Attenuation of ST-segment elevation after ischemic conditioning maneuvers reflects cardioprotection online

  • Georgios Amanakis
  • Petra Kleinbongard
  • Gerd HeuschEmail author
  • Andreas Skyschally
Original Contribution


Ischemic conditioning maneuvers, when induced either locally in the heart or remotely from the heart, reduce infarct size. However, infarct size reduction can be assessed no earlier than hours after established reperfusion. ST-segment elevation and its attenuation might reflect cardioprotection by ischemic conditioning online. Pigs were subjected to regional myocardial ischemia/reperfusion (1 h/3 h). Ischemic conditioning was induced prior to ischemia either locally (preconditioning; IPC; n = 15) or remotely (remote preconditioning; RIPC; n = 21), remotely during ischemia (remote perconditioning; RPER; n = 18), or locally at reperfusion (postconditioning; POCO; n = 9). Pigs without conditioning served as controls (PLA; n = 29). Area at risk and infarct size were measured postmortem, and ST-segment elevation was analyzed in a V2-like electrocardiogram lead. Ischemic conditioning reduced infarct size (PLA 42 ± 11% of area at risk; IPC 18 ± 10%; RIPC 22 ± 12%; RPER 23 ± 12%, POCO 22 ± 11%). With PLA, ST-segment elevation was increased at 5 min ischemia, sustained until 55 min ischemia and further increased at 10 min reperfusion. IPC and RIPC did not impact on ST-segment elevation at 5 min ischemia, but attenuated ST-segment elevation at 55 min ischemia. With RPER, ST-segment elevation was not different from that with PLA at 5 min, but attenuated at 55 min ischemia. POCO abolished the further increase of ST-segment elevation with reperfusion. Cardioprotection by ischemic conditioning is robustly reflected by attenuation of ST-segment elevation online.


Cardioprotection Infarct size Ischemia–reperfusion injury Ischemic conditioning ST-segment elevation 



The data of the present manuscript are the subject of G. Amanakis’s MD thesis. We thank M. Neuhäuser, Department of Mathematics and Technology, Koblenz University of Applied Science, Remagen, Germany, for his advice and revision of statistical analyses.

Author contributions

GA: acquisition, analysis, and interpretation of data, drafting of manuscript. PK: analysis and interpretation of data, drafting of manuscript. GH: study design, interpretation of data, final revision of manuscript. AS: study design, acquisition, and interpretation of data, drafting of manuscript.

Sources of funding

The present study was supported by the German Research Foundation (SFB 1116 B08).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.


