Subscribe to RSS
Circulating MicroRNAs and Monocyte–Platelet Aggregate Formation in Acute Coronary SyndromeFunding The research was funded by the “Medical Scientific Fund of the Mayor of the City of Vienna,” grant number 14016, and by the “Anniversary Fund of the Austrian National Bank,” grant number 16155, to Thomas Gremmel. MicroRNA analysis was performed at TAmiRNA GmbH, Leberstrasse 20, 1110 Vienna, Austria.
Background Monocyte–platelet aggregates (MPAs) are a sensitive marker of in vivo platelet activation in acute coronary syndrome (ACS) and associated with clinical outcomes. MicroRNAs (miRs) play an important role in the regulation of platelet activation, and may influence MPA formation. Both, miRs and MPA, could be influenced by the type of P2Y12 inhibitor.
Aim To study the association of platelet-related miRs with MPA formation in ACS patients on dual antiplatelet therapy (DAPT), and to compare miRs and MPA levels between prasugrel- and ticagrelor-treated patients.
Methods and Results We analyzed 10 circulating platelet-related miRs in 160 consecutive ACS patients on DAPT with low-dose aspirin and either prasugrel (n = 80) or ticagrelor (n = 80). MPA formation was measured by flow cytometry without addition of platelet agonists and after simulation with the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, adenosine diphosphate (ADP), or arachidonic acid (AA). In multivariate regression analyses, we identified miR-21 (β = 9.50, 95% confidence interval [CI]: 1.60–17.40, p = 0.019) and miR-126 (β = 7.50, 95% CI: 0.55–14.44, p = 0.035) as independent predictors of increased MPA formation in vivo and after TLR-1/2 stimulation. In contrast, none of the investigated miRs was independently associated with MPA formation after stimulation with ADP or AA. Platelet-related miR expression and MPA formation did not differ significantly between prasugrel- and ticagrelor-treated patients.
Conclusion Platelet-related miR-21 and miR-126 are associated with MPA formation in ACS patients on DAPT. miRs and MPA levels were similar in prasugrel- and ticagrelor-treated patients.
T.G., S.S., and S.D. designed the research and wrote the manuscript; P.P.W., C.W., J.P., P.H., and B.E. performed the experiments; S.S. and T.G. analyzed the results; P.P.W., P.H., S.L., S.P., C.W., J.P., B.E., S.D., C.H., and J.W. critically read and revised the manuscript.
Received: 06 July 2020
Accepted: 18 November 2020
14 January 2021 (online)
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Ridker PM, Everett BM, Thuren T. et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017; 377 (12) 1119-1131
- 2 Freedman JE, Loscalzo J. Platelet-monocyte aggregates: bridging thrombosis and inflammation. Circulation 2002; 105 (18) 2130-2132
- 3 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 U S A 1996; 93 (21) 11877-11882
- 4 Gremmel T, Koppensteiner R, Kaider A, Eichelberger B, Mannhalter C, Panzer S. Impact of variables of the P-selectin - P-selectin glycoprotein ligand-1 axis on leukocyte-platelet interactions in cardiovascular disease. Thromb Haemost 2015; 113 (04) 806-812
- 5 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 (03) 615-621
- 6 Michelson AD, Barnard MR, Krueger LA, Valeri CR, Furman MI. 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 (13) 1533-1537
- 7 Gremmel T, Frelinger III AL, Michelson AD. Platelet physiology. Semin Thromb Hemost 2016; 42 (03) 191-204
- 8 Furman MI, Benoit SE, Barnard MR. et al. Increased platelet reactivity and circulating monocyte-platelet aggregates in patients with stable coronary artery disease. J Am Coll Cardiol 1998; 31 (02) 352-358
- 9 Furman MI, Barnard MR, Krueger LA. et al. Circulating monocyte-platelet aggregates are an early marker of acute myocardial infarction. J Am Coll Cardiol 2001; 38 (04) 1002-1006
- 10 Zeng S, Zhou X, Ge L. et al. Monocyte subsets and monocyte-platelet aggregates in patients with unstable angina. J Thromb Thrombolysis 2014; 38 (04) 439-446
- 11 Tapp LD, Shantsila E, Wrigley BJ, Pamukcu B, Lip GY. The CD14++CD16+ monocyte subset and monocyte-platelet interactions in patients with ST-elevation myocardial infarction. J Thromb Haemost 2012; 10 (07) 1231-1241
- 12 Wrigley BJ, Shantsila E, Tapp LD, Lip GY. Increased formation of monocyte-platelet aggregates in ischemic heart failure. Circ Heart Fail 2013; 6 (01) 127-135
