine concentrations as raw and dichotomized data based on ROC curve analysis. The sensitivity, the specificity of constructed models, and the accuracy of a global 10-fold cost validation of the CARTs Thoracic and Cardiovascular Surgeon

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Table 1 Clinical characteristics of patients with history of previous myocardial infarction (group 1) and patients without history of myocardial infarction (group 2) Group 1 (N ¼ 17)

Group 2 (N ¼ 16)

p

Age (y) mean  SD

70.4  5.6

66.7  7.5

0.12

Male gender, n (%)

14 (82.4)

7 (43.8)

< 0.05

Diabetes, n (%)

5 (29.4)

6 (67.5)

0.33

Hypertension, n (%)

11 (64.7)

15 (93.8)

< 0.05

Current smoking, n (%)

7 (41.2)

8 (50.0)

0.62

24.2  3.6

24.7  2.6

0.66

BMI > 25 kg/m , n (%)

6 (35.3)

8 (50.0)

0.39

History of PCI, n (%)

5 (29.4)

2 (12.5)

0.25

History of CABG, n (%)

0 (0)

0 (0)

NS

Thyroid disease, n (%)

0 (0)

2 (12.5)

0.14

Duration of symptoms (mo), the median IQR

12 (6–120)

12 (6–60)

0.51

2

BMI (kg/m ) 2

Abbreviations: BMI, body mass index; CABG, coronary artery bypass grafting; IQR, interquartile range; PCI, percutaneous coronary intervention; SD, standard deviation.

were presented. P values less than 0.05 were considered significant.

Results The study group consisted of 33 patients: 12 women (36.4%) and 21 men (63.6%) aged 68.6  6.1 years. About half of the studied patients had a history of myocardial infarction, twofifths were overweight, one-third had diabetes, nearly 80% had arterial hypertension, almost half of the patients were current smokers, and approximately 20% had a history of previous percutaneous intervention. ►Table 1 presents the comparison of clinical parameters between group 1 with a history of myocardial infarction and group 2 without a history of myocardial infarction. Male

gender and arterial hypertension were significantly more prevalent in group 1 than in group 2. ►Table 2 presents the plasma levels and tissue contents of the investigated adipokines in adipose tissue and their plasma concentrations. The levels of resistin in adipose tissue in the area of internal thoracic artery and epicardial tissue were significantly higher in group 1 than in group 2. The resistin content in adipose tissue had normal log distribution. The resistin log-transformed values of content in pericardial adipose tissue compared with Student t-test obtained statistical significance at p ¼ 0.032, whereas raw data compared with Whitney–Mann U-test obtained statistical significance at p < 0.49. There were no significant differences between concentrations and tissue content of other adipokines, regardless of whether they were assessed by nonparametric

Table 2 Adipokines in plasma and adipose tissue Group 1 (N ¼ 17)

Group 2 (N ¼ 16)

p

Plasma adiponectin (ng/mL)

7.1 (4.9–8.4)

5.6 (4.1–7.6)

0.38

Adiponectin subcutaneous tissue (ng/g)

1.9 (1.5–2.6)

2.5 (2.3–3.2)

0.05

Adiponectin in area of internal thoracic artery (ng/g)

2.6 (1.4–4.2)

2.9 (2.2–4.2)

0.60

Adiponectin in epicardial tissue (ng/g)

2.6 (1.9–3.9)

3.3 (3.0–4.1)

0.16

Apelin in plasma (ng/mL)

3.6 (1.1–5.1)

1.5 (1.0–2.5)

0.19

Apelin in subcutaneous tissue (ng/g)

4.0 (2.7–5.5)

3.3 (2.8–6.3)

0.91

Apelin in area of internal thoracic artery (ng/g)

5.8 (4.4–6.9)

5.5 (3.3–8.5)

0.84

Apelin in epicardial tissue (ng/g)

6.0 (3.1–8.0)

5.8 (3.8–7.3)

0.98

Resistin in plasma (ng/mL)

8.0 (5.9–10.3)

7.7 (6.4–10.9)

