Anti-ischemic and Cardioprotective Effects of Levosimendan

A.A. Eremenko1, M.M. Rybka2

1Russian Research Surgery Center Russian Federation Ministry of Healthcare

2Bakulev Scientific Center for Cardiovascular Surgery Russian Federation Ministry of Healthcare

For correspondence: Rybka Mikhail Mikhailovich — MD, PhD, chief of Anesthesia department, Bakulev Scientific Center for CVSV; e-mail: rybkamikh@mail.ru

For citation: Eremenko AA, Rybka MM. Anti-ischemic and Cardioprotective Effects of Levosimendan. Intensive Care Herald. 2016;4:27–33.


Levosimendan is a Calcium sensitizer, which has been developed for intravenous use in hospitalized patients with decompensated heart failure. The efficacy and tolerability of the drug has been proven in large-scale studies. The review presents the experimental and clinical data about the drug, the basic mechanisms of action and effects of levosimendan, separately set out recommendations for the use of levosimendan in patients undergoing cardiac surgery.

Keywords: levosimendane, organ protection, heart failure

Received: 23.11.2016


References

  1. Haikala H., Linden I.B. Mechanisms of action of calcium-sensitizing drugs. J. Cardiovasc. Pharmacol. 1995; 26(Suppl 1): S10-S19. doi: 10.1097/00005344-199500001-00003.
  2. Kaheinen P., Pollesello P., Levijoki J.H., Haikala H. Levosimendan increases diastolic coronary flow in isolated guinea-pig heart by opening ATP-sensitive potassium channels. J. Cardiovasc. Pharmacol. 2001; 37(4): 367–374. doi: 1097/00005344-200104000-00003.
  3. Pollesello P., Papp Z. The cardioprotective effects of levosimendan: preclinical and clinical evidence. Cardiovasc. Pharmacol. 2007; 50(3): 257–263. doi: 10.1097/FJC.0B013E3180986230.
  4. Kopustinskiene D.M., Pollesello P., Saris N.E. Potassium-specific effects of levosimendan on heart mitochondria. Biochem. Pharmacol. 2004; 68(5): 807–812. doi: 1016/J.BCP.2004.05.018.
  5. Kersten J.R., Montgomery M.W., Pagel P.S., Warltier D.C. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth. Analg. 2000; 90(1): 5–11. doi: 1097/00000539-200001000-00003.
  6. Parissis J.T., Adamopoulos S., Antoniades C. et al. Effects of levosimendan on circulating pro-inflammatory cytokines and soluble apoptosis mediators in patients with decompensated advanced heart failure. J. Cardiol. 2004; 93(10): 1309–1312. doi: 10.1016/J.AMJCARD.2004.01.073.
  7. Ozturk T., Gok S., Nese N. Levosimendan attenuates reperfusion injury in an isolated perfused rat heart model. J. Cardiothorac. Vasc. Anesth. 2010; 24(4): 624–628. doi: 1053/J.JVCA.2009.08.003.
  8. Follath F., Cleland J.G., Just H. et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomiseddouble-blind trial. Lancet. 2002; 360(9328): 196–202. doi: 1016/S0140-6736(02)09455-2.
  9. Slawsky M.T., Colucci W.S., Gottlieb S.S. et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation. 2000; 102(18): 2222–2227. doi: 1161/01.CIR.102.18.2222.
  10. Ukkonen H., Saraste M., Akkila J. et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin. Pharmacol. Ther. 2000; 68(5): 522–531. doi: 1067/MCP.2000.110972.
  11. Mebazaa A., Nieminen M.S., Packer M. et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial. JAMA. 2007; 297(17): 1883–1891. doi: 1001/JAMA.297.17.1883.
  12. Lilleberg J., Laine M., Palkama T. et al. Duration of the haemodynamic action of a 24-h infusion of levosimendan in patients with congestive heart failure. J. Heart Fail. 2007; 9(1): 75–82. doi: 10.1016/J.EJHEART.2006.04.012.
  13. Sonntag S., Sundberg S., Lehtonen L.A., Kleber F.X. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J. Am. Coll. Cardiol. 2004; 43(12): 2177–2182. doi: 1016/J.JACC.2004.02.052.
