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Journal of Diagnostics

December 2014, Volume 1, 2, pp 28-41

Serum Rankl/Osteoprotegerin Complex and Endothelial Progenitor Cells in Chronic Heart Failure

Alexander E. Berezin


Alexander A. Kremzer

Alexander E. Berezin 1

Alexander A. Kremzer 2

  1. State Medical University, Internal Medicine Department, Zaporozhye, Ukraine 1

  2. State Medical University, Clinical Pharmacology Department, Zaporozhye, Ukraine 2

Pages: 28-41

DOI: 10.18488/journal.98/2014.1.2/

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The objectiveof this study was to assess an interrelationship serum RANKL/OPG complex with counts of circulating pro-angiogenic endothelial progenitor cells (EPCs) labeled as CD14+CD309+, and CD14+CD309+Tie2+ in patients with ischemic chronic heart failure (CHF).
Methods: The study retrospectively evolved 153 patients (86 males) aged 48 to 62 years with exiting proven stable coronary artery disease (CAD). Systolic or diastolic CHF was defined among 109 (71.2%) patients. Twenty five 25 individuals were included in the control group. Circulating RANKL (sRANKL) and OPG were measured by high-sensitive ELISA kit at baseline. EPC populations were labeled by flow cytofluorimetry per High-Definition Fluorescence Activated Cell Sorter methodology.
Results: Numerous of EPCs with phenotypes of CD14+CD309+ and CD14+CD309+Tie2+ were significantly lower in CAD patients when compared with healthy subjects. The trend to significant decrease of EPC numerous depending presence of CHF was found. The sRANKLlevel, OPG level, and sRANKL / OPG ratio were significantly higher in CHF subjects as compared to those without CHF (P=0.001). On multivariate analysis, CHF, sRANKL/OPG ratio, OPG, and NT-pro-BNP remained as independent predictors of decreased EPCs with phenotypes of CD14+CD309+ and CD14+CD309+Tie2+. When sRANKL/OPG ratio was added to the standard predictive model (CHF) improved relative integrated discrimination indices by 12.5% for CD14+CD309+ depletion, as well as by 17.3% for CD14+CD309+Tie2+depletion were found. 
Conclusion: We found that sRANKL/OPG ratio remained statistically significant predictor for depletion of pro-angiogenicEPCsin CAD patients.

Contribution/ Originality
The paper’s primary contribution is finding that inflammatory cytokines, such as components of RANKL/OPG complex, areable to negatively modulate the level of circulating pro-angiogenicendothelial progenitor cells labeled as CD14+CD309+, and CD14+CD309+Tie2+ and thereby reduce a reparative potency of vasculature in heart failure patients.




