Authors
Shevchenko Yu.L., Stepanova A.S., Gorokhovatsky Yu.I., Vakhromeeva M.N.
St. George thoracic and cardiovascular surgery clinic Pirogov National Medical and Surgical Center, Moscow
Abstract
Purpose of the study: to study the effect of perioperative use of levosimendan on the restoration of viable myocardium in patients with coronary artery disease with a significantly reduced left ventricular ejection fraction during myocardial revascularization.
An open, prospective, randomized study was conducted, including 98 patients. The patients were divided into two groups. In group I (n = 55), levosimendan infusion was used perioperatively. Administration of the drug (loading dose of 12 mcg/kg/min for 10 minutes) began after induction of anesthesia and continued infusion at all stages of the operation and in the immediate postoperative period. The total time of drug administration was 24 hours. In group II (n = 43), standard drugs were used to correct the circulatory system. It was found that the inclusion of levosimendan in a comprehensive program of cardioprotection caused a more rapid recovery of hibernated myocardium. This assumption is based on the fact that in patients of group I, the use of levosimendan led to a decrease in the volume of hibernation after surgery, in comparison with the preoperative level, by 42%. At the same time, in group II of patients operated on without the use of the drug, the percentage reduction in the volume of viable myocardium was 13%. In addition, a clear dependence of the state of the pumping function of the heart on the hemodynamic effects of levosimendan was discovered. Thus, in patients of group I, an increase in cardiac index was detected from 2.23±0.49 to 2.96±0.52 l./min./m2 (p<0.05), an increase in minute blood volume from 4.51± 0.99 to 6.04±1.1 l./min. (p<0.05), decrease in pulmonary valve wedge pressure from 13.3±4.6 to 9.8±3.07 mmHg. (p<0.05). In addition, levosimendan had a clear anti-ischemic effect. This was expressed in a lower concentration of troponin I in patients of group I, in comparison with patients of group II, at the stage of the study after surgery (I group – 2.78 ± 2.31 ng./ml., II group – 3.45 ±4.9 ng./ml., p<0.05). It should be noted that, simultaneously with a decrease in the volume of hibernated myocardium, in patients of group I there was an increase in the ejection fraction of the left ventricle from 40% to 49% (p<0.05). The data presented indicate an improvement in the functional state of the myocardium against the background of the prevention of ischemic and reperfusion disorders with levosimendan. It was noted that the preoperative volume of hibernated myocardium and the usefulness of reperfusion could have an additional influence on the implementation of the protective effects of levosimendan. Thus, there is some reason to believe that myocardial conditioning with levosimendan improved contractility in the reperfusion zones of hibernated myocardium during coronary artery bypass surgery in patients with ischemic left ventricular dysfunction.
Keywords: ischemic heart disease, levosimendan, hibernated myocardium, reperfusion, cardioprotection, myocardial revascularization.
References
1. Kunst G, Klein AA. Peri-operative anaesthetic myocardial preconditioning and protection – cellular mechanisms and clinical relevance in cardiac anaesthesia. Anaesthesia. 2015; 70(4): 467-482. doi: 10.1111/anae.12975.
2. Lomivorotov VV, Efremov SM, Kirov MY. Low-Cardiac-Output syndrome after cardiac surgery. J Cardiothorac Vasc Anesth. 2017; 31(1): 291-308. doi: 10.1053/j.jvca.2016.05.029.
3. Bridgewater B. Adult Cardiac Surgeons of North West England. Mortality data in adult cardiac surgery for named surgeons: retrospective examination of prospectively collected data on coronary artery surgery and aortic valve replacement. BMJ. 2005; 330(7490): 506-510. doi: 10.1136/bmj. 330.7490.506.
4. Lomivorotov VV, Yeremenko AA, Boboshko VA, et al. Perioperative use of levosimendan in cardiac surgery. Patologija krovoobrashhenija i kardiohirurgija. 2015; 19(2): 113-123 (In Russ.) doi: 10.21688/1681-3472-2015-2-113-123.