0.75

Resistin in subcutaneous tissue (ng/g)

12.8 (6.0–33.6)

17.6 (6.7–23.5)

0.81

Resistin in area of internal thoracic artery (ng/g)

24.6 (12.8–67.6)

19.3 (13.5–28.8)

0.25

Resistin epicardial tissue (ng/g)

37.2 (8.9–121.5)

15.0 (7.1–24.1)

0.049

Notes: Data are presented as median and interquartile range. Group 1–patients with previous myocardial infarction; group 2–patients without previous myocardial infarction. Thoracic and Cardiovascular Surgeon

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Fig. 1 Scatterplot of the resistin content in pericardial adipose tissue in studied groups. Group 1—patients with history of myocardial infarction. Group 2—patients without previous myocardial infarction.

test or parametric test when log-transformed values obtained normal distribution. In ►Fig. 1, the scatterplot of resistin content in epicardial tissue in the studied groups is presented.

Multivariate Analysis By means of logistic regression analysis, it was found that previous myocardial infarction is associated with male sex, older age, and higher content of resistin in epicardial adipose tissue (►Table 3). Cutoff points for age and resistin content in epicardial adipose tissue were assessed by ROC curve analysis. ROC curve analysis found that the cutoff point for resistin epicardial adipose tissue level was 26 ng/g to distinguish a population with and without history of previous myocardial infarction: area under the curve was 0.702; 95% confidence interval, 0.518–0.848; p ¼ 0.027 (►Fig. 2). It was also calculated that age above 66 years was related to history of previous myocardial infarction: area under the curve, 0.64; 95% confidence interval, 0.455–0.799; p ¼ 0.14 (►Fig. 3). After dichotomization of age and resistin content in epicardial tissue at cutoff points obtained during ROC curve analysis, CART analysis was performed. The analysis confirmed that

Rachwalik et al.

Fig. 2 ROC curve for resistin in pericardial adipose tissue in studied groups. Area under the curve, 0.702; 95% confidence interval, 0.518– 0.848; p ¼ 0.027.

higher resistin level, male gender, and older age were related to previous myocardial infarction (►Fig. 4). Global 10-fold cross validation for the CART analysis was 0.85; standard deviation in cost validation was 0.05. The positive predictive value was 92.9% and negative predictive value was 78.9%.

Discussion Adipose tissue is an active endocrine organ that secretes adipokines, which regulate metabolism, insulin resistance, and vascular function.3,13–18 The determination of the role of adipokines in the pathogenesis of cardiovascular complications is hampered by their local secretion and action. Cardiac surgery offers unique circumstances in which it is possible to collect the tissues during standard procedure without exposing the patient to additional complications. The main finding of the study is that higher levels of resistin in epicardial adipose tissue are associated with a positive history of previous myocardial infarction.

Table 3 Odds ratio and 95% confidence interval for history of previous myocardial infarction according to multiple logistic regression analysis Resistin in area of internal thoracic artery

Male gender

Odds ratio (unit change)

1.06

94.4

1.33

95%

1.01

2.6

1.01

þ95%

1.11

3,414.9

1.75

Odds ratio (range)

5,166.01

94.36

971.44

95%

3.58

2.61

1.42

þ95%

7,458,844.00

3,414.86

663,281.5

p

0.023

0.015

0.04

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Fig. 3 ROC curve for age. Area under the curve, 0.64; 95% confidence interval, 0.455–0.799; p ¼ 0.14.

Both human clinical studies and in vitro experimental studies support the pathophysiological role of resistin in the progression of atherosclerosis and coronary artery disease by influencing the angiogenesis, thrombosis, and vascular smooth muscle cell migration and proliferation.3,16–21 Resistin reduces both endothelium-dependent and endothelium-independent vasorelaxation.22 Patients with chronic coronary artery disease and ACS had an elevated plasma level

Fig. 4 Classification tree for previous myocardial infarction.