  1. V. L. Roger, "The heart failure epidemic," Int J Environ Res Public Health, vol. 7, pp. 1807–1830, 2010.
  2. P. Rajendran, T. Rengarajan, and J. Thangavel, "The vascular endothelium and human diseases," Int J Biol Sci., vol. 9, pp. 1057-69, 2013.
  3. Y. Matsuzawa, S. Sugiyama, and H. Sumida, "Peripheral endothelial function and cardiovascular events in high-risk patients," J Am Heart Assoc., vol. 2, p. e000426, 2013.
  4. J. Wang and T. Guo, "Metabolic remodeling in chronic heart failure," J Zhejiang Univ Sci B., vol. 14, pp. 688–95, 2013.
  5. C. Balion, A. Don-Wauchope, and S. Hill, "Use of natriuretic peptide measurement in the management of heart failure," Comparative Effectiveness Reviews, No.126. AHRQ Publication No. 13(14)-EHC118-EF, 2013.
  6. J. M. Hill, G. Zalos, and J. P. Halcox, "Circulating endothelial progenitor cells, vascular function, and cardiovascular risk," N Engl J Med., vol. 348, pp. 593-600, 2003.
  7. A. C. Alba, S. D. Lalonde, and V. Rao, "Changes in circulating progenitor cells are associated with outcome in heart failure patients: A longitudinal study," Can J Cardiol., vol. 29, pp. 1657-64, 2013.
  8. C. Alba, D. H. Delgado, and V. Rao, "Are endothelial progenitor cells a prognostic factor in patients with heart failure?," Expert Rev Cardiovasc Ther., vol. 10, pp. 167-175, 2012.
  9. T. E. Hadj Othmane, G. Speer, and B. Fekete, "Osteoprotegerin: Regulator, protector and marker," Orv Hetil, vol. 149, pp. 1971-80, 2008.
  10. G. Loncar, B. Bozic, and V. Cvorovic, "Relationship between RANKL and neuroendocrine activation in elderly males with heart failure," Endocrine, vol. 37, pp. 148-56, 2010.
  11. A. E. Kearns, S. Khosla, and P. J. Kostenuik, "Receptor activator of nuclear factor kappa B ligand and osteoprotegerin regulation of bone remodeling in health and disease," Endocr Rev., vol. 29, pp. 155-92, 2008.
  12. D. M. Leistner, F. H. Seeger, and A. Fischer, "Elevated levels of the mediator of catabolic bone remodeling RANKL in the bone marrow environment link chronic heart failure with osteoporosis," Circ Heart Fail, vol. 5, pp. 769-77, 2012.
  13. K. K. Doumouchtsis, A. I. Kostakis, and S. K. Doumouchtsis, "sRANKL/osteoprotegerin complex and biochemical markers in a cohort of male and female hemodialysis patients," J Endocrinol Invest., vol. 30, pp. 762-6, 2007.
  14. J. J. V. McMurray, S. Adamopoulos, and S. D. Anker, "ESC guidelines for the diagnosis and treatment of acute and chronic heart failure," Eur Heart J., vol. 33, pp. 1787–847, 2012.
  15. D. A. Bluemke, S. A. chenbach, and M. Budoff, "Noninvasive coronary artery imaging: Magnetic resonance angiography and multidetector computed tomography angiography. A scientific statement from the American heart association committee on cardiovascular imaging and intervention of the council on cardiovascular radiology and intervention, and the councils on clinical cardiology and cardiovascular disease in the young," Circulation, vol. 118, pp. 586–606, 2008.
  16. M. J. Budoff, S. Achenbach, and R. S. Blumenthal, "Intervention AHACoCIa, intervention AHACoCRa, American heart association committee on cardiac imaging CoCC. Assessment of coronary artery disease by cardiac computed tomography: A scientific statement from the American heart association committee on cardiovascular imaging and intervention, council on cardiovascular radiology and intervention, and committee on Cardiac imaging, council on clinical cardiology," Circulation, vol. 114, pp. 1761-1791, 2006.
  17. N. B. Schiller, P. M. Shah, and M. Crawford, "Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American society of echocardiography committee on standards, subcommittee on quantitation of two-dimensional echocardiograms," J Am Soc Echocardiogr., vol. 2, pp. 358–367, 1989.
  18. D. Pellerin, R. Sharma, P. Elliott, and C. Veyrat, "Tissue doppler, strain, and strain rate echocardiography for the assessment of left and right systolic ventricular function," Heart, vol. 89, pp. 39-17, 2003.
  19. A. S. Levey, L. A. Stevens, and C. H. Schmid, "for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), A new equation to estimate glomerular filtration rate," Ann Intern Med., vol. 150, pp. 604-12, 2009.
  20. J. W. Tung, D. R. Parks, and W. A. Moore, "New approaches to fluorescence compensation and visualization of FACS data," Clin Immunol., vol. 11, pp. 277-83, 2004.
