Levosimendan inhibits release of reactive oxygen species in polymorphonuclear leukocytes in vitro and in patients with acute heart failure and septic shock: a prospective observational study

Abstract

IntroductionLevosimendan is an extensively investigated inodilator showing also cardioprotective and antiinflammatory effects. The aim of our study was to explore the influence of levosimendan on polymorphonuclear leucocytes (PMN), a main source of reactive oxygen species, in vitro and in patients with acute heart failure or septic myocardial depression.MethodsPMN isolated from healthy volunteers were incubated with levosimendan in vitro. After stimulation with N-formyl-Met-Leu-Phe (fMLP) or phorbol 12-myristate 13-acetate (PMA) respiratory burst was quantified using a fluorescent dye. Apoptosis and expression of cell adhesion molecules of PMN were measured by flow cytometry. For determination of in vivo effects patients with acute heart failure (n = 16) or septic cardiac failure (n = 9) receiving levosimendan treatment were enrolled consecutively. PMN were isolated to measure respiratory burst activity before treatment as well as one and two hours after initiation of levosimendan administration. Furthermore inflammatory, hemodynamic and renal function parameters were obtained.ResultsIn vitro, levosimendan suppressed respiratory burst activity in fMLP or PMA stimulated PMN in a dose dependent manner by 30 ± 11% (P < 0.001) at 100 ng/mL and by 27 ± 17% (P < 0.001) at 1000 ng/mL respectively. Markers of apoptosis and PMN cell adhesion molecule expression remained unaffected by levosimendan treatment.In vivo, levosimendan treatment for two hours resulted in a significant reduction of PMA stimulated oxidative burst by 45% (P < 0.01) and fMLP stimulated oxidative burst by 49% (P < 0.05) in patients with acute heart failure. In patients suffering from septic shock levosimendan treatment decreased oxidative burst activity in unstimulated, fMLP and PMA stimulated PMN by 48% (P < 0.05), 46% (P < 0.01) and 43% (P < 0.01) respectively.ConclusionsLevosimendan appears to exert distinct immunomodulatory effects by decreasing oxidative burst activity of PMN. This property might contribute to the previously described cardioprotective effects of the drug.

Myocardial depression in sepsis: From pathogenesis to clinical manifestations and treatment

“…However, in certain situations, it may be advantageous; for example, levosimendan is a Ca 2+ sensitizer and inodilator, with immunomodulatory and antiapoptotic properties. Experimental data show that levosimendan may also have beneficial antioxidant properties, especially on cardiomyocytes [125,129], and decrease the oxidative burst activity of PMNs [130]. Levosimendan improved LV contractility in endotoxic rabbit models [131].…”

Levosimendan reduces mortality in patients with severe sepsis and septic shock: A meta-analysis of randomized trials

“…Twenty-five studies were reviewed in complete form. Major exclusions were due to lack of mortality data (n = 2) [42,43] or of a randomized design (n = 14) [44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59]. Finally, seven articles (246 participants) were included in the meta-analysis [30-36] ( Table 1).…”

“…Considering these pathophysiological events, levosimendan can find a role in the treatment of severe sepsis and septic shock.Levosimendan may decrease mortality in septic patients thank to its immunomodulatory and anti-inflammatory properties, properties well described in experimental studies[18][19][20][21].Unfortunately, there are few randomized trials analyzing the effect of levosimendan in septic patients. Ideally, a large randomized controlled trial on the lookout for the eventual beneficial effects of levosimendan in septic setting should be performed.…”

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

“…Small studies that have investigated the use of levosimendan in patients with septic shock have shown improvements in hemodynamic variables, 10 microcirculatory flow, 11 and renal 10 and hepatic 12 function, as compared with dobutamine. Other important noninotropic effects have also been shown, including antiinflammatory, 13 antioxidative, 14 and antiapoptotic 15 effects and possibly protection from ischemia and reperfusion injury. 16 A recent meta-analysis supported the use of levosimendan in patients with sepsis, but only 125 patients in total had been treated.…”