Secondary Logo

Journal Logo

Potential of the Cardiovascular Drug Levosimendan in the Management of Amyotrophic Lateral Sclerosis

An Overview of a Working Hypothesis

Al-Chalabi, Ammar MD, PhD*; Heunks, Leo M. A. MD, PhD; Papp, Zoltán MD, PhD; Pollesello, Piero PhD§

Journal of Cardiovascular Pharmacology: November 2019 - Volume 74 - Issue 5 - p 389–399
doi: 10.1097/FJC.0000000000000728
Drugs in the Pipeline – Invited Review

Abstract: Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a neuromuscular disorder characterized by progressive weakness, and eventual paralysis. Previous attempts to improve the muscle response in ALS patients and thereby maintain respiratory function and delay progression of disability have produced some mixed results. Continuing this line of investigation, levosimendan has been shown to enhance in vitro the contractility of the diaphragm muscle fibers of non-ALS patients and to improve in vivo diaphragm neuromuscular efficiency in healthy subjects. Possible positive effects on respiratory function in people with ALS were seen in an exploratory phase 2 study, and a phase 3 clinical trial is now underway to evaluate the potential benefit of an oral form of levosimendan on both respiratory and overall functions in patients with ALS. Here, we will review the various known pharmacologic effects of levosimendan, considering their relevance to people living with ALS.

*Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom;

Department of Intensive Care Medicine, Amsterdam UMC, VUmc, Amsterdam, The Netherlands;

Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; and

§Orion Pharma, Espoo, Finland.

Reprints: Piero Pollesello, PhD, Orion Pharma, P.O.Box 65, FIN-02101 Espoo, Finland (e-mail:

A. Al-Chalabi is a consultant for Orion Pharma and has been the Principal investigator for clinical trials was sponsored or supported by Orion Pharma. Z. Papp has received lecture honoraria from Orion Pharma; L. M. A. Heunks received a grant from Orion Pharma to run a clinical trial; P. Pollesello is an employee of Orion Pharma.

Received May 09, 2019

Accepted July 23, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work, provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Back to Top | Article Outline


Levosimendan is an inodilator that, in intravenous formulation, has been used for nearly 20 years to treat acute heart failure and to support heart function in various therapy settings involving low cardiac output. In addition to an inotropic effect due to calcium sensitization of cardiac troponin C (cTnC)1, the drug has a number of other well-documented effects, including vasodilation and cardioprotection.2 More recently, effects of levosimendan on skeletal muscle have attracted interest and suggest a possible clinical value of levosimendan in managing people with amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder, characterized by progressive weakness and eventual paralysis. An oral formulation of levosimendan is currently in advanced clinical development for the treatment of ALS. We will review the various known actions of levosimendan, considering their relevance to people living with ALS.

Back to Top | Article Outline


ALS is an adult-onset condition characterized by a progressive muscular paralysis attributable to degeneration of motor neurons in the brain and spinal cord.3 Initial focal weakness spreads to involve most skeletal muscles, including the diaphragm and other respiratory muscles and results in progressive weakness and loss of functional independence. Death typically occurs within a few years of diagnosis, frequently from respiratory failure or complications secondary to degeneration of the motor neurons supplying the diaphragm and other respiratory muscles.4,5

A defining aspect of ALS is the involvement of both upper and lower motor neurons, although there may be a predominance of one type during the early stages of the disease.6 Spinal onset is the most common (∼60%), symptoms first emerging in one or more of the limbs, manifested by problems such as weakness, foot-drop, or deterioration of manual dexterity. Bulbar-onset ALS accounts for some one-third of cases and is associated with slurring and hoarseness of speech and swallowing difficulties. Occasional cases of respiratory-onset ALS are also encountered (∼3%–5% of all diagnoses).7–10 Behavioral changes are common in patients with ALS: some 30% of patients have evidence of executive dysfunction at presentation with up to 80% affected by stage 4 disease,11 and frontotemporal dementia has a close association with ALS.12–19 Irrespective of the initial presentation, the relentless spread of the disease results in progressive disability,20 with increasing difficulty in walking, handling or lifting objects, speaking, and swallowing, including dyspnea because of respiratory failure, leading ultimately to death.

ALS is the most frequent neurodegenerative disorder of midlife. In Europe and the United States, the incidence is 1–2/100,000 person-years, with an overall prevalence of 3–5 patients/100,000 at any one time. The lifetime risk of ALS is 1 in 300 by age 80.21 The incidence and prevalence of ALS increase with age,22,23 and, consequently, the incidence will nearly double over the next 100 years as the population ages.24

The causes of ALS are unclear. About 5% of cases are familial, with a first-degree relative affected, although familial ALS is not well defined among neurologists. Causative gene variants are found in up to 80% of those with a family history and about 14% of those without.3,25,26 Even in those not carrying a large effect Mendelian gene, the heritability of ALS is about 60%, suggesting a significant genetic component. No environmental factor has been consistently identified as greatly increasing ALS risk. Although a number of associations (such as athleticism, serving in the armed forces etc.) have been proposed, the importance of these factors in precipitating the disease is not clear. Irrespective of the cause of the disease, various pathophysiological abnormalities (Fig. 1) can be identified in ALS (Box 1).



Back to Top | Article Outline

BOX 1. Cited Here...

Pathophysiological Abnormalities Identified in ALS

  • Disturbances in protein quality control and aggregation of abnormal proteins.
  • Endoplasmic reticulum stress.
  • Disturbance of multiple aspects of RNA metabolism.
  • Microglial activation and production of extracellular superoxide.
  • Reduced energy supply from oligodendrocytes to motor axons.
  • Release of toxins from astrocytes that target motor neurons.
  • Disruption of the cytoskeleton and impaired axonal transport.
  • Glutamate excitotoxicity.

Prion-like spread of ALS is also a possible mechanism, with cell-to-cell transmission of one or more misfolded proteins within the motor neuron network.27–29

Although reinnervation of denervated motor units may delay the onset of symptoms in the early course of ALS, later in the disease, these larger motor units are also lost leading to permanent weakness and muscle atrophy. The first neurons to die off in ALS are those associated with the fast-fatigable motor units.30,31

Back to Top | Article Outline

Management of ALS

There is no cure for ALS at present. The focus of medical care is toward supportive and palliative measures intended to preserve or maintain quality of life for patients and to ease the burden of care for the family and others; these interventions are often delivered through specialist multidisciplinary clinics.32–34

The medical repertoire is limited. Riluzole, which modulates glutamatergic neurotransmission (and is thus believed to attenuate glutamate excitotoxicity) and is a noncompetitive antagonist at N-methyl-D-aspartate receptors, has been shown to modestly improve 1-year survival, to delay progression from early to intermediate stages of ALS and to prolong the late stage.35–37

The free-radical scavenger edaravone has also been shown to slow the rate of progression of ALS, but this effect has been robustly demonstrated only for a small proportion of the ALS patient population, defined by very strict selection/status criteria.37,38 It is administered by repeated intravenous infusion (10 days per 28-day cycle) and, although approved in the United States and Canada, is not available in the European Union. Currently, no treatment is approved to enhance motor function in ALS.

