Basic Research in Cardiology

, Volume 106, Issue 1, pp 13–23 | Cite as

MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction

  • Benjamin Meder
  • Andreas Keller
  • Britta Vogel
  • Jan Haas
  • Farbod Sedaghat-Hamedani
  • Elham Kayvanpour
  • Steffen Just
  • Anne Borries
  • Jessica Rudloff
  • Petra Leidinger
  • Eckart Meese
  • Hugo A. Katus
  • Wolfgang RottbauerEmail author
Original Contribution


MicroRNAs (miRNAs) are important regulators of adaptive and maladaptive responses in cardiovascular diseases and hence are considered to be potential therapeutical targets. However, their role as novel biomarkers for the diagnosis of cardiovascular diseases still needs to be systematically evaluated. We assessed here for the first time whole-genome miRNA expression in peripheral total blood samples of patients with acute myocardial infarction (AMI). We identified 121 miRNAs, which are significantly dysregulated in AMI patients in comparison to healthy controls. Among these, miR-1291 and miR-663b show the highest sensitivity and specificity for the discrimination of cases from controls. Using a novel self-learning pattern recognition algorithm, we identified a unique signature of 20 miRNAs that predicts AMI with even higher power (specificity 96%, sensitivity 90%, and accuracy 93%). In addition, we show that miR-30c and miR-145 levels correlate with infarct sizes estimated by Troponin T release. The here presented study shows that single miRNAs and especially miRNA signatures derived from peripheral blood, could be valuable novel biomarkers for cardiovascular diseases.


Cardiovascular diseases Diagnosis Myocardial infarction Biomarker MicroRNA 



This work was supported in parts by funding of the German Ministry of Research Education (BMBF 01EX0806) and by grants from the Postdoc-Fellowship of the medical faculty of the University of Heidelberg.

Conflict of interest

A. Keller and A. Borries are employed by febit biomed GmbH. All other authors declare that they have no conflict of interest.

Supplementary material

395_2010_123_MOESM1_ESM.ppt (283 kb)
Supplementary material 1 (PPT 283 kb)


