Istaroxime in acute heart failure: the holy grail is at HORIZON?

Chioncel, Ovidiu; Collins, Sean P.; Butler, Javed

doi:10.1002/ejhf.1843

Cited by 8 publications

(5 citation statements)

References 19 publications

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“…tachyarrhythmias, increased myocardial oxygen consumption and myocardial ischaemia. 8,10 Istaroxime is a derivative of androstenedione, chemically unrelated to cardiac glycosides, that exerts its effects through dual mechanisms of action: (1) the inhibition of the Na + /K + -ATPase activity, thereby causing an increase in intracellular calcium, which increases cardiomyocyte contractility (inotropy); and (2) the activation of the sarcoplasmic reticulum calcium ATPase isoform 2a (SERCA2a) by modulating SERCA-phospholamban interaction, promoting sarcoplasmic reticulum calcium reuptake, thus improving both relaxation (lusitropy) and contractility, 11 as well as potentially reducing risk for arrhythmias. Istaroxime has been shown to improve pulmonary capillary wedge pressure and diastolic cardiac function and produces dose-related increases in systolic BP (SBP) without activating the adrenergic system.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of istaroxime in patients with acute heart failure‐related pre‐cardiogenic shock – a multicentre, randomized, double‐blind, placebo‐controlled, parallel group study (SEISMiC)

Metra

Chioncel

Cotter

et al. 2022

European J of Heart Fail

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Aims We examined the effects of istaroxime in patients hospitalized for acute heart failure (AHF) related Society for Cardiovascular Angiography and Interventions (SCAI) stage B pre‐cardiogenic shock (CS). Methods and results Sixty patients with AHF without acute myocardial infarction with pre‐CS, defined as systolic blood pressure (SBP) <90 mmHg without hypoperfusion, venous lactate ≥2 mmol/L and/or mechanical or inotropic support, were randomized to istaroxime 1.0–1.5 μg/kg/min or placebo for 24 h. The primary endpoint, the adjusted area under the curve (AUC) change in SBP from time of treatment to 6 h, was 53.1 (standard error [SE] 6.88) mmHg × hour versus 30.9 (SE 6.76) mmHg × hour with istaroxime versus placebo (p = 0.017). Adjusted SBP AUC at 24 h was 291.2 (SE 27.5) versus 208.7 (SE 27.0) mmHg × hour (p = 0.025). At 24 h, some echocardiographic measurements improved with istaroxime versus placebo including cardiac index (+0.21 L/min/m2; p = 0.016), left atrial area (−1.8 cm2; p = 0.008), and left ventricular end‐systolic volume (−12.0 ml; p = 0.034). There were no significant differences in pulse pressure, laboratory measurements, serious adverse events or adverse events between the treatment groups except for more nausea, vomiting and infusion site pain in the istaroxime‐treated patients. In a post‐hoc analysis, patients receiving ≤1.0 μg/kg/min versus 1.5 μg/kg/min had similar increase in blood pressure, but a trend towards less adverse events. Conclusion In a phase 2a study of patients with AHF related pre‐CS, istaroxime improved blood pressure and some echocardiography measures related to heart failure and was well tolerated.

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Section: Introductionmentioning

confidence: 99%

Safety and efficacy of istaroxime in patients with acute heart failure‐related pre‐cardiogenic shock – a multicentre, randomized, double‐blind, placebo‐controlled, parallel group study (SEISMiC)

Metra

Chioncel

Cotter

et al. 2022

European J of Heart Fail

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“…Istaroxime, a new HF drug, acts through a dual pathway: Na + /K + ATPase blockage and potentiation of Ca 2+ uptake into sarcoplasmic reticulum (SR) mediated by the SERCA2a. This is at the basis of its inotropic and lusitropic effects, due to the ability of dissociating SERCA from its inhibitory protein phospholamban with a lower risk of Ca 2+ triggered arrhythmias (113).…”

Section: Drugs Acting On Intracellular Calcium Dysregulationmentioning

confidence: 99%

Novelties in the pharmacological approaches for chronic heart failure: new drugs and cardiovascular targets

Correale

Tricarico

Croella

et al. 2023

Front. Cardiovasc. Med.

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Despite recent advances in chronic heart failure (HF) management, the prognosis of HF patients is poor. This highlights the need for researching new drugs targeting, beyond neurohumoral and hemodynamic modulation approach, such as cardiomyocyte metabolism, myocardial interstitium, intracellular regulation and NO-sGC pathway. In this review we report main novelties on new possible pharmacological targets for HF therapy, mainly on new drugs acting on cardiac metabolism, GCs-cGMP pathway, mitochondrial function and intracellular calcium dysregulation.

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“…However, the combination of gene therapy with mechanical circulatory support did not show positive outcomes in the SERCA-LVAD trial due to the small cohort of patients and safety concerns [ 190 ]. In turn, istaroxime demonstrates both rapid calcium return with myocardial relaxation via SERCA2 stimulation and contractility improvement by Na+/K+-AT P-ase inhibition [ 191 ]. Therefore, it has also been clinically tested to examine the occurrence of cardiac adverse events, such as arrhythmia [ 192 ].…”

Section: Combination Of Mechanical Unloading and Pharmacotherapy For ...mentioning

confidence: 99%

Novel Targets for a Combination of Mechanical Unloading with Pharmacotherapy in Advanced Heart Failure

Jędrzejewska

Braczko

Kawecka

et al. 2022

IJMS

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LVAD therapy is an effective rescue in acute and especially chronic cardiac failure. In several scenarios, it provides a platform for regeneration and sustained myocardial recovery. While unloading seems to be a key element, pharmacotherapy may provide powerful tools to enhance effective cardiac regeneration. The synergy between LVAD support and medical agents may ensure satisfying outcomes on cardiomyocyte recovery followed by improved quality and quantity of patient life. This review summarizes the previous and contemporary strategies for combining LVAD with pharmacotherapy and proposes new therapeutic targets. Regulation of metabolic pathways, enhancing mitochondrial biogenesis and function, immunomodulating treatment, and stem-cell therapies represent therapeutic areas that require further experimental and clinical studies on their effectiveness in combination with mechanical unloading.

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Istaroxime in acute heart failure: the holy grail is at HORIZON?

Abstract: This article refers to 'Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial' by V. Carubelli et al., published in this issue on pages 1684-1693.

Cited by 8 publications

References 19 publications

Safety and efficacy of istaroxime in patients with acute heart failure‐related pre‐cardiogenic shock – a multicentre, randomized, double‐blind, placebo‐controlled, parallel group study (SEISMiC)

Safety and efficacy of istaroxime in patients with acute heart failure‐related pre‐cardiogenic shock – a multicentre, randomized, double‐blind, placebo‐controlled, parallel group study (SEISMiC)

Novelties in the pharmacological approaches for chronic heart failure: new drugs and cardiovascular targets

Novel Targets for a Combination of Mechanical Unloading with Pharmacotherapy in Advanced Heart Failure

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