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

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hERG channel trafficking: novel targets in drug-induced long QT syndrome

Biochemical Society Transactions ◽

10.1042/bst0351060 ◽

2007 ◽

Vol 35 (5) ◽

pp. 1060-1063 ◽

Cited By ~ 93

Author(s):

A. Dennis ◽

L. Wang ◽

X. Wan ◽

E. Ficker

Keyword(s):

Long Qt Syndrome ◽

Heat Shock Protein 90 ◽

Delayed Rectifier ◽

Cardiac Events ◽

Long Qt ◽

Drug Induced ◽

Α Subunit ◽

Human Cardiomyocytes ◽

Qt Syndrome ◽

Therapeutic Compounds

The cardiac potassium channel hERG (human ether-a-go-go-related gene) encodes the α-subunit of the rapid delayed rectifier current IKr in the heart, which contributes to terminal repolarization in human cardiomyocytes. Direct block of hERG/IKr channels by a large number of therapeutic compounds produces acLQTS [acquired LQTS (long QT syndrome)] characterized by drug-induced QT prolongation and torsades de pointes arrhythmias. The cardiotoxicity associated with unintended hERG block has prompted pharmaceutical companies to screen developmental compounds for hERG blockade and made hERG a major target in drug safety programmes. More recently, a novel form of acLQTS has been discovered that may go undetected in most conventional safety assays. Several therapeutic compounds have been identified that reduce hERG/IKr currents not by direct block but by inhibition of hERG/IKr trafficking to the cell surface. Important examples are antineoplastic Hsp90 (heat-shock protein 90) inhibitors such as (i) geldanamycin, (ii) the leukaemia drug arsenic trioxide, (iii) the antiprotozoical pentamidine, (iv) probucol, a cholesterol-lowering drug, and (v) fluoxetine, a widely used antidepressant. Increased awareness of drug-induced hERG trafficking defects will help to further reduce the potentially lethal adverse cardiac events associated with acLQTS.

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Elucidating the role of Cavin1 in drug-induced long QT syndrome (diLQTS)

Archives of Cardiovascular Diseases Supplements ◽

10.1016/j.acvdsp.2021.04.195 ◽

2021 ◽

Vol 13 (2) ◽

pp. 228-229

Author(s):

Z. Al Sayed ◽

C. Pereira ◽

C. Jouve ◽

J. Hulot

Keyword(s):

Long Qt Syndrome ◽

Long Qt ◽

Drug Induced ◽

Qt Syndrome

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Long Qt Syndrome Mutations In Caveolin-3 Cause Loss Of The Kir2.1-mediated Inward Rectifier Potassium Current (iK1)

Biophysical Journal ◽

10.1016/j.bpj.2008.12.2381 ◽

2009 ◽

Vol 96 (3) ◽

pp. 462a

Author(s):

Amanda Vega ◽

Lee L. Eckhardt ◽

Jonathan C. Makielski

Keyword(s):

Long Qt Syndrome ◽

Potassium Current ◽

Inward Rectifier ◽

Long Qt ◽

Qt Syndrome ◽

Inward Rectifier Potassium Current

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QT and JT dispersion in the drug-induced long QT syndrome in anaesthetized rabbits is accurately detected by a three-lead surface ECG measurement

Journal of Pharmacological and Toxicological Methods ◽

10.1016/j.vascn.2003.10.003 ◽

2004 ◽

Vol 49 (2) ◽

pp. 71-79 ◽

Cited By ~ 8

Author(s):

H.R. Lu ◽

K. Van Ammel ◽

E. Vlaminckx ◽

F. De Clerck

Keyword(s):

Long Qt Syndrome ◽

Long Qt ◽

Drug Induced ◽

Surface Ecg ◽

Qt Syndrome

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Drug-induced long qt syndrome

Jounal of arrhythmology ◽

10.35336/va-2020-3-42-52 ◽

2020 ◽

Vol 27 (3) ◽

pp. 42-52

Author(s):

G. A. Golovina ◽

K. V. Zaphiraki ◽

E. D. Kosmacheva

Keyword(s):

Long Qt Syndrome ◽

Qt Interval ◽

Diagnosis And Treatment ◽

Fatal Complication ◽

Long Qt ◽

Drug Induced ◽

Long Qt Interval ◽

Qt Syndrome

In this review drug-induced long QT interval syndrome is described. The authors discuss approaches for the prevention, diagnosis, and treatment of this potentially fatal complication.

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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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