© 2006 European Society of Cardiology
Response to Letters to the Editor: Short-term effects of levosimendan and prostaglandin E1 on haemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure
Department of Cardiology, University of Vienna Waehringer Guertel 18-20, A-1090 Vienna, Austria
* Tel.: +43 1 40400 4614; fax: +43 1 4081 148. E-mail address: deddo_moertl{at}yahoo.de
Received November 7, 2005; We appreciate the interest of Parissis et al. and McLachlan and Mossop in our work [1]. Both letters focus on the limited duration of levosimendan-induced decreases of BNP in our study and mention the role of interleukin-6 (IL-6) in this context.
The evidence for prolonged reductions in BNP and IL-6 after levosimendan is still sparse. One study has described a decrease in BNP lasting 5 days [2] and Parissis et al. report unpublished data showing a BNP and IL-6 reduction lasting for 2-3 weeks.
The pharmacokinetics of the levosimendan metabolite OR-1896, show that its most pronounced haemodynamic actions occur 2 to 3 days after completion of the levosimendan infusion and have almost disappeared after 7 days [3]. This is in agreement with the pattern of BNP-levels in our study and any putative direct levosimendan action that lasts significantly longer must be interpreted with caution. Sustained reductions in BNP or IL-6 might be due to factors beyond direct levosimendan action, which might also help to explain discrepant findings.
In patients with decompensated heart failure and volume overload ("wet" [4]), recompensation using conventional drugs such as vasodilators, diuretics, and inotropic agents to reduce filling pressures has also been shown to reduce BNP [5,6] and improve prognosis if a stable recompensated haemodynamic state is maintained [7]. Since BNP is correlated with filling pressures, we can assume that by maintained reduction of filling pressures, BNP levels can also be reduced, independent of a specific drug action.
In contrast, the majority of our patients with advanced decompensated chronic heart failure despite optimized therapy (100% angiotensin converting enzyme inhibitors, 80% β-blockers and optimized diuretic therapy) had no clinical signs of volume overload ("dry" [4]). This is also illustrated by the need for volume substitution and the high rate of hypotension during levosimendan infusion. In this patient population, clinical and haemodynamic improvement is limited to the duration of the intervention and without further options to improve background therapy, only chronic interventions (PGE1, surgery) may persistently stabilise the patient.
IL-6 and BNP independently predict adverse events in severe heart failure [8], which questions the clinical relevance of the experimental evidence for a direct link between IL-6 and BNP production. Furthermore, to our knowledge, there is no evidence for direct levosimendan-induced IL-6 suppression, thus the mechanism of BNP-reductions via levosimendan-induced IL-6 reductions remains to be evaluated. Moreover, independent of levosimendan, IL-6 can be reduced simply by recompensation of acutely decompensated heart failure, and changes in IL-6 could be correlated to respective changes in wedge pressures during acute treatment [9].
In conclusion, considering the lack of evidence of direct levosimendan-induced decreases in IL-6 and BNP and the pharmacokinetics of OR-1896, sustained decreases in BNP and IL-6 over 2-3 weeks are more likely to be an expression of successful maintenance of a favourable haemodynamic state after recompensation than a direct effect of levosimendan.
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- Moertl D., Berger R., Huelsmann M., Bojic A., Pacher R. Short-term effects of levosimendan and prostaglandin E1 on hemodynamic parameters and B-type natriuretic peptide levels in patients with decompensated chronic heart failure. Eur J Heart Fail (2005) 7:1156–1163.
[Abstract/Free Full Text] - Avgeropoulou C., Andreadou I., Markantonis-Kyroudis S., et al. The Ca2+-sensitizer levosimendan improves oxidative damage, BNP and pro-inflammatory cytokine levels in patients with advanced decompensated heart failure in comparison to dobutamine. Eur J Heart Fail (2005) 7:882–887.
[Abstract/Free Full Text] - Kivikko M., Antila S., Eha J., Lehtonen L., Pentikainen P.J. Pharmacokinetics of levosimendan and its metabolites during and after a 24-hour continuous infusion in patients with severe heart failure. Int J Clin Pharmacol Ther (2002) 40:465–471.[Web of Science][Medline]
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[Abstract/Free Full Text] - Johnson W., Omland T., Hall C., et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol (2002) 39:1623–1629.
[Abstract/Free Full Text] - Kawamura A., Yoshikawa T., Takahashi T., et al. Randomized trial of phosphodiesterase inhibitors versus catecholamines in patients with acutely decompensated heart failure. Jpn Circ J (2001) 65:858–862.[CrossRef][Medline]
- Steimle A.E., Stevenson L.W., Chelimsky-Fallick C., et al. Sustained hemodynamic efficacy of therapy tailored to reduce filling pressures in survivors with advanced heart failure. Circulation (1997) 96:1165–1172.
[Abstract/Free Full Text] - Gwechenberger M., Hulsmann M., Berger R., et al. Interleukin-6 and B-type natriuretic peptide are independent predictors for worsening of heart failure in patients with progressive congestive heart failure. J Heart Lung Transplant (2004) 23:839–844.[CrossRef][Web of Science][Medline]
- Suzuki H., Sato R., Sato T., et al. Time-course of changes in the levels of interleukin 6 in acutely decompensated heart failure. Int J Cardiol (2005) 100:415–420.[CrossRef][Web of Science][Medline]
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