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DOI: 10.1055/s-0043-1776305
Platelet Function and Maturity and Related microRNA Expression in Whole Blood in Patients with ST-Segment Elevation Myocardial Infarction
Funding We received financial support from the Department of Clinical Biochemistry, Aarhus University Hospital, Denmark, Snedkermester Sophus Jacobsen and hustru Astrid Jacobsens Foundation, Murermester Lauritz Peter Christensen og hustru Kirsten Sigrid Christensens Foundation, A.P. Moeller og Hustru Chastine Mc-Kinney Møllers Fond til almene Formaal (A.P. Moellers Foundation), Fabrikant Karl G. Andersens Foundation, Helga og Peter Kornings Foundation, Familien Hede Nielsens Foundation, Danish Cardiovascular Academy, Overlæge Johan Boserup og Lise Boserups Legat, Carl og Ellen Hertz legat til Dansk Læge- og Naturvidenskab, Torben og Alice Frimodts Foundation, Arvid Nilssons Foundation, Direktør Emil C Hertz og Hustru Inger Hertz' Foundation, Raimond og Dagmar Ringgård-Bohns Foundation, Eva og Henry Frænkels Mindefond, Jørgen Møllers Foundation, and Frimodt-Heineke Foundation. The funding sources had no influence on the study.
Abstract
Background Reduced effect of antiplatelet therapy has been reported in patients with ST-segment elevation myocardial infarction (STEMI). MicroRNAs (miRs) may influence platelet function and maturity, and subsequently the effect of antiplatelet therapy.
Objectives We aimed to explore the association between miR expression and platelet function and maturity in patients with acute STEMI and healthy individuals.
Methods We performed an observational study of STEMI patients admitted directly to primary percutaneous coronary intervention. Patients were treated with antiplatelet therapy according to guidelines. Within 24 hours after admission, blood samples were obtained to measure: the expression of 10 candidate miRs, platelet function markers using advanced flow cytometry, platelet aggregation, serum thromboxane B2, and platelet maturity markers. Furthermore, blood samples from healthy individuals were obtained to determine the normal variation.
Results In total, 61 STEMI patients and 50 healthy individuals were included. STEMI patients had higher expression of miR-21–5p, miR-26b-5p, and miR-223–3p and lower expression of miR-150–5p, miR423–5p, and miR-1180–3p than healthy individuals. In STEMI patients, the expression of miR-26b-5p showed the most consistent association with platelet function (all p-values <0.05, Spearman's rho ranging from 0.27 to 0.41), while the expression of miR-150–5p and miR-223–3p showed negative associations with platelet function. No association between miR expression and platelet maturity markers was observed.
Conclusion In patients with STEMI, the expression of six miRs was significantly different from healthy individuals. The expression of miR-26b-5p may affect platelet function in acute STEMI patients and potentially influence the effect of antiplatelet therapy.
Keywords
platelets - microRNAs - myocardial infarction - platelet function tests - platelet maturityAuthors' Contribution
All authors designed the research study; O.B.P. collected the data and performed the first data analysis; all authors contributed to interpretation of data and writing the article.
Publication History
Received: 24 July 2023
Accepted: 29 September 2023
Article published online:
16 October 2023
© 2023. Thieme. All rights reserved.
