Plasma calprotectin and its association with cardiovascular disease manifestations, obesity and the metabolic syndrome in type 2 diabetes mellitus patients

BMC Cardiovascular Disorders

Lars Melholt Rasmussen¹  Jordi Dahl³  Jan Erik Henriksen²  Mikael Kjær Poulsen⁴  Mads Nybo¹  Lise Pedersen¹ 

[1] Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Sdr. Boulevard 29, 5000 Odense C, Denmark;Department of Endocrinology, Diabetes Research Center, Odense University Hospital, Sdr. Blvd 29, 5000 Odense C, Denmark;Department of Cardiology, Odense University Hospital, Sdr. Blvd 29, 5000 Odense C, Denmark;Department of Cardiology, Sygehus Lillebælt, Kabbeltoft 25, 7100 Vejle, Denmark

关键词: Reference range;    Automated assay;    Metabolic syndrome;    Obesity;    Type 2 diabetes;    Inflammation;    Cardiovascular disease;    MRP8/14;    Calprotectin;   

Others  :  1088397
DOI  :  10.1186/1471-2261-14-196

 received in 2014-09-01, accepted in 2014-12-16,  发布年份 2014

【 摘 要 】

Background

Plasma calprotectin is a potential biomarker of cardiovascular disease (CVD), insulin resistance (IR), and obesity. We examined the relationship between plasma calprotectin concentrations, CVD manifestations and the metabolic syndrome (MetS) in patients with type 2 diabetes mellitus (T2DM) in order to evaluate plasma calprotectin as a risk assessor of CVD in diabetic patients without known CVD.

Methods

An automated immunoassay for determination of plasma calprotectin was developed based on a fecal Calprotectin ELIA, and a reference range was established from 120 healthy adults. Plasma calprotectin concentrations were measured in 305 T2DM patients without known CVD. They were screened for carotid arterial disease, peripheral arterial disease (PAD), and myocardial ischemia (MI) by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy.

Results

The reference population had a median plasma calprotectin concentration of 2437 ng/mL (2.5-97.5% reference range: 1040–4262 ng/mL). The T2DM patients had significantly higher concentrations (3754 ng/mL, p < 0.0001), and within this group plasma calprotectin was significantly higher in patients with MetS (p < 0.0001) and also in patients with autonomic neuropathy, PAD, and MI compared with patients without (p < 0.001, p = 0.021 and p = 0.043, respectively). Plasma calprotectin was by linear regression analysis found independently associated with BMI, C-reactive protein, and HDL cholesterol. However, plasma calprotectin did not predict autonomic neuropathy, PAD, MI or CVD when these variables entered the multivariable regression analysis as separate outcome variables.

Conclusion

T2DM patients had higher concentrations of plasma calprotectin, which were associated with obesity, MetS status, autonomic neuropathy, PAD, and MI. However, plasma calprotectin was not an independent predictor of CVD, MI, autonomic neuropathy or PAD.

