Long‐term effects of levosimendan infusion on inflammatory processes and sFas in patients with severe heart failure

Abstract

Background: The calcium sensitizer levosimendan improves myocardial contractility in patients with heart failure, although its effects on inflammation and apoptosis are unknown. Aim: To examine the effects of levosimendan on markers of inflammation and apoptosis, over a period of 30 d following a 24 h infusion, in patients with heart failure. Methods: Thirty four patients with severe heart failure were randomised to receive a 24 h infusion of levosimendan or placebo, in a doubleblind trial. Haemodynamic evaluation and blood sampling were performed at baseline, 24 h, 30 h, 48 h, 7 d and 30 d after the end of the infusion. Results: Seven patients (1 levosimendan, 6 placebo), were excluded during follow-up. In the remaining 27 patients, levosimendan decreased serum IL-6 and sFAS, 24 h after the infusion ( p < 0.01 and p < 0.05 vs baseline), an effect sustained for 7 -30 d. Serum TNF-a and sTNF-R1 were decreased between 48 h ( p < 0.01 vs baseline for both) and 7 d ( p < 0.05 vs baseline for sTNF-R1) after infusion. Serum sTNF-R2 was decreased at 24 h ( p < 0.05 vs baseline) and remained lower than baseline for at least 7 d ( p < 0.05). Conclusions: These findings indicate that levosimendan decreases the expression of proinflammatory cytokines, TNF-a receptors and sFAS, immediately after infusion, an effect which persists for 7 -30 d.

Orally Available Levosimendan Dose-Related Positive Inotropic and Lusitropic Effect in Conscious Chronically Instrumented Normal and Heart Failure Dogs

“…Enhancing the calcium sensitivity of the contractile proteins and phos- phodiesterase III inhibition are believed to contribute to the LS-induced positive inotropic action (Edes et al, 1995;Haikala and Linden, 1995;Endoh, 2002). Activation of ATPdependent potassium channels in vascular smooth muscle cells and mitochondrial membranes (Yokoshiki et al, 1997a,b;Kaheinen et al, 2001) as well as recent demonstrated actions of LS, such as increased activity of the Na ϩ -Ca 2ϩ exchanger (Hasenfuss et al, 1998) and anti-ischemic (Moiseyev et al, 2002;Avgeropoulou et al, 2005), anti-inflammatory, and antiapoptotic properties (Follath et al, 2002;Parissis et al, 2004;Trikas et al, 2006) may also contribute to the dose-related enhancements of LV contractile performance and relaxation. Our findings are supported by evidence in vitro indicating that LS accelerates and does not impair relaxation in isolated cardiac muscle from endstage failing human hearts (Hasenfuss et al, 1998) and by a most recent clinical combined hemodynamic and Doppler echocardiographic study in severe HF patients.…”

“…In contrast to dobutamine, LS does not increase myocardial oxygen demand and has anti-ischemic and antiarrhythmic actions (Pagel et al, 1997;Ukkonen et al, 2000;Moiseyev et al, 2002;Avgeropoulou et al, 2005). In patients with severe HF, LS exerts anti-inflammatory and antiapoptotic properties (Follath et al, 2002;Parissis et al, 2004;Trikas et al, 2006). Compared with dobutamine, LS demonstrated superior hemodynamic improvement and safety for treatment of acute, decompensated HF (Follath et al, 2002) and myocardial infarction complicated by LV dysfunction and HF.…”

İleri kalp yetersizliği hastalarında levosimendanın eritrosit dağılım genişliği üzerine etkisi

“…Levosimendan tedavisine bağlı BNP, NT-proBNP, IL-6, TNF-α düzeylerinde anlamlı azalma olduğu gösteril-miştir (12)(13)(14)(15). Çavuşoğlu ve ark.…”

“…(8)(9)(10)(11). Daha önce yapılan çalışmalarda, levosimendanın IL-6 ve TNF-α gibi proinflamatuar sitokin düzeylerini azalttığı gösterilmiştir (12,13). Bu çalışmada, ileri kalp yetersizliği hastalarında pozitif inotropi amacıyla kullanı-lan proinflamtuar sitokinler üzerinde olumlu yönde etkisi olduğu bildirilmiş olan levosimendan tedavisinin, kronik inflamasyonun bir göstergesi olan hemogram parametrelerinden RDW ve ekokardiyografik parametreler üzerin-deki etkilerinin araştırılması amaçlandı.…”

Repetitive use of levosimendan in advanced heart failure: need for stronger evidence in a field in dire need of a useful therapy

“…Levosimendan also exhibits neurohormonal and anti-inflammatory effects, reducing brain natriuretic peptide (BNP) level, as well as tumor necrosis factor alfa (TNF-α), interleukin-6 (IL-6), and proapoptotic factors sFas and Fas-ligand levels [29][30][31][32]. In addition, levosimendan improves both right ventricular function [33] and endothelial function, and has a beneficial effect on coronary blood flow [34,35].…”