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References
- 1 Puymirat E, Simon T, Cayla G. et al; USIK, USIC 2000, and FAST-MI investigators. Acute myocardial infarction: changes in patient characteristics, management, and 6-month outcomes over a period of 20 years in the FAST-MI program (French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction) 1995 to 2015. Circulation 2017; 136 (20) 1908-1919
- 2 Krumholz HM, Normand ST, Wang Y. Twenty-year trends in outcomes for older adults with acute myocardial infarction in the United States. JAMA Netw Open 2019; 2 (03) e191938
- 3 Patrono C, Morais J, Baigent C. et al. Antiplatelet agents for the treatment and prevention of coronary atherothrombosis. J Am Coll Cardiol 2017; 70 (14) 1760-1776
- 4 Steen DL, Khan I, Andrade K, Koumas A, Giugliano RP. Event rates and risk factors for recurrent cardiovascular events and mortality in a contemporary post acute coronary syndrome population representing 239 234 patients during 2005 to 2018 in the United States. J Am Heart Assoc 2022; 11 (09) e022198
- 5 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109 (25) 3171-3175
- 6 Gurbel PA, Bliden KP, Guyer K. et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study. J Am Coll Cardiol 2005; 46 (10) 1820-1826
- 7 Rocca B, Dragani A, Pagliaccia F. Identifying determinants of variability to tailor aspirin therapy. Expert Rev Cardiovasc Ther 2013; 11 (03) 365-379
- 8 Würtz M, Grove EL. Interindividual variability in the efficacy of oral antiplatelet drugs: definitions, mechanisms and clinical importance. Curr Pharm Des 2012; 18 (33) 5344-5361
- 9 Freynhofer MK, Gruber SC, Grove EL, Weiss TW, Wojta J, Huber K. Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing. Thromb Haemost 2015; 114 (03) 459-468
- 10 Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16 (07) 421-433
- 11 Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease?. Circ Res 2012; 110 (03) 483-495
- 12 Condrat CE, Thompson DC, Barbu MG. et al. miRNAs as biomarkers in disease: latest findings regarding their role in diagnosis and prognosis. Cells 2020; 9 (02) 276
- 13 Willeit P, Zampetaki A, Dudek K. et al. Circulating microRNAs as novel biomarkers for platelet activation. Circ Res 2013; 112 (04) 595-600
- 14 Pedersen OB, Grove EL, Kristensen SD, Nissen PH, Hvas AM. MicroRNA as biomarkers for platelet function and maturity in patients with cardiovascular disease. Thromb Haemost 2022; 122 (02) 181-195
- 15 Kaudewitz D, Skroblin P, Bender LH. et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res 2016; 118 (03) 420-432
- 16 Pedersen OB, Hvas AM, Grove EL. et al. Association of whole blood microRNA expression with platelet function and turnover in patients with coronary artery disease. Thromb Res 2022; 211: 98-105
- 17 Ibanez B, James S, Agewall S. et al; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
- 18 Kok MG, Halliani A, Moerland PD, Meijers JC, Creemers EE, Pinto-Sietsma SJ. Normalization panels for the reliable quantification of circulating microRNAs by RT-qPCR. FASEB J 2015; 29 (09) 3853-3862
- 19 Schaefer A, Jung M, Miller K. et al. Suitable reference genes for relative quantification of miRNA expression in prostate cancer. Exp Mol Med 2010; 42 (11) 749-758
- 20 Jang JS, Simon VA, Feddersen RM. et al. Quantitative miRNA expression analysis using fluidigm microfluidics dynamic arrays. BMC Genomics 2011; 12: 144
- 21 Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25 (04) 402-408
- 22 Pedersen OB, Pasalic L, Grove EL, Kristensen SD, Hvas AM, Nissen PH. Advanced flow cytometry using the SYTO-13 Dye for the assessment of platelet reactivity and maturity in whole blood. Methods Protoc 2023; 6 (01) 8
- 23 Rubak P, Nissen PH, Kristensen SD, Hvas AM. Investigation of platelet function and platelet disorders using flow cytometry. Platelets 2016; 27 (01) 66-74
