© 2006 European Society of Cardiology
Levosimendan and plasma BNP levels: Do inflammatory cytokines regulate BNP in chronic decompensated heart failure?
Department of Medical Imaging, St. Vincent's Hospital Melbourne, Australia
* Corresponding author. E-mail address: reperfusion{at}hotmail.com
Received September 18, 2005; We read with interest the recent study by Moertl et al. [1]. In this study the investigators demonstrated that in chronic decompensated heart failure patients, therapeutic PGE1 as opposed to levosimendan produced a sustained reduction in plasma B-type natriuretic peptide (BNP) levels. This finding suggests that PGE1 would be superior to levosimendan in treating decompensated heart failure on the basis of a sustained reduction in circulating plasma BNP [1]. However, we would like to make the point that recently published studies have found the opposite, that is, following an acute 24 h infusion of levosimendan, a sustained decrease in plasma BNP for up to 5 days was observed [2].
Levosimendan (Simdax) is a calcium-sensitising drug that stabilises the troponin molecule in cardiac muscle, thus prolonging its effects on contractile proteins, with concomitant vasodilating properties. Intravenous levosimendan (12-24 µg/kg loading dose followed by 0.1-0.2 µg/kg/min for 24 h, adjusted for response and tolerability) is approved for the short-term treatment of acute severe decompensated heart failure. Treatment with levosimendan in advanced decompensated heart failure exerts beneficial haemodynamic, anti-inflammatory and antioxidant effects. These effects of levosimendan may explain the decrease in BNP levels as global cardiac function and metabolic demands of the myocardium improve along with a reduction is systemic inflammation.
The question therefore remains, why in the Moertl et al. study [1] was the reduction in plasma BNP not maintained following initial treatment with levosimendan? Firstly we know that levosimendan profoundly reduces circulating inflammatory cytokines such as IL-6 [2,3]. IL-6 is an inflammatory mediator that is increased in the plasma of decompensated heart failure patients. IL-6 is also an independent prognostic factor for mortality in these heart failure patients [4].
While it has been previously suggested that IL-6 and BNP are independent predictors of outcome in decompensated heart failure [4] there is emerging evidence to suggest that inflammatory cytokines and BNP may be more closely associated. For example, an increase in circulating BNP but not ANP is observed coincident with cardiac allograft rejection, which is reversed following treatment with anti-lymphocyte therapy, suggesting that pro-inflammatory cytokines may uniquely modulate BNP gene expression and secretion [5].
Secondly, we know that PGE1 also down-regulates inflammatory cytokines and promotes the balance in favour of protective cytokines. For example, PGE1 may suppress the production of IL-6 and IL-8 but not IL-10, which may be related to its myocardial protective effect in cardiac by-pass surgery patients [6]. The use of PGE1 in the study of Moertl et al. [1] may have suppressed plasma BNP because of an improvement in direct cardiac function or by a down regulation of IL-6 that in turn reduced the expression of BNP. However, because Moertl et al. [1] did not measure IL-6 in the plasma we can only speculate about this as a probable mechanism.
Moertl et al. [1] did not measure cytokines and they also used a very low dose of levosimendan which may not have been adequate to suppress cytokines despite promoting an improvement in cardiac function. Therefore, we suggest that it may be more prudent to measure cytokines as well as BNP to see if there is a benefit in reducing systemic inflammation associated with decompensated heart failure.
Another emerging issue is which natriuretic peptide to measure, for example, there is experimental evidence to suggest that ANP expression is not influenced by cytokines. Thus it could be hypothesized that ANP would be a satisfactory measure of heart failure regression, while BNP a measure of inflammatory response combined with improved cardiac function. However, until we know more about the responses of natriuretic peptides to therapies such as levosimendan in terms of its actions on ANP and inflammatory cytokines, a strategy of monitoring NT-proBNP or BNP to guide therapy cannot be universally advocated, although further research is certainly required.
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[Abstract/Free Full Text] - Avgeropoulou C., Andreadou I., Markantonis-Kyroudis S., et al. The Ca(2+)-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(5):882–887. (Aug.)
[Abstract/Free Full Text] - Kyrzopoulos S., Adamopoulos S., Parissis J.T., et al. Levosimendan reduces plasma B-type natriuretic peptide and interleukin 6, and improves central hemodynamics in severe heart failure patients. Int J Cardiol (2005) 99(3):409–413. (Mar 30).[CrossRef][Web of Science][Medline]
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