Download PDF
Thromb Haemost 2023; 123(03): 307-316
DOI: 10.1055/s-0042-1760258
Cellular Haemostasis and Platelets

Expression of microRNA Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease

Oliver Buchhave Pedersen 
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Erik Lerkevang Grove 
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Peter H. Nissen
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Sanne Bøjet Larsen
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
,
Leonardo Pasalic
4   Department of Clinical and Laboratory Haematology, Institute of Clinical Pathology and Medical Research, Westmead University Hospital, Sydney, Australia
5   Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
,
Steen Dalby Kristensen
2   Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
,
Anne-Mette Hvas 
1   Thrombosis and Haemostasis Research Unit, Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
3   Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints


Abstract

Background New biomarkers are warranted to identify patients with coronary artery disease (CAD) at high risk of recurrent cardiovascular events. It has been reported that the expression of microRNAs (miRs) may influence the development of CAD.

Objectives We aimed to investigate whether the expression of selected candidate miRs is a predictor of cardiovascular events in a cohort of stable CAD patients.

Methods We performed a single-center prospective study of 749 stable CAD patients with a median follow-up of 2.8 years. We investigated the expression of nine candidate miRs and their relation to cardiovascular events in this cohort. The primary endpoint was the composite of nonfatal myocardial infarction (MI), stent thrombosis (ST), ischemic stroke, and cardiovascular death. The composite of nonfatal MI and ST was analyzed as a secondary endpoint. Furthermore, nonfatal MI, ST, ischemic stroke, and all-cause mortality were analyzed as individual endpoints.

Results Employing receiver operating characteristic curves, it was shown that compared with traditional cardiovascular risk factors alone, combining the expression of miR-223–3p with existing traditional cardiovascular risk factors increased the predictive value of ST (area under the curve: 0.88 vs. 0.77, p = 0.04), the primary composite endpoint (0.65 vs. 0.61, p = 0.049), and the secondary endpoint of the composite of nonfatal MI and ST (0.68 vs. 0.62, p = 0.04).

Conclusion Among patients with CAD, adding miR-223–3p expression to traditional cardiovascular risk factors may improve prediction of cardiovascular events, particularly ST. Clinical trials confirming these findings are warranted.

Keywords

coronary artery disease - microRNAs - myocardial infarction - risk factors

Author Contributions

All authors designed the research study; S.B.L. collected the data, O.B.P. performed the data analyses; all authors contributed to writing of the paper.