  14. Givertz M.M., Andreou C., Conrad C.H., Colucci W.S. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation. 2007; 115(10): 1218–1224. doi: 1161/CIRCULATIONAHA.106.668640.
  15. Moiseyev V.S., Poder P., Andrejevs N. et al. Safety and efficacy of a novel calciumsensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN). Eur. Heart J. 2002; 23(18): 1422–1432. doi: 10.1053/EUHJ.2001.3158.
  16. McCully J.D., Levitsky S. Mitochondrial ATP-sensitive potassium channels in surgical cardioprotection. Arch. Biochem. Biophys. 2003; 420(2): 237–245. doi: 1016/J.ABB.2003.06.003.
  17. Du Toit E.F., Genis A., Opie L.H. et al. A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated guinea-pig heart. Br. J. Pharmacol. 2008; 154(1): 41–50. doi: 1038/BJP.2008.52.
  18. Papp J.G., Pollesello P., Varoo A.F., Vegh A.S. Effect of levosimendan and milrinone on regional myocardial ischemia/reperfusion — induced arrhythmias in dogs. Cardiovasc. Pharmacol. Ther. 2006; 11(2): 129–135. doi: 10.1177/1074248406289286.
  19. Metzsch C., Liao Q., Steen S., Algotsson Levosimendan cardioprotection reduces the metabolic response during temporary regional coronary occlusion in an open chest pig model. Acta Anaesthesiol. Scand. 2007; 51(1): 86–93. doi: 10.1111/J.1399-6576.2006.01162.X.
  20. Das D.K., Maulik N. Mitochondrial function in cardiomyocytes: target for cardioprotection. Curr. Opin. Anaesthesiol. 2005; 18(1): 77–82. doi: 1097/00001503-200502000-00012.
  21. Zingman L.V., Alekseev A.E., Hodgson-Zingman D.M., Terzic A. ATP-sensitive potassium channels: metabolic sensing and cardioprotection. J. Appl. Physiol. (1985). 2007; 103(5): 1888–1893. doi: 1152/JAPPLPHYSIOL.00747.2007.
  22. Alkan M., Celik A., Bilge M. et al. The effect of levosimendan on post myocardial ischaemia reperfusion lung damage in rats in which experimental diabetes was induced. J. Surg. Res. 2015; 193(2): 920–925. doi: 1016/J.JSS.2014.08.038.
  23. Zager R.A., Johnson A.C., Lund S. et al. Levosimendan protects against experimental endotoxemic acute renal failure. Am. J. Physiol. Renal. Physiol. 2006; 290(6): 1453–1462. doi: 1152/AJPRENAL.00485.2005.
  24. Torraco A., Carrozzo R., Piemonte F. et al. Effects of levosimendan on mitochondrial function in patients with septic shock: a randomized trial. Biochimie. 2014; 102: 166–173. doi: 1016/J.BIOCHI.2014.03.006.
  25. Roehl A.B., Zoremba N., Kipp N. et al. The effects of levosimendan on brain metabolism during initial recovery from global transient ischaemia/hypoxia. BMC Neurol. 2012; 12: 81. doi: 10.1186/1471-2377-12-81.
  26. Goetzenich A., Hatam N., Preuss S. et al. The role of hypoxia-inducible factor-1α and vascular endothelial growth factor in late-phase preconditioning with xenon, isoflurane and levosimendan in rat cardiomyocytes. Interact. Cardiovasc. Thorac. Surg. 2013; 18(3): 321–328. doi: 1093/ICVTS/IVT450.
  27. Downey J.M., Cohen M.V. Why do we still not have cardioprotective drugs? Circ. J. 2009; 73(7): 1171–1177. doi: 10.1253/CIRCJ.CJ-09-0338.
  28. Orriach Guerrero J.L., Ramirez Fernandez A., Iglesias P. et al. Preoperative levosimendan. A new way for organoprotection. Curr. Pharm. Des. 2014; 20(34): 5476–5483. doi: 2174/1381612820666140325121452.
  29. Levijoki J., Pollesello P., Kaheinen P., Haikala H. Improved survival with simendan after experimental myocardial infarction in rats. J. Pharmacol. 2001; 419(2–3): 243–248. doi: 10.1016/S0014-2999(01)00997-9.
  30. Hein M., Roehl A.B., Baumert J.H. et al. Anti-ischemic effects of inotropic agents in experimental right ventricular infarction. Acta Anaesthesiol. Scand. 2009; 53(7): 941–948. doi: 1111/J.1399-6576.2009.01994.X.
  31. Krychtiuk K.A., Watzke L., Kaun C. et al. Levosimendan exerts anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. Thromb. Haemost. 2014; 113(2): 350–362. doi: 1160/TH14-06-0549.