Trial registration number

NCT00298844

【 授权许可】

   
2014 Pedersen et al.; licensee BioMed Central.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Hessian PA, Edgeworth J, Hogg N: MRP-8 and MRP-14, two abundant Ca(2+)-binding proteins of neutrophils and monocytes. J Leukoc Biol 1993, 53:197-204.
• [2]Sorg C: The calcium binding proteins MRP8 and MRP14 in acute and chronic inflammation. Behring Inst Mitt 1992, 91:126-137.
• [3]Leclerc E, Fritz G, Vetter SW, Heizmann CW: Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 2009, 1793:993-1007.
• [4]Ehrchen JM, Sunderkotter C, Foell D, Vogl T, Roth J: The endogenous Toll-like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer. J Leukoc Biol 2009, 86:557-566.
• [5]Bjarnason I, Sherwood R: Fecal calprotectin: a significant step in the noninvasive assessment of intestinal inflammation. J Pediatr Gastroenterol Nutr 2001, 33:11-13.
• [6]Croce K, Gao H, Wang Y, Mooroka T, Sakuma M, Shi C, Sukhova GK, Packard RR, Hogg N, Libby P, Simon DI: Myeloid-related protein-8/14 is critical for the biological response to vascular injury. Circulation 2009, 120:427-436.
• [7]Burkhardt K, Schwarz S, Pan C, Stelter F, Kotliar K, Von EM, Sollinger D, Lanzl I, Heemann U, Baumann M: Myeloid-related protein 8/14 complex describes microcirculatory alterations in patients with type 2 diabetes and nephropathy. Cardiovasc Diabetol 2009, 8:10. BioMed Central Full Text
• [8]Altwegg LA, Neidhart M, Hersberger M, Muller S, Eberli FR, Corti R, Roffi M, Sutsch G, Gay S, Von EA, Wischnewsky MB, Luscher TF, Maier W: Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes. Eur Heart J 2007, 28:941-948.
• [9]Morrow DA, Wang Y, Croce K, Sakuma M, Sabatine MS, Gao H, Pradhan AD, Healy AM, Buros J, McCabe CH, Libby P, Cannon CP, Braunwald E, Simon DI: Myeloid-related protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute coronary syndrome in the pravastatin or atorvastatin evaluation and infection therapy: thrombolysis in myocardial infarction (PROVE IT-TIMI 22) trial. Am Heart J 2008, 155:49-55.
• [10]Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, Sakuma M, Shi C, Zago AC, Garasic J, Damokosh AI, Dowie TL, Poisson L, Lillie J, Libby P, Ridker PM, Simon DI: Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events. Circulation 2006, 113:2278-2284.
• [11]Kannel WB, McGee DL: Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979, 59:8-13.
• [12]Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H: Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 2001, 44(Suppl 2):S14-S21.
• [13]Poulsen MK, Henriksen JE, Dahl J, Johansen A, Moller JE, Gerke O, Vach W, Haghfelt T, Beck-Nielsen H, Hoilund-Carlsen PF: Myocardial ischemia, carotid, and peripheral arterial disease and their interrelationship in type 2 diabetes patients. J Nucl Cardiol 2009, 16:878-887.
• [14]Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998, 15:539-553.
• [15]Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28:412-419.
• [16]Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C: Definition of metabolic syndrome: report of the national heart, lung, and blood institute/American heart association conference on scientific issues related to definition. Circulation 2004, 109:433-438.
• [17]Poulsen MK, Nybo M, Dahl J, Hosbond S, Poulsen TS, Johansen A, Hoilund-Carlsen PF, Beck-Nielsen H, Rasmussen LM, Henriksen JE: Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus. Cardiovasc Diabetol 2011, 10:76. BioMed Central Full Text
• [18]zur Schulze WA, Foell D, Frosch M, Vogl T, Sorg C, Roth J: Myeloid related proteins MRP8/MRP14 may predict disease flares in juvenile idiopathic arthritis. Clin Exp Rheumatol 2004, 22:368-373.
• [19]Nijhuis J, Rensen SS, Slaats Y, van Dielen FM, Buurman WA, Greve JW: Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity (Silver Spring) 2009, 17:2014-2018.
• [20]Greenberg AS, Obin MS: Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr 2006, 83:461S-465S.
• [21]Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr: Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003, 112:1796-1808.
• [22]Sekimoto R, Kishida K, Nakatsuji H, Nakagawa T, Funahashi T, Shimomura I: High circulating levels of S100A8/A9 complex (calprotectin) in male Japanese with abdominal adiposity and dysregulated expression of S100A8 and S100A9 in adipose tissues of obese mice. Biochem Biophys Res Commun 2012, 419:782-789.
• [23]Catalan V, Gomez-Ambrosi J, Rodriguez A, Ramirez B, Rotellar F, Valenti V, Silva C, Gil MJ, Fernandez-Real JM, Salvador J: Increased levels of calprotectin in obesity are related to macrophage content: impact on inflammation and effect of weight loss. Mol Med 2011, 17:1157-1167.
• [24]Mortensen OH, Nielsen AR, Erikstrup C, Plomgaard P, Fischer CP, Krogh-Madsen R, Lindegaard B, Petersen AM, Taudorf S, Pedersen BK: Calprotectin–a novel marker of obesity. PLoS One 2009, 4:e7419.
• [25]Hirata A, Kishida K, Nakatsuji H, Hiuge-Shimizu A, Funahashi T, Shimomura I: High serum S100A8/A9 levels and high cardiovascular complication rate in type 2 diabetics with ultrasonographic low carotid plaque density. Diabetes Res Clin Pract 2012, 97:82-90.
• [26]Peng WH, Jian WX, Li HL, Hou L, Wei YD, Li WM, Xu YW: Increased serum myeloid-related protein 8/14 level is associated with atherosclerosis in type 2 diabetic patients. Cardiovasc Diabetol 2011, 10:41. BioMed Central Full Text
• [27]Ortega FJ, Sabater M, Moreno-Navarrete JM, Pueyo N, Botas P, Delgado E, Ricart W, Fruhbeck G, Fernandez-Real JM: Serum and urinary concentrations of calprotectin as markers of insulin resistance and type 2 diabetes. Eur J Endocrinol 2012, 167:569-578.
• [28]Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, Wang S, Fortier M, Greenberg AS, Obin MS: Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res 2005, 46:2347-2355.
• [29]Eue I, Langer C, Eckardstein A, Sorg C: Myeloid related protein (MRP) 14 expressing monocytes infiltrate atherosclerotic lesions of ApoE null mice. Atherosclerosis 2000, 151:593-597.
• [30]Baumann M, Schmaderer C, Burkhardt K, Haller B, Heemann U, Dugi K, Von EM: MRP8/14 is associated with systemic inflammation in stable coronary atherosclerosis in men. Eur J Clin Investig 2011, 41:1261-1267.
• [31]Micha R, Imamura F, von Wyler BM, Solomon DH, Hernan MA, Ridker PM, Mozaffarian D: Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol 2011, 108:1362-1370.
• [32]Kannel WB, McGee DL: Diabetes and cardiovascular disease. The framingham study. JAMA 1979, 241:2035-2038.