Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of spontaneous SR Ca2+ release

AbstractEarly afterdepolarization (EAD) is known to cause lethal ventricular arrhythmias in long QT syndrome (LQTS). In this study, dynamical mechanisms of EAD formation in human ventricular myocytes (HVMs) were investigated using the mathematical model developed by ten Tusscher & Panfilov (Am J Physiol Heart Circ Physiol, 2006). We explored how the rapid (IKr) and slow (IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current (ICaL), Na+/Ca2+ exchanger current (INCX), and intracellular Ca2+ handling via the sarcoplasmic reticulum (SR) contribute to initiation, termination and modulation of phase-2 EADs during pacing in relation to bifurcation phenomena in non-paced model cells. Dynamical behaviors of the non-paced model cell were determined by calculating stabilities of equilibrium points (EPs) and limit cycles, and bifurcation points. EADs during pacing were reproduced by numerical simulations. Results are summarized as follows: 1) A modified version of the ten Tusscher-Panfilov model with accelerated ICaL inactivation could reproduce bradycardia-related EADs and β-adrenergic stimulation-induced EADs in LQTS. 2) Two types of EADs with different initiation mechanisms, ICaL reactivation–dependent and spontaneous SR Ca2+ release–mediated EADs, were detected. 3) Spontaneous SR Ca2+ releases occurred at higher Ca2+ uptake rates, attributable to the instability of steady-state intracellular Ca2+ concentrations. Dynamical mechanisms of EAD formation and termination in the paced model cell are closely related to stability changes (bifurcations) in dynamical behaviors of the non-paced model cell, but they are model-dependent. Nevertheless, the modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of EAD-related arrhythmias in LQTS.Key pointsWe investigated dynamical mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of the human ventricular myocyte model developed by ten Tusscher and Panfilov.A modified version of ten Tusscher-Panfilov model with accelerated inactivation of the L-type Ca2+ channel current could reproduce phase-2 EADs in long QT syndrome type 1 and 2 cardiomyocytes.Dynamical mechanisms of EAD formation in the paced model cell are closely related to stability and bifurcations of the non-paced model cell.EAD mechanisms in the modified ten Tusscher-Panfilov model are different from those in other human ventricular myocyte models in the following respects: 1) EAD formation is partially attributable to spontaneous sarcoplasmic reticulum Ca2+ releases; and 2) EAD termination (action potential repolarization) during pacing requires the slowly-activating delayed-rectifier K+ channel current.The modified ten Tusscher-Panfilov model would be useful for systematically investigating possible dynamical mechanisms of initiation and termination of EAD-related arrhythmias in LQTS.

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Dynamical mechanisms of phase-2 early afterdepolarizations in human ventricular myocytes: insights from bifurcation analyses of two mathematical models

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00115.2016 ◽

2017 ◽

Vol 312 (1) ◽

pp. H106-H127 ◽

Cited By ~ 18

Author(s):

Yasutaka Kurata ◽

Kunichika Tsumoto ◽

Kenshi Hayashi ◽

Ichiro Hisatome ◽

Mamoru Tanida ◽

...

Keyword(s):