Noninvasive ventilation (NIV) has become the standard treatment for the management of respiratory insufficiency in ALS, with evidence for both preservation of quality of life (including a reduced rate of decline of respiratory function) and increased survival time.39

Invasive (tracheostomized) ventilation is an option selected by only a small proportion of patients with ALS.40

Notwithstanding the benefits of noninvasive and invasive mechanical ventilation, poor respiratory function remains a major source of disability, fatigue, morbidity, and mortality in ALS patients, and new therapies to support respiratory muscles, either alone or in association with NIV, could be of great clinical value.

Back to Top | Article Outline


Amelioration of symptoms of ALS by improving the muscle response to the diminished motor nerve activity, to maintain respiratory function and delay progression of disability is a clearly attractive objective but has yielded mixed results.

Tirasemtiv is a fast-skeletal muscle fiber activator reported to sensitize the sarcomere to calcium. Enhancement of muscle contractile force and functional indices was recorded in isolated nerve-muscle preparations in human volunteer studies41,42 and in an experimental model of ALS [superoxide dismutase 1 (SOD1) transgenic mouse]. A meta-analysis of 3 small studies in a total of 143 patients with ALS demonstrated significant, concentration-dependent improvements in maximum voluntary ventilation, sniff nasal inspiratory pressure, and muscle strength using handheld dynamometry.43

In a placebo-controlled phase 2 study (BENEFIT-ALS), which randomized 596 patients with ALS and slow vital capacity (SVC) >50% predicted, a 12-week course of tirasemtiv therapy did not affect the primary endpoint of functional measures [ALS Functional Rating Scale-Revised (ALSFRS-R)44] but was associated with a significantly slower decline in SVC (mean difference 5.54 ± 1.19%; P = 0.0006) and muscle strength (P = 0.0158). A treatment effect on SVC was still apparent 4 weeks after cessation of therapy (Δ4.91%; P = 0.0002).45

These encouraging findings were not reproduced, however, in the subsequent phase 3 study VITALITY-ALS ( identifier: NCT02496767). That study, conducted in patients with possible, probable, or definite ALS, diagnosed within 24 months and with SVC at baseline ≥70% predicted, randomized participants to placebo or to tirasemtiv at doses of 250, 375, or 500 mg/d for 48 weeks. No statistically significant effect of therapy was identified on the study primary endpoint of change from baseline in SVC after 24 weeks or on any secondary endpoints evaluated at 48 weeks.46 Full analysis of VITALITY-ALS is ongoing, but the investigators have proposed that poor tolerability of the target doses, in particular central nervous system adverse events, may have contributed to the study failure. Subgroup analysis of VITALITY-ALS restricted to patients who are able to tolerate the target doses of tirasemtiv produced indications of a beneficial effect on SVC.47

The development of reldesemtiv (CK-2127107), a follow-up molecule to tirasemtiv with the same mode of action, but which is reported not to cross the blood brain barrier, is ongoing. Reldesemtiv had been previously studied in a phase 2 clinical trial designed to assess its potential effect versus placebo on exercise tolerance, assessed as change from baseline in constant work rate endurance time over 2 weeks, in approximately 40 patients with chronic obstructive pulmonary disease (COPD). In October 2018, it was announced that the trial had recorded no statistically significant treatment differences on either its primary or any secondary endpoints.48 At the same time, it was also announced that a phase 1b clinical trial designed to assess the effect of reldesemtiv versus placebo on skeletal muscle fatigue in approximately 60 patients aged 70–89 years, with limited mobility, had met its predefined criteria for lack of efficacy of reldesemtiv and that patients enrolment had been halted.48

The phase 2 clinical trial FORTITUDE-ALS compared the effects of 3 dose levels of reldesemtiv versus placebo in 458 patients living with ALS during 12 weeks of treatment. The primary and secondary endpoints of dose response in SVC and ALSFRS-R compared with placebo at 12 weeks were not met although there were promising trends reported on both endpoints, as well as a measure of muscle strength, when the dose groups were combined in post hoc analyses.49 At the moment, a regulatory phase 3 clinical trial has not yet started.

Back to Top | Article Outline


The calcium sensitizer levosimendan50 was initially developed for intravenous use as an inotrope in patients with acute heart failure; it is now used in a wider range of cardiac-related situations in which inotropic therapy is considered appropriate.51–58

The principal pharmacologically relevant action of levosimendan is its inotropic effect, attributable to a novel mechanism of action distinctly different from those of conventional adrenergic agents.1 In brief, levosimendan is a calcium sensitizer that promotes contractility through its calcium-dependent interaction with cTnC. Levosimendan targets the hydrophobic pocket in the tertiary structure of cTnC59–64: its effective binding site and the locus of its calcium-sensitizing effect are in the regulatory or N domain of cTnC and seem to be strongly predicated on the presence of a chiral methyl group and a hydrazine moiety in the drug's own molecular structure.65–68 The binding of levosimendan to its target is calcium-dependent and reversible69 and, thus, does not disturb relaxation.70–72

Levosimendan has additional pharmacological effects mediated by the opening of ATP-dependent potassium channels (KATP channels) in vascular smooth muscle cells73–76 and cardiomyocytes.77–80 Owing to this, levosimendan causes vasodilatation,76 reduction of preload and afterload,81 increase in peripheral perfusion,82 reduction of pulmonary capillary wedge pressure,83 and a selective dilation of the afferent arterioles in the renal glomeruli causing an increase in glomerular filtration.84

Levosimendan also opens the KATP channels in mitochondria in cardiomyocytes,85 which has been associated with cardioprotection, infarct size reduction, and mitigation of ischemia/reperfusion injuries in a range of experimental and clinical studies.86 In addition, levosimendan inhibits the phosphodiesterase (PDE)-III isoform, with a great selectivity against all other isoforms including PDE-IV.87

Levosimendan has been linked to a range of pleiotropic actions, including antiapoptotic and anti-inflammatory properties (see Farmakis et al2 for a review) and has also been shown to increase cerebral blood flow.88–90 Interestingly, levosimendan has been shown to enhance the contractility of both slow and fast muscle fibers in the isolated diaphragm from patients with COPD,91 at least at high concentrations. Such pleiotropic effects are considered to be relevant to the overall therapeutic action of the drug.1,92

