Aop: 433

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

hERG inhibition leading to cardiac toxicity

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
hERG inhibition leading to cardiac toxicity

Graphical Representation

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool
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Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Egemen Bilgin

Yeditepe University, Department of Pharmaceutical Toxicology, Turkey

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Egemen Bilgin   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Egemen Bilgin
  • Shihori Tanabe
  • Stefan Scholz

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite
This AOP was last modified on January 24, 2022 15:27

Revision dates for related pages

Page Revision Date/Time
Binding to hERG channel December 13, 2021 04:54
hERG channel biogenesis interference December 13, 2021 04:55
Direct hERG channel blockage December 13, 2021 04:56
Induction of hERG trafficking defects December 13, 2021 04:58
Inhibition of Ikr December 13, 2021 05:02
Prolongation of Action Potential December 13, 2021 05:01
Prolongation of QT interval December 13, 2021 05:03
Torsade de Pointes December 13, 2021 05:03
Sudden cardiac death December 13, 2021 05:05
Binding to hERG channel leads to Direct hERG channel blockage December 13, 2021 05:10
hERG channel biogenesis interference leads to Induction of hERG trafficking defects December 13, 2021 05:11
Direct hERG channel blockage leads to Inhibition of Ikr December 13, 2021 05:12
Induction of hERG trafficking defects leads to Inhibition of Ikr December 13, 2021 05:13
Inhibition of Ikr leads to Prolongation of Action Potential December 13, 2021 05:14
Prolongation of Action Potential leads to Prolongation of QT interval December 13, 2021 05:14
Prolongation of QT interval leads to Torsade de Pointes December 13, 2021 05:15
Torsade de Pointes leads to Sudden cardiac death December 13, 2021 05:15

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Cardiotoxicity is an imperative cause of removal of compounds in preclinical and clinical stage. So far it has used various animal models for cardiotoxicity, but a precise molecular involvement for toxicity has not yet been clarified. Cardiotoxicity typically manifests itself in QT interval prolongation on the electrocardiogram (ECG) and potentially fatal ventricular arrhythmia. Abnormal cardiac electrical activity generally occurs with the result of the unexpected inhibition of human ether-à-go-go-related gene (hERG). hERG inhibition results in prolongation of the QT interval on the ECG, and this prolongation is associated with ventricular repolarization within the cardiac cycle.

Directly blocking hERG channels or inhibiting hERG channels trafficking leads to inhibition of delayed-rectifier potassium current (Ikr) whose outcome is prolongation of action potential that ends up a serious cardiac situation called long QT syndrome characterized by drug-induced QT prolongation, torsade de pointes (TdP), a potentially lethal arrhythmia, and a sudden death. This AOP may be one of the pathways induced by direct or indirect hERG channel inhibitors, which suggest the pathway networks of cardiotoxicity.

[Abbreviation]: AOP: adverse outcome pathway, ECG: electrocardiogram, Ikr: delayed-rectifier potassium current, TdP: torsade de pointes

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1956 Binding to hERG channel Binding to hERG channel
MIE 1957 hERG channel biogenesis interference hERG channel biogenesis interference
KE 1958 Direct hERG channel blockage Direct hERG channel blockage
KE 1959 Induction of hERG trafficking defects Induction of hERG trafficking defects
KE 1960 Inhibition of Ikr Inhibition of Ikr
KE 1961 Prolongation of Action Potential Prolongation of Action Potential
KE 1962 Prolongation of QT interval Prolongation of QT interval
KE 1963 Torsade de Pointes Torsade de Pointes
AO 1964 Sudden cardiac death Sudden cardiac death

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages High

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Unspecific High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

Homo sapiens

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Support for Essentiality of KEs

Defining Question

High (Strong)

Moderate

Low (Weak)

Are downstream KEs and/or the AO prevented if an upstream KE is blocked?

Direct evidence from experimental studies illustrating essentiality for at least one of the important KEs.

Indirect evidence that sufficient modification of an expected modulating factor attenuates or augments a KE.

No or contradictory experimental evidence of the essentiality of any of the KEs.

KE1:

Direct hERG Channel Blockage

Strong

The human ether-a-go-go related gene (hERG) or KCNH2 gene encodes a voltage-gated potassium channel known as the hERG channel. This channel plays a key role in cardiac action potential repolarization. Reduced function of hERG causes potential action prolongation and increases the risk for potentially fatal ventricular arrhythmia, torsades de pointes [1].

KE2:

Induction of hERG trafficking defect

Strong

Prolongation of the AP can result from decreased inactivation of the inward Na+ or Ca++ currents, increased activation of the Ca++ current, inhibition of one or more of the outward K+ currents or altered potassium channel trafficking and protein synthesis [2].

KE3:

Inhibition of Ikr

Strong

Consequences of IKr blockade that may combine to facilitate TdP arrhythmia.AP (action potential) prolongation is a proximate effect of IKr blockade at the cellular level and in the ECG is reflected by QT interval (QTi) prolongation [3].

