International Journal of Legal Medicine

, Volume 132, Issue 2, pp 509–518 | Cite as

Biomechanical stress in myocardial infarctions: can endothelin-1 and growth differentiation factor 15 serve as immunohistochemical markers?

  • M. Falk
  • R. Huhn
  • F. Behmenburg
  • St Ritz-Timme
  • F. Mayer
Original Article


Myocardial infarctions go along with biomechanical stress, i.e. stretching of muscle fibres, and the expression of certain marker molecules. We tested if two of those markers, endothelin-1 (ET-1) and growth differentiation factor 15 (GDF-15), can be used as immunohistochemical markers for myocardial ischaemia/infarctions. The study included experiments with an animal model, the isolated perfused Langendorff heart, as well as the investigation of human tissue samples drawn during autopsies. The overall picture of our results showed that GDF-15 is very sensitive and expressed very fast, not only as a consequence of ischaemia/infarctions, but also under other circumstances. Even an expression only caused by agony had to be discussed. ET-1, on the other hand, was less sensitive but only positive in those human cases with ischaemia/infarction that also showed typical alterations in conventional histology. Therefore, both markers did not proof to be a suitable diagnostic tool for myocardial infarctions. However, positive staining for ET-1 was also seen in rats’ hearts that suffered from arrhythmias after electric shock and in the myocardium of the right ventricle in human control cases in which a right heart failure has to be discussed. Thus, especially ET-1 should be subject of further studies that focus on these pathologies.


