Atrial fibrillation is associated with high levels of monocyte-platelet-aggregates and increased CD11b expression in patients with aortic stenosis

Christian Pfluecke; Katharina Berndt; Sandy Wydra; Daniel Tarnowski; Peggy Barthel; Silvio Quick; Stefan Ulbrich; Marian Christoph; Nadine Waessnig; Uwe Speiser; Carsten Wunderlich; David M. Poitz; Ruth H. Strasser; Karim Ibrahim

doi:10.1160/TH15-06-0477

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(05): 993-1000
DOI: 10.1160/TH15-06-0477

Cellular Haemostasis and Platelets

Schattauer GmbH

Atrial fibrillation is associated with high levels of monocyte-platelet-aggregates and increased CD11b expression in patients with aortic stenosis

Authors

Christian Pfluecke

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Katharina Berndt

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Sandy Wydra

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Daniel Tarnowski

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Peggy Barthel

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Silvio Quick

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Stefan Ulbrich

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Marian Christoph

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Nadine Waessnig

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Uwe Speiser

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Carsten Wunderlich

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
David M. Poitz

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Ruth H. Strasser

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany
Karim Ibrahim

¹Heart Center Dresden, University Hospital, Technische Universität Dresden, Dresden, Germany

Abstract

Summary

A growing body of evidence suggests a pivotal role of inflammatory processes in AF in a bidirectional manner. Infiltrating leukocytes seem to promote both structural and electrical remodelling processes in patients with AF. Monocyte-platelets-aggregates (MPAs) are sensitive markers of both platelets and monocyte activation. So far it is not clear whether the content of MPAs is affected by AF. The present study examined the content of MPAs and the activation of monocytes in elderly patients with an aortic stenosis in dependence of AF. These patients are known to have a high prevalence of AF. Flow-cytometric quantification analysis demonstrated that patients with AF have an increased content of MPAs (207 ± 13 cells/μl vs 307 ± 21 cells/μl, p<0.001), and enhanced expression of CD11b on monocytes (p<0.001), compared to patients in stable sinus rhythm (SR). The number of CD14⁺/CD16⁺ monocytes were only slightly elevated in patients with AF. These findings were seen in patients with permanent AF. But also patients with paroxysmal AF, even when presenting in SR, the MPAs were increased by 50 % (p<0.05) as well as the CD11b expression, which was twice as high (p<0.05) compared to stable SR. These results demonstrate for the first time a dependency of MPAs and CD11b expression on monocytes in the presence of AF and support the notion of a close relationship between AF, thrombogenesis and inflammation. The content of MPAs and the extent of activation on monocytes appear promising as biomarkers for paroxysmal AF and as possible future targets for developing novel pharmacological therapeutic strategies.

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

Keywords

Atrial fibrillation - monocytes - monocyte-platelet aggregates - stroke - inflammation

