Abstract
Background
Levosimendan improves cardiac contractility without increasing oxygen consumption. However, its effects on ischemia were not supported with the utilization of a noninvasive parameter of myocardial characterization.
Hypothesis
The changes observed in integrated backscatter (IBS) may be reflective of change in myocardial ischemia. In this study, the effect of levosimendan on ischemia detected by IBS was evaluated in patients with ischemic heart failure (HF).
Methods
Patients who had LVEF < 40% and NYHA III–IV symptoms of HF were included in this study. Patients were randomized to levosimendan (n = 21), or to dobutamine (n = 25) groups. The cyclic variation of integrated backscatter (CVIBS) was determined as the difference between the maximal and minimal values in a cardiac cycle, average of three consecutive beats. CVIBS was taken from the mid‐anteroseptal, mid‐inferior, and mid‐posterolateral areas of the parasternal short axis images before the drug administration and at the end of the 24‐hour infusion period.
Results
Baseline characteristics and concomitant medications were similar in both groups. A significant reduction in CVIBS was detected in anteroseptal (7.6 ± 1.4 dB versus 5.9 ± 0.8 dB, p = 0.01), inferior wall (7.4 ± 0.8 dB versus 6.7 ± 1.5 dB, p = 0.03), and posterolateral wall (9.0 ± 1.2 dB versus 8.2 ± 0.6 dB, p = 0.04) after dobutamine administration, while no significant changes were observed in the levosimendan group in all walls.
Conclusions
Unlike dobutamine, levosimendan may not induce myocardial ischemia as shown by CVIBS at commonly used dosages in the setting of decompensated HF without active ischemia. Copyright © 2009 Wiley Periodicals, Inc.
Full Text
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References
- 1. Bayram M, De Luca L, Massie BM, Gheorghiade M. Dobutamine, milrinone and dopamine in acute heart failure syndromes: a reassessment. Am J Cardiol. 2005; 96: 47G–58G. [DOI] [PubMed] [Google Scholar]
- 2. Caldicott LD, Hawley K, Heppel R, Woodmansey PA, Channer KS. Intravenous enoximone or dobutamine for severe heart failure after acute myocardial infarction: a randomized double‐blind trial. Eur Heart J. 1993; 14: 696–700. [DOI] [PubMed] [Google Scholar]
- 3. Karlsberg RP, DeWood MA, DeMaria AN, Berk MR, Lasher KP. Comparative efficacy of short‐term intravenous infusions of milrinone and dobutamine in acute congestive heart failure following acute myocardial infarction. Milrinone‐Dobutamine Study Group. Clin Cardiol. 1996; 19: 21–30. [DOI] [PubMed] [Google Scholar]
- 4. Gillespie TA, Ambos HD, Sobel BE, Roberts R. Effects of dobutamine in patients with acute myocardial infarction. Am J Cardiol. 1977; 39: 588–594. [DOI] [PubMed] [Google Scholar]
- 5. Thackray S, Easthaugh J, Freemantle N, Cleland JG. The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure–a meta‐regression analysis. Eur J Heart Fail. 2002; 4: 515–529. [DOI] [PubMed] [Google Scholar]
- 6. Hasenfuss G, Pieske B, Castell M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998; 98: 2141–2147. [DOI] [PubMed] [Google Scholar]
- 7. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation. 2000; 102: 2222–2227. [DOI] [PubMed] [Google Scholar]
- 8. Gheorghiade M, Teerlink JR, Mebazaa A. Pharmacology of new agents for acute heart failure syndromes. Am J Cardiol. 2005; 96: 68G–73G. [DOI] [PubMed] [Google Scholar]
- 9. Soei LK, Sassen LM, Fan DS, et al. Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium. Circulation. 1994; 90: 959–969. [DOI] [PubMed] [Google Scholar]
- 10. Pieske B. Levosimendan in regional myocardial ischemia. Cardiovasc Drugs Ther. 2002; 16: 379–381. [DOI] [PubMed] [Google Scholar]
- 11. Duygu H, Ozerkan F, Zoghi M, et al. Objective ischemic evidence in patients with myocardial bridging: ultrasonic tissue characterization with dobutamine stress integrated backscatter. J Am Soc Echocardiogr. 2007; 20(6): 717–723. [DOI] [PubMed] [Google Scholar]
- 12. Lin LC, Yen RF, Hwang JJ, et al. Ultrasonic tissue characterization evaluates myocardial viability and ischemia in patients with coronary artery disease. Ultrasound Med Biol. 2000; 26: 759–769. [DOI] [PubMed] [Google Scholar]