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of resistin.5,23,24 The resistin plasma level was positively correlated with leucocyte count and high-sensitivity C-reactive protein (hs-CRP) as indicators of inflammation and endothelial activation.25 However, in an apparently healthy man, plasma level of resistin is not a predictor of future cardiovascular events.26 The obtained results of elevated content of resistin in epicardial adipose tissue in patients with a history of myocardial infarction compared with patients without a history of myocardial infarction may shed light on the mechanisms of development of the complications of atherosclerotic processes. The results are concordant with those presented by Langheim et al who had reported higher levels of resistin in epicardial tissue of patients scheduled for urgent coronary artery surgery with a history of ACS than those with elective coronary surgery or controls, who underwent valve replacement surgery with no significant stenosis in the coronary arteries.27 The authors had reported that in both groups with significant coronary arteriosclerosis (stable group and the group with ACS), the concentration of resistin was higher than in the control group.27 The data were not sufficient to determine whether an increased secretion of resistin in ACS is secondary to activation of proinflammatory state in the ACS, or if it is a consequence of chronically elevated levels of resistin in patients predisposed to the atherosclerotic complications.27 The second finding is a lack of associations between history of previous myocardial infarction and circulating

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Funding This study was funded by a grant from Wroclaw Medical University, no. 636 ST.

References 1 Hamm CW, Bassand JP, Agewall S, et al; ESC Committee for Practice

Strengths and Limitations The main strength of the presented analysis consists of the possibility to directly measure the adipokine content of adipose tissue. The main limitation is lack of a control group without coronary artery disease. Patients referred for cardiac surgery are burdened with cardiovascular diseases, and although patients with indications for valve replacement may serve as a control group, they are typically burdened with heart failure, which could affect the level of cytokines. The second limitation of the study is the relatively small size of the study group, making it difficult to conduct a multivariate analysis. A similar problem applies to other studies on tissue levels of adipokines.3,16,23 The third concern is that the level of adipokines in adipose tissue may increase during coronary bypass grafting.29 However, in the study, the tissue samples were taken in both groups studied at the onset of cardiopulmonary surgery, so it should not influence the obtained results. The lack of a control group may constitute the most important shortage of the study. However, a control group is difficult to design because patients with valvular heart disease, without coronary artery heart disease, had cardiac insufficiency which in turn may influence adipokines concentration.30

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Conclusion

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The resistin content in epicardial adipose tissue in patients with advanced coronary atherosclerosis seems higher in those with history of myocardial infarction. Increased resistin epicardial content appears to be related to previous myocardial infarction independent of the other established risk factors such as age and male gender. The importance of paracrine function of adipose pericardial tissue in the occurrence of complications of atherosclerosis merits further investigations.

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Acknowledgments M.R., D.Z., D.D., and W.K. were involved in the concept/ design; M.R., D.D., and W.K. were involved in the data acquisition; M.R. and D.Z. analyzed and interpreted the data; M.R. and D.Z. provided the statistics; M.R., D.Z., and D.D. drafted the article; W.K. revised and approved the article; and M.R., D.Z., D.D., and W.K. approved and submitted the final version.

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Conflict of Interest None declared.