Full Text

References

References
1 Camm AJ, Kirchhof P, Lip GY. et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace 2010; 12: 1360-1420.
2 Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012; 60: 2263-2270.
3 Lim HS, Willoughby SR, Schultz C. et al. Effect of atrial fibrillation on atrial thrombogenesis in humans: impact of rate and rhythm. J Am Coll Cardiol 2013; 61: 852-860.
4 Michelson AD, Barnard MR, Hechtman HB. et al. In vivo tracking of platelets: circulating degranulated platelets rapidly lose surface P-selectin but continue to circulate and function. Proc Natl Acad Sci USA 1996; 93: 11877-11882.
5 Michelson AD, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are a more sensitive marker of in vivo platelet activation than platelet surface P-selectin: studies in baboons, human coronary intervention, and human acute myocardial infarction. Circulation 2001; 104: 1533-1537.
6 Burdess A, Michelsen AE, Brosstad F. et al. Platelet activation in patients with peripheral vascular disease: reproducibility and comparability of platelet markers. Thromb Res 2012; 129: 50-55.
7 Wrigley BJ, Shantsila E, Tapp LD. et al. Increased formation of monocyte-platelet aggregates in ischemic heart failure. Circ Heart Fail 2013; 6: 127-135.
8 Shantsila E, Lip GY. The role of monocytes in thrombotic disorders. Insights from tissue factor, monocyte-platelet aggregates and novel mechanisms. Thromb Haemost 2009; 102: 916-924.
9 Pfluecke C, Tarnowski D, Plichta L. et al. Monocyte-platelet aggregates and CD11b expression as markers for thrombogenicity in atrial fibrillation. Clin Res Cardiol. 2015 Epub ahead of print.
10 Lukasik M, Dworacki G, Kufel-Grabowska J. et al. Upregulation of CD40 ligand and enhanced monocyte-platelet aggregate formation are associated with worse clinical outcome after ischaemic stroke. Thromb Haemost 2012; 107: 346-355.
11 Engelmann MD, Svendsen JH. Inflammation in the genesis and perpetuation of atrial fibrillation. Eur Heart J 2005; 26: 2083-2092.
12 Conen D, Ridker PM, Everett BM. et al. A multimarker approach to assess the influence of inflammation on the incidence of atrial fibrillation in women. Eur Heart J 2010; 31: 1730-1736.
13 Lazzerini PE, Capecchi PL, Acampa M. et al. Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation. Autoimmun Rev. 2014 Epub ahead of print.
14 Friedrichs K, Klinke A, Baldus S. Inflammatory pathways underlying atrial fibrillation. Trends Mol Med 2011; 17: 556-563.
15 Frustaci A, Chimenti C, Bellocci F. et al. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997; 96: 1180-1184.
16 Friedrichs K, Adam M, Remane L. et al. Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins. PLoS One 2014; 9: e89307.
17 Saba S, Janczewski AM, Baker LC. et al. Atrial contractile dysfunction, fibrosis, and arrhythmias in a mouse model of cardiomyopathy secondary to cardiacspecific overexpression of tumor necrosis factor-{alpha}. Am J Physiol Heart Circ Physiol 2005; 289: H1456-H1467.
18 Hristov M, Weber C. Differential role of monocyte subsets in atherosclerosis. Thromb Haemost 2011; 106: 757-762.
19 Belge KU, Dayyani F, Horelt A. et al. The proinflammatory CD14+CD16+DR++ monocytes are a major source of TNF. J Immunol 2002; 168: 3536-3542.
20 Imanishi T, Ikejima H, Tsujioka H. et al. Association of monocyte subset counts with coronary fibrous cap thickness in patients with unstable angina pectoris. Atherosclerosis 2010; 212: 628-635.
21 Merino A, Buendia P, Martin-Malo A. et al. Senescent CD14+CD16+ monocytes exhibit proinflammatory and proatherosclerotic activity. J Immunol 2011; 186: 1809-1815.
22 Morgan E, Varro R, Sepulveda H. et al. Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol 2004; 110: 252-266.
23 Aurigemma C, Scalone G, Tomai F. et al. Persistent enhanced platelet activation in patients with acute myocardial infarction and coronary microvascular obstruction: clinical implications. Thromb Haemost 2014; 111: 122-130.
24 Jurk K, Ritter MA, Schriek C. et al. Activated monocytes capture platelets for heterotypic association in patients with severe carotid artery stenosis. Thromb Haemost 2010; 103: 1193-1202.
25 Lievens D, von Hundelshausen P. Platelets in atherosclerosis. Thromb Haemost 2011; 106: 827-838.
26 Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol 2010; 30: 2357-2361.
27 van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol 2009; 85: 195-204.
28 Singh MV, Davidson DC, Kiebala M. et al. Detection of circulating plateletmonocyte complexes in persons infected with human immunodeficiency virus type-1. J Virol Methods 2012; 181: 170-176.
29 Gremmel T, Ay C, Riedl J. et al. Platelet-specific markers are associated with monocyte-platelet aggregate formation and thrombin generation potential in advanced atherosclerosis. Thromb Haemost 2016; 115: 615-621.
30 Alberti S, Angeloni G, Tamburrelli C. et al. Platelet-leukocyte mixed conjugates in patients with atrial fibrillation. Platelets 2009; 20: 235-241.
31 Makowski M, Smorag I, Bissinger A. et al. Effect of sinus rhythm restoration on platelet function in patients with lone atrial fibrillation. Int J Cardiol 2014; 172: e22-e23.
32 Mitusch R, Siemens HJ, Garbe M. et al. Detection of a hypercoagulable state in nonvalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost 1996; 75: 219-223.
33 Hu YF, Yeh HI, Tsao HM. et al. Impact of circulating monocyte CD36 level on atrial fibrillation and subsequent catheter ablation. Heart Rhythm 2011; 8: 650-656.
34 Shinohara H, Fukuda N, Soeki T. et al. Relationship between flow dynamics in the left atrium and hemostatic abnormalities in patients with nonvalvular atrial fibrillation. Jpn Heart J 1998; 39: 721-730.
35 Ito K, Date T, Ikegami M. et al. An immunohistochemical analysis of tissue thrombin expression in the human atria. PLoS One 2013; 8: e65817.
36 Lip GY, Patel JV, Hughes E. et al. High-sensitivity C-reactive protein and soluble CD40 ligand as indices of inflammation and platelet activation in 880 patients with nonvalvular atrial fibrillation: relationship to stroke risk factors, stroke risk stratification schema, and prognosis. Stroke 2007; 38: 1229-1237.
37 Varon D, Shai E. Platelets and their microparticles as key players in pathophysiological responses. J Thromb Haemost 2015; 13 (Suppl. 01) S40-S46.
38 Hayashi M, Takeshita K, Inden Y. et al. Platelet activation and induction of tissue factor in acute and chronic atrial fibrillation: involvement of mononuclear cell-platelet interaction. Thromb Res 2011; 128: e113-e118.
39 Brambatti M, Connolly SJ, Gold MR. et al. Temporal relationship between subclinical atrial fibrillation and embolic events. Circulation 2014; 129: 2094-2099.
40 Passacquale G, Vamadevan P, Pereira L. et al. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PLoS One 2011; 6: e25595.
41 Liuba I, Ahlmroth H, Jonasson L. et al. Source of inflammatory markers in patients with atrial fibrillation. Europace 2008; 10: 848-853.
42 Halonen J, Halonen P, Jarvinen O. et al. Corticosteroids for the prevention of atrial fibrillation after cardiac surgery: a randomized controlled trial. J Am Med Assoc 2007; 297: 1562-1567.
43 Kling D, Stucki C, Kronenberg S. et al. Pharmacological control of platelet-leukocyte interactions by the human anti-P-selectin antibody inclacumab--preclinical and clinical studies. Thromb Res 2013; 131: 401-410.
44 Willecke F, Tiwari S, Rupprecht B. et al. Interruption of classic CD40L-CD40 signalling but not of the novel CD40L-Mac-1 interaction limits arterial neointima formation in mice. Thromb Haemost 2014; 112: 379-389.

Supplementary Material

Online Supplementary Material (PDF) (PDF) (opens in new window)