  1. 1.
    (1983) Risk stratification and survival after myocardial infarction. N Engl J Med 309:331–336Google Scholar
  2. 2.
    Adachi T, Nakanishi M, Otsuka Y, Nishimura K, Hirokawa G, Goto Y, Nonogi H, Iwai N (2010) Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clin Chem 56:1183–1185CrossRefPubMedGoogle Scholar
  3. 3.
    Ai J, Zhang R, Li Y, Pu J, Lu Y, Jiao J, Li K, Yu B, Li Z, Wang R, Wang L, Li Q, Wang N, Shan H, Yang B (2010) Circulating microRNA-1 as a potential novel biomarker for acute myocardial infarction. Biochem Biophys Res Commun 391:73–77CrossRefPubMedGoogle Scholar
  4. 4.
    Aliferis CF, Statnikov A, Tsamardinos I, Schildcrout JS, Shepherd BE, Harrell FE Jr (2009) Factors influencing the statistical power of complex data analysis protocols for molecular signature development from microarray data. PLoS One 4:e4922CrossRefPubMedGoogle Scholar
  5. 5.
    Benjamini Y, Hochberg Y (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Statist Soc B 57:289–300Google Scholar
  6. 6.
    Bose D, von Birgelen C, Zhou XY, Schmermund A, Philipp S, Sack S, Konorza T, Mohlenkamp S, Leineweber K, Kleinbongard P, Wijns W, Heusch G, Erbel R (2008) Impact of atherosclerotic plaque composition on coronary microembolization during percutaneous coronary interventions. Basic Res Cardiol 103:587–597CrossRefPubMedGoogle Scholar
  7. 7.
    Cai B, Pan Z, Lu Y (2010) The roles of microRNAs in heart diseases: a novel important regulator. Curr Med Chem 17:407–411CrossRefPubMedGoogle Scholar
  8. 8.
    Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, Guo J, Zhang Y, Chen J, Guo X, Li Q, Li X, Wang W, Wang J, Jiang X, Xiang Y, Xu C, Zheng P, Zhang J, Li R, Zhang H, Shang X, Gong T, Ning G, Zen K, Zhang CY (2008) Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res 18:997–1006CrossRefPubMedGoogle Scholar
  9. 9.
    Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM (2005) miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci USA 102:13944–13949CrossRefPubMedGoogle Scholar
  10. 10.
    D’Alessandra Y, Devanna P, Limana F, Straino S, Di Carlo A, Brambilla PG, Rubino M, Carena MC, Spazzafumo L, De Simone M, Micheli B, Biglioli P, Achilli F, Martelli F, Maggiolini S, Marenzi G, Pompilio G, Capogrossi MC (2010) Circulating microRNAs are new and sensitive biomarkers of myocardial infarction. Eur Heart J. doi: 10.1093/eurheartj/ehq167
  11. 11.
    Dong S, Cheng Y, Yang J, Li J, Liu X, Wang X, Wang D, Krall TJ, Delphin ES, Zhang C (2009) MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J Biol Chem 284:29514–29525CrossRefPubMedGoogle Scholar
  12. 12.
    Dresios J, Aschrafi A, Owens GC, Vanderklish PW, Edelman GM, Mauro VP (2005) Cold stress-induced protein Rbm3 binds 60S ribosomal subunits, alters microRNA levels, and enhances global protein synthesis. Proc Natl Acad Sci USA 102:1865–1870CrossRefPubMedGoogle Scholar
  13. 13.
    Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, Herias V, van Leeuwen RE, Schellings MW, Barenbrug P, Maessen JG, Heymans S, Pinto YM, Creemers EE (2009) miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 104:170–178Google Scholar
  14. 14.
    Fleissner F, Jazbutyte V, Fiedler J, Gupta SK, Yin X, Xu Q, Galuppo P, Kneitz S, Mayr M, Ertl G, Bauersachs J, Thum T (2010) Short communication: asymmetric dimethylarginine impairs angiogenic progenitor cell function in patients with coronary artery disease through a microRNA-21-dependent mechanism. Circ Res 107:138–143CrossRefPubMedGoogle Scholar
  15. 15.
    Gallego-Delgado J, Lazaro A, Osende JI, Barderas MG, Blanco-Colio LM, Duran MC, Martin-Ventura JL, Vivanco F, Egido J (2005) Proteomic approach in the search of new cardiovascular biomarkers. Kidney Int Suppl (99):S103–S107Google Scholar
  16. 16.
    Gerszten RE, Wang TJ (2008) The search for new cardiovascular biomarkers. Nature 451:949–952CrossRefPubMedGoogle Scholar
  17. 17.
    Giannitsis E, Roth HJ, Leithauser RM, Scherhag J, Beneke R, Katus HA (2009) New highly sensitivity assay used to measure cardiac troponin T concentration changes during a continuous 216-km marathon. Clin Chem 55:590–592CrossRefPubMedGoogle Scholar
  18. 18.
    Griffiths-Jones S (2006) miRBase: the microRNA sequence database. Methods Mol Biol 342:129–138PubMedGoogle Scholar
  19. 19.
    Hochberg Y (1988) A sharper Bonferroni procedure for multiple tests of significance. Biometrica 75:185–193CrossRefGoogle Scholar
  20. 20.
    Hoekstra M, van der Lans CA, Halvorsen B, Gullestad L, Kuiper J, Aukrust P, van Berkel TJ, Biessen EA (2010) The peripheral blood mononuclear cell microRNA signature of coronary artery disease. Biochem Biophys Res Commun 394:792–797CrossRefPubMedGoogle Scholar
  21. 21.
    Jennewein C, von Knethen A, Schmid T, Brune B (2010) MicroRNA-27b contributes to lipopolysaccharide-mediated peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA destabilization. J Biol Chem 285:11846–11853CrossRefPubMedGoogle Scholar
  22. 22.
    Katus HA, Remppis A, Looser S, Hallermeier K, Scheffold T, Kubler W (1989) Enzyme linked immuno assay of cardiac troponin T for the detection of acute myocardial infarction in patients. J Mol Cell Cardiol 21:1349–1353CrossRefPubMedGoogle Scholar
  23. 23.
    Konstandin MH, Aksoy H, Wabnitz GH, Volz C, Erbel C, Kirchgessner H, Giannitsis E, Katus HA, Samstag Y, Dengler TJ (2009) Beta2-integrin activation on T cell subsets is an independent prognostic factor in unstable angina pectoris. Basic Res Cardiol 104:341–351CrossRefPubMedGoogle Scholar