5. Boboshko VA, Zibareva EI, Lomivorotov VV. Levosimendan: current and possible areas of clinical application: a review. vestnik intensivnoj terapii im. A.I. Saltanova. 2023; 3: 122-136. (In Russ.) doi: 10.21320/1818-474X-2023-3-122-136.
6. Kunst G. From coronary steal to myocardial, renal, and cerebral protection: more questions than answers in anaesthetic preconditioning? Br J Anaesth. 2014; 112(6): 958-960. doi: 10.1093/bja/aeu007.
7. Lomivorotov VV, Efremov SM, Pokushalov EA, et al. Randomized trial of fish oil infusion to prevent atrial fibrillation after cardiac surgery: data from an implantable continuous cardiac monitor. J Cardiothorac Vasc Anesth. 2014; 28(5): 1278-1284. doi: 10.1053/j.jvca.2014.02.019.
8. Mebazaa A, Pitsis AA, Rudiger A, et al. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care. 2010; 14(2): 201. doi: 10.1186/cc8153.
9. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002; 97(1): 215-252. doi: 10.1097/00000542-200207000-00030.
10. Chen JC, Kaul P, Levy JH, et al. Myocardial infarction following coronary artery bypass graft surgery increases healthcare resource utilization. Crit Care Med. 2007; 35(5): 1296-1301. doi: 10.1097/01.CCM.0000262403. 08546.A2.
11. Neumann FJ, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization [published correction appears in Eur Heart J. 2019; 40(37): 3096. doi: 10.1093/eurheartj/ehz507]. Eur Heart J. 2019; 40(2): 87-165. doi: 10.1093/eurheartj/ehy394.
12. Bax JJ, Poldermans D, Elhendy A, et al. Sensitivity, specificity, and predictive accuracies of various noninvasive techniques for detecting hibernating myocardium. Curr Probl Cardiol. 2001; 26(2): 147-186. doi: 10.1067/ mcd.2001.109973.
13. Romero J, Xue X, Gonzalez W, Garcia MJ. CMR imaging assessing viability in patients with chronic ventricular dysfunction due to coronary artery disease: a meta-analysis of prospective trials. JACC Cardiovasc Imaging. 2012; 5(5): 494-508. doi: 10.1016/j.jcmg.2012.02.009.
14. Panza JA, Ellis AM, Al-Khalidi HR, et al. Myocardial viability and long-term outcomes in ischemic cardiomyopathy. N Engl J Med. 2019; 381(8): 739-748. doi: 10.1056/NEJMoa1807365.
15. Bax JJ, Poldermans D, Elhendy A, et al. Improvement of left ventricular ejection fraction, heart failure symptoms and prognosis after revascularization in patients with chronic coronary artery disease and viable myocardium detected by dobutamine stress echocardiography. J Am Coll Cardiol. 1999; 34(1): 163-169. doi: 10.1016/s0735-1097(99)00157-6.
16. Wolff G, Dimitroulis D, Andreotti F, et al. Survival benefits of invasive versus conservative strategies in heart failure in patients with reduced ejection fraction and coronary artery disease: a meta-analysis. Circ Heart Fail. 2017; 10(1): e003255. doi: 10.1161/CIRCHEARTFAILURE.116.003255.
17. Allman KC, Shaw LJ, Hachamovitch R, et al. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002; 39(7): 1151-1158. doi: 10.1016/s0735-1097(02)01726-6.
18. Bourque JM, Hasselblad V, Velazquez EJ, et al. Revascularization in patients with coronary artery disease, left ventricular dysfunction, and viability: a meta-analysis. Am Heart J. 2003; 146(4): 621-627. doi: 10.1016/S0002-8703(03)00428-9.
19. Beanlands RS, Nichol G, Huszti E, et al. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol. 2007; 50(20): 2002-2012. doi: 10.1016/j.jacc.2007.09.006.