K4:

Prolongation of Action Potential

Strong

Inhibition of hERG channels tends to lengthen the cardiac action potential and the duration from the start of the the QRS complex to the end of the T wave in the electrocardiogram (QTinterval) [4].

KE5:

Prolongation of QT interval

Strong

Drug-induced QT prolongation leading to serious ventricular arrhythmias, such as torsade de pointes (TdP), poses a major safety consideration for the development and use of new drug candidates. TdP is always associated with prolongation of the QT interval of the surface ECG [5].

KE6:

Torsade de Pointes

Strong

Long QT syndrome (LQTS), an abnormality of cardiac muscle repolarization that is characterized by the prolongation of the QT interval in the electrocardiogram, was implicated as a predisposing factor for torsades de pointes, a polymorphic ventricular tachycardia that can spontaneously degenerate to ventricular fibrillation and cause sudden death [6].

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Support for Biological Plausibility of KERs

MIE1 to KE1

Binding to hERG channel leads to Direct hERG channel blockage

Biological Plausibility of the MIE1 => KE1 is STRONG.

Abnormal cardiac electrical activity is most often a side effect from unintended block of the promiscuous drug target the human ether-à-go-go-related gene (hERG)— the delayed rectifier K+ channel in the heart. Numerous drugs interact with the promiscuous target hERG [7].

Many drugs covering a broad spectrum of pharmaceutical classes have been withdrawn from the market or have had their usage limited due to blockage of the hERG, e.g., astemizole, terfenadine, cisapride, sertindole, terolidine, droperidol, lidoflazine, and grepafloxacin [8].

MIE2 to KE2

hERG channel biogenesis interference leads to Induction of hERG trafficking defects

Biological Plausibility of the MIE2 => KE2 is STRONG.

There are drugs such as probucol, fluoxetine, arsenic, and pentamidine,

which do not block hERG channels but are torsadogenic due to abnormal potassium channel protein synthesis or trafficking [2].

In addition to direct hERG channel block, multiple pharmacological agents can cause hERG deficiency (with hERG channel block or independently) by the inhibition of its biogenesis and trafficking [9].

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 [10].

KE1 to KE3

Direct hERG channel blockage leads to Inhibition of Ikr

Biological Plausibility of the KE1 => KE3 is STRONG.

Some antagonists of the H1 histamine receptor, such as astemizole and terfenadine, which belong to the second generation (i.e. are devoid of sedative effects), can block the HERG channel, causing a decrease in the IKr current [11].

The Kv11.1 channel, a voltage-gated potassium channel previously known as human ether-à-go-go related gene (hERG), encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, IKr, which contributes to phase 3 repolarization in cardiac action potentials [12].

KE2 to KE3

Induction of hERG trafficking defects leads to Inhibition of Ikr

Biological Plausibility of the KE2 => KE3 is STRONG.

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). If this current is suppressed, repolarization is slowed and QT interval prolongation is observed in the ECG. Because the synthesis of the hERG channels is particularly complicated, the IKr current can be suppressed not only by direct inhibition of the hERG  , but also by any interference in their synthesis and/or intracellular trafficking [13].

KE3 to KE4

Inhibition of Ikr leads to Prolongation of Action Potential

Biological Plausibility of the KE3 => KE4 is STRONG.

hERG encodes a voltage-gated potassium channel which is a key component in formation of the cardiac action potential. This channel carries delayed rectifying potassium current (IKr) which underlies repolarization of the cardiac action potential. Pharmacological blockade of the hERG channel results in a slowing of repolarization of the action potential which is reflected as a prolongation of action potential duration [14].

Rapidly activating K current (IKr) blockers prolong action potential (AP) duration (APD) in a reverse-frequency-dependent manner [15].

Virtually every case of a prolonged duration of cardiac action potential related to drug exposure (acquired LQTS) can be traced to one specific mechanism: blockade of IKr current in the heart [16].

KE4 to KE5

Prolongation of Action Potential leads to Prolongation of QT interval

Biological Plausibility of the KE4 => KE5 is STRONG.

Rationale

The acquired long QT syndrome is both a threat to public health and a major stumbling block for drug development. It is most often caused through unintended blockade of the cardiac repolarizing potassium channel, IKr, encoded by the Human Ether-a-go-go related gene (hERG). Blockade of hERG channel was found to be associated with an increased duration of ventricular repolarization and prolongation of QT interval (long QT syndrome, or LQTS) [17].

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). If this current is suppressed, repolarization is slowed and QT interval prolongation is observed in the ECG [13].

KE5 to KE6

Prolongation of QT interval leads to Torsade de Pointes

Biological Plausibility of the KE5 => KE6 is STRONG.

The human ether-a-go-go related gene (hERG) or KCNH2 gene encodes a voltage-gated potassium channel known as the hERG channel. This channel plays a key role in cardiac action potential repolarization. Reduced function of hERG causes potential action prolongation and increases the risk for potentially fatal ventricular arrhythmia, torsades de pointes [1].

The blockade of the human ether-a-go-go-related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk [18].

Drug-induced QT prolongation leading to serious ventricular arrhythmias, such as torsade de pointes (TdP), poses a major safety consideration for the development and use of new drug candidates [5].