In animal studies on primary and secondary stroke, levosimendan significantly reduced stroke-induced mortality and morbidity, and its vasodilatory effects seemed to have a role in increasing blood volume in cerebral microvessels and large vessels in various zones of the brain.88

Levosimendan has an extensively documented safety profile in its cardiovascular-approved indications.51,52,56,93 The most frequently recorded adverse events are hypotension, headache, atrial fibrillation, hypokalemia, and tachycardia.50 In clinical use, short-term treatment with i.v. levosimendan exhibits sustained efficacy because of the formation of an active metabolite.94

Back to Top | Article Outline


Respiratory Muscle Weakness and Dysfunction

Two isoforms of the contraction-regulatory protein troponin C (TnC) are expressed in muscular tissues, the fast-twitch and slow-twitch (or cardiac) TnC.95 The 2 proteins have distinctive calcium-binding properties that affect their actions as subunits of the troponin complexes. In adult muscle, the fast-twitch isoform gene is expressed exclusively in fast-twitch skeletal muscle, whereas the cardiac isoform gene (cTnC) is expressed both in the myocardium and in slow-twitch skeletal muscle.96 The diaphragm is normally composed of a substantial proportion of slow-twitch fibers (approximately 50%), but other skeletal muscle also contains a proportion of slow-twitch fibers and thus also a proportion of cTnC.97

Levosimendan, which has been described as a cTnC-specific binder,98 can thus also have an effect on the diaphragm and skeletal muscle. In addition, levosimendan has been suggested to have a direct effect also on fast-twitch fibers, at least at high concentration.92

Back to Top | Article Outline

Preclinical Experience With Levosimendan on the Diaphragm and Skeletal Muscle

Levosimendan has been shown to enhance the contractility of muscle fibers in the isolated diaphragm from COPD patients by improving calcium sensitivity (Fig. 2).92 Similar findings have been reported from use of levosimendan in ex vivo diaphragm samples in a coronary ligation model of heart failure in rats.99 In addition, levosimendan has also been shown to attenuate oxidative tissue damage in the diaphragms of mechanically ventilated mice with septic shock.100



In rats with an antibody-induced form of myasthenia gravis, treatment with oral levosimendan (0.25 mg/kg; n = 4) was associated with enhanced exercise time, compared with baseline, in a treadmill test performed 2 hours after dosing (Fig. 3; P = 0.06).101



Back to Top | Article Outline

Other Effects of Levosimendan Potentially Relevant in ALS

In addition to promotion or preservation of respiratory muscle contractility, the multifaceted pharmacology of levosimendan may also provide supplementary clinical impact in patients with ALS through a range of pharmacological effects (see Farmakis et al2 and Papp et al86 for reviews). These possibilities require detailed investigation before any conclusions can be reached about their clinical relevance in ALS.

Back to Top | Article Outline

Brain Circulation

Evidence has been assembled for correlations between diminished cerebral perfusion, grey matter atrophy, and aspects of ALS, notably those associated with decline in cognition.102–104 In addition, it has been reported that low oxygen tension is associated with increased instability of the SOD1 protein and, by implication, a greater risk of aggregation of dysfunctional forms of that protein, leading to the development of ALS.105

Levosimendan has been shown to increase blood flow in the brain in situations of stroke in Dahl salt-sensitive rats or subarachnoid hemorrhage89–91 in modified double-hemorrhage,106 endothelin-1 (ET-1)–dependent vasoconstriction after experimental-induced subarachnoid hemorrhage107 and injection of autologous blood into the cisterna magna model in rabbits.108 Cerebral blood flow velocity was also increased in patients with a recent ischemic stroke or TIA receiving oral levosimendan up to 2 mg daily.91 Similar possible effects in ALS would be a matter of interest.

Back to Top | Article Outline

Endoplasmic Reticulum Stress Relief

Endoplasmic reticulum (ER) stress seems to play a prominent role in the pathogenesis of ALS.109 Long-term ER stress leads to cell death through apoptotic signaling cascades. This process provides a link to neurodegeneration.110

Observations in vitro on human cardiomyocyte progenitor cell-derived cardiomyocytes indicate that levosimendan attenuates the ischemia/reperfusion–induced ER stress mechanism.111

Back to Top | Article Outline

Prevention of Programmed Cell Death

During research into the mechanisms of ALS, it was discovered that transfected neuronal cells expressing mutant SOD1 cDNA were dying by apoptosis, a form of programmed cell death. A role for mutant SOD1 genes in apoptosis of neuronal cells is supported by various lines of experimental evidence.110,112,113

Levosimendan has been reported to display antiapoptotic effects in a range of in vitro (in H9C2 cells), ex vivo, and in vivo (in rats and pigs) experimental studies.114–118 Multiple mechanisms of antiapoptosis have been identified, including the activation of survival signaling through opening of mitochondrial KATP channels, the modulation of nitric oxide release,119–121 reduction in the expression and activity of caspase-3, and modulation of nuclear factor kappa-B (NF-κB). Cardioprotective effects explained at least in part by an antiapoptotic effect of levosimendan have been also described also in humans.122,123

Back to Top | Article Outline

Antioxidative and Anti-inflammatory Effects

Neuronal damage and death in ALS are caused by a combination of excitotoxic, inflammatory, and oxidative insults (see Redler and Dokholyhan124 for a survey of the many factors that may be implicated and the role of cytosolic calcium overload as a possible prime mover in the emergence of inflammation and a prooxidative state).

Levosimendan has been shown to have both anti-inflammatory effects125–129 and antioxidative properties.2,130 Given the complex pathophysiology of ALS, these properties may give levosimendan a potential to influence these pathological processes, although their final role in disease progression is not completely understood.

Back to Top | Article Outline

Mitochondria-Protective Effects

Pathological changes in ALS are closely associated with pronounced and progressive changes in mitochondrial morphology, bioenergetics, and calcium homeostasis.128 Levosimendan has been shown in experimental investigations to exert a range of effects by opening ATP-dependent (KATP)86,131–134 and calcium-dependent (BK) potassium channels135 that may mitigate mitochondrial damage and dysfunction and that may be relevant to its use in ALS.114,117,118,136,137

Back to Top | Article Outline


Healthy Volunteer Data

The effects of levosimendan on diaphragm function have been studied in healthy volunteers ( identifier: NCT01101620).138 Thirty subjects were randomized to placebo or levosimendan infusion for 40 minutes with an inspiratory loading test before and after treatment. An inspiratory loading test resulted in significant loss of diaphragm contractility during placebo treatment but not during treatment with levosimendan, suggesting that the drug preserved diaphragm contractility. That finding was associated with improved neuromechanical efficiency of the diaphragm during levosimendan infusion (Fig. 4).



