Number and Function of Bone-Marrow Derived Angiogenic Cells and Coronary Flow Reserve in Women without Obstructive Coronary Artery Disease: A Substudy of the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE)
Background In women with ischemia and no obstructive coronary artery disease, the Women's Ischemic Syndrome Evaluation (WISE) observed that microvascular coronary dysfunction (MCD) is the best independent predictor of adverse cardiovascular events. Since coronary microvascular tone is regulated in part by endothelium, we hypothesized that circulating endothelial cells (CEC), which reflect endothelial injury, and the number and function of bone-marrow derived angiogenic cells (BMDAC), which could help repair damaged endothelium, may serve as biomarkers for decreased coronary flow reserve (CFR) and MCD. Methods We studied 32 women from the WISE cohort. CFR measurements in response to intracoronary adenosine were taken as an index of MCD. We enumerated BMDAC colonies and CEC in peripheral blood samples. BMDAC function was assessed by assay of migration of CD34+ cells toward SDF-1 and measurement of bioavailable nitric oxide (NO). These findings were compared with a healthy reference group and also entered into a multivariable model with CFR as the dependent variable. Results Compared with a healthy reference group, women with MCD had lower numbers of BMDAC colonies [16 (0, 81) vs. 24 (14, 88); P = 0.01] and NO [936 (156, 1875) vs. 1168 (668, 1823); P = 0.02]. Multivariable regression analysis showed strong correlation of CFR to the combination of BMDAC colony count and CD34+ cell function (migration and NO) (R2 = 0.45; P<0.05). Conclusions The BMDAC function and numbers of BMDAC colonies are decreased in symptomatic women with MCD and are independently associated with CFR. These circulating cells may provide mechanistic insights into MCD in women with ischemia.
References
[1]
Douglas PS, Patel MR, Bailey SR, Dai D, Kaltenbach L, et al. (2011) Hospital variability in the rate of finding obstructive coronary artery disease at elective, diagnostic coronary angiography. J Am Coll Cardiol 58: 801–809.
[2]
Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, et al. (2012) Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J 33: 734–744.
[3]
Gulati M, Cooper-DeHoff RM, McClure C, Johnson BD, Shaw LJ, et al. (2009) Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med 169: 843–850.
[4]
Merz CN, Kelsey SF, Pepine CJ, Reichek N, Reis SE, et al. (1999) The Women's Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. J Am Coll Cardiol 33: 1453–1461.
[5]
Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, et al. (2010) Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J Am Coll Cardiol 55: 2825–2832.
[6]
Wessel TR, Arant CB, McGorray SP, Sharaf BL, Reis SE, et al. (2007) Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE). Clin Cardiol 30: 69–74.
[7]
Mutin M, Canavy I, Blann A, Bory M, Sampol J, et al. (1999) Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 93: 2951–2958.
[8]
Quilici J, Banzet N, Paule P, Meynard J-B, Mutin M, et al. (2004) Circulating endothelial cell count as a diagnostic marker for non-ST-elevation acute coronary syndromes. Circulation 110: 1586–1591.
[9]
Damani S, Bacconi A, Libiger O, Chourasia AH, Serry R, et al. (2012) Characterization of circulating endothelial cells in acute myocardial infarction. Sci Transl Med 4: 126–133.
[10]
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, et al. (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967.
[11]
Hill JM, Zalos G, Halcox JPJ, Schenke WH, Waclawiw MA, et al. (2003) Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med 348: 593–600.
Sbarbati R, de Boer M, Marzilli M, Scarlattini M, Rossi G, et al. (1991) Immunologic detection of endothelial cells in human whole blood. Blood 77: 764–769.
[14]
Bardin N, Anfosso F, Masse JM, Cramer E, Sabatier F, et al. (2001) Identification of CD146 as a component of the endothelial junction involved in the control of cell-cell cohesion. Blood 98: 3677–3684.
[15]
Koc M, Bihorac A, Segal MS (2003) Circulating endothelial cells as potential markers of the state of the endothelium in hemodialysis patients. Am J Kidney Dis 42: 704–712.
[16]
Bellamy MF, Goodfellow J, Tweddel AC, Dunstan FD, Lewis MJ, et al. (1998) Syndrome X and endothelial dysfunction. Cardiovasc Res 40: 410–417.
