Review
Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan

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Abstract

The molecular background of the Ca2+-sensitizing effect of levosimendan relates to its specific interaction with the Ca2+-sensor troponin C molecule in the cardiac myofilaments. Over the years, significant preclinical and clinical evidence has accumulated and revealed a variety of beneficial pleiotropic effects of levosimendan and of its long-lived metabolite, OR-1896. First of all, activation of ATP-sensitive sarcolemmal K+ channels of smooth muscle cells appears as a powerful vasodilator mechanism. Additionally, activation of ATP-sensitive K+ channels in the mitochondria potentially extends the range of cellular actions towards the modulation of mitochondrial ATP production and implicates a pharmacological mechanism for cardioprotection. Finally, it has become evident, that levosimendan possesses an isoform-selective phosphodiesterase-inhibitory effect. Interpretation of the complex mechanism of levosimendan action requires that all potential pharmacological interactions are analyzed carefully in the framework of the currently available evidence. These data indicate that the cardiovascular effects of levosimendan are exerted via more than an isolated drug–receptor interaction, and involve favorable energetic and neurohormonal changes that are unique in comparison to other types of inodilators.

Introduction

Troponins of cardiac thin myofilaments are central in the regulation of the contractile process. Cardiac troponin C (cTNC), one of the 3 troponin subunits, acts as a Ca2+-operated molecular switch, turning myocardial force production on and off during cardiac systoles and diastoles. Consequently, the kinetics and the extent of systolic contraction and diastolic relaxation are both coordinated by the Ca2+-binding characteristics of cTnC. For example, the increase in the amplitude of the intracellular Ca2+ transient – in response to the activation of the β-adrenergic – cAMP – protein kinase A signaling pathway – augments force production through an increase in the Ca2+ saturation of cTnC. This manner of myocardial force augmentation is associated with a significant increase in myocardial oxygen demand, which is a limit to the pharmacological utilization of the β-adrenergic signaling pathway in the diseased heart. Therefore, during the past years intense pharmacological research has evolved to circumvent the seemingly tight connection between myocardial positive inotropy and myocardial oxygen wastage [1], [2] in the hope that fine tuning of myofilament Ca2+-responsiveness (e.g. by Ca2+-sensitizers, direct myosin activators) [1] and/or of intracellular Ca2+-cycling (e.g. sarcoplasmic reticulum Ca2+-pump (SERCA) gene transfer) [2] will promote myocardial contractility in a clinically desirable way.

Levosimendan (the (−) enantiomer of {[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono}propanedinitrile), a myofilament Ca2+-sensitizer positive inotropic drug with vasodilator properties was introduced for the treatment of acute heart failure more than a decade ago. During the subsequent years the base of data accumulated for levosimendan has come to exceed that for any other positive inotropic drug in routine clinical use. The initial optimism, fueled by the promising improvement in short-term outcome of early clinical trials in patients with decompensated heart failure (LIDO) or developing heart failure acute myocardial infarction (RUSSLAN) [3], [4],has been tempered by less favorable impact on long-term outcome in the large-scale clinical trials SURVIVE and REVIVE [5]. Nevertheless, the results of recent meta-analyses [6], [7], [8] offer encouraging perspectives on the usefulness of levosimendan in circumstances of acute heart failure.

The mechanism of action of levosimendan is complex as it involves: 1) an active long-lived metabolite, OR-1896 (the (−) enantiomer of N-[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl] acetamide), and 2) interactions with more than one molecular target within the cardiovascular system (Table 1, Fig. 1). This multiplicity of effects has been variably simplified as an advantageous or disadvantageous feature of levosimendan. One has therefore to consider all interactions and weigh their relative significance carefully when evaluating levosimendan-induced cardiovascular effects in the context of patient selection, timing, dosing and combination therapy [9].

This document has been developed from a consensus reached by experts on the clinically significant actions of levosimendan and is intended to serve as a reference when positioning levosimendan among the currently available drugs for the management of acute heart failure. To this end, we provide a brief overview on the mechanisms of action of levosimendan with direct clinical relevance, and attempt to dispel the accumulated ambiguity in respect of its cardiovascular effects.

