Transient Outward K
            <sup>+</sup>
            Current (I
            <sub>to</sub>
            ) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1

Choi, Bum Rak; Li, Weiyan; Terentyev, Dmitry; Kabakov, Anatoli Y.; Zhong, Mingwang; Rees, Colin M.; Terentyeva, Radmila; Kim, Tae Yun; Qu, Zhilin; Peng, Xuwen; Koren, Gideon

doi:10.1161/circep.117.005414

Cited by 19 publications

(14 citation statements)

References 43 publications

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“…In contrast, the function and gating kinetics of various cardiac potassium channels are very similar in dogs, rabbits, and humans with I Kr and I Ks as main repolarizing ion currents in all three species (Varro et al, 1993;Nerbonne, 2000;Nerbonne and Kass, 2005;Jost et al, 2013), with slight inter-species differences: In humans and dogs-just as in most mammals-I to is formed of two distinct subtypes named as I to,fast and I to,slow -with fast and slow recovery from inactivation, determined by Kv3.4 and Kv1.4, respectively (Patel and Campbell, 2005) as opposed to rabbits, where I to,slow is the primary transient Kv current in the left ventricle (Fedida and Giles, 1991), while in the right ventricle I to, fast and its role in LQT1 related arrhythmogenesis has recently been confirmed (Choi et al, 2018). The repolarization capacity of rabbits and dogs is more robust than that in humans due to higher I K1 , I Kr , and I Ks current densities (Jost et al, 2013;Husti et al, 2015) ( Figure 1C).…”

Section: Choice Of Models: Species Differences In Repolarizing Currentsmentioning

confidence: 91%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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Drug-induced proarrhythmia constitutes a potentially lethal side effect of various drugs. Most often, this proarrhythmia is mechanistically linked to the drug's potential to interact with repolarizing cardiac ion channels causing a prolongation of the QT interval in the ECG. Despite sophisticated screening approaches during drug development, reliable prediction of proarrhythmia remains very challenging. Although drug-induced long-QT-related proarrhythmia is often favored by conditions or diseases that impair the individual's repolarization reserve, most cellular, tissue, and whole animal model systems used for drug safety screening are based on normal, healthy models. In recent years, several transgenic rabbit models for different types of long QT syndromes (LQTS) with differences in the extent of impairment in repolarization reserve have been generated. These might be useful for screening/prediction of a drug's potential for long-QT-related proarrhythmia, particularly as different repolarizing cardiac ion channels are impaired in the different models. In this review, we summarize the electrophysiological characteristics of the available transgenic LQTS rabbit models, and the pharmacological proof-of-principle studies that have been performed with these models-highlighting the advantages and disadvantages of LQTS models for proarrhythmia research. In the end, we give an outlook on potential future directions and novel models.

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Section: Choice Of Models: Species Differences In Repolarizing Currentsmentioning

confidence: 91%

Transgenic Rabbit Models in Proarrhythmia Research

et al. 2020

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“…Therefore, in the core of the genesis of phase‐2 EADs, the activation and inactivation kinetics of I Ca,L generate the oscillations while the slow increase of I Ks [can be the slow increase of I Kr , such as in the condition of LQT1 (Choi et al, 2018)] competes with the window I Ca,L (and late I Na ) to bring the system into and out of the oscillatory regime. Other currents play auxiliary roles in facilitating the genesis and termination of EADs.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, increasing inward currents may reduce the occurrence of phase-2 EADs, which may be the reason that increasing I Ca,L conductance (e.g., Figure 6d) or I NCX (e.g., Figure 5e) can also reduce the propensity of phase-2 EADs. Therefore, in the core of the genesis of phase-2 EADs, the activation and inactivation kinetics of I Ca,L generate the oscillations while the slow increase of I Ks [can be the slow increase of I Kr , such as in the condition of LQT1 (Choi et al, 2018)] competes with the window I Ca,L (and late I Na ) to bring the system into and out of the oscillatory regime. Other currents play auxiliary roles in facilitating the genesis and termination of EADs.…”

Section: Mechanisms Of Phase-2 Eadsmentioning

confidence: 99%

Mechanisms of phase‐3 early afterdepolarizations and triggered activities in ventricular myocyte models