  32. Pataricza J., Ambrus N., Pollesello P. et al. Inhibition of thrombin-induced platelet aggregation by levosimendan is modified by small changes in albumin concentration in vitro. Exp. Clin. Cardiol. 2013; 18(1): 1–4.
  33. Camici P.G., Prasad S.K., Rimoldi O.E. Stunning, hibernation, and assessment of myocardial viability. Circulation. 2008; 117(1): 103–114. doi: 1161/CIRCULATIONAHA.107.702993.
  34. Wu X., Wu J., Yan X., Zhang Y. Enhancement of myocardial function and reduction of injury with levosimendan after percutaneous coronary intervention for acute myocardial infarction: a pilot study. Cardiology. 2014; 128(2): 202–208. doi: 1159/000360933.
  35. Husebye T., Eritsland J., Muller C. et al. Levosimendan in acute heart failure following primary percutaneous coronary intervention-treated acute ST-elevation myocardial infarction. Results from the LEAF trial: a randomized, placebo-controlled study. J. Heart Fail. 2013; 15(5): 565–572. doi: 10.1093/EURJHF/HFS215.
  36. Eriksson H.I., Jalonen J.R., Heikkinen L.O. et al. Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann. Thorac. Surg. 2009; 87(2): 448–454. doi: 1016/J.ATHORACSUR.2008.10.029.
  37. Tritapepe L., De Santis V., Vitale D. et al. Levosimendan pre-treatment improves outcomes in patients undergoing coronary artery bypass graft surgery. J. Anaesth. 2009; 102(2): 198–204. doi: 10.1093/BJA/AEN367.
  38. Lahtinen P., Pitkanen O., Polonen P. et al. Levosimendan reduces heart failure after cardiac surgery: a prospective, randomized, placebo-controlled trial. Crit. Care Med. 2011; 39(10): 2263–2270. doi: 1097/CCM.0B013E3182227B97.
  39. Lomivorotov V.V., Boboshko V.A., Efremov S.M. et al. Levosimendan versus an intra-aortic balloon pump in high-risk cardiac patients. J. Cardiothorac. Vasc. Anesth. 2012; 26(4): 596–603. doi: 1053/J.JVCA.2011.09.006.
  40. Abacilar A.F., Dogan O.F. Levosimendan use decreases atrial fibrillation in patients after coronary artery bypass grafting: a pilot study. Heart Surg. Forum. 2013; 16(5): E287– doi: 10.1532/HSF98.2013190.
  41. Maharaj R., Metaxa V. Levosimendan and mortality after coronary revascularisation: a meta-analysis of randomised controlled trials. Crit. Care. 2011; 15(3): R140. doi: 1186/CC10263.
  42. Harrison R.W., Hasselblad V., Mehta R.H. et al. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. Cardiothorac. Vasc. Anesth. 2013; 27(6): 1224–1232. doi: 10.1053/J.JVCA.2013.03.027.
  43. Toller W., Algotsson L., Guarracino F. et al. Perioperative use of levosimendan: best practice in operative settings. J. Cardiothorac. Vasc. Anesth. 2013; 27(2): 361–366. doi: 1053/J.JVCA.2012.04.007.
  44. Guarracino F., Cariello C., Danella A. et al. Effect of levosimendan on ventriculo-arterial coupling in patients with ischemic cardiomyopathy. Acta Anaesthesiol. Scand. 2007; 51: 1217–1224. doi: 1111/J.1399–6576.2007.01428.X.
  45. De Luca L., Sardella G., Proietti P. et al. Effects of levosimendan on left ventricular diastolic function after primary angioplasty for acute anterior myocardial infarction: a Doppler echocardiographic study. J. Am. Soc. Echocardiogr. 2006; 19: 172–177. doi: 1016/J.ECHO.2005.08.016.
  46. Qiao L, Xu C, Li X, et al. Heart calcium sensitizer on morbidity and mortality of high-risk surgical patients with MODS: systematic review and meta-analysis. Int. J. Clin. Exp. Med. 2015; 8: 17712–17720. PMCID: PMC4694261.
  47. Avalos R, MartinezSanz R, Jimenez JJ, et al. Levosimendan preconditioning in patients undergoing elective cardiac surgery with poor ejection fraction. preliminary results. Cardiothorac. Surg. 2015; 10(Suppl 1): A310. doi: 10.1186/1749-8090-10-S1-A310.