Ventricular Myocytes ◽

Equilibrium Points ◽

Pump Current ◽

Myocardial Cell ◽

Delayed Rectifier ◽

Ventricular Myocyte ◽

Phase 2 ◽

Early Afterdepolarization ◽

Bifurcation Structures ◽

Dynamic States

Early afterdepolarization (EAD) is known as a cause of ventricular arrhythmias in long QT syndromes. We theoretically investigated how the rapid ( IKr) and slow ( IKs) components of delayed-rectifier K+ channel currents, L-type Ca2+ channel current ( ICaL), Na+/Ca2+ exchanger current ( INCX), Na+-K+ pump current ( INaK), intracellular Ca2+ (Cai) handling via sarcoplasmic reticulum (SR), and intracellular Na+ concentration (Nai) contribute to initiation, termination, and modulation of phase-2 EADs, using two human ventricular myocyte models. Bifurcation structures of dynamical behaviors in model cells were explored by calculating equilibrium points, limit cycles (LCs), and bifurcation points as functions of parameters. EADs were reproduced by numerical simulations. The results are summarized as follows: 1) decreasing IKs and/or IKr or increasing ICaL led to EAD generation, to which mid-myocardial cell models were especially susceptible; the parameter regions of EADs overlapped the regions of stable LCs. 2) Two types of EADs (termination mechanisms), IKs activation–dependent and ICaL inactivation–dependent EADs, were detected; IKs was not necessarily required for EAD formation. 3) Inhibiting INCX suppressed EADs via facilitating Ca2+-dependent ICaL inactivation. 4) Cai dynamics (SR Ca2+ handling) and Nai strongly affected bifurcations and EAD generation in model cells via modulating ICaL, INCX, and INaK. Parameter regions of EADs, often overlapping those of stable LCs, shifted depending on Cai and Nai in stationary and dynamic states. 5) Bradycardia-related induction of EADs was mainly due to decreases in Nai at lower pacing rates. This study demonstrates that bifurcation analysis allows us to understand the dynamical mechanisms of EAD formation more profoundly. NEW & NOTEWORTHY We investigated mechanisms of phase-2 early afterdepolarization (EAD) by bifurcation analyses of human ventricular myocyte (HVM) models. EAD formation in paced HVMs basically depended on bifurcation phenomena in non-paced HVMs, but was strongly affected by intracellular ion concentrations in stationary and dynamic states. EAD generation did not necessarily require IKs.

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Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome

Circulation ◽

10.1161/01.cir.103.23.2851 ◽

2001 ◽

Vol 103 (23) ◽

pp. 2851-2856 ◽

Cited By ~ 181

Author(s):

Gan-Xin Yan ◽

Ying Wu ◽

Tengxian Liu ◽

Jixin Wang ◽

Roger A. Marinchak ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Long Qt Syndrome ◽

Polymorphic Ventricular Tachycardia ◽

Phase 2 ◽

Long Qt ◽

Acquired Long Qt Syndrome ◽

Early Afterdepolarization ◽

Qt Syndrome

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Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

AJP Cell Physiology ◽

10.1152/ajpcell.00494.2010 ◽

2011 ◽

Vol 301 (1) ◽

pp. C75-C85 ◽

Cited By ~ 24

Author(s):

Jennifer L. Smith ◽

Christie M. McBride ◽

Parvathi S. Nataraj ◽

Daniel C. Bartos ◽

Craig T. January ◽

...

Keyword(s):

Golgi Apparatus ◽

Long Qt Syndrome ◽

Functional Expression ◽

Delayed Rectifier ◽

Temperature Sensitive ◽

Missense Mutations ◽

Long Qt ◽

Delayed Rectifier Current ◽

Golgi Compartment ◽

Qt Syndrome

The human ether-a-go-go related gene ( hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.

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Early Afterdepolarization Abolished by Potassium Channel Opener in a Patient with Idiopathic Long QT Syndrome

Journal of Cardiovascular Electrophysiology ◽

10.1111/j.1540-8167.1995.tb00400.x ◽

1995 ◽

Vol 6 (4) ◽

pp. 279-282 ◽

Cited By ~ 36

Author(s):

TETSUYA SATO ◽

YOSHIKI HATA ◽

MIKA YAMAMOTO ◽

HIROSHI MORITA ◽

KOZO MIZUO ◽

...

Keyword(s):

Potassium Channel ◽

Long Qt Syndrome ◽

Potassium Channel Opener ◽

Long Qt ◽

Channel Opener ◽

Early Afterdepolarization ◽

Qt Syndrome

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Balance Between Rapid Delayed Rectifier K + Current and Late Na + Current on Ventricular Repolarization

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.119.008130 ◽

2020 ◽

Vol 13 (4) ◽

Author(s):

Bence Hegyi ◽

Ye Chen-Izu ◽

Leighton T. Izu ◽

Sridharan Rajamani ◽

Luiz Belardinelli ◽

...

Keyword(s):