Supplementary Material



Publication History

Received: 18 July 2022

Accepted: 11 November 2022

Article published online:
05 January 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 (WHO) WHO. Cardiovascular diseases (CVDs). 2022 Accessed December 8, 2022 at: https://www.who.int/health-topics/cardiovascular-diseases#tab=tab_1
    PubMedGoogle Scholar
  • 2 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
    CrossrefPubMedGoogle Scholar
  • 3 Fox KAA, Metra M, Morais J, Atar D. The myth of 'stable' coronary artery disease. Nat Rev Cardiol 2020; 17 (01) 9-21
    CrossrefPubMedGoogle Scholar
  • 4 Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005; 111 (25) 3481-3488
    CrossrefPubMedGoogle Scholar
  • 5 Jonas S, Izaurralde E. Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet 2015; 16 (07) 421-433
    CrossrefPubMedGoogle Scholar
  • 6 Fichtlscherer S, De Rosa S, Fox H. et al. Circulating microRNAs in patients with coronary artery disease. Circ Res 2010; 107 (05) 677-684
    CrossrefPubMedGoogle Scholar
  • 7 Olson EN. MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease. Sci Transl Med 2014; 6 (239) 239ps3
    CrossrefPubMedGoogle Scholar
  • 8 Feinberg MW, Moore KJ. MicroRNA regulation of atherosclerosis. Circ Res 2016; 118 (04) 703-720
    CrossrefPubMedGoogle Scholar
  • 9 Mitchell PS, Parkin RK, Kroh EM. et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 2008; 105 (30) 10513-10518
    CrossrefPubMedGoogle Scholar
  • 10 Creemers EE, Tijsen AJ, Pinto YM. Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease?. Circ Res 2012; 110 (03) 483-495
    CrossrefPubMedGoogle Scholar
  • 11 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) E276
    CrossrefPubMedGoogle Scholar
  • 12 Kaudewitz D, Zampetaki A, Mayr M. MicroRNA biomarkers for coronary artery disease?. Curr Atheroscler Rep 2015; 17 (12) 70
    CrossrefPubMedGoogle Scholar
  • 13 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
    PubMedGoogle Scholar
  • 14 Yang X, Du X, Ma K. et al. Circulating miRNAs related to long-term adverse cardiovascular events in STEMI patients: a nested case-control study. Can J Cardiol 2021; 37 (01) 77-85
    CrossrefPubMedGoogle Scholar
  • 15 Baek D, Villén J, Shin C, Camargo FD, Gygi SP, Bartel DP. The impact of microRNAs on protein output. Nature 2008; 455 (7209): 64-71
    CrossrefPubMedGoogle Scholar
  • 16 Larsen SB, Grove EL, Neergaard-Petersen S, Würtz M, Hvas AM, Kristensen SD. Reduced antiplatelet effect of aspirin does not predict cardiovascular events in patients with stable coronary artery disease. J Am Heart Assoc 2017; 6 (08) e006050
    CrossrefPubMedGoogle Scholar
  • 17 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 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
    CrossrefPubMedGoogle Scholar
  • 19 Jang JS, Simon VA, Feddersen RM. et al. Quantitative miRNA expression analysis using fluidigm microfluidics dynamic arrays. BMC Genomics 2011; 12: 144
    CrossrefPubMedGoogle Scholar
  • 20 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
    Google Scholar
  • 21 Schmidt M, Pedersen L, Sørensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol 2014; 29 (08) 541-549
    CrossrefPubMedGoogle Scholar
  • 22 Schmidt M, Maeng M, Jakobsen CJ. et al. Existing data sources for clinical epidemiology: the Western Denmark Heart Registry. Clin Epidemiol 2010; 2: 137-144
    CrossrefPubMedGoogle Scholar
  • 23 Juel K, Helweg-Larsen K. The Danish registers of causes of death. Dan Med Bull 1999; 46 (04) 354-357
    PubMedGoogle Scholar
  • 24 Wildenschild C, Mehnert F, Thomsen RW. et al. Registration of acute stroke: validity in the Danish Stroke Registry and the Danish National Registry of Patients. Clin Epidemiol 2013; 6: 27-36
    CrossrefPubMedGoogle Scholar
  • 25 DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988; 44 (03) 837-845
    Google Scholar
  • 26 Aimo A, Januzzi Jr JL, Vergaro G. et al. Left ventricular ejection fraction for risk stratification in chronic systolic heart failure. Int J Cardiol 2018; 273: 136-140
    CrossrefPubMedGoogle Scholar
  • 27 Singh S, de Ronde MWJ, Kok MGM. et al. MiR-223-3p and miR-122-5p as circulating biomarkers for plaque instability. Open Heart 2020; 7 (01) e001223
    CrossrefPubMedGoogle Scholar
  • 28 Pan Y, Liang H, Liu H. et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J Immunol 2014; 192 (01) 437-446
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 Landry P, Plante I, Ouellet DL, Perron MP, Rousseau G, Provost P. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol 2009; 16 (09) 961-966
    CrossrefPubMedGoogle Scholar
  • 31 Kahner BN, Shankar H, Murugappan S, Prasad GL, Kunapuli SP. Nucleotide receptor signaling in platelets. J Thromb Haemost 2006; 4 (11) 2317-2326
    CrossrefPubMedGoogle Scholar
  • 32 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
    CrossrefPubMedGoogle Scholar
  • 33 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
    CrossrefPubMedGoogle Scholar
  • 34 Shi R, Ge L, Zhou X. et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res 2013; 131 (06) 508-513
    CrossrefPubMedGoogle Scholar
  • 35 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
    CrossrefPubMedGoogle Scholar
  • 36 Calvente CJ, Tameda M, Johnson CD. et al. Neutrophils contribute to spontaneous resolution of liver inflammation and fibrosis via microRNA-223. J Clin Invest 2019; 129 (10) 4091-4109
    CrossrefPubMedGoogle Scholar
  • 37 Johnnidis JB, Harris MH, Wheeler RT. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 2008; 451 (7182): 1125-1129
    CrossrefPubMedGoogle Scholar
  • 38 Chen L, Hou X, Zhang M. et al. MicroRNA-223-3p modulates dendritic cell function and ameliorates experimental autoimmune myocarditis by targeting the NLRP3 inflammasome. Mol Immunol 2020; 117: 73-83
    CrossrefPubMedGoogle Scholar
  • 39 Zhou K, Wei Y, Li X, Yang X. MiR-223-3p targets FOXO3a to inhibit radiosensitivity in prostate cancer by activating glycolysis. Life Sci 2021; 282: 119798
    CrossrefPubMedGoogle Scholar
  • 40 Xu J, Wang B, Liu ZT, Lai MC, Zhang ML, Zheng SS. miR-223-3p regulating the occurrence and development of liver cancer cells by targeting FAT1 gene. Math Biosci Eng 2019; 17 (02) 1534-1547
    CrossrefPubMedGoogle Scholar
  • 41 Li S, Feng Y, Huang Y. et al. MiR-223-3p regulates cell viability, migration, invasion, and apoptosis of non-small cell lung cancer cells by targeting RHOB. Open Life Sci 2020; 15 (01) 389-399
    CrossrefPubMedGoogle Scholar
  • 42 Becker DM, Segal J, Vaidya D. et al. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA 2006; 295 (12) 1420-1427
    CrossrefPubMedGoogle Scholar