- 24 Lee JA, Spidlen J, Boyce K. et al; International Society for Advancement of Cytometry Data Standards Task Force. MIFlowCyt: the minimum information about a flow cytometry experiment. Cytometry A 2008; 73 (10) 926-930
- 25 Pedersen OH, Nissen PH, Hvas AM. Platelet function investigation by flow cytometry: sample volume, needle size, and reference intervals. Platelets 2018; 29 (02) 199-202
- 26 Tóth O, Calatzis A, Penz S, Losonczy H, Siess W. Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96 (06) 781-788
- 27 Sibbing D, Aradi D, Alexopoulos D. et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019; 12 (16) 1521-1537
- 28 Nagalla S, Shaw C, Kong X. et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood 2011; 117 (19) 5189-5197
- 29 La Rosa G, Biasucci LM, Mandolini C. et al. Platelet miRNA-26b down-regulates multidrug resistance protein 4 in patients on chronic aspirin treatment. J Cardiovasc Med (Hagerstown) 2018; 19 (10) 611-613
- 30 Fejes Z, Póliska S, Czimmerer Z. et al. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost 2017; 117 (03) 529-542
- 31 Jakob P, Kacprowski T, Briand-Schumacher S. et al. Profiling and validation of circulating microRNAs for cardiovascular events in patients presenting with ST-segment elevation myocardial infarction. Eur Heart J 2017; 38 (07) 511-515
- 32 Bidzhekov K, Gan L, Denecke B. et al. microRNA expression signatures and parallels between monocyte subsets and atherosclerotic plaque in humans. Thromb Haemost 2012; 107 (04) 619-625
- 33 Kaur A, Mackin ST, Schlosser K. et al. Systematic review of microRNA biomarkers in acute coronary syndrome and stable coronary artery disease. Cardiovasc Res 2020; 116 (06) 1113-1124
- 34 Stojkovic S, Wadowski PP, Haider P. et al. Circulating MicroRNAs and monocyte-platelet aggregate formation in acute coronary syndrome. Thromb Haemost 2021; 121 (07) 913-922
- 35 Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res 2016; 118 (04) 703-720
- 36 Faraldi M, Gomarasca M, Sansoni V, Perego S, Banfi G, Lombardi G. Normalization strategies differently affect circulating miRNA profile associated with the training status. Sci Rep 2019; 9 (01) 1584
- 37 Farina NH, Wood ME, Perrapato SD. et al. Standardizing analysis of circulating microRNA: clinical and biological relevance. J Cell Biochem 2014; 115 (05) 805-811
- 38 Zampetaki A, Mayr M. Analytical challenges and technical limitations in assessing circulating miRNAs. Thromb Haemost 2012; 108 (04) 592-598
- 39 Grove EL, Hvas AM, Johnsen HL. et al. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. Thromb Haemost 2010; 103 (06) 1245-1253
- 40 Procyk G, Klimczak-Tomaniak D, Sygitowicz G, Tomaniak M. Circulating and platelet MicroRNAs in cardiovascular risk assessment and antiplatelet therapy monitoring. J Clin Med 2022; 11 (07) 1763
- 41 Grove EL, Hvas AM, Kristensen SD. Immature platelets in patients with acute coronary syndromes. Thromb Haemost 2009; 101 (01) 151-156
- 42 Cesari F, Marcucci R, Caporale R. et al. Relationship between high platelet turnover and platelet function in high-risk patients with coronary artery disease on dual antiplatelet therapy. Thromb Haemost 2008; 99 (05) 930-935
- 43 Cesari F, Marcucci R, Gori AM. et al. Reticulated platelets predict cardiovascular death in acute coronary syndrome patients. Insights from the AMI-Florence 2 Study. Thromb Haemost 2013; 109 (05) 846-853
- 44 Kieffer N, Guichard J, Farcet JP, Vainchenker W, Breton-Gorius J. Biosynthesis of major platelet proteins in human blood platelets. Eur J Biochem 1987; 164 (01) 189-195
- 45 Barwari T, Eminaga S, Mayr U. et al. Inhibition of profibrotic microRNA-21 affects platelets and their releasate. JCI Insight 2018; 3 (21) e123335
- 46 Becker KC, Kwee LC, Neely ML. et al. Circulating MicroRNA profiling in non-ST elevated coronary artery syndrome highlights genomic associations with serial platelet reactivity measurements. Sci Rep 2020; 10 (01) 6169