scholarly journals Estimating the Probability of Cellular Arrhythmias with Simplified Statistical Models that Account for Experimentally Observed Uncertainty

2020 ◽  
Author(s):  
Qingchu Jin ◽  
Joseph L. Greenstein ◽  
Raimond L. Winslow
Keyword(s):  
Long Qt Syndrome ◽  
Cardiac Myocyte ◽  
Delayed Rectifier ◽  
Model Parameters ◽  
Parameter Uncertainties ◽  
Long Qt ◽  
Simplified Approach ◽  
Logistic Regression Models ◽  
Delayed Rectifier Current ◽  
Qt Syndrome

AbstractEarly after-depolarizations (EADs) are action potential (AP) repolarization abnormalities that can trigger lethal arrhythmias in, for example, Long QT Syndrome and heart failure. Simulations using biophysically-detailed cardiac myocyte models can reveal how model parameters influence the probability of these cellular arrhythmias, however such analyses often pose a huge computational burden. Here, we develop a simplified approach in which logistic regression models (LRMs) are used to define a mapping between the parameters of complex cell models and the probability of EADs. Specifically, we develop an LRM for predicting the probability of EADs (P(EAD)) as a function of slow-activating delayed rectifier current (IKs) parameters, and for identifying those parameters with greatest influence on P(EAD). This LRM, which requires negligible computational resources, is also used to demonstrate how uncertainties in experimentally measured values of IKs model parameters influence P(EAD). We refer to this as arrhythmia sensitivity analysis. In the investigation of five different IKs parameters associated with Long QT syndrome 1 (LQTS1) mutations, the predicted P(EAD) when rank ordered for 6 LQTS1 mutations matches the trend in risk from patients with the same mutations as measured by clinical cardiac event rates. We also demonstrate the degree to which parameter uncertainties map to uncertainty of P(EAD), with IKs conductance having the greatest impact. These results demonstrate the potential for arrhythmia risk prediction using model-based approaches for estimation of P(EAD).

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

2011 ◽  
Vol 301 (1) ◽  
pp. C75-C85 ◽  
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.

scholarly journals Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long QT syndrome

2008 ◽  
Vol 79 (1) ◽  
pp. 61-69 ◽  
Author(s):  
Thomas G. Diness ◽  
Yung-Hsin Yeh ◽  
Xiao Yan Qi ◽  
Denis Chartier ◽  
Yukiomi Tsuji ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Acquired Long Qt Syndrome ◽  
Qt Syndrome

scholarly journals Molecular Pathophysiology of Congenital Long QT Syndrome

2017 ◽  
Vol 97 (1) ◽  
pp. 89-134 ◽  
Author(s):  
M. S. Bohnen ◽  
G. Peng ◽  
S. H. Robey ◽  
C. Terrenoire ◽  
V. Iyer ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
Clinical Management ◽  
Cardiac Electrophysiology ◽  
Channel Structure ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Delayed Rectifier Current ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia. Here we review the molecular determinants, pathogenesis, and pharmacology of congenital Long QT Syndrome. We examine mechanisms of dysfunction associated with three critical cardiac currents that comprise the majority of congenital Long QT Syndrome cases: 1) IKs, the slow delayed rectifier current; 2) IKr, the rapid delayed rectifier current; and 3) INa, the voltage-dependent sodium current. Less common subtypes of congenital Long QT Syndrome affect other cardiac ionic currents that contribute to the dynamic nature of cardiac electrophysiology. Through the study of mutations that cause congenital Long QT Syndrome, the scientific community has advanced understanding of ion channel structure-function relationships, physiology, and pharmacological response to clinically employed and experimental pharmacological agents. Our understanding of congenital Long QT Syndrome continues to evolve rapidly and with great benefits: genotype-driven clinical management of the disease has improved patient care as precision medicine becomes even more a reality.

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

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.

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

2013 ◽  
Vol 6 (5) ◽  
pp. 1002-1009 ◽  
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

scholarly journals 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

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.

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

2010 ◽  
Vol 299 (3) ◽  
pp. H643-H655 ◽  
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.

scholarly journals Inhibition of Cardiac Delayed Rectifier K + Current by Overexpression of the Long-QT Syndrome HERG G628S Mutation in Transgenic Mice

1998 ◽  
Vol 83 (6) ◽  
pp. 668-678 ◽  
Author(s):  
Philip Babij ◽  
G. Roger Askew ◽  
Bart Nieuwenhuijsen ◽  
Chien-Min Su ◽  
Terry R. Bridal ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Long Qt Syndrome ◽  
Delayed Rectifier ◽  
Long Qt ◽  
K Current ◽  
Cardiac Delayed Rectifier ◽  
Qt Syndrome

scholarly journals Risk of drug-induced Long QT Syndrome associated with the use of repurposed COVID-19 drugs: A systematic review

