The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity

Lebek, Simon; Plößl, A.; Baier, Maria J.; Mustroph, Julian; Tarnowski, Daniel; Lücht, Charlotte M.; Schopka, Simon; Flörchinger, Bernhard; Schmid, Çhristof; Zausig, York; Pagratis, Nikos; Marchand, Bruno; Koltun, Dmitry O.; Hung, WaiLok K.; Ahmadyar, Shekeba; Belardinelli, Luiz; Maier, Lars S.; Wagner, Stefan

doi:10.1016/j.yjmcc.2018.03.020

Cited by 47 publications

(52 citation statements)

References 49 publications

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“…ectopic beats and preventing the recurrence of myocardial spontaneity in these areas (14). We have used the development of SCs in isolated human atrial trabeculae as a proxy for these ectopic beats (6,7,27) trigger spontaneous muscle activity by increasing intracellular Ca 2ϩ and inducing sarcoplasmic reticulum Ca 2ϩ overload (2,9,46). Independently, both triggers increased the development of SCs; however, the combination of high [Ca 2ϩ ] o and ␤ 1/2adrenergic stimulation did not further enhance the development of SCs, suggesting no synergistic arrhythmogenic effect of both triggers under our conditions.…”

Section: Discussionmentioning

confidence: 99%

“…In the intact heart, premature or spontaneous contractions (SCs), ectopic beats outside the origin of the normal cardiac impulse of the sinoatrial node, can initiate arrhythmogenic episodes in the atria (20) and ventricles (37). In isolated human atrial trabeculae, the occurrence of premature or SCs has been used as a proxy for atrial arrhythmias (6,7,27). Based on this and previous findings that components of EAT can acutely and directly alter cardiomyocyte contractility medium (13), we hypothesized that superfusate of fresh (1 h) and medium of 24 h-cultured human EAT would directly increase the propensity of SCs in human atrial muscles and that this effect would be augmented under triggered (Ca 2ϩ overload and ␤-adrenergic stimulation) conditions.…”

Section: Introductionmentioning

confidence: 99%

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Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility

Babakr

Fomison-Nurse

Hout

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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Epicardial adipose tissue (EAT) deposition has a strong clinical association with atrial arrhythmias; however, whether a direct functional interaction exists between EAT and the myocardium to induce atrial arrhythmias is unknown. Therefore, we aimed to determine whether human EAT can be an acute trigger for arrhythmias in human atrial myocardium. Human trabeculae were obtained from right atrial appendages of patients who have had cardiac surgery ( n = 89). The propensity of spontaneous contractions (SCs) in the trabeculae (proxy for arrhythmias) was determined under physiological conditions and during known triggers of SCs (high Ca2+, β-adrenergic stimulation). To determine whether EAT could trigger SCs, trabeculae were exposed to superfusate of fresh human EAT, and medium of 24 h-cultured human EAT treated with β1/2 (isoproterenol) or β3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and β1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute β3-adrenergic stimulation did not trigger SCs. Exposure of trabeculae to either superfusate of fresh human EAT or untreated medium of 24 h-cultured human EAT did not induce SCs; however, specific β3-adrenergic stimulation of EAT did trigger SCs in the trabeculae, either when applied to fresh (31%) or cultured (50%) EAT. Additionally, fresh EAT increased trabecular contraction and relaxation, whereas media of cultured EAT only increased function when treated with the β3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on β3-adrenergic rather than β1/2-adrenergic stimulation of EAT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility

Babakr

Fomison-Nurse

Hout

et al. 2020

American Journal of Physiology-Endocrinology and Metabolism

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“…In this study, this compound did not impair contractile function in failing human ventricular trabeculae and blunted the negative force-frequency relationship. Meanwhile, it increased the Ca 2+ transient amplitude in isolated failing ventricular myocytes and reduced premature atrial contractions and afterdepolarizations in atrial cardiomyocytes ( Lebek et al, 2018 ). Additionally, Dries et al (2018a) recently showed that the specific CaMKII peptide inhibitor (AIP) significantly reduced the hyperactivity of RyRs in non-coupled regions without affecting spark frequency at coupled sites ( Dries et al, 2018a ).…”

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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“…Another pyrimidine-based, ATP-competitive molecule, GS-680, has been developed by Gilead Sciences (Lebek et al, 2018). GS-680 has a reported CaMKIId biochemical IC50 of 2.3 nM, with values 3.1-, 8.7-, and 22.5-fold less potent for CaMKIIɣ, a, and b, suggesting a selective potency of CaMKII inhibition for isotypes expressed within the myocardium, minimizing the risk of neuronal side effects.…”

Section: Pharmacologic Inhibitors Of Camkiimentioning

confidence: 99%

Challenges and Opportunities for Therapeutic Targeting of Calmodulin Kinase II in Heart

2020

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Heart failure remains a major health burden around the world. Despite great progress in delineation of molecular mechanisms underlying development of disease, standard therapy has not advanced at the same pace. The multifunctional signaling molecule Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) has received considerable attention over recent years for its central role in maladaptive remodeling and arrhythmias in the setting of chronic disease. However, these basic science discoveries have yet to translate into new therapies for human patients. This review addresses both the promise and barriers to developing translational therapies that target CaMKII signaling to abrogate pathologic remodeling in the setting of chronic disease. Efforts in small molecule design are discussed, as well as alternative targeting approaches that exploit novel avenues for compound delivery and/or genetic approaches to affect cardiac CaMKII signaling. These alternative strategies provide hope for overcoming some of the challenges that have limited the development of new therapies.

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The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity

Cited by 47 publications

References 49 publications

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility

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

Challenges and Opportunities for Therapeutic Targeting of Calmodulin Kinase II in Heart

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