Interdependence between osteoprotegerin and active von Willebrand factor in long-term cardiovascular mortality prediction in patients undergoing percutaneous coronary intervention

Jolanta M. Siller-Matula; Irene M. Lang; Christian Schoergenhofer; Mark Roest; Bernd Jilma

doi:10.1160/TH17-02-0087

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2017; 117(09): 1730-1738
DOI: 10.1160/TH17-02-0087

Coagulation and Fibrinolysis

Schattauer GmbH

Interdependence between osteoprotegerin and active von Willebrand factor in long-term cardiovascular mortality prediction in patients undergoing percutaneous coronary intervention

Authors

Jolanta M. Siller-Matula

¹Department of Cardiology, Medical University of Vienna, Vienna, Austria

²1^stDepartment of Cardiology, Poznan University of Medical Sciences, Poland
Irene M. Lang

¹Department of Cardiology, Medical University of Vienna, Vienna, Austria
Christian Schoergenhofer

³Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Mark Roest

⁴Synapse Research Institution, Maastricht, The Netherlands
Bernd Jilma

³Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

Abstract

Summary

The interdependence of the predictive accuracy of serum osteoprotegerin (OPG) and von Willebrand factor (vWF) levels for long-term cardiovascular outcomes has not been investigated so far. This was a prospective observational cohort study in 361 patients with coronary artery disease undergoing percutaneous coronary intervention (PCI). Baseline levels of OPG, vWF, active vWF (act vWF) and ristocetin cofactor activity (vWF:RICO) were measured. Cardiovascular mortality was recorded over a median of five years. OPG concentrations >3.7 µg/ml emerged as the strongest predictor of cardiovascular (CV) death: 30 % of patients died during the five-year follow-up in this group, as compared to 10 % in patients with OPG ≤3.7 µg/ml (p<0.001). Act vWF had a significant prognostic impact on CV mortality when OPG levels were low (≤3.7 µg/ml): patients with act vWF concentration >1 µg/ml died in 14 %, whereas those with act vWF values ≤1 µg/ml had a mortality rate of 1 % (p=0.015). We stratified patients into three groups: high OPG, low OPG/high act vWF and low OPG/low act vWF. Patients with high OPG values had a 13-fold higher risk for CV death than those with low OPG/low act vWF concentrations (adj. HR: 12.6; 95 %CI: 1.7–94.7; p=0.014), and a two-fold higher risk as compared to those patients with low OPG/high act vWF concentrations (adj. HR: 2.0; 95 %CI: 1.1–3.7; p=0.03) in the adjusted Cox regression analysis. In conclusion, elevated OPG at the time of PCI was a strong independent predictor of five-years cardiovascular mortality, whereas act vWF had a significant prognostic impact on CV mortality when OPG levels were low.

Keywords

Osteoprotegerin - active von Willebrand factor - cardiovascular death - coronary artery disease - mortality

