Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs

Bossu, Alexandre; Kostense, Amée; Beekman, Henriette D.M.; Houtman, Marien J C; Heyden, Marcel A G van der; Vos, Marc A.

doi:10.1016/j.phrs.2018.05.001

Cited by 12 publications

(9 citation statements)

References 32 publications

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“…This study has also demonstrated that istaroxime shortens AP repolarization in the zebrafish heart and isolated zebrafish pln R14del cardiomyocytes, a phenomenon previously reported in vitro and in vivo in the chronic atrioventricular block dog model 58 . Under physiological conditions, the removal of Ca 2+ from the cytosol is achieved via SR Ca 2+ reuptake and via the forward mode of the NCX.…”

Section: Discussionsupporting

confidence: 80%

Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

Kamel

Opbergen

Koopman

et al. 2020

Preprint

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The heterozygous phospholamban (PLN) p.Arg14del (R14del) mutation is found in patients with dilated or arrhythmogenic cardiomyopathy. The PLN R14del mutation triggers cardiac contractile dysfunction and arrhythmogenesis by affecting intracellular Ca2+ dynamics. Little is known about the physiological processes preceding PLN R14del induced cardiomyopathy, which is characterized by sub-epicardial accumulation of fibrofatty tissue, and a specific drug treatment is currently lacking. Here, we addressed these issues using a knock-in PLN R14del zebrafish model. Hearts from adult zebrafish with the R14del mutation display age-related remodeling with sub-epicardial inflammation and fibrosis. Echocardiography revealed contractile pulsus alternans before overt structural changes occurred, which correlated at the cellular level with action potential duration (APD) alternans. These functional alterations are preceded by diminished Ca2+ transient amplitudes in embryonic hearts. We found that istaroxime treatment ameliorates the in vivo Ca2+ dysregulation, rescues the cellular APD alternans, while it improves cardiac relaxation. Thus, we present novel insight into the pathophysiology of PLN R14del cardiomyopathy and identify istaroxime as a potential novel drug for its treatment.

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Section: Discussionsupporting

confidence: 80%

Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

Kamel

Opbergen

Koopman

et al. 2020

Preprint

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“…Therefore, defibrillation is scored with 50, 75 or 100 points depending on the number of consecutive defibrillations necessary to terminate one TdP episode (1, 2, ≥3, respectively). [40,46]…”

Section: Relation Of Short-term Variability Of Repolarisation To Sevementioning

confidence: 99%

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

Smoczyńska

Beekman

Vos

2019

Arrhythm Electrophysiol Rev

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Ventricular remodelling can make the heart more susceptible to ventricular arrhythmias like torsades de pointes. Understanding the underlying mechanisms of initiation of ventricular arrhythmias and the determining factors for its severity has the potential to uncover new interventions. Beat-to-beat variation of repolarisation, quantified as short-term variability of repolarisation (STV), has been identified as an important factor contributing to arrhythmogenesis. This article provides an overview of experimental data about STV in relation to the initiation of torsades de pointes in a canine model of complete chronic atrioventricular block susceptible to torsades de pointes arrhythmias. Furthermore, it explores STV in relation to the severity of the arrhythmic outcome.

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“…Other direct therapies to activate SERCA2 or inhibit PLN binding have been studied. Istaroxime, a Na + /K + ATPase inhibitor which also stimulates SERCA, has been shown to have a moderate antiarrhythmic effect (Figure 4) (Bossu et al, 2018). Several clinical trials have assessed istaroxime in HF, highlighting the promise of the drug in cardiac disorders.…”

Section: Sercamentioning

confidence: 99%

“…Several clinical trials have assessed istaroxime in HF, highlighting the promise of the drug in cardiac disorders. However, it is worth noting is not known if higher doses of istaroxime could stimulate further arrhythmic episodes through Na + /K + ATPase inhibition (Bossu et al, 2018).…”

Section: Sercamentioning

confidence: 99%

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

2020

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Diseases of the heart, such as heart failure and cardiac arrhythmias, are a growing socioeconomic burden. Calcium (Ca 2+) dysregulation is key hallmark of the failing myocardium and has long been touted as a potential therapeutic target in the treatment of a variety of cardiovascular diseases (CVD). In the heart, Ca 2+ is essential for maintaining normal cardiac function through the generation of the cardiac action potential and its involvement in excitation contraction coupling. As such, the proteins which regulate Ca 2+ cycling and signaling play a vital role in maintaining Ca 2+ homeostasis. Changes to the expression levels and function of Ca 2+-channels, pumps and associated intracellular handling proteins contribute to altered Ca 2+ homeostasis in CVD. The remodeling of Ca 2+-handling proteins therefore results in impaired Ca 2+ cycling, Ca 2+ leak from the sarcoplasmic reticulum and reduced Ca 2+ clearance, all of which contributes to increased intracellular Ca 2+. Currently, approved treatments for targeting Ca 2+ handling dysfunction in CVD are focused on Ca 2+ channel blockers. However, whilst Ca 2+ channel blockers have been successful in the treatment of some arrhythmic disorders, they are not universally prescribed to heart failure patients owing to their ability to depress cardiac function. Despite the progress in CVD treatments, there remains a clear need for novel therapeutic approaches which are able to reverse pathophysiology associated with heart failure and arrhythmias. Given that heart failure and cardiac arrhythmias are closely associated with altered Ca 2+ homeostasis, this review will address the molecular changes to proteins associated with both Ca 2+handling and-signaling; their potential as novel therapeutic targets will be discussed in the context of pre-clinical and, where available, clinical data.

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Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs

Cited by 12 publications

References 32 publications

Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

Istaroxime treatment ameliorates calcium dysregulation in a zebrafish model for Phospholamban R14del cardiomyopathy

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

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