  24. 24.
    Kurz K, Schild C, Isfort P, Katus HA, Giannitsis E (2009) Serial and single time-point measurements of cardiac troponin T for prediction of clinical outcomes in patients with acute ST-segment elevation myocardial infarction. Clin Res Cardiol 98:94–100CrossRefPubMedGoogle Scholar
  25. 25.
    Lainscak M, Anker MS, von Haehling S, Anker SD (2009) Biomarkers for chronic heart failure: diagnostic, prognostic, and therapeutic challenges. Herz 34:589–593CrossRefPubMedGoogle Scholar
  26. 26.
    Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefPubMedGoogle Scholar
  27. 27.
    Leidinger P, Keller A, Borries A, Reichrath J, Rass K, Jager SU, Lenhof HP, Meese E (2010) High-throughput miRNA profiling of human melanoma blood samples. BMC Cancer 10:262CrossRefPubMedGoogle Scholar
  28. 28.
    Manzano-Fernandez S, Boronat-Garcia M, Albaladejo-Oton MD, Pastor P, Garrido IP, Pastor-Perez FJ, Martinez-Hernandez P, Valdes M, Pascual-Figal DA (2009) Complementary prognostic value of cystatin C, N-terminal pro-B-type natriuretic peptide and cardiac troponin T in patients with acute heart failure. Am J Cardiol 103:1753–1759CrossRefPubMedGoogle Scholar
  29. 29.
    Meder B, Katus HA, Rottbauer W (2008) Right into the heart of microRNA-133a. Genes Dev 22:3227–3231CrossRefPubMedGoogle Scholar
  30. 30.
    Meredith D, Panchatcharam M, Miriyala S, Tsai YS, Morris AJ, Maeda N, Stouffer GA, Smyth SS (2009) Dominant-negative loss of PPARgamma function enhances smooth muscle cell proliferation, migration, and vascular remodeling. Arterioscler Thromb Vasc Biol 29:465–471CrossRefPubMedGoogle Scholar
  31. 31.
    Mukoyama M, Nakao K, Saito Y, Ogawa Y, Hosoda K, Suga S, Shirakami G, Jougasaki M, Imura H (1990) Increased human brain natriuretic peptide in congestive heart failure. N Engl J Med 323:757–758CrossRefPubMedGoogle Scholar
  32. 32.
    Newton PJ, Betihavas V, Macdonald P (2009) The role of b-type natriuretic peptide in heart failure management. Aust Crit Care 22:117–123CrossRefPubMedGoogle Scholar
  33. 33.
    Porela P, Pulkki K, Voipio-Pulkki LM, Pettersson K, Leppanen V, Nevalainen TJ (2000) Level of circulating phospholipase A2 in prediction of the prognosis of patients with suspected myocardial infarction. Basic Res Cardiol 95:413–417CrossRefPubMedGoogle Scholar
  34. 34.
    Rottbauer W, Greten T, Muller-Bardorff M, Remppis A, Zehelein J, Grunig E, Katus HA (1996) Troponin T: a diagnostic marker for myocardial infarction and minor cardiac cell damage. Eur Heart J 17(Suppl F):3–8PubMedGoogle Scholar
  35. 35.
    Team-RDC (2008) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  36. 36.
    Thum T, Gross C, Fiedler J, Fischer T, Kissler S, Bussen M, Galuppo P, Just S, Rottbauer W, Frantz S, Castoldi M, Soutschek J, Koteliansky V, Rosenwald A, Basson MA, Licht JD, Pena JT, Rouhanifard SH, Muckenthaler MU, Tuschl T, Martin GR, Bauersachs J, Engelhardt S (2008) MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456:980–984CrossRefPubMedGoogle Scholar
  37. 37.
    Tzivoni D, Koukoui D, Guetta V, Novack L, Cowing G (2008) Comparison of Troponin T to creatine kinase and to radionuclide cardiac imaging infarct size in patients with ST-elevation myocardial infarction undergoing primary angioplasty. Am J Cardiol 101:753–757CrossRefPubMedGoogle Scholar
  38. 38.
    Voellenkle C, van Rooij J, Cappuzzello C, Greco S, Arcelli D, Di Vito L, Melillo G, Rigolini R, Costa E, Crea F, Capogrossi MC, Napolitano M, Martelli F (2010) MicroRNA signatures in peripheral blood mononuclear cells of chronic heart failure patients. Physiol Genomics 42:420–426CrossRefPubMedGoogle Scholar
  39. 39.
    Vorwerk S, Ganter K, Cheng Y, Hoheisel J, Stahler PF, Beier M (2008) Microfluidic-based enzymatic on-chip labeling of miRNAs. N Biotechnol 25:142–149CrossRefPubMedGoogle Scholar
  40. 40.
    Wang GK, Zhu JQ, Zhang JT, Li Q, Li Y, He J, Qin YW, Jing Q (2010) Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans. Eur Heart J 31:659–666PubMedGoogle Scholar
  41. 41.
    Xin M, Small EM, Sutherland LB, Qi X, McAnally J, Plato CF, Richardson JA, Bassel-Duby R, Olson EN (2009) MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev 23:2166–2178CrossRefPubMedGoogle Scholar
  42. 42.
    Xu P, Vernooy SY, Guo M, Hay BA (2003) The Drosophila microRNA Mir-14 suppresses cell death and is required for normal fat metabolism. Curr Biol 13:790–795CrossRefPubMedGoogle Scholar
  43. 43.
    Zhao Y, Samal E, Srivastava D (2005) Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436:214–220CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Benjamin Meder
    • 1
  • Andreas Keller
    • 2
  • Britta Vogel
    • 1
  • Jan Haas
    • 1
  • Farbod Sedaghat-Hamedani
    • 1
  • Elham Kayvanpour
    • 1
  • Steffen Just
    • 1
  • Anne Borries
    • 2
  • Jessica Rudloff
    • 1
  • Petra Leidinger
    • 3
  • Eckart Meese
    • 3
  • Hugo A. Katus
    • 1
  • Wolfgang Rottbauer
    • 1
    • 4
    Email author
  1. 1.Department of Internal Medicine IIIUniversity of HeidelbergHeidelbergGermany
  2. 2.Biomarker Discovery Center HeidelbergHeidelbergGermany
  3. 3.Department of Human Genetics, Medical SchoolSaarland UniversityHomburgGermany
  4. 4.Department of Medicine IIUniversity of UlmUlmGermany

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