Levosimendan: Molecular mechanisms and clinical implications

Papp, Zoltán; Édes, István; Fruhwald, Sonja; Hert, Stefan De; Salmenperä, Markku; Leppikangas, Heli; Mebazaa, Alexandre; Landoni, Giovanni; Grossini, Elena; Caimmi, Philippe Primo; Morelli, Andrea; Guarracino, Fabio; Schwinger, Robert H. G.; Meyer, Sven; Algotsson, Lars; Wikström, Bernt Gerhard; Jörgensen, Kirsten; Filippatos, Gerasimos; Parissis, John; González, Martín J. García; Parkhomenko, Alexander; Yilmaz, Mehmet Birhan; Kivikko, Matti; Pollesello, Piero; Folláth, Ferenc

doi:10.1016/j.ijcard.2011.07.022

Cited by 256 publications

(127 citation statements)

References 97 publications

(114 reference statements)

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“…Of these, levosimendan is the most widely studied to date, licensed in some South American and European countries for use as a positive inotropic agent in acute decompensated systolic heart failure. Levosimendan has been shown to improve cardiac output and decrease symptoms of heart failure 134 . However, its use has been limited by associated cardiac arrhythmias and hypotension, and recent Phase III trials demonstrated no improvement in overall mortality 135,136 , though some meta-analyses suggest some mortality benefit 137 .…”

Section: Drugs That Bind the Regulatory Domain Cntncmentioning

confidence: 99%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

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106

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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Section: Drugs That Bind the Regulatory Domain Cntncmentioning

confidence: 99%

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

106

105

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“…Levosimendan has been developed for the treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. The pharmacology of levosimendan includes positive inotropy with energy-sparing effects, positive effects on ventriculo-arterial coupling, peripheral vasodilation and increasing tissue perfusion, anti-stunning effects and anti-inflammatory and anti-apoptotic effects [9]. Levosimendan has been shown to protect cardiomyocytes from undergoing apoptosis, which depends on ATP-sensitive K+ channels [29].…”

Section: Discussionmentioning

confidence: 99%

“…Levosimendan has been developed for the treatment of acute heart failure and other cardiac conditions where the use of an inodilator is considered appropriate. At least three major pharmacological actions have been identified [9], i.e. (i) the selective binding to Ca2+-saturated cardiac troponin C, (ii) the opening of ATP-sensitive potassium (KATP) channels in the vasculature, and (iii) the opening of KATP channels in the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Levosimendan Pretreatment Inhibits Myocardial Apoptosis in Swine after Coronary Microembolization

Wang

Han

Zhou

et al. 2017

Cell Physiol Biochem

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Background/Aims: In addition to its cardiotonic effect, levosimendan has been thought to have multiple cardiovascular benefits, including anti-inflammatory and anti-apoptotic. Phosphatase and tensin homolog deleted on chromosome ten (PTEN) has been revealed to be up-regulated in circumstances of coronary microembolization (CME), and the PTEN signaling pathway mediates myocardial apoptosis in swine after CME. However, whether this functional protein could be modified by pretreatment of levosimendan in models of CME has not been disclosed yet. Methods: Swine CME was induced by intra-coronary injection of inertia plastic microspheres (diameter 42µm) into left anterior descending coronary, with or without pretreatment of levosimendan or PTEN siRNA. Echocardiologic measurements, Terminal-deoxynucleotidyl Transferase Mediated Nick End Labeling (TUNEL) staining and western blotting were applied to assess their functional, morphological and molecular effects in CME. Results: PTEN mRNA and protein were aberrantly up-regulated in cardiomyocytes following CME. Furthermore, down-regulation of PTEN in vivo via siRNA was associated with an improved cardiac function, attenuated myocardial apoptosis, and concomitantly inhibited expressions of key proapoptotic proteins such as caspase-3. Interestingly, levosimendan could markedly attenuate PTEN expression and inhibit myocardial apoptosis, therefore partially reverse cardiac dysfunction. Conclusion: Modulation of PTEN was probably as a potential mechanism involved in the beneficial effects of pretreatment of levosimendan to cardiac function and apoptosis in animal models of CME.

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“…Diese günstigen Veränderun-gen waren auch noch nach Beendigung der Levosimendantherapie nachweisbar, was auf die lange Halbwertszeit der Metaboliten zurückzuführen sein dürfte. Bei ischämischer RV-Insuffizienz und nach chirurgischen Maßnahmen an den Mitralklappen bewirkt Levosimendan eine Verbesserung der RV-Funktion und eine Abnahme des PVR [51]. Bei chronischer PH reduziert Levosimendan den PAPm sowie den PVR und verbessert die gemischtvenöse Sauerstoffsättigung [52].…”

Section: Kalzium-sensitizerunclassified

Management von Patienten mit pulmonaler Hypertonie

et al. 2012

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Due to the increased survival of patients with pulmonary hypertension, even non-cardiac anesthesiologists will see these patients more frequently for anesthesia. The hemodynamic goal in the perioperative period is to avoid an increase in pulmonary vascular resistance (PVR) and to reduce a possibly pre-existing elevated PVR. Acute increases of chronically elevated PVR may result from hypoxia, hypercapnia, acidosis, hypothermia, elevated sympathetic output and also release of endogenous or application of exogenous pulmonary vasoconstrictors. Early recognition and treatment of these changes might be life saving in these patients. Drug interventions to perioperatively reduce PVR include administration of pulmonary vasodilators, such as oxygen, prostacyclines (epoprostenol, iloprost), phosphodiesterase III (milrinone) and V (sildenafil) inhibitors, as well as nitrates and nitric oxide. Along with the concept of selective pulmonary vasodilation inhalative administration of pulmonary vasodilators has benefits compared to intravenous administration. New therapeutic strategies, such as inhalational iloprost, inhalational milrinone and intravenous sildenafil can be introduced without significant technical support even in smaller departments.

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Levosimendan: Molecular mechanisms and clinical implications

Cited by 256 publications

References 97 publications

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Levosimendan Pretreatment Inhibits Myocardial Apoptosis in Swine after Coronary Microembolization

Management von Patienten mit pulmonaler Hypertonie

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