EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2

Klipp, Robert C.; Li, Na; Wang, Qiongling; Word, Tarah A.; Sibrian‐Vazquez, Martha; Strongin, Robert M.; Wehrens, Xander H.T.; Abramson, Jonathan J.

doi:10.1016/j.hrthm.2017.12.017

Cited by 29 publications

(39 citation statements)

References 35 publications

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“…Direct inhibition of ‘leaky’ RyRs could also be an interesting target to diminish proarrhythmic Ca 2+ leak. A recent paper showed the utility of a tetracaine-derived compound, EL20, which was able to limit arrhythmogenic Ca 2+ waves in a CPVT model by only limiting Ca 2+ release from RyRs associated with calmodulin ( Klipp et al, 2018 ). Should this have utility in HF should be the subject of further investigation.…”

Section: Therapeutic Interventionsmentioning

confidence: 99%

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Johnson

Antoons

2018

Front. Physiol.

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Heart failure (HF) is associated with elevated sympathetic tone and mechanical load. Both systems activate signaling transduction pathways that increase cardiac output, but eventually become part of the disease process itself leading to further worsening of cardiac function. These alterations can adversely contribute to electrical instability, at least in part due to the modulation of Ca2+ handling at the level of the single cardiac myocyte. The major aim of this review is to provide a definitive overview of the links and cross talk between β-adrenergic stimulation, mechanical load, and arrhythmogenesis in the setting of HF. We will initially review the role of Ca2+ in the induction of both early and delayed afterdepolarizations, the role that β-adrenergic stimulation plays in the initiation of these and how the propensity for these may be altered in HF. We will then go onto reviewing the current data with regards to the link between mechanical load and afterdepolarizations, the associated mechano-sensitivity of the ryanodine receptor and other stretch activated channels that may be associated with HF-associated arrhythmias. Furthermore, we will discuss how alterations in local Ca2+ microdomains during the remodeling process associated the HF may contribute to the increased disposition for β-adrenergic or stretch induced arrhythmogenic triggers. Finally, the potential mechanisms linking β-adrenergic stimulation and mechanical stretch will be clarified, with the aim of finding common modalities of arrhythmogenesis that could be targeted by novel therapeutic agents in the setting of HF.

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Section: Therapeutic Interventionsmentioning

confidence: 99%

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Johnson

Antoons

2018

Front. Physiol.

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“…Regardless of the concerns above, the findings of Klipp et al 8 should bring new hope to CPVT patients, at least those harboring analogous RyR2 mutations, or others in even different proteins that ultimately evoke similar RyR2 conformational changes. Restoration of calmodulin to other defective channels (L-type Ca 2+ channels) has attracted attention as a viable therapy for some arrhythmia (long-QT) syndromes, and investigators are opting for adenovirus-mediated delivery of the normal calmodulin gene, 11 but many hurdles still lie ahead for this genetic approach.…”

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confidence: 97%

“…In this issue of Heart Rhythm, Klipp et al 8 tested a novel derivative of tetracaine, EL20, to prevent arrhythmias in a mouse model of CPVT. The rationale for using tetracaine as the parent molecule of these new drugs is well justified, since tetracaine has long been recognized as a blocker of passive RyR2 Ca 2+ leak.…”

mentioning

confidence: 99%

“…While Xu et al 9 used a CPVT mouse harboring the RyR2-R2474S mutation, Klipp et al. 8 inferred a similar mechanism in the RyR2-R176Q mouse, making the pathogenic conformational state more generally applicable. Second, and perhaps more importantly from a therapeutic standpoint, wild type RyR2 channels (supposedly replete with calmodulin) are impervious to EL20 at doses that would otherwise block mutant (and calmodulin-depleted) RyR2 channels.…”

mentioning

confidence: 99%

“…EL20 is after all a derivative of tetracaine, a high-affinity voltage-dependent sodium channel blocker, and as such, some effects on cardiac impulse initiation and conduction could be expected. Although Klipp et al 8 assure the reader that no ECG effects were apparent after EL20 administration in CPVT mice, there was no systematic approach to discard this possibility, at least in mice. Flecainide, another high-affinity voltage-dependent sodium channel blocker, worsens arrhythmias in structurally-compromised hearts, such as those of heart failure patients, and until now it is only a hope that EL20 may lack significant side effects on structurally normal hearts, such as those of CPVT patients.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Tetracaine derivatives for catecholaminergic polymorphic ventricular tachycardia: New drugs for correction of diastolic Ca 2+ leak?

Valdivia

2018

Heart Rhythm

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Using hiPSC‐CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

Arslanova

Shafaattalab

et al. 2021

Current Protocols

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal inherited cardiac arrhythmia condition, triggered by physical or acute emotional stress, that predominantly expresses early in life. Gain‐of‐function mutations in the cardiac ryanodine receptor gene (RYR2) account for the majority of CPVT cases, causing substantial disruption of intracellular calcium (Ca2+) homeostasis particularly during the periods of β‐adrenergic receptor stimulation. However, the highly variable penetrance, patient outcomes, and drug responses observed in clinical practice remain unexplained, even for patients with well‐established founder RyR2 mutations. Therefore, investigation of the electrophysiological consequences of CPVT‐causing RyR2 mutations is crucial to better understand the pathophysiology of the disease. The development of strategies for reprogramming human somatic cells to human induced pluripotent stem cells (hiPSCs) has provided a unique opportunity to study inherited arrhythmias, due to the ability of hiPSCs to differentiate down a cardiac lineage. Employment of genome editing enables generation of disease‐specific cell lines from healthy and diseased patient‐derived hiPSCs, which subsequently can be differentiated into cardiomyocytes. This paper describes the means for establishing an hiPSC‐based model of CPVT in order to recapitulate the disease phenotype in vitro and investigate underlying pathophysiological mechanisms. The framework of this approach has the potential to contribute to disease modeling and personalized medicine using hiPSC‐derived cardiomyocytes. © 2021 Wiley Periodicals LLC.

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EL20, a potent antiarrhythmic compound, selectively inhibits calmodulin-deficient ryanodine receptor type 2

Cited by 29 publications

References 35 publications

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Arrhythmogenic Mechanisms in Heart Failure: Linking β-Adrenergic Stimulation, Stretch, and Calcium

Tetracaine derivatives for catecholaminergic polymorphic ventricular tachycardia: New drugs for correction of diastolic Ca 2+ leak?

Using hiPSC‐CMs to Examine Mechanisms of Catecholaminergic Polymorphic Ventricular Tachycardia

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