Plasma osteoprotegerin is related to carotid and peripheral arterial disease, but not to myocardial ischemia in type 2 diabetes mellitus

Mikael K Poulsen, Mads Nybo, Jordi Dahl, Susanne Hosbond, Tina S Poulsen, Allan Johansen, Poul F Høilund-Carlsen, Henning Beck-Nielsen, Lars M Rasmussen, Jan E Henriksen, Mikael K Poulsen, Mads Nybo, Jordi Dahl, Susanne Hosbond, Tina S Poulsen, Allan Johansen, Poul F Høilund-Carlsen, Henning Beck-Nielsen, Lars M Rasmussen, Jan E Henriksen

Abstract

Background: Cardiovascular disease (CVD) is frequent in type 2 diabetes mellitus patients due to accelerated atherosclerosis. Plasma osteoprotegerin (OPG) has evolved as a biomarker for CVD. We examined the relationship between plasma OPG levels and different CVD manifestations in type 2 diabetes.

Methods: Type 2 diabetes patients without known CVD referred consecutively to a diabetes clinic for the first time (n = 305, aged: 58.6 ± 11.3 years, diabetes duration: 4.5 ± 5.3 years) were screened for carotid arterial disease, peripheral arterial disease, and myocardial ischemia by means of carotid artery ultrasonography, peripheral ankle and toe systolic blood pressure measurements, and myocardial perfusion scintigraphy (MPS). In addition, plasma OPG concentrations and other CVD-related markers were measured.

Results: The prevalence of carotid arterial disease, peripheral arterial disease, and myocardial ischemia was 42%, 15%, and 30%, respectively. Plasma OPG was significantly increased in patients with carotid and peripheral arterial disease compared to patients without (p < 0.001, respectively), however, this was not the case for patients with myocardial ischemia versus those without (p = 0.71). When adjusted for age, HbA1c and U-albumin creatinine ratio in a multivariate logistic regression analysis, plasma OPG remained strongly associated with carotid arterial disease (adjusted OR: 2.12; 95% CI: 1.22-3.67; p = 0.008), but not with peripheral arterial disease or myocardial ischemia.

Conclusions: Increased plasma OPG concentration is associated with carotid and peripheral arterial disease in patients with type 2 diabetes, whereas no relation is observed with respect to myocardial ischemia on MPS. The reason for this discrepancy is unknown.

Trial registration: ClinicalTrials.gov NCT00298844.

Figures

Figure 1
Figure 1
Plasma osteoprotegerin in patients with and without carotid or peripheral arterial disease or myocardial ischemia. OPG = osteoprotegerin. CAD = carotid arterial disease. PAD = peripheral arterial disease. MI = myocardial ischemia on MPS.