The mean neuromechanical efficiency of the diaphragms of participants during levosimendan treatment was improved by 21% (P < 0.05) during unloaded breathing and during the second loading task compared with the first loading task, whereas no change was observed in the placebo group. This improved neuromechanical efficiency in people receiving levosimendan was sustained throughout the loading task.

In addition, stimulation of the phrenic nerves revealed a diminished contractile response of the diaphragm after the first loading task with placebo but no diminution with levosimendan. Neither levosimendan nor placebo altered subjective sensations of respiratory effort.

Back to Top | Article Outline

Levosimendan Clinical Trials in ALS Patients

Some preliminary possible positive effects of short-term orally administered levosimendan in patients with ALS were seen in a post hoc analysis of the LEVALS study ( identifier: NCT02487407).139 This phase II trial, based on a randomized, double-blind, placebo-controlled, crossover design, evaluated the efficacy and safety of oral levosimendan in 66 patients with definite or probable ALS. Patients had symptoms of ALS for between 12 and 48 months before the study and were required to have early respiratory decline [defined as baseline seated SVC between 60% and 90% (mean 75.3%) of that predicted for age, height, and sex]. Participants were allowed to use riluzole but not assisted ventilation or gastrostomy of any type.

The patients received 2 weeks of treatment with oral levosimendan 2 mg/d (1 mg twice daily), levosimendan 1 mg/d, and placebo in a random order during 3 study periods separated by a 2- to 3-week washout period.

The primary endpoint was the percentage change from baseline in SVC (measured in the sitting position) after 14 days of treatment. A statistically significant treatment effect on this endpoint was not recorded. However, poststudy analysis of outcomes revealed significant and dose-dependent treatment effects of levosimendan on supine SVC after a 14-day treatment period, with average increments in supine SVC of +0.77% and 2.38% for 1 mg and 2 mg/d levosimendan, respectively, compared with an average 3.62% decrement in the placebo group (P = 0.018 and 0.001, respectively).

The observation of a treatment effect of levosimendan in the supine position is clinically relevant. Orthopnea, and the consequent interruption of sleep, is a common early indication of respiratory dysfunction in ALS, presumably because of splinting of the weakened diaphragm by abdominal organs, and changes in pulmonary function in the supine position may be a better predictor of progression of ALS than those detected while sitting.

Levosimendan seemed well tolerated by patients with ALS. Headache (levosimendan 2 mg, 28.8%; levosimendan 1 mg, 16.9%; placebo, 3.4%) and an increased heart rate (levosimendan 2 mg, 18.6%; levosimendan 1 mg, 5.1%; placebo, 1.7%) were more common with levosimendan than placebo and showed a dose-dependent increase in frequency, although the hypotension that has been associated with intravenous use of levosimendan was not reported during blinded treatment. The administration of the drug did not result in any increase of supraventricular and ventricular tachyarrhythmias.139

The LEVALS study provided, with qualifications, the first clinical evidence that levosimendan might preserve or slow the rate of decline of respiratory function in patients with ALS. A necessary next step is to demonstrate that the effect of levosimendan on SVC (which is essentially a laboratory test) is translated into clinically relevant benefits on patients' daily function. This information should come from the REFALS phase 3 trial [Effects of Oral levosimendan (ODM-109) on Respiratory Function in Patients With ALS; NCT03505021] that is ongoing in North America, Europe, and Australia.

REFALS will evaluate the effects of levosimendan (target dose 2 mg), compared with placebo, in 450 patients with ALS during 48 weeks of treatment. The primary endpoint will be supine SVC at 12 weeks, but key secondary endpoints include the ALSFRS-R through 48 weeks (determined as the Combined Assessment of Function and Survival) and the time to respiratory event (eg, the initiation of NIV treatment). In addition, reflecting the common challenge with orthopnea in these patients, the study is also applying scales of sleep quality and sleepiness as an alternative approach to understanding the potential clinical benefit of levosimendan to people with ALS.

Although much is already known about safety of both the IV and oral forms of levosimendan in heart failure, the REFALS study is also essential to characterize the safety and tolerability of levosimendan in this unique patient population. If effective, treatment with levosimendan may be relatively prolonged and in patients with typically rather less comorbidity than those with heart failure. The extensive safety assessments in REFALS are key to defining the benefit-to-risk profile of levosimendan in the treatment of ALS. A long-term open-extension study (NCT03948178) will provide further insights into the long-term safety and efficacy of oral levosimendan.

Back to Top | Article Outline


Although most researchers are understandably focused on strategies to slow or stop the progression of ALS, such options are not yet in sight for most patients. Treatments that can improve symptoms or maintain daily function for longer are clearly of great potential value for patients suffering from this devastating disease. The declining respiratory function alone is a major cause of disability, fatigue, morbidity, and mortality in ALS, quite apart from the loss of function in other skeletal muscles. The prospect of new treatments (Box 2) that might bring some symptomatic relief to patients living with ALS, even if the overall course of the disease is not altered, is thus very welcome.

Back to Top | Article Outline

BOX 2. Cited Here...

Prospect of New Treatments for Symptomatic Relief to Patients Living With ALS

  • Reldesemtiv (Cytokinetics, USA): phase II concluded.
  • Levosimendan (Orion Pharma, Finland): phase III running.

Whether drugs that directly enhance muscle function will have sufficient effect to bring significant benefit in ALS remains to be seen. Encouraging early hints were seen with tirasemtiv, only to be disappointed in the ensuing phase 3 trial. As regards reldesemtiv, a phase III has still to be initiated.

Although tirasemtiv and reldesemtiv are selective activators of fast skeletal muscle fibers, levosimendan primarily acts on slow fibers through cTnC. This distinction may be clinically important, not least considering that fast muscle fibers seem to be the first to die as muscle atrophies in ALS140; this hints at an additional potential effect later in the disease course and perhaps a different profile of clinical activity than a purely fast skeletal muscle activator. Of importance is the fact that because of its unique mechanism of action, levosimendan does not increase oxygen consumption.55,141,142

Although the direct activity of levosimendan on skeletal muscle is clearly the main effect of interest in relation to ALS, a number of the other activities of the drug raise some intriguing possibilities in the context of this disease (Fig. 5). There are not only well-documented beneficial effects of levosimendan on peripheral (and brain) circulation but also on autophagy, ER stress, apoptosis, inflammation, and mitochondrial function, all of which could also be of value in the progression of ALS if they also occur in neurons and/or muscle cells. Although the clinical value of drugs with these actions remains unproven in ALS, levosimendan may yet prove to be more than a skeletal muscle activator in ALS.



There remains much to learn before the effects of levosimendan in ALS are clear. Most of the data related to mode of action discussed in this article were generated in models quite distinct from those used in ALS, and it is a moot point whether such activities will also be evident and significant in more relevant models to ALS. The relative effects and contribution of levosimendan active metabolite when the drug is administered p.o. also need to be clarified further.