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Guidelines. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent STsegment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32(23):2999–3054 Iacobellis G, Corradi D, Sharma AM. Epicardial adipose tissue: anatomic, biomolecular and clinical relationships with the heart. Nat Clin Pract Cardiovasc Med 2005;2(10):536–543 Baker AR, Silva NF, Quinn DW, et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc Diabetol 2006;5:1–7 Mazurek T, Zhang L, Zalewski A, et al. Human epicardial adipose tissue is a source of inflammatory mediators. Circulation 2003; 108(20):2460–2466 Korah TE, Ibrahim HH, Badr EA, ElShafie MK. Serum resistin in acute myocardial infarction patients with and without diabetes mellitus. Postgrad Med J 2011;87(1029):463–467 Lubos E, Messow CM, Schnabel R, et al. Resistin, acute coronary syndrome and prognosis results from the AtheroGene study. Atherosclerosis 2007;193(1):121–128 Li L, Han JL, Mao JM, Guo LJ, Gao W. Association between serum resistin level and cardiovascular events in postmenopausal women with acute coronary syndrome undergoing percutaneous coronary intervention. Chin Med J (Engl) 2013;126(6):1058–1062 Chu S, Ding W, Li K, Pang Y, Tang C. Plasma resistin associated with myocardium injury in patients with acute coronary syndrome. Circ J 2008;72(8):1249–1253 Qiao XZ, Yang YM, Xu ZR, Yang LA. Relationship between resistin level in serum and acute coronary syndrome or stable angina pectoris. J Zhejiang Univ Sci B 2007;8(12):875–880 Breiman L, Friedman JH, Olshen RA, et al. Classification and Regression Trees. Belmont, CA: Wadsworth International Group; 1984 Rudnicki J, Zyśko D, Kozłowski D, et al. The choice of surgical specialization by medical students and their syncopal history. PLoS ONE 2013;8(1):e55236 StatSoft Electronic Statistics Textbook. . Available at: http://www. statsoft.com/textbook/classification-and-regression-trees/ Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature 2001;409(6818):307–312 Ohmori R, Momiyama Y, Kato R, et al. Associations between serum resistin levels and insulin resistance, inflammation, and coronary artery disease. J Am Coll Cardiol 2005;46(2):379–380 Xu A, Wang Y, Lam KS, Vanhoutte PM. Vascular actions of adipokines molecular mechanisms and therapeutic implications. Adv Pharmacol 2010;60:229–255 Henrichot E, Juge-Aubry CE, Pernin A, et al. Production of chemokines by perivascular adipose tissue: a role in the pathogenesis of atherosclerosis? Arterioscler Thromb Vasc Biol 2005;25(12): 2594–2599 Sahin-Efe A, Katsikeris F, Mantzoros CS. Advances in adipokines. Metabolism 2012;61(12):1659–1665 Lee SE, Kim HS. Human resistin in cardiovascular disease. J Smooth Muscle Res 2012;48(1):27–35 Ross R. Atherosclerosis is an inflammatory disease. Am Heart J 1999;138(5, Pt 2):S419–S420 Gan AM, Butoi ED, Manea A, et al. Inflammatory effects of resistin on human smooth muscle cells: up-regulation of fractalkine and

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levels of resistin or level of resistin in the perivascular fat of the internal thoracic artery. These findings support the theory that the effect of endocrine function of the adipose tissue is rather local than systemic. Perivascular adipose tissue surrounding atherosclerotic aortas have significantly greater inflammatory cell infiltration in comparison with a normal aorta. It may represent a source for the adventitial inflammatory infiltrates which in turn could promote aortic wall degeneration and aortic dilatation.28

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its receptor, CX3CR1 expression by TLR4 and Gi-protein pathways. Cell Tissue Res 2013;351(1):161–174 Chuang TY, Au LC, Wang LC, Ho LT, Yang DM, Juan CC. Potential effect of resistin on the ET-1-increased reactions of blood pressure in rats and Ca2þ signaling in vascular smooth muscle cells. J Cell Physiol 2012;227(4):1610–1618 Kougias P, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C. Adipocytederived cytokine resistin causes endothelial dysfunction of porcine coronary arteries. J Vasc Surg 2005;41(4):691–698 Yaseen F, Jaleel A, Aftab J, Zuberi A, Alam E. Circulating levels of resistin, IL-6 and lipid profile in elderly patients with ischemic heart disease with and without diabetes. Biomarkers Med 2012; 6(1):97–102 Wang H, Chen DY, Cao J, He ZY, Zhu BP, Long M. High serum resistin level may be an indicator of the severity of coronary disease in acute coronary syndrome. Chin Med Sci J 2009;24(3):161–166 Hu WL, Qiao SB, Hou Q, Yuan JS. Plasma resistin is increased in patients with unstable angina. Chin Med J (Engl) 2007;120(10):871–875

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Increased content of resistin in epicardial adipose tissue of patients with advanced coronary atherosclerosis and history of myocardial infarction.

The aim of the study was to assess whether the plasma level and content of adipokines, in adipose tissue, is associated with a medical history of myoc...
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