  21. Balion, A. Don-Wauchope, and S. Hill, "Use of natriuretic peptide measurement in the management of heart failure," Comparative Effectiveness Reviews No. 126. AHRQ Publication No. 13(14)-EHC118-EF, 2013.
  22. Vesbianu, C. Vesbianu, P. Bernstein, and R. Kouides, "Plasma brain natriuretic peptide—an independent predictor of mortality and rehospitalization in congestive heart failure - a meta-analysis," World Heart J., vol. 1, pp. 349–54, 2008.
  23. G. Lippi and G. Cervellin, "Risk assessment of post-infarction heart failure. Systematic review on the role of emerging biomarkers," Crit Rev Clin Lab Sci., vol. 51, pp. 13-29, 2014.
  24. T. Ueland, A. Yndestad, and E. Øie, "Dysregulated osteoprotegerin/ RANK ligand/RANK axis in clinical and experimental heart failure," Circulation, vol. 111, pp. 2461-8, 2005.
  25. A. Yndestad, D. J. Kristian, and E. H. Geir, "Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure," Cardiovasc Res., vol. 54, pp. 175–82, 2002.
  26. M. Anderson, E. Maraskovsky, and W. L. Billingsley, "A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function," Nature, vol. 390, pp. 175–9, 1997.
  27. S. Kiechl, G. Schett, and J. Schwaiger, "Soluble receptor activator of nuclear factor-?B ligand and risk for cardiovascular disease," Circulation, vol. 116, pp. 385–91, 2007.
  28. A. Van Campenhout and J. Golledge, "Osteoprotegerin, vascular calcification and atherosclerosis," Atherosclerosis, vol. 204, pp. 321–329, 2009.
  29. S. Kiechl, G. Schett, and G. Wenning, "Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease," Circulation, vol. 109, pp. 2175–80, 2004.
  30. A. M. Blázquez-Medela, L. García-Ortiz, and M. A. Gómez-Marcos, "Osteoprotegerin is associated with cardiovascular risk in hypertension and/or diabetes," Eur. J Clin. Invest., vol. 42, pp. 548–56, 2012.
  31. S. Jono, Y. Ikari, and A. Shioi, "Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease," Circulation, vol. 106, pp. 1192-4, 2002.
  32. M. Schoppet, A. M. Sattler, and J. R. Schaefer, "Increased osteoprotegerin serum levels in men with coronary artery disease," J Clin Endocrinol Metab., vol. 88, pp. 1024-8, 2003.
  33. T. Ueland, R. Jemtland, and K. Godang, "The prognostic value of osteoprotegerin in patients with acute myocardial infarction," J Am Coll Cardiol., vol. 44, pp. 1970-6, 2004.
  34. C. Giaginis, A. Papadopouli, and A. Zira, "Correlation of plasma osteoprotegerin (OPG) and receptor activator of the nuclear factor ?B ligand (RANKL) levels with clinical risk factors in patients with advanced carotid atherosclerosis," Med Sci Monit., vol. 18, pp. CR597-604, 2012.
  35. M. Bjerre, K. Munk, and A. D. Sloth, "High osteoprotegerin levels predict MACCE in STEMI patients, but are not associated with myocardial salvage," Scand Cardiovasc J., vol. 1, p. 7, 2014.
  36. M. Bjerre, "Osteoprotegerin (OPG) as a biomarker for diabetic cardiovascular complications," Springerplus, vol. 2, p. 658, 2013.
  37. B. B. Løgstrup, D. E. Høfsten, and T. B. Christophersen, "Microvascular dysfunction is associated with plasma osteoprotegerin levels in patients with acute myocardial infarction," Coron Artery Dis., vol. 24, pp. 487-92, 2013.
  38. R. Mogelvang, S. Haahr-Pedersen, and M. Bjerre, "Osteoprotegerin improves risk detection by traditional cardiovascular risk factors and hs-CRP," Heart, vol. 99, pp. 106-10, 2013.
  39. M. Montagnana, G. Lippi, E. Danese, and G. C. Guidi, "The role of osteoprotegerin in cardiovascular disease," Ann Med., vol. 45, pp. 254-64, 2013.
  40. Schweikle, T. Baessler, and S. Yildirim, "Osteoprotegerin positively regulates hematopoietic progenitor cells," Curr Stem Cell Res Ther., vol. 7, pp. 72-7, 2012.
  41. J. Y. Kim, Y. J. Park, and K. J. Kim, "Osteoprotegerin causes apoptosis of endothelial progenitor cells by induction of oxidative stress," Arthritis Rheum., vol. 65, pp. 2172-82, 2013.
  42. L. Liu, Z. Z. Liu, and H. Chen, "Oxidized low-density lipoprotein and ?-glycerophosphate synergistically induce endothelial progenitor cell ossification," Acta Pharmacol Sin., vol. 32, pp. 1491-7, 2011.
  43. Y. Mei, M. D. Thompson, R. A. Cohen, and X. Tong, "Autophagy and oxidative stress in cardiovascular diseases," Biochim Biophys Acta, vol. pii: S0925-4439, pp. 00133-1, 2014.
  44. N. Parajuli, V. B. Patel, and W. Wang, "Loss of NOX2 (gp91phox) prevents oxidative stress and progression to advanced heart failure," Clin Sci (Lond), vol. 127, pp. 331-40, 2014.


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