References

    1. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229–234. doi: 10.1056/NEJM199807233390404.
    1. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241:2035–2038. doi: 10.1001/jama.241.19.2035.
    1. Adler AI, Stevens RJ, Neil A, Stratton IM, Boulton AJ, Holman RR. UKPDS 59: hyperglycemia and other potentially modifiable risk factors for peripheral vascular disease in type 2 diabetes. Diabetes Care. 2002;25:894–899. doi: 10.2337/diacare.25.5.894.
    1. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287:2570–2581. doi: 10.1001/jama.287.19.2570.
    1. Burchfiel CM, Curb JD, Rodriguez BL, Abbott RD, Chiu D, Yano K. Glucose intolerance and 22-year stroke incidence. The Honolulu Heart Program. Stroke. 1994;25:951–957. doi: 10.1161/01.STR.25.5.951.
    1. Avignon A, Sultan A, Piot C. et al.Osteoprotegerin: a novel independent marker for silent myocardial ischemia in asymptomatic diabetic patients. Diabetes Care. 2007;30:2934–2939. doi: 10.2337/dc07-0992.
    1. Norman PE, Davis WA, Bruce DG, Davis TM. Peripheral arterial disease and risk of cardiac death in type 2 diabetes: the Fremantle Diabetes Study. Diabetes Care. 2006;29:575–580. doi: 10.2337/diacare.29.03.06.dc05-1567.
    1. Young LH, Wackers FJ, Chyun DA. et al.Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA. 2009;301:1547–1555. doi: 10.1001/jama.2009.476.
    1. Rasmussen LM, Ledet T. Osteoprotegerin and diabetic macroangiopathy. Horm Metab Res. 2005;37(Suppl1):90–94.
    1. Olesen P, Ledet T, Rasmussen LM. Arterial osteoprotegerin: increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-alpha. Diabetologia. 2005;48:561–568. doi: 10.1007/s00125-004-1652-8.
    1. Bucay N, Sarosi I, Dunstan CR. et al.osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev. 1998;12:1260–1268. doi: 10.1101/gad.12.9.1260.
    1. Simonet WS, Lacey DL, Dunstan CR. et al.Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell. 1997;89:309–319. doi: 10.1016/S0092-8674(00)80209-3.
    1. Helske S, Kovanen PT, Lindstedt KA. et al.Increased circulating concentrations and augmented myocardial extraction of osteoprotegerin in heart failure due to left ventricular pressure overload. Eur J Heart Fail. 2007;9:357–363. doi: 10.1016/j.ejheart.2006.10.015.
    1. Ueland T, Jemtland R, Godang K. et al.Prognostic value of osteoprotegerin in heart failure after acute myocardial infarction. J Am Coll Cardiol. 2004;44:1970–1976. doi: 10.1016/j.jacc.2004.06.076.
    1. Poulsen MK, Henriksen JE, Dahl J. et al.Myocardial ischemia, carotid, and peripheral arterial disease and their interrelationship in type 2 diabetes patients. J Nucl Cardiol. 2009;16:878–887. doi: 10.1007/s12350-009-9118-5.
    1. 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. doi: 10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>;2-S.
    1. Li R, Duncan BB, Metcalf PA. et al.B-mode-detected carotid artery plaque in a general population. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Stroke. 1994;25:2377–2383. doi: 10.1161/01.STR.25.12.2377.
    1. Chambless LE, Folsom AR, Clegg LX. et al.Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000;151:478–487.
    1. Gundersen J. Segmental measurements of systolic blood pressure in the extremities including the thumb and the great toe. Acta Chir Scand Suppl. 1972;426:1–90.
    1. Klocke FJ, Baird MG, Lorell BH. et al.ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging) Circulation. 2003;108:1404–1418. doi: 10.1161/01.CIR.0000080946.42225.4D.
    1. Browner WS, Lui LY, Cummings SR. Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. J Clin Endocrinol Metab. 2001;86:631–637. doi: 10.1210/jc.86.2.631.
    1. Kiechl S, Schett G, Wenning G. et al.Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109:2175–2180. doi: 10.1161/.
    1. Chung AW, Booth AD, Rose C, Thompson CR, Levin A, van BC. Increased matrix metalloproteinase 2 activity in the human internal mammary artery is associated with ageing, hypertension, diabetes and kidney dysfunction. J Vasc Res. 2008;45:357–362. doi: 10.1159/000119755.
    1. Ishiyama M, Suzuki E, Katsuda J. et al.Associations of coronary artery calcification and carotid intima-media thickness with plasma concentrations of vascular calcification inhibitors in type 2 diabetic patients. Diabetes Res Clin Pract. 2009;85:189–196. doi: 10.1016/j.diabres.2009.04.023.
    1. Golledge J, McCann M, Mangan S, Lam A, Karan M. Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis. Stroke. 2004;35:1636–1641. doi: 10.1161/01.STR.0000129790.00318.a3.
    1. Lundby-Christensen L, Almdal TP, Carstensen B, Tarnow L, Wiinberg N. Carotid intima-media thickness in individuals with and without type 2 diabetes: a reproducibility study. Cardiovasc Diabetol. 2010;9:40. doi: 10.1186/1475-2840-9-40.
    1. Ziegler S, Kudlacek S, Luger A, Minar E. Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease. Atherosclerosis. 2005;182:175–180. doi: 10.1016/j.atherosclerosis.2005.01.042.
    1. Nybo M, Rasmussen LM. The capability of plasma osteoprotegerin as a predictor of cardiovascular disease: a systematic literature review. Eur J Endocrinol. 2008;159:603–608. doi: 10.1530/EJE-08-0554.
    1. Prior JO, Quinones MJ, Hernandez-Pampaloni M. et al.Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation. 2005;111:2291–2298. doi: 10.1161/01.CIR.0000164232.62768.51.
    1. Altinova AE, Toruner F, Akturk M, Relationship between serum osteoprotegerin, glycemic control, renal function and markers of atherosclerosis in type 2 diabetes. Scand J Clin Lab Invest. 2011.
    1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589. doi: 10.1056/NEJMoa0806470.
    1. Lambers Heerspink HJ, Brinkman JW, Bakker SJ, Gansevoort RT, de ZD. Update on microalbuminuria as a biomarker in renal and cardiovascular disease. Curr Opin Nephrol Hypertens. 2006;15:631–636. doi: 10.1097/01.mnh.0000247496.54882.3f.
    1. Schoppet M, Al-Fakhri N, Franke FE. et al.Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Monckeberg's sclerosis and atherosclerosis. J Clin Endocrinol Metab. 2004;89:4104–4112. doi: 10.1210/jc.2003-031432.
    1. Ovchinnikova O, Gylfe A, Bailey L. et al.Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice--brief report. Arterioscler Thromb Vasc Biol. 2009;29:1478–1480. doi: 10.1161/ATVBAHA.109.188185.
    1. Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA, Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. J Biol Chem. 2000;275:20959–20962. doi: 10.1074/jbc.C000290200.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する