Section snippets

Levosimendan and its active metabolite OR-1896

During the metabolism of levosimendan approximately 5% of the drug is converted to the metabolite OR-1855 (the (−) enantiomer of 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenylamine) in the large intestine, and then acetylated in the liver to form the active metabolite OR-1896. Binding to plasma proteins is 98% for levosimendan but only 40% for OR-1896: this explains why a relatively low total plasma level of the metabolite may evoke clinically significant effects [10]. Unlike

Ca2+-sensitization

Levosimendan interacts with the Ca2+-saturated cTnC and this forms the basis of its Ca2+-sensitizing mechanism [13]. The binding site for levosimendan on cTnC has been localized to a hydrophobic region of its N-domain near the so-called D/E linker region [14], [15]. There are important hydrogen-bond donor and acceptor groups on the pyridazinone ring and on the mesoxalonitrile–hydrazone moieties of levosimendan that bind to cTnC. Hence, it is likely that these groups form hydrogen bonds with

Vasodilation

Levosimendan and OR-1896 evoke prominent vasodilatory responses [25], [26], [27]. Levosimendan has the potential to open ATP-sensitive K+ channels [28], and consequent hyperpolarization of vascular smooth muscle cells has been suggested to explain the drug's vasodilatory effects. In line with this proposal, inhibitors of ATP-sensitive K+ channels mitigate vasodilatation induced by levosimendan or OR-1896, although these pharmacological approaches also suggested that other types of K+ channels

Phosphodiesterase inhibition

Both levosimendan and OR-1896 are highly selective inhibitors of the phosphodiesterase (PDE) III isoform. An interaction between levosimendan-evoked positive inotropy or lusitropy and cAMP signaling has been suggested from some experimental studies [33], [34], [35], [36]. However, it is recognized that an increase in intracellular cAMP concentration through PDE-inhibition depends on a complex interplay among the available PDE isoforms, their subcellular localization and parallel signaling

Neurohormones, cytokines and biomarkers

In heart failure a direct relationship exists between mortality and brain natriuretic peptide (BNP) production [46], [47], and levosimendan evokes a robust decrease in circulating BNP levels [5], [48], [49], [50]. Neurohumoral alterations seen following levosimendan administrations are interesting because an increasing number of enzymes, hormones, biologic substances, and other markers of cardiac stress and malfunction, as well as myocyte injury – collectively referred to as biomarkers – are

Energetic considerations

When the effects on cardiovascular energy balance are addressed all the myocardial and systemic effects of levosimendan and of its metabolite have to be taken into account including positive inotropy, peripheral and coronary vasodilation, potential mitochondrial effects and parallel neurohumoral alterations [57]. In short, a Ca2+-sensitizing mechanism at the level of the cardiomyocytes is energetically advantageous, because in the absence of augmented Ca2+ transients no extra energy requirement

Cardioprotection

Levosimendan administration is associated with a reduction in preload and afterload [63] and an increase in coronary blood flow [61], plus an energetically favorable type of increase in myocardial contractility [59]. Improved myocardial tissue perfusion might contribute to a cardioprotective effect of levosimendan. In addition, experimental studies have produced evidence that the levosimendan-evoked reduction in infarct size (anti-ischemic effect) may be complemented by the opening of cardiac

Clinical implications

According to recent cardiology guidelines the application of inotropic agents may be considered in heart failure patients with low systolic blood pressure or low measured cardiac index in the presence of signs of hypoperfusion or congestion, whereas vasodilators are recommended at an early stage for acute heart failure patients without symptomatic hypotension (SBP < 90 mm Hg) or serious obstructive valvular disease. For levosimendan, a Class IIa recommendation at level of evidence B has been

Conclusions

Classically, Ca2+-sensitization and vasodilation are referred to as the cornerstones of the mechanisms of action of levosimendan. These effects develop in response to specific interactions between levosimendan or OR-1896 and cTnC in cardiomyocytes, and levosimendan or OR-1896 and ATP-sensitive K+ channels in the vascular beds. On top of these well-known inodilator effects, cardioprotection emerges as the third facet of levosimendan during acute and chronic heart failure. The molecular mechanism

Acknowledgment

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [99].

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