Zhang

2021

Physiol Rep

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Early afterdepolarizations (EADs) are abnormal depolarizations during the repolarizing phase of the action potential, which are associated with cardiac arrhythmogenesis. EADs are classified into phase‐2 and phase‐3 EADs. Phase‐2 EADs occur during phase 2 of the action potential, with takeoff potentials typically above −40 mV. Phase‐3 EADs occur during phase 3 of the action potential, with takeoff potential between −70 and −50 mV. Since the amplitude of phase‐3 EADs can be as large as that of a regular action potential, they are also called triggered activities (TAs). This also makes phase‐3 EADs and TAs much more arrhythmogenic than phase‐2 EADs since they can propagate easily in tissue. Although phase‐2 EADs have been widely observed, phase‐3 EADs and TAs have been rarely demonstrated in isolated ventricular myocytes. Here we carry out computer simulations of three widely used ventricular action potential models to investigate the mechanisms of phase‐3 EADs and TAs. We show that when the T‐type Ca2+ current (ICa,T) is absent (e.g., in normal ventricular myocytes), besides the requirement of increasing inward currents and reducing outward currents as for phase‐2 EADs, the occurrence of phase‐3 EADs and TAs requires a substantially large increase of the L‐type Ca2+ current and the slow component of the delayed rectifier K+ current. The presence of ICa,T (e.g., in neonatal and failing ventricular myocytes) can greatly reduce the thresholds of these two currents for phase‐3 EADs and TAs. This implies that ICa,T may play an important role in arrhythmogenesis in cardiac diseases.

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“…Thus, it seems reasonable to speculate www.nature.com/scientificreports www.nature.com/scientificreports/ that the p.P888L polymorphism contributes to increase the expressivity of these syndromes. Finally, mathematical models and experiments in ventricular cardiomyocytes demonstrated that a large and slowly inactivating I to can paradoxically exacerbate occurrence of early afterdepolarizations (EADs) and EADs-related arrhythmias in large mammals including humans [39][40][41] . Indeed, by lowering the plateau voltage during the early phase 1 of the AP plateau, I to delays the subsequent activation of other slower time and voltage-dependent outward currents (mainly I Ks ), thus diminishing their contribution to repolarization reserve during phases 2 and 3 of the AP, and thereby facilitating EADs.…”

Section: Discussionmentioning

confidence: 99%

The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval

Tinaquero

Crespo-García

Utrilla

et al. 2020

Sci Rep

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Synapse-Associated Protein 97 (SAP97) is an anchoring protein that in cardiomyocytes targets to the membrane and regulates Na + and K + channels. Here we compared the electrophysiological effects of native (WT) and p.P888L SAP97, a common polymorphism. Currents were recorded in cardiomyocytes from mice trans-expressing human WT or p.P888L SAP97 and in Chinese hamster ovary (CHO)transfected cells. The duration of the action potentials and the QT interval were significantly shorter in p.P888L-SAP97 than in WT-SAP97 mice. Compared to WT, p.P888L SAP97 significantly increased the charge of the Ca-independent transient outward (I to,f) current in cardiomyocytes and the charge crossing Kv4.3 channels in CHO cells by slowing Kv4.3 inactivation kinetics. Silencing or inhibiting Ca/calmodulin kinase II (CaMKII) abolished the p.P888L-induced Kv4.3 charge increase, which was also precluded in channels (p.S550A Kv4.3) in which the CaMKII-phosphorylation is prevented. Computational protein-protein docking predicted that p.P888L SAP97 is more likely to form a complex with CaMKII than WT. The Na + current and the current generated by Kv1.5 channels increased similarly in WT-SAP97 and p.P888L-SAP97 cardiomyocytes, while the inward rectifier current increased in WT-SAP97 but not in p.P888L-SAP97 cardiomyocytes. The p.P888L SAP97 polymorphism increases the I to,f , a CaMKII-dependent effect that may increase the risk of arrhythmias. Proper function of cardiac ion channels requires them to be targeted and retained within specific myocyte membrane domains in proximity with specific regulatory molecules 1. Alterations of ion channel synthesis, membrane trafficking, and/or posttranslational modifications may lead to ion channel function defects that can give rise to acquired or genetically determined arrhythmogenic syndromes 2. Cardiac Synapse-Associated Protein 97 (SAP97) is an anchoring protein of the MAGUK family encoded by the DLG1 gene 3. Its molecule contains different protein-protein interaction domains including three PDZ, one Src-homology-3 (SH3), and one guanylate-kinase (GUK) like domains 4. SAP97 is one of a number of proteins that target ion channels to specialized domains of the plasma membrane and modulate their activity 4. Cardiac SAP97 interacts with Kir2.1-2.3 channels responsible for the inward rectifier current (I K1) 5,6 and silencing of SAP97 in cardiomyocytes or in genetically modified mice

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Transient Outward K ⁺ Current (I _to ) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1

Cited by 19 publications

References 43 publications

Transgenic Rabbit Models in Proarrhythmia Research

Transgenic Rabbit Models in Proarrhythmia Research

Mechanisms of phase‐3 early afterdepolarizations and triggered activities in ventricular myocyte models

The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval

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Transient Outward K + Current (I to ) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1

Cited by 19 publications

References 43 publications

Transgenic Rabbit Models in Proarrhythmia Research

Transgenic Rabbit Models in Proarrhythmia Research

Mechanisms of phase‐3 early afterdepolarizations and triggered activities in ventricular myocyte models

The p.P888L SAP97 polymorphism increases the transient outward current (Ito,f) and abbreviates the action potential duration and the QT interval

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Transient Outward K ⁺ Current (I _to ) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1