  1. 1.
    Bøtker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Bøtker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. CrossRefPubMedGoogle Scholar
  3. 3.
    Buyukates M, Kalaycioglu S, Oz E, Soncul H (2005) Effects of ischemic preconditioning in human heart. J Card Surg 20:241–245. CrossRefPubMedGoogle Scholar
  4. 4.
    Cohen MV, Yang XM, Downey JM (1997) Attenuation of S-T segment elevation during repetitive coronary occlusions truly reflects the protection of ischemic preconditioning and is not an epiphenomenon. Basic Res Cardiol 92:426–434. CrossRefPubMedGoogle Scholar
  5. 5.
    Cooper HA, de Lemos JA, Morrow DA, Sabatine MS, Murphy SA, McCabe CH, Gibson CM, Antman EM, Braunwald E (2002) Minimal ST-segment deviation: a simple, noninvasive method for identifying patients with a patent infarction-related artery after fibrinolytic administration. Am Heart J 144:790–795. CrossRefPubMedGoogle Scholar
  6. 6.
    Deutsch E, Berger M, Kussmaul WG, Hirshfeld JW Jr, Herrmann HC, Laskey WK (1990) Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation 82:2044–2051. CrossRefPubMedGoogle Scholar
  7. 7.
    Edwards RJ, Redwood SR, Lambiase PD, Tomset E, Rakhit RD, Marber MS (2002) Antiarrhythmic and anti-ischaemic effects of angina in patients with and without coronary collaterals. Heart 88:604–610. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Floyd JS, Maynard C, Weston P, Johanson P, Jennings RB, Wagner GS (2009) Effects of ischemic preconditioning and arterial collateral flow on ST-segment elevation and QRS complex prolongation in a canine model of acute coronary occlusion. J Electrocardiol 42:19–26. CrossRefPubMedGoogle Scholar
  9. 9.
    Garcia-Ruiz JM, Fernandez-Jimenez R, Garcia-Alvarez A, Pizarro G, Galan-Arriola C, Fernandez-Friera L, Mateos A, Nuno-Ayala M, Aguero J, Sanchez-Gonzalez J, Garcia-Prieto J, Lopez-Melgar B, Martinez-Tenorio P, Lopez-Martin GJ, Macias A, Perez-Asenjo B, Cabrera JA, Fernandez-Ortiz A, Fuster V, Ibanez B (2016) Impact of the timing of metoprolol administration during STEMI on infarct size and ventricular function. J Am Coll Cardiol 67:2093–2104. CrossRefPubMedGoogle Scholar
  10. 10.
    Gent S, Skyschally A, Kleinbongard P, Heusch G (2017) Ischemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3. Am J Physiol Heart Circ Physiol 312:H478–H484. CrossRefPubMedGoogle Scholar
  11. 11.
    Haroun-Bizri S, Khoury SS, Chehab IR, Kassas CM, Baraka A (2001) Does isoflurane optimize myocardial protection during cardiopulmonary bypass? J Cardiothorac Vasc Anesth 15:418–421. CrossRefPubMedGoogle Scholar
  12. 12.
    Hausenloy DJ, Barrabes JA, Bøtker HE, Davidson SM, Di Lisa F, Downey J, Engstrom T, Ferdinandy P, Carbrera-Fuentes HA, Heusch G, Ibanez B, Iliodromitis EK, Inserte J, Jennings R, Kalia N, Kharbanda R, Lecour S, Marber M, Miura T, Ovize M, Perez-Pinzon MA, Piper HM, Przyklenk K, Schmidt MR, Redington A, Ruiz-Meana M, Vilahur G, Vinten-Johansen J, Yellon DM, Garcia-Dorado D (2016) Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery. Basic Res Cardiol 111:70. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Heusch G, Bøtker HE, Przyklenk K, Redington A, Yellon DM (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Heusch G, Gersh BJ (2017) The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: a continual challenge. Eur Heart J 38:774–784. CrossRefPubMedGoogle Scholar
  15. 15.
    Heusch G, Skyschally A, Schulz R (2011) The in-situ pig heart with regional ischemia/reperfusion—ready for translation. J Mol Cell Cardiol 50:951–963. CrossRefPubMedGoogle Scholar
  16. 16.
    Johnsen J, Pryds K, Salman R, Lofgren B, Kristiansen SB, Botker HE (2016) The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. Basic Res Cardiol 111:10. CrossRefPubMedGoogle Scholar
  17. 17.
    Klabunde RE (2017) Cardiac electrophysiology: normal and ischemic ionic currents and the ECG. Adv Physiol Educ 41:29–37. CrossRefPubMedGoogle Scholar
  18. 18.
    Kleinbongard P, Amanakis G, Skyschally A, Heusch G (2018) Reflection of cardioprotection by remote ischemic perconditioning in attenuated ST-segment elevation during ongoing coronary occlusion in pigs: evidence for cardioprotection from ischemic injury. Circ Res 122:1102–1108. CrossRefPubMedGoogle Scholar
  19. 19.
    Kowallik P, Schulz R, Guth BD, Schade A, Paffhausen W, Gross R, Heusch G (1991) Measurement of regional myocardial blood flow with multiple colored microspheres. Circulation 83:974–982. CrossRefPubMedGoogle Scholar
  20. 20.
    Munk K, Andersen NH, Schmidt MR, Nielsen SS, Terkelsen CJ, Sloth E, Bøtker HE, Nielsen TT, Poulsen SH (2010) Remote ischemic conditioning in patients with myocardial infarction treated with primary angioplasty: impact on left ventricular function assessed by comprehensive echocardiography and gated single-photon emission CT. Circ Cardiovasc Imaging 3:656–662. CrossRefPubMedGoogle Scholar
  21. 21.
    Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136. CrossRefPubMedGoogle Scholar
  22. 22.
    Prasad A, Stone GW, Aymong E, Zimetbaum PJ, McLaughlin M, Mehran R, Garcia E, Tcheng JE, Cox DA, Grines CL, Gersh BJ, CADILLAC trial (2004) Impact of ST-segment resolution after primary angioplasty on outcomes after myocardial infarction in elderly patients: an analysis from the CADILLAC trial. Am Heart J 147:669–675. CrossRefPubMedGoogle Scholar
