Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease

Summary

Normal adults have very few circulating endothelial cells (CECs) in their blood, but increased levels have been shown in association with conditions associated with endothelial damage such as myocardial infarction and stroke. As atrial fibrillation (AF) is associated with a hypercoagulable state and abnormalities of plasma indices of endothelial damage/dysfunction, we hypothesised that CECs would also be raised in this condition, and would correlate with these plasma markers. We measured CECs (by immunofluoresence) as an indicator of frank endothelial damage, alongside 3 plasma indices of endothelial perturbation: von Willebrand factor (vWf), soluble E-selectin and soluble thrombomodulin (sTM) (all ELISA) in 28 patients with chronic ‘stable’ AF, 63 patients with AF plus an acute cardiovascular or cerebrovascular event as positive controls, and 20 healthy subjects in sinus rhythm as negative controls. Chronic ‘stable’AF patients had significantly higher levels of plasma vWf (p<0.001),but comparable numbers of CECs (p=0.1638) in comparison to healthy controls. In patients with AF associated with an acute cardiovascular or cerebrovascular event, levels of CECs (p<0.0001) and sTM (p=0.004), but not vWf or sEsel, were significantly increased in comparison to chronic‘stable’AF patients. Patients with uncomplicated AF have abnormal systemic endothelial damage/dysfunction, as evident by increased plasma vWf levels, but normal numbers of CECs, compared to subjects in sinus rhythm. However, following clinical complications, such as stroke or significant haemodynamic compromise, further endothelial disturbance (as indicated by high levels of sTM and CECs) suggests additional endothelial damage.

Keywords

Circulating endothelial cells - endothelial damage - soluble E-selectin - soluble thrombomodulin - von Willebrand factor - atrial fibrillation

• References

• 1 Lin HJ, Wolf PA, Kelly-Hayes M. et al. Stroke severity in atrial fibrillation: the Framingham study. Stroke 1996; 27: 1760-4.
• 2 Jorgensen HS, Nakayama H, Reith J. et al. Acute stroke with atrial fibrillation: the Copenhagen Stroke Study. Stroke 1996; 27: 1765-9.
• 3 Crenshaw BS, Ward SR, Granger C B. et al. for the GUSTO Trial Investigators. Atrial fibrillation in the setting of acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 1997; 30: 406-13.
• 4 Sakata K, Kurihara H, Iwamori K. et al. Clinical and prognostic significance of atrial fibrillation in acute myocardial infarction. Am J Cardiol 1997; 80: 1522-7.
• 5 Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure: a study of 390 patients. Circulation 1991; 84: 40-8.
• 6 Gustafsson C, Blomback M, Britton M. et al. Coagulation factors and the increased risk of stroke in nonvalvular atrial fibrillation. Stroke 1990; 21: 47-51.
• 7 Lip GY, Lowe GD, Rumley A. et al. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J 1995; 73: 527-33.
• 8 Li-Saw-Hee FL, Blann AD, Gurney D. et al. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J 2001; 22: 1741-7.
• 9 Feng D, D’Agostino RB, Silbershatz H. et al. Hemostatic state and atrial fibrillation (the Framingham Offspring Study). Am J Cardiol 2001; 87: 168-71.
• 10 Li-Saw-Hee FL, Blann AD, Lip GYH. A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation. JACC 2000; 35: 1926-31.
• 11 Mondillo S, Sabatini L, Agricola E. et al. Correlation between left atrial size, prothrombotic state and markers of endothelial dysfunction in patients with lone chronic nonrheumatic atrial fibrillation. Int J Cardiol 2000; 75: 227-32.
• 12 Solovey A, Lin Y, Browne P. et al. Circulating activated endothelial cells in sickle cell anaemia. N Engl J Med 1997; 337: 1584-90.
• 13 Woywodt A, Streiber F, de Groot K. et al. Circulating endothelial cells as markers for ANCAassociated small-vessel vasculitis. Lancet 2003; 361: 206-10.
• 14 Mutunga M, Fulton B, Bullock R. et al. Circulating endothelial cells in patients with septic shock. Am J Respir Crit Care Med 2001; 163: 195-200.
• 15 George F, Brisson C, Poncelet C. et al. Rapid isolation of human endothelial cells from whole blood using S-Endo 1 monoclonal antibody coupled to immuno-magnetic beads: demonstration of endothelial injury after angioplasty. Thromb Haemost 1992; 67: 147-53.
• 16 Mutin M, Canavy I, Blann A. et al. Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells. Blood 1999; 93: 2951-8.
• 17 Makin AJ, Blann AD, Chung N A. et al. Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Relationship with von Willebrand factor and tissue factor. Eur Heart J 2004; 25: 371-6.
• 18 Nadar SK, Lip GYH, Lee KW, Blann AD. Circulating endothelial cells in acute ischaemic stroke. Thromb Haemostas 2005 In press.
• 19 Bull TM, Golpon H, Hebbel R P. et al. Circulating endothelial cells in pulmonary hypertension. Thromb Haemost 2003; 90: 698-703.
• 20 Blann AD, Woywodt A, Bertolini F. et al. Circulating endothelial cells: Biomarker of Vascular Disease. Thromb Haemost 2005; 93: 228-35
• 21 Pigott R, Dillon LP, Hemingway I H. et al. Soluble forms of E-selectin, ICAM- and VCAM-1 are present in the supernatant of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun 1992; 187: 584-9.
• 22 Franciose RJ, Moore EE, Moore F A. et al. Hypoxia/ reoxygenation of human endothelium activates PMNs to detach endothelial cells via a PAF mechanism. J Surg Res 1996; 61: 459-62.
• 23 Gertz SD, Uretsky G, Wajnberg R S. et al. Endothelial cell damage and thrombus formation after partial arterial constriction: relevance to the role of coronary artery spasm in the pathogenesis of myocardial infarction. Circulation 1981; 63: 476-86.
• 24 Pudil R, Pidrman V, Krejsek J. et al. Cytokines and adhesion molecules in the course of acute myocardial infarction. Clin Chim Acta 1999; 280: 127-34.
• 25 Montaner J, Rovira A, Molina C A. et al. Plasmatic level of neuroinflammatory markers predict the extent of diffusion-weighted image lesions in hyperacute stroke. J Cereb Blood Flow Metab 2003; 23: 1403-7.
• 26 Vila N, Castillo J, Davalos A. et al. Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 2000; 31: 2325-9.
• 27 Torre-Amione G, Kapadia S, Benedict C. et al. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies Of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27: 1201-6.
• 28 Kimura H, Gules I, Meguro T. et al. Cytotoxicity of cytokines in cerebral microvascular endothelial cell. Brain Res 2003; 990: 148-56
• 29 Bardin N, George F, Mutin M. et al. S-Endo 1, a panendothelial monoclonal antibody recognizing a novel human endothelial antigen. Tissue Antigens 1996; 48: 531-9.
• 30 Lin Y, Weisdorf DJ, Solovey A. et al. Origins of circulating endothelial cells and endothelial outgrowth from blood. J Clin Invest 2000; 105: 71-7.
• 31 Chong AY, Blann AD, Patel J. et al. Endothelial dysfunction and damage in congestive heart failure: relation of flow-mediated dilation to circulating endothelial cells, plasma indexes of endothelial damage, and brain natriuretic peptide. Circulation 2004; 110 (13) 1794-8.