[17]
Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, et al. (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood 92: 362–367.
[18]
Lin Y, Weisdorf DJ, Solovey A, Hebbel RP (2000) Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 105: 71–77.
[19]
Kalka C, Masuda H, Takahashi T, Kalka-Moll WM, Silver M, et al. (2000) Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci U S A 97: 3422–3427.
[20]
Fadini GP, Coracina A, Baesso I, Agostini C, Tiengo A, et al. (2006) Peripheral blood CD34+KDR+ endothelial progenitor cells are determinants of subclinical atherosclerosis in a middle-aged general population. Stroke 37: 2277–2282.
[21]
Chironi G, Walch L, Pernollet M-G, Gariepy J, Levenson J, et al. (2007) Decreased number of circulating CD34+KDR+ cells in asymptomatic subjects with preclinical atherosclerosis. Atherosclerosis 191: 115–120.
[22]
Schmidt-Lucke C, Rossig L, Fichtlscherer S, Vasa M, Britten M, et al. (2005) Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 111: 2981–2987.
[23]
Porto I, Leone AM, De Maria GL, Hamilton Craig C, Tritarelli A, et al. (2011) Are endothelial progenitor cells mobilized by myocardial ischemia or myocardial necrosis? A cardiac magnetic resonance study. Atherosclerosis 216: 355–358.
[24]
Segal MS, Shah R, Afzal A, Perrault CM, Chang K, et al. (2006) Nitric oxide cytoskeletal-induced alterations reverse the endothelial progenitor cell migratory defect associated with diabetes. Diabetes 55: 102–109.
[25]
Sharaf BL, Pepine CJ, Kerensky RA, Reis SE, Reichek N, et al.. (2001) Detailed angiographic analysis of women with suspected ischemic chest pain (pilot phase data from the NHLBI-sponsored Women's Ischemia Syndrome Evaluation [WISE] Study Angiographic Core Laboratory). Am J Cardiol 87: : 937–941; A3.
[26]
Reis SE, Holubkov R, Lee JS, Sharaf B, Reichek N, et al. (1999) Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women's Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol 33: 1469–1475.
[27]
Vasa M, Fichtlscherer S, Adler K, Aicher A, Martin H, et al. (2001) Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 103: 2885–2890.
[28]
Turan RG, Turan CH, Bozdag-Turan I, Ortak J, Akin I, et al. (2011) Impaired mobilization of CD133(+) bone marrow-derived circulating progenitor cells with an increased number of diseased coronary arteries in ischemic heart disease patients with diabetes. Circ J 75: 2635–2641.
[29]
Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, et al. (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353: 999–1007.
[30]
Shmilovich H, Deutsch V, Roth A, Miller H, Keren G, et al. (2007) Circulating endothelial progenitor cells in patients with cardiac syndrome X. Heart 93: 1071–1076.
[31]
Huang P-H, Chen Y-H, Chen Y-L, Wu T-C, Chen J-W, et al. (2007) Vascular endothelial function and circulating endothelial progenitor cells in patients with cardiac syndrome X. Heart 93: 1064–1070.
[32]
Wang D, Yang XP, Liu YH, Carretero OA, LaPointe MC (1999) Reduction of myocardial infarct size by inhibition of inducible nitric oxide synthase. Am J Hypertens 12: 174–182.
[33]
Tousoulis D, Davies GJ, Asimakopoulos G, Homaei H, Zouridakis E, et al. (2001) Vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 serum level in patients with chest pain and normal coronary arteries (syndrome X). Clin Cardiol 24: 301–304.
[34]
Botker HE, Ingerslev J (2000) Plasma concentrations of von Willebrand factor in patients with angina pectoris secondary to coronary atherosclerosis or cardiac syndrome X. Thromb Res 97: 519–523.
[35]
Quyyumi AA, Cannon RO, Panza JA, Diodati JG, Epstein SE (1992) Endothelial dysfunction in patients with chest pain and normal coronary arteries. Circulation 86: 1864–1871.
[36]
Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G (2004) Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation 109: 2518–2523.
[37]
Masuda H, Alev C, Akimaru H, Ito R, Shizuno T, et al. (2011) Methodological development of a clonogenic assay to determine endothelial progenitor cell potential. Circ Res 109: 20–37.