There is also much to learn about the safety profile of oral levosimendan in patients with ALS. The broad collection of safety data on the use of the drug during the last 2 decades (mostly during short-term use) has been largely reassuring, but that has been mainly in the context of patients with heart failure who were generally hospitalized. The emergence of new, unsuspected adverse reactions seems unlikely after all this time, but the significance of headache and an increased heart rate especially in people living with ALS is still to be understood.

Above all though, is the question of whether this collection of intriguing and promising actions will lead to measurable benefits for people with ALS: the improvement in supine SVC seen in a post hoc analysis in the LEVALS study is an encouraging first step. In addition to replicating that finding, we need to see that the effect is prolonged and leads to a meaningful improvement in patients' symptoms or an ability of people with ALS to function day-to-day: the results of the REFALS study will be eagerly awaited.

Back to Top | Article Outline


1. Pollesello P, Papp Z, Papp JG. Calcium sensitizers: what have we learned over the last 25 years? Int J Cardiol. 2016;203:543–548.
2. Farmakis D, Alvarez J, Gal TB, et al. Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper. Int J Cardiol. 2016;222:303–312.
3. Brown RH, Al-Chalabi A. Amyotrophic lateral sclerosis. N Engl J Med. 2017;377:162–172.
4. Kurian KM, Forbes RB, Colville S, et al. Cause of death and clinical grading criteria in a cohort of amyotrophic lateral sclerosis cases undergoing autopsy from the Scottish Motor Neuron Disease Register. J Neurol Neurosurg Psychiatry. 2009;80:84–87.
5. Paulukonis ST, Roberts EM, Valle JP, et al. Survival and cause of death among a cohort of confirmed amyotrophic lateral sclerosis cases. PLoS One. 2015;10:e0131965.
6. Al-Chalabi A, Hardiman O, Kiernan MC, et al. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol. 2016;15:1182–1194.
7. Gautier G, Verschueren A, Monnier A, et al. ALS with respiratory onset: clinical features and effects of non-invasive ventilation on the prognosis. Amyotroph Lateral Scler. 2010;11:379–382.
8. Van den Berg-Vos RM, Visser J, Kalmijn S, et al. A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes. Arch Neurol. 2009;66:751–757.
9. Visser J, van den Berg-Vos RM, Franssen H, et al. Disease course and prognostic factors of progressive muscular atrophy. Arch Neurol. 2007;64:522–528.
10. Van den Berg-Vos RM, Visser J, Franssen H, et al. Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain. 2003;126:1036–1047.
11. Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018;91:e1370–80.
12. Montuschi A, Iazzolino B, Calvo A, et al. Cognitive correlates in amyotrophic lateral sclerosis: a population-based study in Italy. J Neurol Neurosurg Psychiatry. 2015;86:168–173.
13. Rippon GA, Scarmeas N, Gordon PH, et al. An observational study of cognitive impairment in amyotrophic lateral sclerosis. Arch Neurol. 2006;63:345–352.
14. Lomen-Hoerth C, Anderson T, Miller B. The overlap of amyotrophic lateral sclerosis and frontotemporal dementia. Neurology. 2002;59:1077–1079.
15. Beeldman E, Raaphorst J, Klein Twennaar M, et al. The cognitive profile of ALS: a systematic review and meta-analysis update. J Neurol Neurosurg Psychiatry. 2016;87:611–619.
16. Phukan J, Elamin M, Bede P, et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012;83:102–108.
17. Elamin M, Bede P, Byrne S, et al. Cognitive changes predict functional decline in ALS: a population-based longitudinal study. Neurology. 2013;80:1590–1597.
18. Strong MJ, Abrahams S, Goldstein LH, et al. Amyotrophic lateral sclerosis—frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18:153–174.
19. Elamin M, Phukan J, Bede P, et al. Executive dysfunction is a negative prognostic indicator in patients with ALS without dementia. Neurology. 2011;76:1263–1269.
20. Jones AR, Jivraj N, Balendra R, et al. Health utility decreases with increasing clinical stage in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:285–291.
21. Johnston CA, Stanton BR, Turner MR, et al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol. 2006;253:1642–1643.
22. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013;14:248–264.
23. Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41:118–130.
24. Gowland A, Opie-Martin S, Scott KM, et al. Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116. Amyotroph Lateral Scler Frontotemporal Degener. 2019:1–11.
25. Al-Chalabi A. Perspective: don't keep it in the family. Nature. 2017;550:S112.
26. van Rheenen W, Shatunov A, Dekker AM, et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat Genet. 2016;48:1043–1048.
27. Polymenidou M, Cleveland DW. The seeds of neurodegeneration: prion-like spreading in ALS. Cell. 2011;147:498–508.
28. Smethurst P, Sidle KC, Hardy J. Review: prion-like mechanisms of transactive response DNA binding protein of 43 kDa (TDP-43) in amyotrophic lateral sclerosis (ALS). Neuropathol Appl Neurobiol. 2015;41:578–597.
29. Ludolph AC, Brettschneider J. TDP-43 in amyotrophic lateral sclerosis—is it a prion disease? Eur J Neurol. 2015;22:753–761.
30. Hegedus J, Putman CT, Tyreman N, et al. Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol. 2008;586:3337–3351.
31. Saxena S, Caroni P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron. 2011;71:35–48.
32. EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis, Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)—revised report of an EFNS task force. Eur J Neurol. 2012;19:360–375.
33. Chiò A, Bottacchi E, Buffa C, et al; PARALS. Positive effects of tertiary centres for amyotrophic lateral sclerosis on outcome and use of hospital facilities. J Neurol Neurosurg Psychiatry. 2006;77:948–950.
34. Martin S, Trevor-Jones E, Khan S, et al. The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18:569–575.
35. Fang T, Al Khleifat A, Meurgey JH, et al. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018;17:416–422.
36. de Jongh AD, van Eijk RPA, van den Berg LH. Evidence for a multimodal effect of riluzole in patients with ALS? J Neurol Neurosurg Psychiatry. 2019;90:1183–1184.