2020 ◽  
Author(s):  
Veronique Michaud ◽  
Pamela Dow ◽  
Sweilem B. Al Rihani ◽  
Malavika Deodhar ◽  
Meghan Arwood ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Qt Interval ◽  
Adverse Event Reporting System ◽  
Torsade De Pointes ◽  
World Health ◽  
Delayed Rectifier ◽  
Long Qt ◽  
Drug Induced ◽  
Repurposed Drugs ◽  
Qt Syndrome

ABSTRACTBackgroundThe World Health Organization first declared SARS-CoV-2 (COVID-19) a pandemic on March 11, 2020. There are currently no vaccines or therapeutic agents proven efficacious to treat COVID-19. So, whether existing approved drugs could be repurposed and used off-label for the treatment of novel COVID-19 disease is being explored.MethodsA thorough literature search was performed to gather information on the pharmacological properties and toxicity of 6 drugs (azithromycin, chloroquine, favipiravir, hydroxychloroquine, lopinavir/ritonavir, remdesivir) proposed to be repurposed to treat COVID-19. Researchers emphasized affinity of these drugs to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether-a-go-go gene (hERG), their propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Risk of drug-induced Long QT Syndrome (LQTS) for these drugs was quantified by comparing six indices used to assess such risk and by querying the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System database with specific key words. Data are also provided to compare the level of risk for drug-induced LQTS by these drugs to 23 other, well-recognized, torsadogenic compounds.ResultsEstimators of LQTS risk levels indicated a very-high or high risk for all COVID-19 repurposed drugs except for azithromycin, although cases of TdP have been reported following the administration of this drug. There was an excellent agreement among the various indices used to assess risk of drug-induced LQTS for the six repurposed drugs and the 23 torsadogenic compounds.ConclusionThe risk-benefit assessment for the use of repurposed drugs to treat COVID-19 is complicated since benefits are currently anticipated, not proven. Mandatory monitoring of the QT interval shall be performed as such monitoring is possible for hospitalized patients or by the use of biodevices for outpatients initiated on these drugs.

Abstract 17137: Unmasking Pathological Mechanisms of Long QT Syndrome KCNH2 H70R Variant Using Human iPSC-Cardiomyocytes

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Li Feng ◽  
Gina Kim ◽  
Catherine A Eichel ◽  
Fang Liu ◽  
Evi Lim ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Herg Channel ◽  
Patient Specific ◽  
Delayed Rectifier ◽  
Pas Domain ◽  
Loss Of Function ◽  
Long Qt ◽  
Unrelated Control ◽  
Qt Syndrome ◽  
Human Ipsc

Introduction: Inherited long QT syndrome type 2 (LQT2) results from loss-of-function mutations in the KCNH2 gene encoding the hERG channel, which conducts I Kr , the rapid component of the delayed rectifier K + current. The N-terminal Per-Arnt-Sim (PAS) domain present on the hERG1a subunit, but not the hERG1b subunit, is the site of multiple LQT2-linked missense variants. The mechanism of loss of function by many of these missense PAS variants is unclear given conflicting results from different heterologous expression systems expressing hERG1a. Hypothesis: Patient-specific LQT2 human iPSC-cardiomyocytes (hiPSC-CMs) which naturally express hERG1a/1b carrying the KCNH2 H70R variant in the PAS domain will exhibit loss of I Kr associated with APD prolongation due to impaired channel protein trafficking. Methods and Results: Human iPSCs were derived from a patient carrying the LQT2-associated PAS domain mutation KCNH2 H70R, which has been reported to cause impaired hERG channel trafficking without effects on channel gating when expressed in HEK 293 cells but accelerated deactivation kinetics of I hERG when expressed in Xenopus laevis oocytes. Two clones of KCNH2 H70R and unrelated control hiPSCs (DF19-9-11T) were differentiated using monolayer-base, small molecule protocol to CMs, evaluated with whole-cell patch clamp. Action potentials from single hiPSC-CMs paced at 1Hz were prolonged in the hERG-H70R group compared to control (APD 90 439.9 ± 15.3 ms vs. 363.7 ± 29.0ms, p =0.003, H70R: n=11, control: n=9, Temp 36 ± 1°C). Voltage clamp studies showed hERG-H70R hiPSC-CMs had a significantly smaller peak tail I Kr current density (1.1 ± 0.3 vs. 2.9 ± 0.5 pA/pF, p <0.001, H70R: n=11, control: n=7, Temp 36 ± 1°C). The voltage dependence of I Kr activation (V½ and k) were not affected by the mutation; however, the fast (τf) and slow (τs) deactivation time constants were significantly decreased in hERG-H70R hiPSC-CMs. Further, Western blot characterization revealed impaired trafficking of hERG-H70R channels relative to control. Conclusions: The LQT2 PAS domain variant hERG-H70R results in loss of function of I Kr by both reduced membrane trafficking and accelerated deactivation of hERG in a hiPSC-CMs model which informs therapeutic approaches.

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