  23. 23.
    Pryds K, Terkelsen CJ, Sloth AD, Munk K, Nielsen SS, Schmidt MR, Botker HE, Investigators C (2016) Remote ischaemic conditioning and healthcare system delay in patients with ST-segment elevation myocardial infarction. Heart 102:1023–1028. CrossRefPubMedGoogle Scholar
  24. 24.
    Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic “preconditioning” protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899. CrossRefPubMedGoogle Scholar
  25. 25.
    Rossello X, Hall AR, Bell RM, Yellon DM (2016) Characterization of the Langendorff perfused isolated mouse heart model of global ischemia-reperfusion Injury: impact of ischemia and reperfusion length on infarct size and LDH release. J Cardiovasc Pharmacol Ther 21:286–295. CrossRefPubMedGoogle Scholar
  26. 26.
    Rossello X, He Z, Yellon DM (2018) Myocardial infarct size reduction provided by local and remote ischaemic preconditioning: references values from the Hatter Cardiovascular Institute. Cardiovasc Drugs Ther 1:1. CrossRefGoogle Scholar
  27. 27.
    Rossello X, Ibanez B (2018) Infarct size reduction by targeting ischemic injury: back to square one. Circ Res 122:1041–1043. CrossRefPubMedGoogle Scholar
  28. 28.
    Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, White PA, Kristiansen SB, Sorensen K, Dzavik V, Redington AN, Kharbanda RK (2007) Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol Heart Circ Physiol 292:H1883–H1890. CrossRefPubMedGoogle Scholar
  29. 29.
    Shattock MJ, Lawson CS, Hearse DJ, Downey JM (1996) Electrophysiological characteristics of repetitive ischemic preconditioning in the pig heart. J Mol Cell Cardiol 28:1339–1347. CrossRefPubMedGoogle Scholar
  30. 30.
    Skyschally A, Amanakis G, Neuhauser M, Kleinbongard P, Heusch G (2017) Impact of electrical defibrillation on infarct size and no-reflow in pigs subjected to myocardial ischemia-reperfusion without and with ischemic conditioning. Am J Physiol Heart Circ Physiol 313:H871–H878. CrossRefPubMedGoogle Scholar
  31. 31.
    Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G (2015) Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res 117:279–288. CrossRefPubMedGoogle Scholar
  32. 32.
    Skyschally A, Kleinbongard P, Lieder HR, Gedik N, Stoian L, Amanakis G, Elbers E, Heusch G (2018) Humoral transfer and intra-myocardial signal transduction of protection by remote ischemic perconditioning in pigs, rats, and mice. Am J Physiol Heart Circ Physiol 315:H159–H172. CrossRefPubMedGoogle Scholar
  33. 33.
    Skyschally A, Schulz R, Heusch G (1993) Cordat II: a new program for data acquisition and on-line calculation of hemodynamic and regional myocardial dimension parameters. Comput Biol Med 23:359–367. CrossRefPubMedGoogle Scholar
  34. 34.
    Skyschally A, Walter B, Schultz HR, Heusch G (2013) The antiarrhythmic dipeptide ZP1609 (danegaptide) when given at reperfusion reduces myocardial infarct size in pigs. Naunyn Schmiedebergs Arch Pharmacol 386:383–391. CrossRefPubMedGoogle Scholar
  35. 35.
    Staat P, Rioufol G, Piot C, Cottin Y, Cung TT, L’Huillier I, Aupetit J-F, Bonnefoy E, Finet G, Andre-Fouet X, Ovize M (2005) Postconditioning the human heart. Circulation 112:2143–2148. CrossRefPubMedGoogle Scholar
  36. 36.
    Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O (2016) Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J Am Coll Cardiol 67:1674–1683. CrossRefPubMedGoogle Scholar
  37. 37.
    Sun X, Cai J, Fan X, Han P, Xie Y, Chen J, Xiao Y, Kang YJ (2013) Decreases in electrocardiographic R-wave amplitude and QT interval predict myocardial ischemic infarction in Rhesus monkeys with left anterior descending artery ligation. PLoS One 8:e71876. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhäuser M, Peters J, Jakob H, Heusch G (2013) Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 382:597–604. CrossRefPubMedGoogle Scholar
  39. 39.
    Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R, Penta de Peppo A, Chiariello L, Gioffrè PA (1994) Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation 90:700–705. CrossRefPubMedGoogle Scholar
  40. 40.
    Valle-Caballero MJ, Fernandez-Jimenez R, Diaz-Munoz R, Mateos A, Rodriguez-Alvarez M, Iglesias-Vazquez JA, Saborido C, Navarro C, Dominguez ML, Gorjon L, Fontoira JC, Fuster V, Garcia-Rubira JC, Ibanez B (2016) QRS distortion in pre-reperfusion electrocardiogram is a bedside predictor of large myocardium at risk and infarct size (a METOCARD-CNIC trial substudy). Int J Cardiol 202:666–673. CrossRefPubMedGoogle Scholar
  41. 41.
    Wagner NB, Sevilla DC, Krucoff MW, Lee KL, Pieper KS, Kent KK, Bottner RK, Selvester RH, Wagner GS (1988) Transient alterations of the QRS complex and ST segment during percutaneous transluminal balloon angioplasty of the left anterior descending coronary artery. Am J Cardiol 62:1038–1042. CrossRefPubMedGoogle Scholar
  42. 42.
    Zhao Z-Q, Corvera JS, Halkos ME, Kerendi F, Wang N-P, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Georgios Amanakis
    • 1
  • Petra Kleinbongard
    • 1
  • Gerd Heusch
    • 1
    Email author
  • Andreas Skyschally
    • 1
  1. 1.Institut für Pathophysiologie, Westdeutsches Herz- und GefäßzentrumUniversitätsklinikum EssenEssenGermany

Personalised recommendations