37. Khairoalsindi OA, Abuzinadah AR. Maximizing the survival of amyotrophic lateral sclerosis patients: current perspectives. Neurol Res Int. 2018;2018:6534150.
38. Writing Group; Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16:505–512.
39. Radunovic A, Annane D, Rafiq MK, et al. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2017;CD004427.
40. Nakayama Y, Shimizu T, Mochizuki Y, et al. Predictors of impaired communication in amyotrophic lateral sclerosis patients with tracheostomy-invasive ventilation. Amyotroph Lateral Scler Frontotemporal Degener. 2015;17:38–46.
41. Hansen R, Saikali KG, Chou W, et al. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve. 2014;50:925–931.
42. Russell AJ, Hartman JJ, Hinken AC, et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med. 2012;18:452–455.
43. Shefner JM, Wolff AA, Meng L. The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14:582–585.
44. Gordon PH, Miller RG, Moore DH. ALSFRS-R. Amyotroph lateral scler other motor. Neuron Disord. 2004;5(suppl 1):90–93.
45. Shefner JM, Wolff AA, Meng L, et al. A randomized, placebo-controlled, double-blind phase IIb trial evaluating the safety and efficacy of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:426–435.
46. Andrews JA, Cudkowicz ME, Hardiman O, et al. VITALITY-ALS, a phase III trial of tirasemtiv, a selective fast skeletal muscle troponin activator, as a potential treatment for patients with amyotrophic lateral sclerosis: study design and baseline characteristics. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19:259–266.
47. Wolff AA, Cockroft BM, Malik FI, et al. Impact of time since diagnosis on response to tirasemtiv, a fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis: a subgroup analysis of VITALITY-ALS. 29th International Symposium on ALS/MND, Glasgow, United Kingdom, December 2018.
48. From the Developer's Web Site. Available at: Accessed May 6, 2019.
50. Nieminen MS, Fruhwald S, Heunks LM, et al. Levosimendan: current data, clinical use and future development. Heart Lung Vessel. 2013;5:227–245.
51. Follath F, Cleland JG, Just H, et al. Steering Committee and Investigators of the Levosimendan Infusion versus Dobutamine (LIDO) Study. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet. 2002;360:196–202.
52. Slawsky MT, Colucci WS, Gottlieb SS, et al. Acute hemodynamic and clinical effects of levosimendan in patients with severe heart failure. Study Investigators. Circulation. 2000;102:2222–2227.
53. Nieminen MS, Akkila J, Hasenfuss G, et al. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol. 2000;36:1903–1912.
54. Lilleberg J, Nieminen MS, Akkila J, et al. Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J. 1998;19:660–668.
55. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during levosimendan infusion in congestive heart failure. Clin Pharmacol Ther. 2000;68:522–531.
56. Mebazaa A, Nieminen MS, Filippatos GS, et al. Levosimendan vs. dobutamine: outcomes for acute heart failure patients on beta-blockers in SURVIVE. Eur J Heart Fail. 2009;11:304–311.
57. Sonntag S, Sundberg S, Lehtonen LA, et al. The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia. J Am Coll Cardiol. 2004;43:2177–2182.
58. Givertz MM, Andreou C, Conrad CH, et al. Direct myocardial effects of levosimendan in humans with left ventricular dysfunction: alteration of force-frequency and relaxation-frequency relationships. Circulation. 2007;115:1218–1224.
59. Pollesello P, Ovaska M, Kaivola J, et al. Binding of a new Ca2+ sensitizer, levosimendan, to recombinant human cardiac troponin C. A molecular modelling, fluorescence probe, and proton nuclear magnetic resonance study. J Biol Chem. 1994;269:28584–28590.
60. Sorsa T, Pollesello P, Solaro RJ. The contractile apparatus as a target for drugs against heart failure: interaction of levosimendan, a calcium sensitiser, with cardiac troponin c. Mol Cell Biochem. 2004;266:87–107.
61. Haikala H, Kaivola J, Nissinen E, et al. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol. 1995;27:1859–1866.
62. Haikala H, Linden IB. Mechanisms of action of calcium-sensitizing drugs. J Cardiovasc Pharmacol. 1995;26(suppl 1):S10–S19.
63. Haikala H, Pollesello P. Calcium sensitivity enhancers. IDrugs. 2000;3:1199–1205.
64. Sorsa T, Heikkinen S, Abbott MB, et al. Binding of levosimendan, a calcium sensitizer, to cardiac troponin C. J Biol Chem. 2001;276:9337–9343.
65. Robertson IM, Baryshnikova OK, Li MX, et al. Defining the binding site of levosimendan and its analogues in a regulatory cardiac troponin C-troponin I complex. Biochemistry. 2008;47:7485–7495.
66. Robertson IM, Sun YB, Li MX, et al. A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex. J Mol Cell Cardiol. 2010;49:1031–1041.
67. Sorsa T, Pollesello P, Permi P, et al. Interaction of levosimendan with cardiac troponin C in the presence of cardiac troponin I peptides. J Mol Cell Cardiol. 2003;35:1055–1061.
68. Levijoki J, Pollesello P, Kaivola J, et al. Further evidence for the cardiac troponin C mediated calcium sensitization by levosimendan: structure-response and binding analysis with analogs of levosimendan. J Mol Cell Cardiol. 2000;32:479–491.
69. Klein BA, Reiz B, Robertson IM, et al. Reversible covalent reaction of levosimendan with cardiac troponin C in vitro and in situ. Biochemistry. 2018;57:2256–2265.
70. Hillestad V, Kramer F, Golz S, et al. Long-term levosimendan treatment improves systolic function and myocardial relaxation in mice with cardiomyocyte-specific disruption of the Serca2 gene. J Appl Physiol. 2013;115:1572–1580.
71. Bowman P, Haikala H, Paul RJ. Levosimendan, a calcium sensitizer in cardiac muscle, induces relaxation in coronary smooth muscle through calcium desensitization. J Pharmacol Exp Ther. 1999;288:316–325.
72. Pagel PS, Harkin CP, Hettrick DA, et al. Levosimendan (OR-1259), a myofilament calcium sensitizer, enhances myocardial contractility but does not alter isovolumic relaxation in conscious and anesthetized dogs. Anesthesiology. 1994;81:974–987.
73. Yokoshiki H, Katsube Y, Sunagawa M, et al. Levosimendan, a novel Ca2+ sensitizer, activates the glibenclamide-sensitive K+ channel in rat arterial myocytes. Eur J Pharmacol. 1997;333:249–259.
74. Pataricza J, Hõhn J, Petri A, et al. Comparison of the vasorelaxing effect of cromakalim and the new inodilator, levosimendan, in human isolated portal vein. J Pharm Pharmacol. 2000;52:213–217.
