TGF-β1 content in atherosclerotic plaques, TGF-β1 serum concentrations and incident coronary events
Christian Herder
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorWouter Peeters
Experimental Cardiology Laboratory
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorAstrid Zierer
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorDominique P. V. de Kleijn
Experimental Cardiology Laboratory
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Search for more papers by this authorFrans L. Moll
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorMahir Karakas
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
Search for more papers by this authorMichael Roden
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Department of Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorChrista Meisinger
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorBarbara Thorand
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Search for more papers by this authorGerard Pasterkamp
Experimental Cardiology Laboratory
Senior authors contributed equally.
Search for more papers by this authorWolfgang Koenig
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
Senior authors contributed equally.
Search for more papers by this authorChristian Herder
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorWouter Peeters
Experimental Cardiology Laboratory
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorAstrid Zierer
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorDominique P. V. de Kleijn
Experimental Cardiology Laboratory
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Search for more papers by this authorFrans L. Moll
Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
Search for more papers by this authorMahir Karakas
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
Search for more papers by this authorMichael Roden
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Department of Metabolic Diseases, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
Search for more papers by this authorChrista Meisinger
Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
Search for more papers by this authorBarbara Thorand
Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
Search for more papers by this authorGerard Pasterkamp
Experimental Cardiology Laboratory
Senior authors contributed equally.
Search for more papers by this authorWolfgang Koenig
Department of Internal Medicine II-Cardiology, University of Ulm Medical Center, Ulm, Germany
Senior authors contributed equally.
Search for more papers by this authorAbstract
Eur J Clin Invest 2012; 42 (3): 329–337
Background We tested the hypothesis that high TGF-β1 content in atherosclerotic plaques and high TGF-β1 serum levels are associated with lower risk of coronary events in two independent prospective studies.
Materials and methods In the prospective Athero-Express biobank study, total TGF-β1 plaque levels were measured in 632 atherosclerotic lesions from patients who underwent carotid endarterectomy. In a population-based case-cohort study within the Monitoring of trends and determinants in cardiovascular disease (MONICA)/Cooperative Health Research in the Region of Augsburg (KORA) Augsburg studies, baseline total TGF-β1 serum levels were measured in 333 individuals with and 1728 without incident coronary events.
Results Patients with TGF-β1 content in their plaques above the study median did not have a lower risk of coronary events than patients with lower TGF-β1 levels [adjusted HR (95% CI) 1·46 (0·83–2·53); P = 0·16; mean follow-up 2·6 ± 0·7 years] in the Athero-Express biobank study. Cox proportional hazard models adjusting for age, sex, body mass index, metabolic factors, lifestyle factors and survey did not reveal a significant association between TGF-β1 serum levels and incident coronary events [HR (95% CI) for increasing TGF-β1 tertiles 1·0, 1·22 (0·88–1·68), 1·13 (0·82–1·57); P = 0·47; mean follow-up: 10·8 ± 4·6 years] in the MONICA/KORA Augsburg studies.
Conclusion Our results indicate that high TGF-β1 content in human atherosclerotic plaques and high serum levels of TGF-β1 are not associated with reduced risk of coronary events.
References
- 1 Koenig W, Khuseyinova N. Biomarkers of atherosclerotic plaque instability and rupture. Arterioscler Thromb Vasc Biol 2007; 27: 15–26.
- 2 Li MO, Wan YY, Sanjabi S, Robertson AKL, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu Rev Immunol 2006; 24: 99–146.
- 3 Frutkin AD, Otsuka G, Stempien-Otero A, Sesti C, Du L, Jaffe M et al. TGF-β1 limits plaque growth, stabilizes plaque structure, and prevents aortic dilatation in apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol 2009; 29: 1251–7.
- 4 Mallat Z, Tedgui A. The role of transforming growth factor beta in atherosclerosis: novel insights and future perspectives. Curr Opin Lipidol 2002; 13: 523–9.
- 5 Grainger DJ, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med 1995; 1: 74–9.
- 6 Wang XL, Liu SX, Wilcken DE. Circulating transforming growth factor beta 1 and coronary artery disease. Cardiovasc Res 1997; 34: 404–10.
- 7 Erren M, Reinecke H, Junker R, Fobker M, Schulte H, Schurek JO et al. Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol 1999; 19: 2355–63.
- 8 Os I, Djurovic S, Seljeflot I, Berg K. Transforming growth factor (TGF)-beta1 inversely related to vascular cell adhesion molecule-1 in postmenopausal women with coronary artery disease. A possible mechanism for the putative cardioprotective role of TGF-beta1? J Intern Med 2002; 251: 223–7.
- 9 Hellings WE, Peeters W, Moll FL, Piers SRD, van Setten J, Van der Spek PJ et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome. A prognostic study. Circulation 2010; 121: 1941–50.
- 10 de Kleijn DPV, Moll FL, Hellings WE, Ozsarlak-Sozer G, de Bruin P, Doevendans PA et al. Local atherosclerotic plaques are a source of prognostic biomarkers for adverse cardiovascular events. Arterioscler Thromb Vasc Biol 2010; 30: 612–9.
