Prognostic relevance of circulating endothelial progenitor cells in patients with chronic heart failure

Summary

Novel strategies for a tailored risk prediction in chronic heart failure (CHF) are crucial to identify patients at very high risk for an improved patient management and to specify treatment regimens. Endothelial progenitor cells (EPCs) are an important endogenous repair mechanism with the ability to counteract endothelial injury and the possibility of new vessel formation. We hypothesised that exhaustion of circulating EPCs may be a suitable prognostic biomarker in patients with CHF. EPCs, defined as CD34⁺CD45^dimKDR⁺ cells, were analysed using fluorescence-activated cell sorting. EPCs were measured in 185 patients with CHF including 87 (47%) patients with ischaemic aetiology and 98 (53%) patients with non-ischaemic CHF and followed for a median time of 2.7 years. During this period, 34.7% of patients experienced the primary study endpoint all-cause mortality. EPC count was a significant and independent inverse predictor of mortality with an hazard ratio hazard ratio (HR) per increase of one standard deviation (1-SD) of 0.47 (95% confidence interval [CI]: 0.35–0.61; p<0.001) and remained significant after multivariable adjustment for a comprehensive set of cardiovascular risk factors and potential confounders with a HR per 1-SD of 0.54 (95% CI: 0.4–0.73; p<0.001). EPCs further demonstrated additional prognostic information indicated by improvements in C-statistic, net reclassification index and integrated discrimination increment. In conclusion, in our study circulating EPCs turned out as strong and independent inverse predictors of mortality underlining the importance of an impaired endothelial repair mechanism in the pathophysiology and progression of CHF.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Ischaemic heart disease - outcome - vasculogenesis

• References

• 1 Braunwald E.. Heart failure. JACC Heart Fail 2013; 1: 1-20.
• 2 Marti CN, Gheorghiade M, Kalogeropoulos AP. et al. Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 2012; 60: 1455-1469.
• 3 Richardson MR, Yoder MC.. Endothelial progenitor cells: quo vadis?. J Mol Cell Cardiol 2011; 50: 266-272.
• 4 Grisar JC, Haddad F, Gomari FA. et al. Endothelial progenitor cells in cardiovascular disease and chronic inflammation: from biomarker to therapeutic agent. Biomark Med 2011; 5: 731-744.
• 5 Werner N, Kosiol S, Schiegl T. et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 2005; 353: 999-1007.
• 6 Schmidt-Lucke C, Rossig L, Fichtlscherer S. et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 2005; 111: 2981-2987.
• 7 Du F, Zhou J, Gong R. et al. Endothelial progenitor cells in atherosclerosis. Front Biosci 2012; 17: 2327-2349.
• 8 Fadini GP, Losordo D, Dimmeler S.. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res 2012; 110: 624-637.
• 9 Van Craenenbroeck EM, Van Craenenbroeck AH, van Ierssel S. et al. Quantification of circulating CD34+/KDR+/CD45dim endothelial progenitor cells: analytical considerations. Int J Cardiol 2013; 167: 1688-1695.
• 10 Hristov M, Schmitz S, Nauwelaers F. et al. A flow cytometric protocol for enumeration of endothelial progenitor cells and monocyte subsets in human blood. J Immunol Methods 2012; 381: 9-13.
• 11 Pencina MJ, D’Agostino Sr. RB, Steyerberg EW.. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 2011; 30: 11-21.
• 12 Shantsila E, Watson T, Lip GY.. Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 2007; 49: 741-752.
• 13 Valgimigli M, Rigolin GM, Fucili A. et al. CD34+ and endothelial progenitor cells in patients with various degrees of congestive heart failure. Circulation 2004; 110: 1209-1212.
• 14 Kissel CK, Lehmann R, Assmus B. et al. Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure. J Am Coll Cardiol 2007; 49: 2341-2349.
• 15 Nonaka-Sarukawa M, Yamamoto K, Aoki H. et al. Circulating endothelial progenitor cells in congestive heart failure. Int J Cardiol 2007; 119: 344-348.
• 16 Shantsila E, Wrigley BJ, Shantsila A. et al. Monocyte-derived and CD34+/KDR+ endothelial progenitor cells in heart failure. J Thromb Haemost 2012; 10: 1252-1261.
• 17 Alba AC, Delgado DH, Rao V. et al. Are endothelial progenitor cells a prognostic factor in patients with heart failure?. Expert Rev Cardiovasc Ther 2012; 10: 167-175.
• 18 Michowitz Y, Goldstein E, Wexler D. et al. Circulating endothelial progenitor cells and clinical outcome in patients with congestive heart failure. Heart 2007; 93: 1046-1050.
• 19 Alba AC, Lalonde SD, Rao V. et al. Changes in circulating progenitor cells are associated with outcome in heart failure patients: a longitudinal study. Can J Cardiol 2013; 29: 1657-1664.
• 20 Heeschen C, Lehmann R, Honold J. et al. Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischaemic heart disease. Circulation 2004; 109: 1615-1622.
• 21 Van Craenenbroeck EM, Hoymans VY, Beckers PJ. et al. Exercise training improves function of circulating angiogenic cells in patients with chronic heart failure. Basic Res Cardiol 2010; 105: 665-676.
• 22 Erbs S, Hollriegel R, Linke A. et al. Exercise training in patients with advanced chronic heart failure (NYHA Illb) promotes restoration of peripheral vasomotor function, induction of endogenous regeneration, and improvement of left ventricular function. Circ Heart Fail 2010; 3: 486-494.
• 23 Steiner S, Niessner A, Ziegler S. et al. Endurance training increases the number of endothelial progenitor cells in patients with cardiovascular risk and coronary artery disease. Atherosclerosis 2005; 181: 305-310.
• 24 O'Connor CM, Whellan DJ, Lee KL. et al. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. J Am Med Assoc 2009; 301: 1439-1450.
• 25 Mann DL.. Innate immunity and the failing heart: the cytokine hypothesis revisited. Circ Res 2015; 116: 1254-1268.
• 26 George J, Goldstein E, Abashidze S. et al. Circulating endothelial progenitor cells in patients with unstable angina: association with systemic inflammation. Eur Heart J 2004; 25: 1003-1008.
• 27 Shintani S, Murohara T, Ikeda H. et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation 2001; 103: 2776-2779.
• 28 Chen TG, Zhong ZY, Sun GF. et al. Effects of tumour necrosis factor-alpha on activity and nitric oxide synthase of endothelial progenitor cells from peripheral blood. Cell Prolif 2011; 44: 352-359.
• 29 Fan Y, Ye J, Shen F. et al. Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab 2008; 28: 90-98.
• 30 Grisar J, Aletaha D, Steiner CW. et al. Depletion of endothelial progenitor cells in the peripheral blood of patients with rheumatoid arthritis. Circulation 2005; 111: 204-211.
• 31 Rauscher FM, Goldschmidt-Clermont PJ, Davis BH. et al. Aging, progenitor cell exhaustion, and atherosclerosis. Circulation 2003; 108: 457-463.
• 32 Heiss C, Keymel S, Niesler U. et al. Impaired progenitor cell activity in age-related endothelial dysfunction. J Am Coll Cardiol 2005; 45: 1441-1448.
• 33 Williamson K, Stringer SE, Alexander MY.. Endothelial progenitor cells enter the aging arena. Front Physiol 2012; 3: 30.
• 34 Hohensinner PJ, Rychli K, Zorn G. et al. Macrophage-modulating cytokines predict adverse outcome in heart failure. Thromb Haemost 2010; 103: 435-441.