- 13 Zhou X, Liu XL, Ji WJ. et al. The kinetics of circulating monocyte subsets and monocyte-platelet aggregates in the acute phase of ST-elevation myocardial infarction: associations with 2-year cardiovascular events. Medicine (Baltimore) 2016; 95 (18) e3466
- 14 Valgimigli M, Bueno H, Byrne RA. et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS [in Polish]. Kardiol Pol 2017; 75 (12) 1217-1299
- 15 Allen N, Barrett TJ, Guo Y. et al. Circulating monocyte-platelet aggregates are a robust marker of platelet activity in cardiovascular disease. Atherosclerosis 2019; 282: 11-18
- 16 Gremmel T, Kopp CW, Seidinger D. et al. The formation of monocyte-platelet aggregates is independent of on-treatment residual agonists'-inducible platelet reactivity. Atherosclerosis 2009; 207 (02) 608-613
- 17 Stojkovic S, Nossent AY, Haller P. et al. MicroRNAs as regulators and biomarkers of platelet function and activity in coronary artery disease. Thromb Haemost 2019; 119 (10) 1563-1572
- 18 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
- 19 Kaudewitz D, Skroblin P, Bender LH. et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
- 20 Zhang YY, Zhou X, Ji WJ. et al. Decreased circulating microRNA-223 level predicts high on-treatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis 2014; 38 (01) 65-72
- 21 Chyrchel B, Totoń-Żurańska J, Kruszelnicka O. et al. Association of plasma miR-223 and platelet reactivity in patients with coronary artery disease on dual antiplatelet therapy: a preliminary report. Platelets 2015; 26 (06) 593-597
- 22 Gremmel T, Xhelili E, Steiner S, Koppensteiner R, Kopp CW, Panzer S. Response to antiplatelet therapy and platelet reactivity to thrombin receptor activating peptide-6 in cardiovascular interventions: differences between peripheral and coronary angioplasty. Atherosclerosis 2014; 232 (01) 119-124
- 23 Stojkovic S, Jurisic M, Kopp CW. et al. Circulating microRNAs identify patients at increased risk of in-stent restenosis after peripheral angioplasty with stent implantation. Atherosclerosis 2018; 269: 197-203
- 24 Blondal T, Jensby Nielsen S, Baker A. et al. Assessing sample and miRNA profile quality in serum and plasma or other biofluids. Methods 2013; 59 (01) S1-S6
- 25 Pircher J, Engelmann B, Massberg S, Schulz C. Platelet-neutrophil crosstalk in atherothrombosis. Thromb Haemost 2019; 119 (08) 1274-1282
- 26 Kossmann H, Rischpler C, Hanus F. et al. Monocyte-platelet aggregates affect local inflammation in patients with acute myocardial infarction. Int J Cardiol 2019; 287: 7-12
- 27 Thum T, Gross C, Fiedler J. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 2008; 456 (7224): 980-984
- 28 McClelland AD, Herman-Edelstein M, Komers R. et al. miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin Sci (Lond) 2015; 129 (12) 1237-1249
- 29 Liu G, Friggeri A, Yang Y. et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J Exp Med 2010; 207 (08) 1589-1597
- 30 Wang D, Deuse T, Stubbendorff M. et al. Local microRNA modulation using a novel anti-miR-21-eluting stent effectively prevents experimental in-stent restenosis. Arterioscler Thromb Vasc Biol 2015; 35 (09) 1945-1953
- 31 Barwari T, Eminaga S, Mayr U. et al. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI Insight 2018; 3 (21) 3
- 32 Jäger B, Stojkovic S, Haller PM. et al. Course of platelet miRNAs after cessation of P2Y12 antagonists. Eur J Clin Invest 2019; 49 (08) e13149
- 33 Sheedy FJ, Palsson-McDermott E, Hennessy EJ. et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat Immunol 2010; 11 (02) 141-147
- 34 Garcia A, Dunoyer-Geindre S, Zapilko V, Nolli S, Reny JL, Fontana P. Functional validation of microRNA-126-3p as a platelet reactivity regulator using human haematopoietic stem cells. Thromb Haemost 2019; 119 (02) 254-263
- 35 de Boer HC, van Solingen C, Prins J. et al. Aspirin treatment hampers the use of plasma microRNA-126 as a biomarker for the progression of vascular disease. Eur Heart J 2013; 34 (44) 3451-3457
- 36 Zampetaki A, Kiechl S, Drozdov I. et al. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ Res 2010; 107 (06) 810-817
- 37 Zampetaki A, Willeit P, Tilling L. et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012; 60 (04) 290-299