We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Circulating miRNAs: novel biomarkers of acute coronary syndrome?

    Adam Pleister

    Department of Internal Medicine, Division of Cardiovascular Medicine, The Ohio State University, 473 West 12th Avenue, OH 43210, USA.

    ,
    Helina Selemon

    Davis Heart & Lung Research Institute, The Ohio State University, 473 West 12th Avenue, OH 43210, USA

    ,
    Shane M Elton

    Midwestern University, Glendale, AZ, USA

    &
    Terry S Elton

    * Author for correspondence

    College of Pharmacy, Division of Pharmacology, The Ohio State University, 473 West 12th Avenue, OH 43210, USA.

    Published Online:https://doi.org/10.2217/bmm.13.8

    Acute coronary syndrome refers to any group of clinical symptoms compatible with acute myocardial infarction (AMI). AMI is a major cause of death and disability worldwide with the greatest risk of death within the first hours of AMI onset. Therefore, delays in ‘ruling in’ AMI may increase morbidity and mortality due to the time lag in initiating therapy. Likewise, since the majority of patients presenting with acute chest pain do not have AMI, the rapid ‘ruling out’ of AMI in those patients would increase emergency department triage efficiency, decrease medical costs, and reduce morbidity and mortality. Thus, the identification of novel biomarkers that improve current strategies and/or accurately identify subjects who are at risk of developing acute and chronic manifestations of cardiovascular disease are desperately needed. This article discusses the potential of peripheral blood microRNAs as clinical biomarkers for the diagnosis and prognosis of cardiovascular diseases such as AMI.

    Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

    References

    • Rosamond W, Flegal K, Furie K et al. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation117,e25–e146 (2008).
    • Lloyd-Jones D, Adams RJ, Brown TM et al. Executive summary: heart disease and stroke statistics – 2010 update: a report from the American Heart Association. Circulation121,948–954 (2010).
    • Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet353,89–92 (1999).
    • Gibler WB, Cannon CP, Blomkalns AL et al. Practical implementation of the guidelines for unstable angina/non-ST-segment elevation myocardial infarction in the emergency department. Ann. Emerg. Med.46,185–197 (2005).
    • Pollack CV Jr, Diercks DB, Roe MT, Peterson ED. 2004 American College of Cardiology/American Heart Association guidelines for the management of patients with ST-elevation myocardial infarction: implications for emergency department practice. Ann. Emerg. Med.45,363–376 (2005).
    • Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation110,588–636 (2004).
    • Pollack CV Jr, Antman EM, Hollander JE. 2007 focused update to the ACC/AHA guidelines for the management of patients with ST-segment elevation myocardial infarction: implications for emergency department practice. Ann. Emerg. Med.52,344–355 (2008).
    • Yeghiazarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina pectoris. N. Engl. J. Med.342,101–114 (2000).
    • Braunwald E. Unstable angina: an etiologic approach to management. Circulation98,2219–2222 (1998).
    • 10  Jneid H, Anderson JL, Wright RS et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol.60,645–681 (2012).
    • 11  Harrington RA, Becker RC, Cannon CP et al. Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest133,670S–707S (2008).
    • 12  Antman EM, Cohen M, Bernink PJ et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA284,835–842 (2000).
    • 13  O’Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA Guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation127,529–555 (2013).
    • 14  Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur. Heart. J.30,162–169 (2009).
    • 15  Kurz K, Giannitsis E, Zehelein J, Katus HA. Highly sensitive cardiac troponin T values remain constant after brief exercise – or pharmacologic-induced reversible myocardial ischemia. Clin. Chem.54,1234–1238 (2008).
    • 16  Shave R, George KP, Atkinson G et al. Exercise-induced cardiac troponin T release: a meta-analysis. Med. Sci. Sports Exerc.39,2099–2106 (2007).
    • 17  Gupta S, de Lemos JA. Use and misuse of cardiac troponins in clinical practice. Prog. Cardiovasc. Dis.50,151–165 (2007).
    • 18  Müller-Bardorff M, Weidtmann B, Giannitsis E, Kurowski V, Katus HA. Release kinetics of cardiac troponin T in survivors of confirmed severe pulmonary embolism. Clin. Chem.48,673–675 (2002).
    • 19  Puleo PR, Meyer D, Wathen C et al. Use of a rapid assay of subforms of creatine kinase-MB to diagnose or rule out acute myocardial infarction. N. Engl. J. Med.331,561–566 (1994).
    • 20  Saenger AK, Jaffe AS. Requiem for a heavyweight: the demise of creatine kinase-MB. Circulation118,2200–2206 (2008).
    • 21  Goodman SG, Steg PG, Eagle KA et al. The diagnostic and prognostic impact of the redefinition of acute myocardial infarction: lessons from the Global Registry of Acute Coronary Events (GRACE). Am. Heart J.151,654–660 (2006).
    • 22  Hochholzer W, Buettner HJ, Trenk D et al. New definition of myocardial infarction: impact on long-term mortality. Am. J. Med.121,399–405 (2008).
    • 23  Hochholzer W, Reichlin T, Stelzig C et al. Impact of soluble fms-like tyrosine kinase-1 and placental growth factor serum levels for risk stratification and early diagnosis in patients with suspected acute myocardial infarction. Eur. Heart J.32,326–335 (2011).
    • 24  Macrae AR, Kavsak PA, Lustig V et al. Assessing the requirement for the 6-hour interval between specimens in the American Heart Association Classification of Myocardial Infarction in Epidemiology and Clinical Research Studies. Clin. Chem.52,812–818 (2006).
    • 25  Apple FS, Murakami MM. Cardiac troponin and creatine kinase MB monitoring during in-hospital myocardial reinfarction. Clin. Chem.51,460–463 (2005).
    • 26  Vasile VC, Babuin L, Giannitsis E, Katus HA, Jaffe AS. Relationship of MRI-determined infarct size and cTnI measurements in patients with ST-elevation myocardial infarction. Clin. Chem.54,617–619 (2008).
    • 27  Olatidoye AG, Wu AH, Feng YJ, Waters D. Prognostic role of troponin T versus troponin I in unstable angina pectoris for cardiac events with meta-analysis comparing published studies. Am. J. Cardiol.81,1405–1410 (1998).
    • 28  Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. Lancet354,1757–1762 (1999).