Volltext

Referenzen

References
1 Reid P, Holen I. Pathophysiological roles of osteoprotegerin (OPG). Eur J Cell Biol 2009; 88: 1-17.
2 Hofbauer LC, Shui C, Riggs BL. et al. Effects of immunosuppressants on receptor activator of NF-kappaB ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun 2001; 280: 334-339.
3 Vik A, Mathiesen EB, Noto AT. et al. Serum osteoprotegerin is inversely associated with carotid plaque echogenicity in humans. Atherosclerosis 2007; 191: 128-134.
4 Kiechl S, Werner P, Knoflach M. et al. The osteoprotegerin/RANK/RANKL system: a bone key to vascular disease. Expert Rev Cardiovasc Ther 2006; 04: 801-811.
5 Bjerre M, Hilden J, Kastrup J. et al. Osteoprotegerin independently predicts mortality in patients with stable coronary artery disease: the CLARICOR trial. Scand J Clin Lab Invest 2014; 74: 657-664.
6 Vik A, Mathiesen EB, Brox J. et al. Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromso Study. J Thromb Haemost 2011; 09: 638-644.
7 Mogelvang R, Haahr-Pedersen S, Bjerre M. et al. Osteoprotegerin improves risk detection by traditional cardiovascular risk factors and hsCRP. Heart 2013; 99: 106-110.
8 Fuernau G, Zaehringer S, Eitel I. et al. Osteoprotegerin in ST-elevation myocardial infarction: prognostic impact and association with markers of myocardial damage by magnetic resonance imaging. Int J Cardiol 2013; 167: 2134-2139.
9 Thompson SG, Kienast J, Pyke SD. et al. Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-641.
10 Danesh J, Wheeler JG, Hirschfield GM. et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med 2004; 350: 1387-1397.
11 Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation 2008; 117: 1449-1459.
12 Firbas C, Siller-Matula JM, Jilma B. Targeting von Willebrand factor and platelet glycoprotein Ib receptor. Expert Rev Cardiovasc Ther 2010; 08: 1689-1701.
13 Siller-Matula JM, Merhi Y, Tanguay JF. et al. ARC15105 is a potent antagonist of von Willebrand factor mediated platelet activation and adhesion. Arterioscler Thromb Vasc Biol 2012; 32: 902-909.
14 Paulinska P, Spiel A, Jilma B. Role of von Willebrand factor in vascular disease. Hamostaseologie 2009; 29: 32-38.
15 Fuchs I, Frossard M, Spiel A. et al. Platelet function in patients with acute coronary syndrome (ACS) predicts recurrent ACS. J Thromb Haemost 2006; 04: 2547-2552.
16 Rutten B, Maseri A, Cianflone D. et al. Plasma levels of active Von Willebrand factor are increased in patients with first ST-segment elevation myocardial infarction: a multicenter and multiethnic study. Eur Heart J Acute Cardiovasc Care 2015; 04: 64-74.
17 Groot E, de Groot PG, Fijnheer R. et al. The presence of active von Willebrand factor under various pathological conditions. Curr Opin Hematol 2007; 14: 284-289.
18 Siller-Matula JM, Delle-Karth G, Christ G. et al. Dual non-responsiveness to antiplatelet treatment is a stronger predictor of cardiac adverse events than isolated non-responsiveness to clopidogrel or aspirin. Int J Cardiol 2013; 167: 430-435.
19 Siller-Matula JM, Delle-Karth G, Lang IM, Phenotyping vs. et al. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study. J Thromb Haemost 2012; 10: 529-542.
20 Omland T, Ueland T, Jansson AM. et al. Circulating osteoprotegerin levels and long-term prognosis in patients with acute coronary syndromes. J Am Coll Cardiol 2008; 51: 627-633.
21 Song TJ, Kim J, Yang SH. et al. Association of plasma osteoprotegerin levels with stroke severity and functional outcome in acute ischaemic stroke patients. Biomarkers 2012; 17: 738-744.
22 Morony S, Tintut Y, Zhang Z. et al. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice. Circulation 2008; 117: 411-420.
23 Bennett BJ, Scatena M, Kirk EA. et al. Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/-mice. Arterioscler Thromb Vasc Biol 2006; 26: 2117-224.
24 Kiechl S, Schett G, Wenning G. et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004; 109: 2175-2180.
25 Vik A, Mathiesen EB, Johnsen SH. et al. Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population--the Tromso study. J Thromb Haemost 2010; 08: 898-905.
26 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.
27 Jorsal A, Tarnow L, Flyvbjerg A. et al. Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetologia 2008; 51: 2100-2107.
28 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.
29 Rasmussen LM, Ledet T. Osteoprotegerin and diabetic macroangiopathy. Hormone Metabol Res 2005; 37 (Suppl. 01) 90-94.
30 Wannamethee SG, Whincup PH, Shaper AG. et al. Circulating inflammatory and haemostatic biomarkers are associated with risk of myocardial infarction and coronary death, but not angina pectoris, in older men. J Thromb Haemost 2009; 07: 1605-1611.