20. Cleland JG, Calvert M, Freemantle N, et al. The Heart Failure Revascularisation Trial (HEART). Eur J Heart Fail. 2011; 13(2): 227-233. doi: 10.1093/eurjhf/hfq230.
21. Bonow RO, Maurer G, Lee KL, et al. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. 2011; 364(17): 1617-1625. doi: 10.1056/NEJMoa1100358.
22. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure [published correction appears in Eur Heart J. 2021; 42(48): 4901. doi: 10.1093/eurheartj/ehab670]. Eur Heart J. 2021; 42(36): 3599-3726. doi: 10.1093/eurheartj/ehab368.
23. Shah BN, Khattar RS, Senior R. The hibernating myocardium: current concepts, diagnostic dilemmas, and clinical challenges in the post-STICH era. Eur Heart J. 2013; 34(18): 1323-1336. doi: 10.1093/eurheartj/eht018.
24. Garcia MJ, Kwong RY, Scherrer-Crosbie M, et al. State of the Art: Imaging for myocardial viability: a scientific statement from the American Heart Association. Circ Cardiovasc Imaging. 2020; 13(7): e000053. doi: 10.1161/HCI.0000000000000053.
25. Almeida AG, Carpenter JP, Cameli M, et al. Reviewers: This document was reviewed by members of the 2018–2020 EACVI Scientific Documents Committee: chair of the 2018–2020 EACVI Scientific Documents Committee; 2018–2020 EACVI President:. Multimodality imaging of myocardial viability: an expert consensus document from the European Association of Cardiovascular Imaging (EACVI). Eur Heart J Cardiovasc Imaging. 2021; 22(8): e97-e125. doi: 10.1093/ehjci/jeab053.
26. Shurupova IV, Klyuchnikov IV, Aslanidis IP, et al. Identification of hibernating myocardium in the subacute phase of myocardial infarction. Bulletin of the National Academy of Sciences named after A.N.Bakulev of the Russian Academy of Sciences. 2014; 15(1): 23-32. (In Russ.)
27. Vakhromeeva MN, Vakhrameeva A.Yu. Radionuclide methods in assessment of effectiveness of alternative technologies of myocardial revasculization (In Russ.)
28. Landoni G, Lomivorotov VV, Alvaro G, et al. CHEETAH Study Group. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017; 376(21): 2021-2031. doi: 10.1056/NEJMoa1616325.
29. Rao V, Ivanov J, Weisel RD, et al. Predictors of low cardiac output syndrome after coronary artery bypass. J Thorac Cardiovasc Surg. 1996; 112(1): 38-51. doi: 10.1016/s0022-5223(96)70176-9.
30. Açil T, Türköz R, Açil M, et al. Value of prolonged QRS duration as a predictor of low cardiac output syndrome in patients with impaired left ventricular systolic function who undergo isolated coronary artery bypass grafting. Am J Cardiol. 2006; 98(10): 1357-1362. doi: 10.1016/j.amjcard.2006.06.031.
31. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury. N Engl J Med. 2007; 357(11): 1121-1135. doi: 10.1056/NEJMra071667.
32. Bolli R, Marbán E. Molecular and cellular mechanisms of myocardial stunning. Physiol Rev. 1999; 79(2): 609-634. doi: 10.1152/physrev. 1999.79.2.609.
33. Yavorovsky AG, Meshcheryakov AV. Myocardial dysfunction during cardiac surgery. Guide to cardiac anesthesiology and intensive care. Bunyatyan AA, Trekova NA, Eremenko AA, editors. M.: Medical Information Agency, 2015. P.134-181 (In Russ.)
34. Likhvantsev VV, Moroz VV, Grebenchikov OA, Gorokhovatsky YuI, et al. Ischemic and pharmacological preconditioning (part 2). General reanimatology. 2011; 7(6): 59-65. (In Russ.) doi: 10.15360/1813-9779-2011-6-59.