Heart Failure ◽

Long Qt Syndrome ◽

Therapeutic Potential ◽

Heart Diseases ◽

Ionic Currents ◽

Close Correlation ◽

Delayed Rectifier ◽

Long Qt ◽

Comparable Amount ◽

Qt Syndrome

Background: Rapid delayed rectifier K + current (I Kr ) and late Na + current (I NaL ) significantly shape the cardiac action potential (AP). Changes in their magnitudes can cause either long or short QT syndromes associated with malignant ventricular arrhythmias and sudden cardiac death. Methods: Physiological self AP-clamp was used to measure I NaL and I Kr during the AP in rabbit and porcine ventricular cardiomyocytes to test our hypothesis that the balance between I Kr and I NaL affects repolarization stability in health and disease conditions. Results: We found comparable amount of net charge carried by I Kr and I NaL during the physiological AP, suggesting that outward K + current via I Kr and inward Na + current via I NaL are in balance during physiological repolarization. Remarkably, I Kr and I NaL integrals in each control myocyte were highly correlated in both healthy rabbit and pig myocytes, despite high overall cell-to-cell variability. This close correlation was lost in heart failure myocytes from both species. Pretreatment with E-4031 to block I Kr (mimicking long QT syndrome 2) or with sea anemone toxin II to impair Na + channel inactivation (mimicking long QT syndrome 3) prolonged AP duration (APD); however, using GS-967 to inhibit I NaL sufficiently restored APD to control in both cases. Importantly, I NaL inhibition significantly reduced the beat-to-beat and short-term variabilities of APD. Moreover, I NaL inhibition also restored APD and repolarization stability in heart failure. Conversely, pretreatment with GS-967 shortened APD (mimicking short QT syndrome), and E-4031 reverted APD shortening. Furthermore, the amplitude of AP alternans occurring at high pacing frequency was decreased by I NaL inhibition, increased by I Kr inhibition, and restored by combined I NaL and I Kr inhibitions. Conclusions: Our data demonstrate that I Kr and I NaL are counterbalancing currents during the physiological ventricular AP and their integrals covary in individual myocytes. Targeting these ionic currents to normalize their balance may have significant therapeutic potential in heart diseases with repolarization abnormalities. Visual Overview: A visual overview is available for this article.

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Slow Delayed Rectifier Potassium Current Blockade Contributes Importantly to Drug-Induced Long QT Syndrome

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.113.000239 ◽

2013 ◽

Vol 6 (5) ◽

pp. 1002-1009 ◽

Cited By ~ 24

Author(s):

Christiaan C. Veerman ◽

Arie O. Verkerk ◽

Marieke T. Blom ◽

Christine A. Klemens ◽

Pim N.J. Langendijk ◽

...

Keyword(s):

Long Qt Syndrome ◽

Potassium Current ◽

Delayed Rectifier ◽

Long Qt ◽

Drug Induced ◽

Delayed Rectifier Potassium Current ◽

Qt Syndrome

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Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation

International Journal of Molecular Sciences ◽

10.3390/ijms21249440 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9440

Author(s):

Xiaoan Wu ◽

H. Peter Larsson

Keyword(s):

Cardiac Arrhythmias ◽

Cardiac Death ◽

Delayed Rectifier ◽

Long Qt ◽

Voltage Gated ◽

Important Regulator ◽

Functional Knowledge ◽

Qt Syndrome ◽

Channel Properties ◽

Iks Channel

The delayed rectifier potassium IKs channel is an important regulator of the duration of the ventricular action potential. Hundreds of mutations in the genes (KCNQ1 and KCNE1) encoding the IKs channel cause long QT syndrome (LQTS). LQTS is a heart disorder that can lead to severe cardiac arrhythmias and sudden cardiac death. A better understanding of the IKs channel (here called the KCNQ1/KCNE1 channel) properties and activities is of great importance to find the causes of LQTS and thus potentially treat LQTS. The KCNQ1/KCNE1 channel belongs to the superfamily of voltage-gated potassium channels. The KCNQ1/KCNE1 channel consists of both the pore-forming subunit KCNQ1 and the modulatory subunit KCNE1. KCNE1 regulates the function of the KCNQ1 channel in several ways. This review aims to describe the current structural and functional knowledge about the cardiac KCNQ1/KCNE1 channel. In addition, we focus on the modulation of the KCNQ1/KCNE1 channel and its potential as a target therapeutic of LQTS.

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Promise and Potential Peril With Lumacaftor for the Trafficking Defective Type 2 Long-QT Syndrome-Causative Variants, p.G604S, p.N633S, and p.R685P, Using Patient-Specific Re-Engineered Cardiomyocytes

Circulation Genomic and Precision Medicine ◽

10.1161/circgen.120.002950 ◽

2020 ◽

Vol 13 (5) ◽

pp. 466-475

Author(s):

Bailey J. O’Hare ◽

C.S. John Kim ◽

Samantha K. Hamrick ◽

Dan Ye ◽

David J. Tester ◽

...

