Antiarrhythmic properties of a rapid delayed-rectifier current activator in rabbit models of acquired long 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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Estimating the Probability of Cellular Arrhythmias with Simplified Statistical Models that Account for Experimentally Observed Uncertainty

10.1101/2020.04.09.034843 ◽

2020 ◽

Cited By ~ 1

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).

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Molecular Pathophysiology of Congenital Long QT Syndrome

Physiological Reviews ◽

10.1152/physrev.00008.2016 ◽

2017 ◽

Vol 97 (1) ◽

pp. 89-134 ◽

Cited By ~ 67

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.

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Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current

Clinical and Experimental Pharmacology and Physiology ◽

10.1046/j.1440-1681.2000.03337.x ◽

2000 ◽

Vol 27 (10) ◽

pp. 753-766 ◽

Cited By ~ 117

Author(s):

Harry J Witchel ◽

Jules C Hancox

Keyword(s):

Long Qt Syndrome ◽

Potassium Current ◽

Delayed Rectifier ◽

Long Qt ◽

Acquired Long Qt Syndrome ◽

Delayed Rectifier Potassium Current ◽

Qt Syndrome

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Abstract 5316: hERG 1b as a Potential Target for Inherited and Acquired Long QT Syndrome

Circulation ◽

10.1161/circ.118.suppl_18.s_525-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Gail A Robertson ◽

Harinath Sale ◽

David Tester ◽

Thomas J O’Hara ◽

Pallavi Phartiyal ◽

...

Keyword(s):

Action Potential ◽

Long Qt Syndrome ◽

Time Course ◽

Drug Sensitivity ◽

Long Qt ◽

Hek 293 ◽

Hek 293 Cells ◽

Acquired Long Qt Syndrome ◽

293 Cells ◽

Qt Syndrome

Cardiac I Kr is a critical repolarizing current in the heart and a target for inherited and acquired long QT syndrome. Biochemical studies show that native I Kr channels are heteromers composed of both hERG 1a and 1b subunits, yet our current understanding of I Kr functional properties derives primarily from studies of homo-oligomers of the original hERG 1a isolate. The hERG 1a and 1b subunits are identical except at the amino (NH2) terminus, which in hERG 1b is much shorter and has a unique primary sequence. We compared the biophysical properties of currents produced by hERG 1a and 1a/1b channels expressed in HEK-293 cells at near-physiological temperatures. We found that heteromeric hERG 1a/1b currents are much larger than hERG 1a currents and conduct 80% more charge during an action potential. This surprising difference corresponds to a two-fold increase in the apparent rates of activation and recovery from inactivation, which reduces rectification and facilitates current rebound during repolarization. Kinetic modeling shows these gating differences account quantitatively for the differences in current amplitude between the two channel types. Depending on the action potential model used, loss of 1b predicts an increase in action potential duration of 27 ms (7%) or 41 ms (17%), respectively. Drug sensitivity was also different. Compared to homomeric 1a channels, heteromeric 1a/1b channels were inhibited by E-4031 with a slower time course and a corresponding four-fold positive shift in the IC 50 . Differences in current kinetics and drug sensitivity were modeled by “NH2 mode” gating with conformational states bound by the amino terminus in hERG 1a homomers but not 1a/1b heteromers. The importance of hERG 1b in vivo is supported by the identification of a 1b-specific A8V missense mutation in 1/269 unrelated genotype-negative LQTS patients and absent in 400 control alleles. Mutant 1bA8V expressed alone or with hERG 1a in HEK-293 cells nearly eliminated 1b protein. Thus, mutations specifically disrupting hERG 1b function are expected to reduce cardiac I Kr , prolong QT interval and enhance drug sensitivity, thus representing a potential mechanism underlying inherited or acquired LQTS.

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Pro- and antiarrhythmic effects of fast cardiac pacing in a canine model of acquired long QT syndrome

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-004-0874-0 ◽

2004 ◽

Vol 369 (4) ◽

pp. 447-454 ◽

Cited By ~ 3

Author(s):

Alexander Bauer ◽

J. Kevin Donahue ◽

Frederik Voss ◽

Ruediger Becker ◽

Patricia Kraft ◽

...

Keyword(s):

Long Qt Syndrome ◽

Cardiac Pacing ◽

Canine Model ◽

Long Qt ◽

Acquired Long Qt Syndrome ◽

Qt Syndrome ◽

Antiarrhythmic Effects

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Prolonged QTc: "Mind the Gap"

Bangladesh Critical Care Journal ◽

10.3329/bccj.v2i1.19970 ◽

2014 ◽

Vol 2 (1) ◽

pp. 44-45

Author(s):

Ahmad Mursel Anam ◽

Raihan Rabbani ◽

Farzana Shumy ◽

M Mufizul Islam Polash ◽

M Motiul Islam ◽

...

Keyword(s):

Cardiac Arrest ◽

Long Qt Syndrome ◽

Qt Interval ◽

Torsades De Pointes ◽

Junior Doctors ◽

Long Qt ◽

Acquired Long Qt Syndrome ◽

Prolonged Qt Interval ◽

Prolonged Qt ◽

Qt Syndrome

We report a case of drug induced torsades de pointes, following acquired long QT syndrome. The patient got admitted for shock with acute abdomen. The initial prolonged QT-interval was missed, and a torsadogenic drug was introduced post-operatively. Patient developed torsades de pointes followed by cardiac arrest. She was managed well and discharged without complications. The clinical manifestations of long QT syndromes, syncope or cardiac arrest, result from torsades de pointes. As syncope or cardiac arrest have more common differential diagnoses, even the symptomatic long QT syndrome are commonly missed or misdiagnosed. In acquired long QT syndrome with no prior suggestive feature, it is not impossible to miss the prolonged QT-interval on the ECG tracing. We share our experience so that the clinicians, especially the junior doctors, will be more alert on checking the QT-interval even in asymptomatic patients. DOI: http://dx.doi.org/10.3329/bccj.v2i1.19970 Bangladesh Crit Care J March 2014; 2 (1): 44-45

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