35. De Hert SG, Preckel B, Hollmann MW, Schlack WS. Drugs mediating myocardial protection. Eur J Anaesthesiol. 2009; 26(12): 985-995. doi: 10.1097/EJA.0b013e32832fad8b.
36. Likhvantsev VV, Moroz VV, Grebenchikov OA, Gorokhovatsky YuI, et al. Ischemic and pharmacological preconditioning (part 2). General reanimatology. 2012; 8(1): 61-66. (In Russ.)
37. Gorokhovatsky YuI, Azizova OA, Gudymovich VG. Mehanizmy kardioprotektornogo dejstvija sevoflurana. Vestnik intensivnoj terapii. 2007; 4: 3-13. (In Russ.)
38. Papp Z, Agostoni P, Alvarez J, et al. Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use. J Cardiovasc Pharmacol. 2020; 76(1): 4-22. doi: 10.1097/FJC.0000000000000859.
39. Putzu A, Clivio S, Belletti A, Cassina T. Perioperative levosimendan in cardiac surgery: A systematic review with meta-analysis and trial sequential analysis. Int J Cardiol. 2018; 251: 22-31. doi: 10.1016/j.ijcard.2017.10.077.
40. Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012; 159(2): 82-87. doi: 10.1016/j. ijcard.2011.07.022.
41. Mebazaa A, Pitsis AA, Rudiger A, et al. Clinical review: practical recommendations on the management of perioperative heart failure in cardiac surgery. Crit Care. 2010; 14(2): 201. doi: 10.1186/cc8153.
42. Harrison RW, Hasselblad V, Mehta RH, et al. Effect of levosimendan on survival and adverse events after cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth. 2013; 27(6): 1224-1232. doi: 10.1053/j.jvca. 2013.03.027.
43. Babaev MA, Eremenko AA, Dymova OV, et al. Levosimendan in preoperation therapy for cardiosurgery in patients with chronic heart failure. Russian Journal of Cardiology. 2017; 3: 59-62. (In Russ.) doi: 10.15829/1560-4071-2017-3-59-62.
44. Cholley B, Caruba T, Grosjean S, et al. Effect of levosimendan on low cardiac output syndrome in patients with low ejection fraction undergoing coronary artery bypass grafting with cardiopulmonary bypass: The LICORN randomized clinical trial. JAMA. 2017; 318(6): 548-556. doi: 10.1001/jama.2017.9973.
45. Landoni G, Lomivorotov VV, Alvaro G, et al. Levosimendan for hemodynamic support after cardiac surgery. N Engl J Med. 2017; 376(21): 2021-2031. doi: 10.1056/NEJMoa1616325.
46. Mehta RH, Leimberger JD, van Diepen S, et al. LEVO-CTS Investigators. Levosimendan in patients with left ventricular dysfunction undergoing cardiac surgery. N Engl J Med. 2017; 376(21): 2032-2042. doi: 10.1056/NEJMoa1616218.
47. Guarracino F, Heringlake M, Cholley B, et al. Use of Levosimendan in cardiac surgery: an update after the LEVO-CTS, CHEETAH, and LICORN trials in the light of clinical practice. J Cardiovasc Pharmacol. 2018; 71(1): 1-9. doi: 10.1097/FJC.0000000000000551.
48. Habicher M, Zajonz T, Heringlake M, et al. S3-Leitlinie zur intensivmedizinischen Versorgung herzchirurgischer Patienten : Hämodynamisches Monitoring und Herz-Kreislauf – ein Update. Anaesthesist. 2018; 67(5): 375-379. doi: 10.1007/s00101-018-0433-6.
49. Perutskii DN, Makeeva TI, Konstantinov SL. Osnovnye kontseptsii postinfarktnogo remodelirovaniya miokarda levogo zheludochka. Nauchnye vedomosti BelGU. Ser. Medicina. Farmacija. 2011; 10(105).14: 51-59. (In Russ.)
50. Farmakis D, Alvarez J, Gal TB, et al. Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper. Int J Cardiol. 2016; 222: 303-312. doi: 10.1016/j.ijcard.2016.07.202.