Keyword(s):

Long Qt Syndrome ◽

Induced Pluripotent Stem Cell ◽

Patient Specific ◽

Delayed Rectifier ◽

Long Qt ◽

Novel Therapy ◽

Channel Trafficking ◽

K Current ◽

Qt Syndrome

Background: The KCNH2 -encoded Kv11.1 hERG (human ether-a-go-go related gene) potassium channel is a critical regulator of cardiomyocyte action potential duration (APD). The majority of type 2 long-QT syndrome (LQT2) stems from trafficking defective KCNH2 mutations. Recently, Food and Drug Administration-approved cystic fibrosis protein trafficking chaperone, lumacaftor, has been proposed as novel therapy for LQT2. Here, we test the efficacy of lumacaftor treatment in patient-specific induced pluripotent stem cell-cardiomyocytes (iPSC-CMs) derived from 2 patients with known LQT2 trafficking defective mutations and a patient with novel KCNH2 variant, p.R685P. Methods: Patient-specific iPSC-CM models of KCNH2-G604S, KCNH2-N633S, and KCNH2-R685P were generated from 3 unrelated patients diagnosed with severe LQT2 (rate-corrected QT>500 ms). Lumacaftor efficacy was also tested by ANEPPS, FluoVolt, and ArcLight voltage dye-based APD90 measurements. Results: All 3 mutations were hERG trafficking defective in iPSC-CMs. While lumacaftor treatment failed to rescue the hERG trafficking defect in TSA201 cells, lumacaftor rescued channel trafficking for all mutations in the iPSC-CM model. All 3 mutations conferred a prolonged APD90 compared with control. While lumacaftor treatment rescued the phenotype of KCNH2-N633S and KCNH2-R685P, lumacaftor paradoxically prolonged the APD90 in KCNH2-G604S iPSC-CMs. Lumacaftor-mediated APD90 rescue was affected by rapidly activating delayed rectifier K+ current blocker consistent with the increase of rapidly activating delayed rectifier K+ current by lumacaftor is the underlying mechanism of the LQT2 rescue. Conclusions: While lumacaftor is an effective hERG channel trafficking chaperone and may be therapeutic for LQT2, we urge caution. Without understanding the functionality of the mutant channel to be rescued, lumacaftor therapy could be harmful.

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Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00074.2010 ◽

2010 ◽

Vol 299 (3) ◽

pp. H643-H655 ◽

Cited By ~ 28

Author(s):

Katja E. Odening ◽

Malcolm Kirk ◽

Michael Brunner ◽

Ohad Ziv ◽

Peem Lorvidhaya ◽

...

Keyword(s):

Long Qt Syndrome ◽

Optical Mapping ◽

Delayed Rectifier ◽

Syndrome Type ◽

Long Qt ◽

Av Conduction ◽

Electrophysiological Studies ◽

Qt Syndrome

We have generated transgenic rabbits lacking cardiac slow delayed-rectifier K+ current [ IKs; long QT syndrome type 1 (LQT1)] or rapidly activating delayed-rectifier K+ current [ IKr; long QT syndrome type 2 (LQT2)]. Rabbits with either genotype have prolonged action potential duration and QT intervals; however, only LQT2 rabbits develop atrioventricular (AV) blocks and polymorphic ventricular tachycardia. We therefore sought to characterize the genotype-specific differences in AV conduction and ventricular refractoriness in LQT1 and LQT2 rabbits. We carried out in vivo electrophysiological studies in LQT1, LQT2, and littermate control (LMC) rabbits at baseline, during isoproterenol infusion, and after a bolus of dofetilide and ex vivo optical mapping studies of the AV node/His-region at baseline and during dofetilide perfusion. Under isoflurane anesthesia, LQT2 rabbits developed infra-His blocks, decremental His conduction, and prolongation of the Wenckebach cycle length. In LQT1 rabbits, dofetilide altered the His morphology and slowed His conduction, resulting in intra-His block, and additionally prolonged the ventricular refractoriness, leading to pseudo-AV block . The ventricular effective refractory period (VERP) in right ventricular apex and base was significantly longer in LQT2 than LQT1 ( P < 0.05) or LMC ( P < 0.01), with a greater VERP dispersion in LQT2 than LQT1 rabbits. Isoproterenol reduced the VERP dispersion in LQT2 rabbits by shortening the VERP in the base more than in the apex but had no effect on VERP in LQT1. EPS and optical mapping experiments demonstrated genotype-specific differences in AV conduction and ventricular refractoriness. The occurrence of infra-His blocks in LQT2 rabbits under isoflurane and intra-His block in LQT1 rabbits after dofetilide suggest differential regional sensitivities of the rabbit His-Purkinje system to drugs blocking IKr and IKs.

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