- 13. Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two‐dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two‐Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989; 2(5): 358–367. [DOI] [PubMed] [Google Scholar]
- 14. Yock PG, Dopp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation. 1984; 70: 657–662. [DOI] [PubMed] [Google Scholar]
- 15. Giannuzzi P, Imparato A, Temporelli PL, et al. Doppler‐derived mitral deceleration time of early filling as a strong predictor of pulmonary capillary wedge pressure in post‐infarction patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 1994; 23: 1630–1637. [DOI] [PubMed] [Google Scholar]
- 16. Barzilai B, Vered Z, Mohr GA, et al. Myocardial ultrasonic backscatter for characterization of ischemia and reperfusion: Relationship to wall motion. Ultrasound Med Biol. 1990; 16: 391–398. [DOI] [PubMed] [Google Scholar]
- 17. Takiuchi S, Ito H, Iwakura K, et al. Ultrasonic tissue characterization predicts myocardial viability in early stage of reperfused acute myocardial infarction. Circulation. 1998; 97: 356–362. [DOI] [PubMed] [Google Scholar]
- 18. Castaldo M, Funaro S, Veneroso G, Agati L. Detection of residual tissue viability within the infarct zone in patients with acute myocardial infarction: Ultrasonic integrated backscatter analysis versus dobutamine stress echocardiography. J Am Soc Echocardiogr. 2000; 13: 358–367. [DOI] [PubMed] [Google Scholar]
- 19. Picano E, Faletra F, Marini C, et al. Increased echodensity of transiently asynergic myocardium in humans: a novel echocardiographic sign of myocardial ischemia. J Am Coll Cardiol. 1993; 21: 199–207. [DOI] [PubMed] [Google Scholar]
- 20. Felker GM, O'Connor CM. Inotropic therapy for heart failure: an evidence‐base approach. Am Heart J. 2001; 142: 393–401. [DOI] [PubMed] [Google Scholar]
- 21. Opie LH, Nathan D, Lubbe WF. Biochemical aspects of arrhy‐ thmogenesis and ventricular fibrillation. Am J Cardiol. 1979; 43: 131–148. [DOI] [PubMed] [Google Scholar]
- 22. Luotalahti M, Lammintausta O, Ukkonen H. Levosimendan, a calcium sensitizer and potassium channel opener, is safe and improves left ventricular function in acute myocardial infarction. Circulation. 1998; 98(Suppl. I): 105–106. [Google Scholar]
- 23. Sonntag S, Sundberg S, Lehtonen LA, Kleber FX. 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: 2177–2182. [DOI] [PubMed] [Google Scholar]
- 24. Moiseyev VS, Poder P, Adrejevs N, et al. RUSSLAN Study Investigators. Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. Eur Heart J. 2002; 23: 1422–1432. [DOI] [PubMed] [Google Scholar]
- 25. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low‐output heart failure (the LIDO study): A randomised double‐blind trial. Lancet. 2002; 360: 196–202. [DOI] [PubMed] [Google Scholar]
- 26. Poder P, Eha J, Antila S, et al. Pharmacodynamic interactions of levosimendan and felodipine in patients with coronary heart disease. Cardiovasc Drugs Ther. 2003; 17: 451–458. [DOI] [PubMed] [Google Scholar]
- 27. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide‐sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 1997; 333: 249–259. [DOI] [PubMed] [Google Scholar]
- 28. De Luca L, Proietti P, Celotto A, et al. Levosimendan improves hemodynamics and coronary flow reserve after percutaneous coronary intervention in patients with acute myocardial infarction and left ventricular dysfunction. Am Heart J. 2005; 150: 563–568. [DOI] [PubMed] [Google Scholar]
- 29. Yokoshiki H, Katsube Y, Sunagawa M, Sperelakis N. The novel calcium sensitizer levosimendan activates the ATP‐sensitive K channel in rat ventricular cells. J Pharmacol Exp Ther. 1997; 283: 375–383. [PubMed] [Google Scholar]
- 30. Beanlands RS, Armstrong WF, Hicks RJ, et al. The effects of afterload reduction on myocardial carbon 11‐labeled acetate kinetics and noninvasively estimated mechanical efficiency in patients with dilated cardiomyopathy. J Nucl Cardiol. 1994; 1: 3–16. [DOI] [PubMed] [Google Scholar]
- 31. Bowman P, Haikala H, Paul RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther. 1998; 288: 316–325. [PubMed] [Google Scholar]
- 32. Duygu H, Ozerkan F, Nalbantgil S, et al. Effect of levosimendan on E/E' ratio in patients with ischemic heart failure. Int J Cardiol. 2008; 123(2): 201–203. [DOI] [PubMed] [Google Scholar]