    • 29  Heidenreich PA, Alloggiamento T, Melsop K, McDonald KM, Go AS, Hlatky A. The prognostic value of troponin in patients with non-ST elevation acute coronary syndromes: a meta-analysis. J. Am. Coll. Cardiol.38,478–485 (2001).
    • 30  Panteghini M, Pagani F, Yeo KT et al. Evaluation of imprecision for cardiac troponin assays at low-range concentrations. Clin. Chem.50,327–332 (2004).
    • 31  Wu AH, Feng YJ, Moore R et al. Characterization of cardiac troponin subunit release into serum after acute myocardial infarction and comparison of assays for troponin T and I. American Association for Clinical Chemistry Subcommittee on cTnI Standardization. Clin. Chem.44,1198–1208 (1998).
    • 32  Thygesen K, Alpert JS, Jaffe AS et al. Third universal definition of myocardial infarction. J. Am. Coll. Cardiol.60,1581–1598 (2012).
    • 33  Kavsak PA, Newman AM, Lustig V et al. Long-term health outcomes associated with detectable troponin I concentrations. Clin. Chem.53,220–227 (2007).
    • 34  Waxman DA, Hecht S, Schappert J, Husk G. A model for troponin I as a quantitative predictor of in-hospital mortality. J. Am. Coll. Cardiol.48,1755–1762 (2006).
    • 35  Schulz O, Kirpal K, Stein J et al. Importance of low concentrations of cardiac troponins. Clin. Chem.52,1614–1615 (2006).
    • 36  Daniels LB, Laughlin GA, Clopton P, Maisel AS, Barrett-Connor E. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study. J. Am. Coll. Cardiol.52,450–459 (2008).
    • 37  Kavsak PA, Wang X, Ko DT, MacRae AR, Jaffe AS. Short- and long-term risk stratification using a next-generation, high-sensitivity research cardiac troponin I (hs-cTnI) assay in an emergency department chest pain population. Clin. Chem.55,1809–1815 (2009).
    • 38  deFilippi CR, de Lemos JA, Christenson RH et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA304,2494–2502 (2010).
    • 39  Diamond GA, Kaul S. How would the Reverend Bayes interpret high-sensitivity troponin? Circulation121,1172–1175 (2010).
    • 40  Franz WM, Remppis A, Kandolf R, Kübler W, Katus HA. Serum troponin T: diagnostic marker for acute myocarditis. Clin. Chem.42,340–341 (1996).
    • 41  Babuin L, Vasile VC, Rio Perez JA et al. Elevated cardiac troponin is an independent risk factor for short- and long-term mortality in medical intensive care unit patients. Crit. Care Med.36,759–765 (2008).
    • 42  Allan JJ, Feld RD, Russell AA et al. Cardiac troponin I levels are normal or minimally elevated after transthoracic cardioversion. J. Am. Coll. Cardiol.30,1052–1056 (1997).
    • 43  Ricchiuti V, Apple FS. RNA expression of cardiac troponin T isoforms in diseased human skeletal muscle. Clin. Chem.45,2129–2135 (1999).
    • 44  Jaffe AS, Vasile VC, Milone M, Saenger AK, Olson KN, Apple FS. Diseased skeletal muscle: a noncardiac source of increased circulating concentrations of cardiac troponin T. J. Am. Coll. Cardiol.58,1819–1824 (2011).
    • 45  Emilian C, Goretti E, Prospert F et al. MicroRNAs in patients on chronic hemodialysis (MINOS study). Clin. J. Am. Soc. Nephrol.7,619–623 (2012).
    • 46  Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell75,843–854 (1993).
    • 47  Bushati N, Cohen SM. microRNA functions. Annu. Rev. Cell Dev. Biol.23,175–205 (2007).
    • 48  Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell136,215–233 (2009).
    • 49  Friedman RC, Farh KK, Burge CB, Bartel DP. Most mammalian mRNAs are conserved targets of microRNAs. Genome Res.1,92–105 (2009).
    • 50  Landgraf P, Rusu M, Sheridan R et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell129,1401–1414 (2007).
    • 51  Liu N, Olson EN. MicroRNA regulatory networks in cardiovascular development. Dev. Cell18,510–525 (2010).
    • 52  Leung AK, Sharp PA. MicroRNA functions in stress responses. Mol. Cell40,205–215 (2010).
    • 53  Mendell JT, Olson EN. MicroRNAs in stress signaling and human disease. Cell148,1172–1187 (2012).
    • 54  Rüegger S, Großhans H. MicroRNA turnover: when, how, and why. Trends Biochem. Sci.37,436–446 (2012).
    • 55  Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat. Rev. Mol. Cell Biol.10,126–139 (2009).
    • 56  Fabian MR, Sonenberg N. The mechanics of miRNA mediated gene silencing: a look under the hood of miRISC. Nat. Struct. Mol. Biol.19,586–593 (2012).
    • 57  Shin C. Cleavage of the star strand facilitates assembly of some microRNAs into Ago2-containing silencing complexes in mammals. Mol. Cells26,308–313 (2008).
    • 58  Okamura K, Phillips MD, Tyler DM, Duan H, Chou YT, Lai EC. The regulatory activity of microRNA* species has substantial influence on microRNA and 3’ UTR evolution. Nat. Struct. Mol. Biol.15,354–363 (2008).
    • 59  Packer AN, Xing Y, Harper SQ, Jones L, Davidson BL. The bifunctional microRNA, miR-9/miR-9*, regulates REST and CoREST and is downregulated in Huntington’s disease. J. Neurosci.28,14341–14346 (2008).
