Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent

Gheorghiade, Mihai; Blair, John E.; Filippatos, Gerasimos; Macarie, Cezar; Rużyłło, Witold; Korewicki, J; Bubenek-Turconi, Serban I.; Ceracchi, Maurizio; Bianchetti, Maria; Carminati, Paolo; Kremastinos, Dimitrios Th.; Valentini, Giovanni; Sabbah, Hani N.

doi:10.1016/j.jacc.2008.03.015

Cited by 144 publications

(135 citation statements)

References 20 publications

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“…Istaroxime represents a new class of Na + /K + -ATPase inhibitors and stimulates SERCA, thereby exhibiting inotropic and lusitropic effects [131,132]. In animal models, this new drug exerts inotropic activity comparable with that of digitalis but produces less arrhythmia [133].…”

Section: Novel Therapies For the Septic Heartmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer²

2013

Current Vascular Pharmacology

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Septic shock is characterized by circulatory compromise, microcirculatory alterations and mitochondrial damage, which all reduce cellular energy production. In order to reduce the risk of major cell death and a diminished likelihood of recovery, adaptive changes appear to be activated. As a result, cells and organs may survive in a non-functioning hibernation-like condition. Sepsis-induced cardiac dysfunction may represent an example of such functional shutdown. Sepsis-induced myocardial dysfunction is common, corresponds to the severity of sepsis, and is reversible in survivors. Its mechanisms include the attenuation of the adrenergic response at the cardiomyocyte level, alterations of intracellular calcium trafficking and blunted calcium sensitivity of contractile proteins. All these changes are mediated by cytokines. Treatment includes preload optimization with sufficient fluids. However, excessive volume loading is harmful. The first line vasopressor recommended at present is norepinephrine, while vasopressin can be started as a salvage therapy for those not responding to catecholamines. During early sepsis, cardiac output can be increased by dobutamine. While early administration of catecholamines might be necessary to restore adequate organ perfusion, prolonged administration might be harmful. Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine reduces myocardial oxygen expenditure and ameliorates diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. All these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice. While early administration of catecholamines might be necessary to restore adequate organ perfusion and pressure, prolonged administration might be harmful.Novel therapies for sepsis-induced cardiac dysfunction are discussed in this article. Cardiac inotropy can be increased by levosimendan, istaroxime or omecamtiv mecarbil without greatly increasing cellular oxygen demands. Heart rate reduction with ivabradine will reduce myocardial oxygen expenditure and ameliorate diastolic filling. Beta-blockers additionally reduce local and systemic inflammation. Advances may also come from metabolic interventions such as pyruvate, succinate or high dose insulin substitutions. However, all these potentially advantageous concepts require rigorous testing before implementation in routine clinical practice.-3 -Alain Rudiger & Mervyn Singer: The heart in sepsis

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Section: Novel Therapies For the Septic Heartmentioning

confidence: 99%

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

Rudiger¹,

Singer²

2013

Current Vascular Pharmacology

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“…The resulting modification of the SERCA2a E2 to E1 transition then accelerates Ca 2+ cycling. This would have translational implications through the resulting, positive, effects upon the cardiac contraction-relaxation cycle particularly in failing hearts (Gheorghiade et al, 2008;Shah et al, 2009). To this end, strategies involving cAMP/PKA signalling might contribute to the management of chronic cardiac negative remodelling and failure.…”

Section: Camentioning

confidence: 99%

SERCA2a stimulation by istaroxime: a novel mechanism of action with translational implications

Huang

2013

British J Pharmacology

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Sarcoplasmic reticular (SR) Ca 2+-ATPase (SERCA2a) is central to cardiac electrophysiological and mechanical function. It ensures full diastolic relaxation minimizing delayed after-potentials that would otherwise compromise membrane electrophysiological stability, and optimizes SR Ca 2+ refilling and systolic contraction. Previous studies demonstrated that the small molecule agent istaroxime stimulates SERCA2a-ATPase activity, restoring its function in failing hearts, and enhancing indices of mechanical, and SR Ca 2+ release and re-uptake, activity. Ferrandi et al (2013) now elegantly demonstrate its ability to dissociate the phospholamdan (PB) bound to cardiac SERCA2a, thereby removing the inhibitory effect of PB on SERCA2a. This effect was independent of the cAMP/PKA system and modified a specific SERCA2a reaction step. They used SERCA-enriched SR preparations from a rigorously validated and realistic physiological, canine model of cardiac failure with established Na + -K + -ATPase sensitivity to cardiac glycosides and SR Ca 2+ handling features. These findings potentially translate into a novel management of the major and increasingly important public health challenge of chronic cardiac failure. Agents stimulating rather than inhibiting activity in specific biomolecules, particularly those involving novel mechanisms of action of both pharmacological and translational importance that thereby exert therapeutic effects on common and medically important conditions, merit positive editorial attention. The article by Ferrandi et al. (2013) in this volume decidedly fulfils such criteria. An elegant series of experiments characterizes the mechanisms of action by which the small molecule istaroxime stimulates cardiac sarcoplasmic reticular (SR) Ca 2+ -ATPase (SERCA2a) activity. These findings were then related to possible translations into the management of the major and increasingly important public health challenge of cardiac failure (Khatibzadeh et al., 2012). LINKED ARTICLESERCA2a is thought to have physiologically strategic and intricate roles in cardiac electrophysiological and mechanical function. Its diastolic translocation of released Ca 2+ from cytosol to SR minimizes cytosolic [Ca 2+ ]. This ensures full myocardial relaxation, a normal ventricular diastolic compliance and filling, and minimizes delayed after-potentials that would otherwise compromise membrane electrophysiological stability. These functions thus prevent the diastolic dysfunction and arrhythmic tendency characteristic of cardiac failure. Recent reports from genetically modified RyR2-P2328S hearts have further implicated altered Ca 2+ homeostasis in modulating Na + channel function and the resulting alterations in action potential conduction, which if slowed would produce arrhythmic substrate (King et al., 2013). The

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“…Istaroxime, que ativa SERCA2a e inibe a Na-K ATPase, em estudo de fase II, determinou melhora hemodinâmica 318 .…”

Section: Inibidores De Outros Sistemas Além Do Sistemaunclassified

Atualização da Diretriz Brasileira de Insuficiência Cardíaca Crônica - 2012

2012

Arquivos Brasileiros De Cardiologia

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Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent

Cited by 144 publications

References 20 publications

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

The Heart in Sepsis: From Basic Mechanisms to Clinical Management

SERCA2a stimulation by istaroxime: a novel mechanism of action with translational implications

Atualização da Diretriz Brasileira de Insuficiência Cardíaca Crônica - 2012

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