Levosimendan for sepsis-induced myocardial dysfunction: friend or foe?

Abstract

Sepsis-induced myocardial dysfunction (SIMD) involves reversible myocardial dysfunction. The use of inotropes can restore adequate cardiac output and tissue perfusion, but conventional inotropes, such as dobutamine and adrenaline, have limited efficacy in such situations. Levosimendan is a novel inotrope that acts in a catecholamine-independent manner. However, study results regarding the treatment of SIMD with levosimendan are inconsistent, and the use of levosimendan is highly controversial. In this review, we summarized the therapeutic mechanisms of levosimendan in SIMD and considered recent research on how to improve the efficacy of levosimendan in SIMD. We also analyzed the potential and limitations of levosimendan for the treatment of SIMD to provide ideas for future clinical trials and the clinical application of levosimendan in SIMD.

Keywords: inotropes; levosimendan; organ protection; sepsis; sepsis-induced myocardial cardiac dysfunction.

Figure 1

Basic pharmacology and mechanism of levosimendan. From a pharmacodynamic point of view, levosimendan has a threefold mechanism of action. First, as a calcium sensitizer, levosimendan can enhance myocardial contractility without increasing myocardial oxygen consumption. Then, levosimendan could open ATP- dependent K⁺ channels in the mitochondrial and cytoplasmic membranes of cardiomyocytes and thus has a cardioprotective effect. Finally, levosimendan could open ATP- dependent potassium channels in vascular smooth muscle cells to dilate blood vessels in other organs and improve organ perfusion such as kidneys, gut and so forth. (Created with BioRender.com).

Figure 2

The pharmacological difference between levosimendan and dobutamine. The figure illustrates the distinct mechanisms of action of dobutamine and levosimendan. Dobutamine mainly activates β1-AR, leading to both beneficial effects (blue lines) through increased cAMP production, PKA activation, and enhanced calcium handling to improve contractility, and harmful effects (red lines) via CaMKII-mediated pathways promoting hypertrophy, apoptosis, and arrhythmias. Levosimendan enhances the cAMP-PKA pathway by inhibiting PDE3, amplifying beneficial effects. Solid lines represent direct actions, while dashed lines indicate indirect or secondary effects. β1-AR, Beta-1 Adrenergic Receptor; AC, Adenylyl Cyclase; cAMP, Cyclic Adenosine Monophosphate; PDE, Phosphodiesterase; PDE3, Phosphodiesterase 3; PDE4, Phosphodiesterase 4; PKA, Protein Kinase A; EPAC, Exchange Protein Activated by cAMP; CaMKII, Calcium/Calmodulin-Dependent Protein Kinase II; GRK2, G Protein-Coupled Receptor Kinase 2; 5’-AMP, 5’-Adenosine Monophosphate (Created with BioRender.com).