    • 60  Yang JS, Phillips MD, Betel D et al. Widespread regulatory activity of vertebrate microRNA* species. RNA17,312–326 (2011).
    • 61  Griffiths-Jones S. The microRNA registry. Nucleic Acids Res.32,D109–D111 (2004).
    • 62  Brennecke J, Stark A, Russell RB, Cohen SM. Principles of microRNA-target recognition. PLoS Biol.3,e85 (2005).
    • 63  Guo H, Ingolia NT, Weissman J S, Bartel DP. Mammalian microRNAs predominantly act to decrease target mRNA levels. Nature466,835–840 (2010).
    • 64  Brown BD, Gentner B, Cantore A et al. Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state. Nat. Biotechnol.25,1457–1467 (2007).
    • 65  Mullokandov G, Baccarini A, Ruzo A et al. High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries. Nat. Methods9,840–846 (2012).▪ Over 60% of detected miRNAs had no discernible activity.
    • 66  Salmena L, Poliseno L, Tay Y, Kats L, Pandolfi PP. A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell146,353–358 (2011).
    • 67  Mitchell PS, Parkin RK, Kroh EM et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA105,10513–10518 (2008).
    • 68  Chen X, Ba Y, Ma L et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res.18,997–1006 (2008).
    • 69  Lawrie CH, Gal S, Dunlop HM et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol.141,672–675 (2008).
    • 70  Simons M, Raposo G. Exosomes – vesicular carriers for intercellular communication. Curr. Opin. Cell Biol.21,575–581 (2009).
    • 71  Bang C, Thum T. Exosomes: new players in cell–cell communication. Int. J. Biochem. Cell Biol.44,2060–2064 (2012).
    • 72  Mause SF, Weber C. Microparticles: Protagonists of a novel communication network for intercellular information exchange. Circ. Res.107,1047–1057 (2010).
    • 73  Zernecke A, Bidzhekov K, Noels H et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal.2,ra81 (2009).
    • 74  Wang K, Zhang S, Weber J, Baxter D, Galas DJ. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res.38,7248–7259 (2010).
    • 75  Arroyo JD, Chevillet JR, Kroh EM et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA108,5003–5008 (2011).▪▪ Extracellular Ago2–miRNA complexes are stable in the plasma, raising the possibility that cells release a functional miRNA-induced silencing complex into the circulation.
    • 76  Turchinovich A, Weiz L, Langheinz A, Burwinkel B. Characterization of extracellular circulating microRNA. Nucleic Acids Res.39,7223–7233 (2011).
    • 77  Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol.13,423–433 (2011).▪▪ High-density lipoprotein participates in a mechanism of intercellular communication involving the transport and delivery of miRNAs.
    • 78  Etheridge A, Lee I, Hood L, Galas D, Wang K. Extracellular microRNA: a new source of biomarkers. Mutat. Res.717,85–90 (2011).
    • 79  Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature469,336–342 (2011).
    • 80  van Rooij E, Sutherland LB, Qi X, Richardson JA, Hill J, Olson EN. Control of stress-dependent cardiac growth and gene expression by a microRNA. Science316,575–579 (2007).
    • 81  Condorelli G, Latronico MV, Dorn GW II. MicroRNAs in heart disease: putative novel therapeutic targets? Eur. Heart J.31,649–658 (2010).
    • 82  Olivieri F, Antonicelli R, Lorenzi M et al. Diagnostic potential of circulating miR-499-5p in elderly patients with acute non ST-elevation myocardial infarction. Int. J. Cardiol. doi:10.1016/j.ijcard.2012.01.075 (2012) (Epub ahead of print).▪ Circulating miR-499-5p is a sensitive biomarker of acute non-ST elevation myocardial infarction in the elderly, exhibiting a diagnostic accuracy superior to that of cardiac troponin T in patients with modest elevation at presentation.
    • 83  Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell145,341–355 (2011).
    • 84  Guo M, Mao X, Ji Q et al. miR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome. Immunol. Cell Biol.88,555–564 (2010).
    • 85  Yao R, Ma Y, Du Y et al. The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome. Cell Mol. Immunol.8,486–495 (2011).
    • 86  Zampetaki A, Willeit P, Tilling L et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J. Am. Coll. Cardiol.60,290–299 (2012).▪▪ In subjects with subsequent myocardial infarction, differential coexpression patterns of circulating miRNAs occur around endothelium-enriched miR-126, with platelets being a major contributor to this miRNA signature.
    • 87  Ji X, Takahashi R, Hiura Y, Hirokawa G, Fukushima Y, Iwai N. Plasma miR-208 as a biomarker of myocardial injury. Clin. Chem.55,1944–1949 (2009).
    • 88  Wang GK, Zhu JQ, Zhang JT et al. Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur. Heart J.31,659–666 (2010).▪ Elevated cardiac-specific miR-208a in plasma may be a novel biomarker for the early detection of myocardial injury in humans.