75. Kaheinen P, Pollesello P, Levijoki J, et al. Levosimendan increases diastolic coronary flow in isolated Guinea-pig heart by opening ATP-sensitive potassium channels. J Cardiovasc Pharmacol. 2001;37:367–374.
76. Erdei N, Papp Z, Pollesello P, et al. The levosimendan metabolite OR-1896 elicits vasodilation by activating the K(ATP) and BK(Ca) channels in rat isolated arterioles. Br J Pharmacol. 2006;148:696–702.
77. Maytin M, Colucci WS. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol. 2005;96:26G–31G.
78. Louhelainen M, Vahtola E, Kaheinen P, et al. Effects of levosimendan on cardiac remodeling and cardiomyocyte apoptosis in hypertensive Dahl/Rapp rats. Br J Pharmacol. 2007;150:851–861.
79. Pollesello P, Papp Z. The cardioprotective effects of levosimendan: preclinical and clinical evidence. J Cardiovasc Pharmacol. 2007;50:257–263.
80. du Toit EF, Genis A, Opie LH, et al. A role for the RISK pathway and K(ATP) channels in pre- and post-conditioning induced by levosimendan in the isolated Guinea pig heart. Br J Pharmacol. 2008;154:41–50.
81. Labriola C, Siro-Brigiani M, Carrata F, et al. Hemodynamic effects of levosimendan in patients with low-output heart failure after cardiac surgery. Int J Clin Pharmacol Ther. 2004;42:204–211.
82. Pagel PS, Hettrick DA, Warltier DC. Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol. 1996;119:609–615.
83. Lilleberg J, Sundberg S, Nieminen MS. Dose-range study of a new calcium sensitizer, levosimendan, in patients with left ventricular dysfunction. J Cardiovasc Pharmacol. 1995;26(suppl 1):S63–S69.
84. Lannemyr L, Ricksten SE, Rundqvist B, et al. Differential effects of levosimendan and dobutamine on glomerular filtration rate in patients with heart failure and renal impairment. J Am Heart Assoc. 2018;7:e008455.
85. Kopustinskiene DM, Pollesello P, Saris NE. Potassium-specific effects of levosimendan on heart mitochondria. Biochem Pharmacol. 2004;68:807–812.
86. Papp Z, Édes I, Fruhwald S, et al. Levosimendan: molecular mechanisms and clinical implications: consensus of experts on the mechanisms of action of levosimendan. Int J Cardiol. 2012;159:82–87.
87. Szilágyi S, Pollesello P, Levijoki J, et al. Two inotropes with different mechanisms of action: contractile, PDE-inhibitory and direct myofibrillar effects of levosimendan and enoximone. J Cardiovasc Pharmacol. 2005;46:369–376.
88. Levijoki J, Kivikko M, Pollesello P, et al. Levosimendan alone and in combination with valsartan prevents stroke in Dahl salt-sensitive rats. Eur J Pharmacol. 2015;750:132–140.
89. Varvarousi G, Xanthos T, Sarafidou P, et al. Role of levosimendan in the management of subarachnoid hemorrhage. Am J Emerg Med. 2016;34:298–306.
90. Kivikko M, Kuoppamäki M, Soinne L, et al. Oral levosimendan increases cerebral blood flow velocities in patients with a history of stroke or transient ischemic attack: a pilot safety study. Curr Ther Res Clin Exp. 2015;77:46–51.
91. van Hees HW, Dekhuijzen PN, Heunks LM. Levosimendan enhances force generation of diaphragm muscle from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2009;179:41–47.
92. Maack C, Eschenhagen T, Hamdani N, et al. Treatments targeting inotropy. Eur Heart J. 2018. doi: [epub ahead of print].
93. Bouchez S, Fedele F, Giannakoulas G, et al. Levosimendan in acute and advanced heart failure: an expert perspective on posology and therapeutic application. Cardiovasc Drugs Ther. 2018;32:617–624.
94. Kivikko M, Lehtonen L, Colucci WS. Sustained hemodynamic effects of intravenous levosimendan. Circulation. 2003;107:81–86.
95. Christensen TH, Kedes L. The myogenic regulatory circuit that controls cardiac/slow twitch troponin C gene transcription in skeletal muscle involves E-box, MEF-2, and MEF-3 motifs. Gene Expr. 1999;8:247–261.
96. Parmacek MS, Leiden JM. Structure, function, and regulation of troponin C. Circulation. 1991;84:991–1003.
97. Stuart CA, McCurry MP, Marino A, et al. Slow-twitch fiber proportion in skeletal muscle correlates with insulin responsiveness. J Clin Endocrinol Metab. 2013;98:2027–2036.
98. Pineda-Sanabria SE, Robertson IM, Sun YB, et al. Probing the mechanism of cardiovascular drugs using a covalent levosimendan analog. J Mol Cell Cardiol. 2016;92:174–184.
99. van Hees HW, Andrade Acuña G, Linkels M, et al. Levosimendan improves calcium sensitivity of diaphragm muscle fibres from a rat model of heart failure. Br J Pharmacol. 2011;162:566–573.
100. Schellekens WJ, van Hees HW, Linkels M, et al. Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice. Crit Care. 2015;19:69.
101. Kuoppamäki M, Lindstedt K, Levijoki J, et al. Scientific background for developing oral levosimendan (ODM-109) for the treatment of amyotrophic lateral sclerosis. Theme 3 in vivo experimental models. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(suppl 2):130–151.
102. Shen D, Hou B, Xu Y, et al. Brain structural and perfusion signature of amyotrophic lateral sclerosis with varying levels of cognitive deficit. Front Neurol. 2018;9:364.
103. Rule RR, Schuff N, Miller RG, et al. Gray matter perfusion correlates with disease severity in ALS. Neurology. 2010;74:821–827.
104. Waldemar G, Vorstrup S, Jensen TS, et al. Focal reductions of cerebral blood flow in amyotrophic lateral sclerosis: a [99mTc]-d,l-HMPAO SPECT study. J Neurol Sci. 1992;107:19–28.
105. Keskin I, Forsgren E, Lehmann M, et al. The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension. Acta Neuropathol. 2019;138;85–101.
106. Wanderer S, Mrosek J, Gessler F, et al. Levosimendan reduces prostaglandin F2a-dependent vasoconstriction in physiological vessels and after experimentally induced subarachnoid hemorrhage. Curr Neurovasc Res. 2018;15:72–80.
107. Konczalla J, Wanderer S, Mrosek J, et al. Levosimendan, a new therapeutic approach to prevent delayed cerebral vasospasm after subarachnoid hemorrhage? Acta Neurochir. 2106;158:2075–2083.
108. Cengiz SL, Erdi MF, Tosun M, et al. Beneficial effects of levosimendan on cerebral vasospasm induced by subarachnoid haemorrhage: an experimental study. Brain Inj. 2010;24:877–885.
109. Lautenschlaeger J, Prell T, Grosskreutz J. Endoplasmic reticulum stress and the ER mitochondrial calcium cycle in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2012;13:166–177.
