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 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.

DHPLC analysis of potassium ion channel genes in congenital long QT syndrome

2002 ◽  
Vol 20 (5) ◽  
pp. 382-391 ◽  
Author(s):  
Roselie Jongbloed ◽  
Carlo Marcelis ◽  
Crool Velter ◽  
Pieter Doevendans ◽  
Joep Geraedts ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
Potassium Ion ◽  
Potassium Ion Channel ◽  
Long Qt ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome ◽  
Dhplc Analysis

DHPLC analysis of potassium ion channel genes in congenital long QT syndrome

2003 ◽  
Vol 22 (6) ◽  
pp. 493-493 ◽  
Author(s):  
Roselie Jongbloed ◽  
Carlo Marcelis ◽  
Crool Velter ◽  
Pieter Doevendans ◽  
Joep Geraedts ◽  
...  
Keyword(s):  
Ion Channel ◽  
Long Qt Syndrome ◽  
Potassium Ion ◽  
Potassium Ion Channel ◽  
Long Qt ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome ◽  
Dhplc Analysis

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 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 Diagnosis, management and therapeutic strategies for congenital long QT syndrome

Heart ◽  
2021 ◽  
pp. heartjnl-2020-318259
Author(s):  
Arthur A M Wilde ◽  
Ahmad S Amin ◽  
Pieter G Postema
Keyword(s):  
Risk Stratification ◽  
Ion Channel ◽  
Long Qt Syndrome ◽  
Therapeutic Strategies ◽  
Current Evidence ◽  
Long Qt ◽  
Large Variability ◽  
Qt Interval Prolongation ◽  
Qt Syndrome ◽  
Congenital Long Qt Syndrome

Congenital long QT syndrome (LQTS) is characterised by heart rate corrected QT interval prolongation and life-threatening arrhythmias, leading to syncope and sudden death. Variations in genes encoding for cardiac ion channels, accessory ion channel subunits or proteins modulating the function of the ion channel have been identified as disease-causing mutations in up to 75% of all LQTS cases. Based on the underlying genetic defect, LQTS has been subdivided into different subtypes. Growing insights into the genetic background and pathophysiology of LQTS has led to the identification of genotype–phenotype relationships for the most common genetic subtypes, the recognition of genetic and non-genetic modifiers of phenotype, optimisation of risk stratification algorithms and the discovery of gene-specific therapies in LQTS. Nevertheless, despite these great advancements in the LQTS field, large gaps in knowledge still exist. For example, up to 25% of LQTS cases still remain genotype elusive, which hampers proper identification of family members at risk, and it is still largely unknown what determines the large variability in disease severity, where even within one family an identical mutation causes malignant arrhythmias in some carriers, while in other carriers, the disease is clinically silent. In this review, we summarise the current evidence available on the diagnosis, clinical management and therapeutic strategies in LQTS. We also discuss new scientific developments and areas of research, which are expected to increase our understanding of the complex genetic architecture in genotype-negative patients, lead to improved risk stratification in asymptomatic mutation carriers and more targeted (gene-specific and even mutation-specific) therapies.

scholarly journals Long QT syndrome type 2: mechanism-based therapies

2021 ◽  
Author(s):  
Kofi Oliver Taylor Cox ◽  
Brian Xiangzhi Wang
Keyword(s):  
Long Qt Syndrome ◽  
Cardiac Electrophysiology ◽  
Current Treatment ◽  
Delayed Rectifier ◽  
Adrenergic Blockade ◽  
Syndrome Type ◽  
Long Qt ◽  
Life Threatening ◽  
Qt Syndrome

Long QT syndrome type 2 is a life-threatening disorder of cardiac electrophysiology. It can lead to sudden cardiac death as a result of QT prolongation and can remain undetected until it presents clinically in the form of life-threatening cardiac arrythmias. Current treatment relies on symptom management largely through the use of β-adrenergic blockade and presently no mechanism-based therapies exist to treat the dysfunction in the hERG channels responsible for the rapid delayed rectifier K+ current which is the pathological source of long QT syndrome type 2. We review the pathophysiology, diagnosis and current management of this life-threatening condition and also analyze some promising potential mechanism-based therapies.

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