    • 89  Cheng Y, Tan N, Yang J et al. A translational study of circulating cell-free microRNA-1 in acute myocardial infarction. Clin. Sci. (Lond.)119,87–95 (2010).
    • 90  D’Alessandra Y, Devanna P, Limana F et al. Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur. Heart J.31,2765–2773 (2010).
    • 91  Gidlof O, Andersson P, van der Pals J, Gotberg M, Erlinge D. Cardiospecific microRNA plasma levels correlate with troponin and cardiac function in patients with ST elevation myocardial infarction, are selectively dependent on renal elimination, and can be detected in urine samples. Cardiology118,217–226 (2011).
    • 92  Adachi T, Nakanishi M, Otsuka Y et al. Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clin. Chem.56,1183–1185 (2010).
    • 93  Corsten MF, Dennert R, Jochems S et al. Circulating microRNA-208b and microRNA-499 reflect myocardial damage in cardiovascular disease. Circ. Cardiovasc. Genet.3,499–506 (2010).
    • 94  Kuwabara Y, Ono K, Horie T et al. Increased microRNA-1 and microRNA-133a levels in serum of patients with cardiovascular disease indicate myocardial damage. Circ. Cardiovasc. Genet.4,446–454 (2011).
    • 95  Fichtlscherer S, De Rosa S, Fox H et al. Circulating microRNAs in patients with coronary artery disease. Circ. Res.107,677–684 (2010).
    • 96  De Rosa S, Fichtlscherer S, Lehmann R, Assmus B, Dimmeler S, Zeiher AM. Transcoronary concentration gradients of circulating microRNAs. Circulation124,1936–1944 (2011).
    • 97  Devaux Y, Vausort M, Goretti E et al. Use of circulating microRNAs to diagnose acute myocardial infarction. Clin. Chem.58,559–567 (2012).▪▪ Largest patient cohort, to date, demonstrating that miR-499 and high-sensitivity cardiac troponin T provided comparable diagnostic markers of acute myocardial ischemia.
    • 98  Ai J, Zhang R, Li Y et al. Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem. Biophys. Res. Commun.391,73–77 (2010).
    • 99  Widera C, Gupta SK, Lorenzen JM et al. Diagnostic and prognostic impact of six circulating microRNAs in acute coronary syndrome. J. Mol. Cell. Cardiol.51,872–875 (2011).
    • 100  Goch A, Misiewicz P, Rysz J, Banach M. The clinical manifestation of myocardial infarction in elderly patients. Clin. Cardiol.32,E46–E51 (2009).
    • 101  Meder B, Keller A, Vogel B et al. MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction. Basic Res. Cardiol.106,13–23 (2011).▪ Single miRNAs and especially miRNA signatures derived from peripheral blood can be valuable novel biomarkers for acute myocardial ischemia.
    • 102  Wang R, Li N, Zhang Y, Ran Y, Pu J. Circulating MicroRNAs are promising novel biomarkers of acute myocardial infarction. Intern. Med.50,1789–1795 (2011).
    • 103  Lu Y, Zhang Y, Wang N et al. MicroRNA-328 contributes to adverse electrical remodeling in atrial fibrillation. Circulation122,2378–2387 (2010).
    • 104  Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T helper-1 lymphocyte activation patterns in acute coronary syndromes. J. Am. Coll. Cardiol.45,1939–1945 (2005).
    • 105  Nakasa T, Miyaki S, Okubo A et al. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum.58,1284–1292 (2008).
    • 106  Kiechl S, Lorenz E, Reindl M et al. Toll-like receptor 4 polymorphisms and atherogenesis. N. Engl. J. Med.347,185–192 (2002).
    • 107  Matsumoto S, Sakata Y, Nakatani D et al. A subset of circulating microRNAs are predictive for cardiac death after discharge for acute myocardial infarction. Biochem. Biophys. Res. Commun.427,280–284 (2012).
    • 108  Lee LW, Zhang S, Etheridge A et al. Complexity of the microRNA repertoire revealed by next-generation sequencing. RNA16,2170–2180 (2010).
    • 109  Chen X, Ba Y, Ma L et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res.18,997–1006 (2008).
    • 110  Hu Z, Chen X, Zhao Y et al. Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer. J. Clin. Oncol.28,1721–1726 (2010).
    • 111  Diehl P, Fricke A, Sander L et al. Microparticles: major transport vehicles for distinct microRNAs in circulation. Cardiovasc. Res.93,633–644 (2012).
    • 112  Sondermeijer BM, Bakker A, Halliani A et al. Platelets in patients with premature coronary artery disease exhibit upregulation of miRNA340* and miRNA624*. PLoS One6,e25946 (2011).
    • 113  Minami Y, Satoh M, Maesawa C et al. Effect of atorvastatin on microRNA 221/222 expression in endothelial progenitor cells obtained from patients with coronary artery disease. Eur. J. Clin. Invest.39,359–367 (2009).
    • 114  Pritchard CC, Kroh E, Wood B et al. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev. Res. (Phila)5,492–497 (2012).
    • 115  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.107,810–817 (2010).
    • 116  Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: the present and the future. J. Am. Coll. Cardiol.48,1–11 (2006).
    • 201  miRBase. www.mirbase.org/index.shtml