Immunohistochemistry Myocardial infarctions Right heart failure Animal model 


  1. 1.
    Ortmann C, Pfeiffer H, Brinkmann B (2000) A comparative study on the immunohistochemical detection of early myocardial damage. Int J Legal Med 113:215–220CrossRefPubMedGoogle Scholar
  2. 2.
    Sutton MGSJ, Sharpe N (2000) Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 101:2981–2988. CrossRefPubMedGoogle Scholar
  3. 3.
    Cleutjens JP, Kandala JC, Guarda E et al (1995) Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 27:1281–1292CrossRefPubMedGoogle Scholar
  4. 4.
    Tønnessen T, Giaid A, Saleh D et al (1995) Increased in vivo expression and production of endothelin-1 by porcine cardiomyocytes subjected to ischemia. Circ Res 76:767–772. CrossRefPubMedGoogle Scholar
  5. 5.
    Kempf T (2006) The transforming growth factor-superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 98:351–360. CrossRefPubMedGoogle Scholar
  6. 6.
    Frank D, Kuhn C, Brors B et al (2008) Gene expression pattern in biomechanically stretched cardiomyocytes: evidence for a stretch-specific gene program. Hypertension 51:309–318. CrossRefPubMedGoogle Scholar
  7. 7.
    Cummings PM, Trelka DP, Springer KM (2011) Atlas of forensic histopathology. Cambridge University Press, Cambridge; New YorkCrossRefGoogle Scholar
  8. 8.
    Thomsen H, Schulz A, Bhakdi S (1990) Immunhistochemische C5b-9-komplement-komplex-darstellung in frühstadien der herzmuskelnekrosen am paraffinschnitt. Int J Legal Med 103:199–206CrossRefGoogle Scholar
  9. 9.
    Bi H, Yang Y, Huang J et al (2013) Immunohistochemical detection of S100A1 in the postmortem diagnosis of acute myocardial infarction. Diagn Pathol 8:84CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sabatasso S, Mangin P, Fracasso T et al (2016) Early markers for myocardial ischemia and sudden cardiac death. Int J Legal Med 130:1265–1280. CrossRefPubMedGoogle Scholar
  11. 11.
    Mayer F, Falk M, Huhn R et al (2016) Dityrosine as a marker of acute myocardial infarction? Experiments with the isolated Langendorff heart. Int J Legal Med 130:1053–1060. CrossRefPubMedGoogle Scholar
  12. 12.
    Bootcov MR, Bauskin AR, Valenzuela SM et al (1997) MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc Natl Acad Sci U S A 94:11514–11519CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shi Y, Massagué J (2003) Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113:685–700CrossRefPubMedGoogle Scholar
  14. 14.
    Fairlie WD, Moore AG, Bauskin AR et al (1999) MIC-1 is a novel TGF-beta superfamily cytokine associated with macrophage activation. J Leukoc Biol 65:2–5CrossRefPubMedGoogle Scholar
  15. 15.
    Hsiao EC, Koniaris LG, Zimmers-Koniaris T et al (2000) Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol Cell Biol 20:3742–3751CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Schernthaner C, Lichtenauer M, Wernly B et al (2017) Multibiomarker analysis in patients with acute myocardial infarction. Eur J Clin Investig 47:638–648. CrossRefGoogle Scholar
  17. 17.
    Kempf T, Zarbock A, Widera C et al (2011) GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat Med 17:581–588. CrossRefPubMedGoogle Scholar
  18. 18.
    Tzikas S, Palapies L, Bakogiannis C et al (2017) GDF-15 predicts cardiovascular events in acute chest pain patients. PLoS One 12:e0182314. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Masaki T, Yanagisawa M, Goto K (1992) Physiology and pharmacology of endothelins. Med Res Rev 12:391–421CrossRefPubMedGoogle Scholar
  20. 20.
    Yanagisawa M, Kurihara H, Kimura S et al (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415. CrossRefPubMedGoogle Scholar
  21. 21.
    Loennechen JP, Stoylen A, Beisvag V et al (2001) Regional expression of endothelin-1, ANP, IGF-1, and LV wall stress in the infarcted rat heart. Am J Phys 280:H2902–H2910Google Scholar
  22. 22.
    Oie E, Vinge LE, Tønnessen T et al (1997) Transient, isopeptide-specific induction of myocardial endothelin-1 mRNA in congestive heart failure in rats. Am J Phys 273:H1727–H1736Google Scholar
  23. 23.
    Tønnessen T, Lunde PK, Giaid A et al (1998) Pulmonary and cardiac expression of preproendothelin-1 mRNA are increased in heart failure after myocardial infarction in rats. Localization of preproendothelin-1 mRNA and endothelin peptide. Cardiovasc Res 39:633–643CrossRefPubMedGoogle Scholar
  24. 24.
    Fishbein MC, Maclean D, Maroko PR (1978) Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am J Pathol 90:57PubMedPubMedCentralGoogle Scholar
  25. 25.
    Ono K, Matsumori A, Shioi T et al (1998) Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation 98:149–156CrossRefPubMedGoogle Scholar
  26. 26.
    Yue P, Massie BM, Simpson PC, Long CS (1998) Cytokine expression increases in nonmyocytes from rats with postinfarction heart failure. Am J Physiol Heart Circ Physiol 275:H250–H258CrossRefGoogle Scholar
  27. 27.
    Sakai S, Miyauchi T, Kobayashi M et al (1996) Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 384:353–355. CrossRefPubMedGoogle Scholar
  28. 28.
    Sütsch G, Kiowski W, Yan XW et al (1998) Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 98:2262–2268CrossRefPubMedGoogle Scholar
  29. 29.
    Hirata Y, Takagi Y, Fukuda Y, Marumo F (1989) Endothelin is a potent mitogen for rat vascular smooth muscle cells. Atherosclerosis 78:225–228CrossRefPubMedGoogle Scholar
  30. 30.
    Takuwa N, Takuwa Y, Yanagisawa M et al (1989) A novel vasoactive peptide endothelin stimulates mitogenesis through inositol lipid turnover in Swiss 3T3 fibroblasts. J Biol Chem 264:7856–7861PubMedGoogle Scholar
  31. 31.
    Ito H, Hirata Y, Hiroe M et al (1991) Endothelin-1 induces hypertrophy with enhanced expression of muscle-specific genes in cultured neonatal rat cardiomyocytes. Circ Res 69:209–215CrossRefPubMedGoogle Scholar
  32. 32.
    Molenaar P, O’reilly G, Sharkey A et al (1993) Characterization and localization of endothelin receptor subtypes in the human atrioventricular conducting system and myocardium. Circ Res 72:526–538CrossRefPubMedGoogle Scholar
  33. 33.
    Suzuki T, Kumazaki T, Mitsui Y (1993) Endothelin-1 is produced and secreted by neonatal rat cardiac myocytes in vitro. Biochem Biophys Res Commun 191:823–830. CrossRefPubMedGoogle Scholar
  34. 34.
    Ito H, Hirata Y, Adachi S et al (1993) Endothelin-1 is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest 92:398–403. CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fan Y, Li S, Li X-L et al (2016) Plasma endothelin-1 level as a predictor for poor collaterals in patients with ≥95% coronary chronic occlusion. Thromb Res 142:21–25. CrossRefPubMedGoogle Scholar
  36. 36.
    Skovsted GF, Kruse LS, Berchtold LA et al (2017) Myocardial ischemia-reperfusion enhances transcriptional expression of endothelin-1 and vasoconstrictor ETB receptors via the protein kinase MEK-ERK1/2 signaling pathway in rat. PLoS One 12:e0174119. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Shirai N, Naruko T, Ohsawa M et al (2006) Expression of endothelin-converting enzyme, endothelin-1 and endothelin receptors at the site of percutaneous coronary intervention in humans. J Hypertens 24:711–721. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Institute for Legal MedicineUniversity Hospital DüsseldorfDüsseldorfGermany
  2. 2.Department of AnaesthesiologyUniversity Hospital DüsseldorfDüsseldorfGermany

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