- 11 Peeters W, de Kleijn DP, Vink A, van de Weg S, Schoneveld AH, Sze SK et al. Adipocyte fatty acid binding protein in atherosclerotic plaques is associated with local vulnerability and is predictive for the occurrence of adverse cardiovascular events. Eur Heart J 2011; 32: 1758–68.
- 12 Koenig K, Khuseyinova N, Baumert J, Thorand B, Loewel H, Chambless L et al. Increased concentrations of C-reactive protein and IL-6 but not IL-18 are independently associated with incident coronary events in middle-aged men and women. Results from the MONICA/KORA Augsburg Case-Cohort Study, 1984–2002. Arterioscler Thromb Vasc Biol 2006; 26: 2745–51.
- 13 Peeters W, Hellings WE, de Kleijn DP, de Vries JP, Moll FL, Vink A et al. Carotid atherosclerotic plaques stabilize after stroke: insights into the natural process of atherosclerotic plaque stabilization. Arterioscler Thromb Vasc Biol 2009; 29: 128–33.
- 14 Verhoeven BA, Velema E, Schoneveld AH, de Vries JP, de Bruin P, Seldenrijk CA et al. Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design. Eur J Epidemiol 2004; 19: 1127–33.
- 15 Hellings WE, Pasterkamp G, Vollebregt A, Seldenrijk CA, de Vries JP, Velema E et al. Intraobserver and interobserver variability and spatial differences in histologic examination of carotid endarterectomy specimens. J Vasc Surg 2007; 46: 1147–54.
- 16 Thorand B, Baumert J, Chambless L, Meisinger C, Kolb H, Döring A et al. Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and women from the general population. Arterioscler Thromb Vasc Biol 2006; 26: 398–405.
- 17 Herder C, Illig T, Baumert J, Müller M, Klopp N, Khuseyinova N et al. Macrophage migration inhibitory factor (MIF) and risk for coronary heart disease: results from the MONICA/KORA Augsburg case-cohort study, 1984–2002. Atherosclerosis 2008; 200: 380–8.
- 18 Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–69.
- 19 Luepker RV, Apple FS, Christenson RH, Crow RS, Fortmann SP, Goff D et al. Case definitions for acute coronary heart disease in epidemiology and clinical research studies: a statement from the AHA Council on Epidemiology and Prevention; AHA Statistics Committee; World Heart Federation Council on Epidemiology and Prevention; the European Society of Cardiology Working Group on Epidemiology and Prevention; Centers for Disease Control and Prevention; and the National Heart, Lung, and Blood Institute. Circulation 2003; 108: 2543–9.
- 20 Herder C, Baumert J, Zierer A, Roden M, Meisinger C, Karakas M et al. Immunological and cardiometabolic risk factors in the prediction of type 2 diabetes and coronary events: MONICA/KORA Augsburg Case-Cohort Study. PLoS ONE 2011; 6:e19852.
- 21 Karakas M, Koenig W, Zierer A, Herder C, Rottbauer W, Baumert J et al. Myeloperoxidase is associated with incident coronary heart disease independently of traditional risk factors: results from the MONICA/KORA Augsburg Study. J Intern Med 2011. (doi: 10.1111/j.1365-2796.2011.02397.x).
- 22 Koenig W, Karakas M, Zierer A, Herder C, Baumert J, Meisinger C et al. Oxidized LDL and the risk of coronary heart disease: results from the MONICA/KORA Augsburg Study. Clin Chem 2011; 57: 1196–200.
- 23 Herder C, Zierer A, Koenig W, Roden M, Meisinger C, Thorand B. Transforming growth factor-β1 and incident type 2 diabetes. Results from the MONICA/KORA case-cohort study, 1984–2002. Diabetes Care 2009; 32: 1921–3.
- 24 Von Elm E, Altman DG, Egger M, Pocock SJ, Gotzche PC, Vandenbroucke JP et al. The Strengthening the Report of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370: 1453–7.
- 25 Simera I, Moher D, Hoey J, Schulz KF, Altman DG. A catalogue of reporting guidelines for health research. Eur J Clin Invest 2010; 40: 35–53.
- 26 Barlow WE. Robust variance estimation for the case-cohort design. Biometrics 1994; 50: 1064–72.
- 27 Grainger DJ. Transforming growth factor β and atherosclerosis: so far, so good for the protective cytokine hypothesis. Arterioscler Thromb Vasc Biol 2004; 24: 399–404.
- 28 Grainger DJ. TGF-β and atherosclerosis in man. Cardiovasc Res 2007; 74: 213–22.
- 29 Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamate C, Merval R et al. Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res 2001; 89: 930–4.
- 30 Grainger DJ, Mosedale DE, Metcalfe JC, Böttinger EP. Dietary fat and reduced levels of TGFbeta1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci 2000; 113: 2355–61.
- 31 Walther M, Jallow IK, Jeffries D, Walther B. Bioactive TGF-β levels can be preserved in plasma samples collected into heparin but not EDTA. Cytokine 2009; 48: 267–72.