110. Walker AK, Atkin JD. Stress signaling from the endoplasmic reticulum: a central player in the pathogenesis of amyotrophic lateral sclerosis. IUBMB Life. 2011;63:754–763.
111. Li PC, Yang YC, Hwang GY, et al. Inhibition of reverse-mode sodium-calcium exchanger activity and apoptosis by levosimendan in human cardiomyocyte progenitor cell-derived cardiomyocytes after anoxia and reoxygenation. PLoS One. 2014;9:e85909.
112. Guégan C, Przedborski S. Programmed cell death in amyotrophic lateral sclerosis. J Clin Invest. 2003;111:153–161.
113. Liu C, Hong K, Chen H, et al. Evidence for a protective role of CX3CL1/CX3CR1 axis in a model of amyotrophic lateral sclerosis. Biol Chem. 2019;400:651–661.
114. Grossini E, Bellofatto K, Farruggio S, et al. Levosimendan inhibits peroxidation in hepatocytes by modulating apoptosis/autophagy interplay. PLoS One. 2015;10:e0124742.
115. Brunner SN, Bogert NV, Schnitzbauer AA, et al. Levosimendan protects human hepatocytes from ischemia-reperfusion injury. PLoS One. 2017;12:e0187839.
116. Wang J, Chen H, Zhou Y, et al. Levosimendan pretreatment inhibits myocardial apoptosis in swine after coronary microembolization. Cell Physiol Biochem. 2017;41:67–78.
117. Uberti F, Caimmi PP, Molinari C, et al. Levosimendan modulates programmed forms of cell death through K(ATP) channels and nitric oxide. J Cardiovasc Pharmacol. 2011;57:246–258.
118. Caimmi PP, Molinari C, Uberti F, et al. Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide. Eur J Cardiothorac Surg. 2011;39:e59–67.
119. Aminzadeh A, Mehrzadi S. Cardioprotective effect of levosimendan against homocysteine-induced mitochondrial stress and apoptotic cell death in H9C2. Biochem Biophys Res Commun. 2018;507:395–399.
120. Tawfik MK, El-Kherbetawy MK, Makary S. Cardioprotective and anti-aggregatory effects of levosimendan on isoproterenol-induced myocardial injury in high-fat-fed rats involves modulation of PI3K/Akt/mTOR signaling pathway and inhibition of apoptosis: comparison to cilostazol. J Cardiovasc Pharmacol Ther. 2018;23:456–471.
121. Plaschke K, Bent F, Wagner S, et al. In contrast to its anti-inflammatory and anti-apoptotic peripheral effect, levosimendan failed to induce a long-term neuroprotective effect in a rat model of mild septic encephalopathy: a pilot study. Neurosci Lett. 2014;560:117–121.
122. Soeding PF, Crack PJ, Wright CE, et al. Levosimendan preserves the contractile responsiveness of hypoxic human myocardium via mitochondrial K(ATP) channel and potential pERK 1/2 activation. Eur J Pharmacol. 2011;655:59–66.
123. Hasslacher J, Bijuklic K, Bertocchi C, et al. 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. Crit Care. 2011;15:R166.
124. Redler RL, Dokholyan NV. The complex molecular biology of amyotrophic lateral sclerosis (ALS). Prog Mol Biol Transl Sci. 2012;107:215–262.
125. Revermann M, Schloss M, Mieth A, et al. Levosimendan attenuates pulmonary vascular remodelling. Intensive Care Med. 2011;37:1368–1377.
126. Zager RAA, Johnson AC, Lund S, et al. Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Ren Physiol. 2006;290:F1453–F62.
127. Avgeropoulou C, Andreadou I, Markantonis-Kyroudis S, et al. The Ca2+-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;7:882–887.
128. Adam M, Meyer S, Knors H, et al. Levosimendan displays anti-inflammatory effects and decreases MPO bioavailability in patients with severe heart failure. Sci Rep. 2015;5:9704.
129. Adamopoulos S, Parissis JT, Iliodromitis EK, et al. Effects of levosimendan versus dobutamine on inflammatory and apoptotic pathways in acutely decompensated chronic heart failure. Am J Cardiol. 2006;98:102–106.
130. Karakus E, Halici Z, Albayrak A, et al. Beneficial pharmacological effects of levosimendan on antioxidant status of acute inflammation induced in paw of rat: involvement in inflammatory mediators. Basic Clin Pharmacol Toxicol. 2013;112:156–163.
131. Muyderman H, Chen T. Mitochondrial dysfunction in amyotrophic lateral sclerosis—a valid pharmacological target? Br J Pharmacol. 2014;171:2191–2205.
132. Gödény I, Pollesello P, Edes I, et al. Levosimendan and its metabolite OR-1896 elicit KATP channel-dependent dilation in resistance arteries in vivo. Pharmacol Rep. 2013;65:1304–1310.
133. Kopustinskiene DM, Pollesello P, Saris NE. Levosimendan is a mitochondrial K(ATP) channel opener. Eur J Pharmacol. 2001;428:311–314.
134. Rieg AD, Rossaint R, Verjans E, et al. Levosimendan relaxes pulmonary arteries and veins in precision-cut lung slices - the role of KATP-channels, cAMP and cGMP. PLoS One. 2013;8:e66195.
135. Bunte S, Behmenburg F, Bongartz A, et al. Preconditioning by levosimendan is mediated by activation of mitochondrial ca(2+)-sensitive potassium (mbkca) channels. Cardiovasc Drugs Ther. 2018;32:427–434.
136. Sommer S, Leistner M, Aleksic I, et al. Impact of levosimendan and ischaemia-reperfusion injury on myocardial subsarcolemmal mitochondrial respiratory chain, mitochondrial membrane potential, Ca2+ cycling and ATP synthesis. Eur J Cardiothorac Surg. 2016;49:e54–62.
137. Deschodt-Arsac V, Calmettes G, Raffard G, et al. Absence of mitochondrial activation during levosimendan inotropic action in perfused paced Guinea pig hearts as demonstrated by modular control analysis. Am J Physiol Regul Integr Comp Physiol. 2010;299:R786–R789.
138. Doorduin J, Sinderby CA, Beck J, et al. The calcium sensitizer levosimendan improves human diaphragm function. Am J Respir Crit Care Med. 2012;185:90–95.
139. Al-Chalabi A, Shaw P, Leigh PN, et al. Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry. 2019;90:1165–1170.
140. Frey D, Schneider C, Xu L, et al. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000;20:2534–2542.
141. Ukkonen H, Saraste M, Akkila J, et al. Myocardial efficiency during calcium sensitization with levosimendan: a noninvasive study with positron emission tomography and echocardiography in healthy volunteers. Clin Pharmacol Ther. 1997;61:596–607.
142. Nieminen MS, Pollesello P, Vajda G, et al. Effects of levosimendan on the energy balance: preclinical and clinical evidence. J Cardiovasc Pharmacol. 2009;53:302–310.

levosimendan; ALS; diaphragm; muscle; cardiac troponin C; slow-twitch fibers

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.