51. Kenzhaev ML, Alyavi AL, Kenzhaev SR, et al. Obratimaya disfunktsiya miokarda u bolnyh s ostrymi formami ishemicheskoy bolezni serdtsa. Vestnik ekstrennoj mediciny. 2018; 11(2):100-104. (In Russ.)
52. Kloner RA. Stunned and Hibernating Myocardium: Where Are We Nearly 4 Decades Later? J Am Heart Assoc. 2020; 9(3): e015502. doi: 10.1161/ JAHA.119.015502.
53. Zangrillo A, Biondi-Zoccai G, Mizzi A, et al. Levosimendan reduces cardiac troponin release after cardiac surgery: a meta-analysis of randomized controlled studies. J Cardiothorac Vasc Anesth. 2009; 23(4): 474-478. doi: 10.1053/j.jvca.2008.11.013.
54. Jiménez-Rivera JJ, Álvarez-Castillo A, Ferrer-Rodríguez J et al. Preconditioning with levosimendan reduces postoperative low cardiac output in moderate-severe systolic dysfunction patients who will undergo elective coronary artery bypass graft surgery: a cost-effective strategy. J Cardiothorac Surg. 2020; 15(1): 108. doi: 10.1186/s13019-020-01140-z.
55. Nieminen MS, Buerke M, Cohen-Solál A, et al. The role of levosimendan in acute heart failure complicating acute coronary syndrome: A review and expert consensus opinion. Int J Cardiol. 2016; 218: 150-157. doi: 10.1016/j.ijcard.2016.05.009.
56. Rafaeli IR, Pankov AN, Savelov EA, et al. Free right internal mammary artery graft in bilateral internal mammary artery grafting. Russian Journal of Cardiology and Cardiovascular Surgery. 2018; 11(4): 26‑30. (In Russ.) doi: 10.17116/kardio201811426.
57. Gaudino M, Bakaeen FG, Sandner S, et al. Expert Systematic Review on the Choice of Conduits for Coronary Artery Bypass Grafting: Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS) and The Society of Thoracic Surgeons (STS). Ann Thorac Surg. 2023; 116(4): 659-674. doi: 10.1016/j.athoracsur.2023.06.010.
58. Gaudino M, Dangas GD, Angiolillo DJ, et al. American Heart Association Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; and Stroke Council. Considerations on the management of acute postoperative ischemia after cardiac surgery: a scientific statement from the American Heart Association. Circulation. 2023; 148(5): 442-454. doi: 10.1161/CIR.0000000000001154.
59. Bautin AE, Karpova LI, Marichev AO, et al. Cardioprotective effects of ischemic conditioning. up-to-date information in physiology, experimental evidences and clinical applications. Translational Medicine. 2016; 3(1): 50-62. (In Russ.) doi: 10.18705/2311-4495-2016-3-1-50-62.
60. Caricati-Neto A, Errante PR, Menezes-Rodrigues FS. Recent Advances in Pharmacological and Non-Pharmacological Strategies of Cardioprotection. Int J Mol Sci. 2019; 20(16): 4002. doi: 10.3390/ijms20164002.
61. Shlyakhto EV, Nifontov EM, Galagudza MM. Limitation of ischemic and reperfusion injury of the myocardium using pre- and postconditioning: molecular mechanisms and targets for pharmacotherapy. Kreativnaya kardiologiya. 2007; 2(1): 75-101. (In Russ.)
62. Roth S, Torregroza C, Feige K, et al. Pharmacological conditioning of the heart: an update on experimental developments and clinical implications. Int J Mol Sci. 2021; 22(5): 2519. doi: 10.3390/ijms22052519.
63. Torregroza C, Raupach A, Feige K, et al. Perioperative cardioprotection: general mechanisms and pharmacological approaches. Anesth Analg. 2020; 131(6): 1765-1780. doi: 10.1213/ANE.0000000000005243.