KE6 to AO

Torsade de Pointes leads to Sudden cardiac death

Biological Plausibility of the KE6 => AO is STRONG.

Human hereditary long QT syndrome (LQTS) is a heterogeneous cardiac disorder characterized by a prolonged QT interval on the surface ECG and an increased risk for sudden cardiac death due to life-threatening ‘‘torsade de pointes’’ arrhythmias [19].

The importance of hERG (human ether-a-go-go-related gene1) K channels in normal human cardiac electrical activity became strikingly obvious when inherited mutations in HERG were found to cause long QT syndrome (LQTS)2, a cardiac repolarization disorder that predisposes affected individuals to arrhythmia (rapid irregular heart beats that can lead to fainting and sudden death) [20].

Empirical Support for KERs

Defining Question

High (Strong)

Moderate

Low (Weak)

Does empirical evidence support that a change in KEup leads to an appropriate change in KEdown? Does KEup occur at lower doses, earlier time points, and higher in incidence than KEdown ? Inconsistencies?

Multiple studies showing dependent change in both events following exposure to a wide range of specific stressors. No or few critical data gaps or conflicting data.

Demonstrated dependent change in both events following exposure to a small number of stressors. Some inconsistencies with expected pattern that can be explained by various factors.

Limited or no studies reporting dependent change in both events following exposure to a specific stressor; and/or significant inconsistencies in empirical support across taxa and species

MIE1 => KE1

High

Abnormal cardiac electrical activity is most often a side effect from unintended block of the promiscuous drug target the human ether-à-go-go-related gene (hERG)—the delayed rectifier K+ channel in the heart [7].

MIE2 => KE2

High

In addition to direct hERG channel block, multiple pharmacological agents can cause hERG deficiency (with hERG channel block or independently) by the inhibition of its biogenesis and trafficking [9].

KE1 & KE2 => KE3

High

There are several types of cardiac K+ channels in the heart that are responsible for different phases of the action potential. Three of them are involved in (late) repolarization. One of these channels, known as hERG (human ethera-go-go-related gene,254 or Kv11.1 or KCNH2, the latter is the name of the gene) is extremely sensitive to inhibition by many compounds. It mediates the so-called rapid component of the delayed rectifier current (IKr current). Most drugs that cause QT interval prolongation are direct inhibitors of the channel, but there are many compounds that block their synthesis/trafficking or interfere at both levels [13].

KE3 => KE4

Moderate

Since almost all compounds that produce TdP in man also inhibit the rapid form of the delayed rectifier potassium current IKr, encoded by the hERG gene, the blockade of this channel and derived electrophysiological consequences on the cellular level including prolongation of action potential duration (APD) [21].

Inhibition of the hERG channel does not always translate into APD prolongation. Martin et al. (2004) investigated the APD prolonging potential of ten hERG blockers in the canine Purkinje fiber model. Only four compounds demonstrated convincing monotonic concentration-dependent APD prolongation. Comparable levels of hERG block did not result in the same APD prolongation [22].

KE4 => KE5

High

The QT interval of the human electrocardiogram (ECG) is a marker of the duration of the cellular action potential (AP) [23].

Loss of hERG function is associated with long-QT syndrome type-2 (LQT2), characterized by impaired ventricular repolarization, extended action potential duration and increased risk of potentially fatal torsades de pointes arrhythmia [24].

KE5 => KE6

Low

Prolongation of the QT interval in telemetered dogs and primates has a high predictive value for QT interval prolongation in man (ILSI workshop ‘‘Cardiovascular Risk Assessment’’, Washington June 3–4, 2003). But accumulating evidence suggests that only a weak correlation exists between QT prolongation and TdP in humans [21].

Although QT prolongation is an essentialfirst stepin  TdP,  it  is  usually  not  considered  sufficient  toinduce TdP [25].

KE6 => AO

Low

Around 50% of patients with Torsades de Pointes are asymptomatic. The most common symptoms reported are syncope, palpitations, and dizziness. However, cardiac death is the presenting symptom in up to 10% of patients [26].

The administration of an IKr current blocking agent may  significantly prolong the QT interval in these silent carriers predisposing them to TdP and sudden cardiac death [27].

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

The WOE analysis indicates that many KEs and KERs lack especially experimental evidence, but overall the analysis supports the qualitative AOP. For sudden cardiac death, a major drawback is moving from a qualitative AOP to a quantitative AOP. The most pressing future need is an adequate and robust experimental model system for the evaluation of relationships between doses, concentrations and responses within a temporal framework of the AOP. 

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

The AOP may be useful in the risk assessment on several types molecules including drugs, as well as other types of chemicals, biocides, or pesticides. This AOP elucidating the pathway from direct and/or indirect hERG inhibition to sudden cardiac death may provide important insights into the potential toxicity of direct and/or indirect hERG inhibitors.

References

List of the literature that was cited for this AOP. More help

1. Choi K-E, Balupuri A, Kang NS. The Study on the hERG Blocker Prediction Using Chemical Fingerprint Analysis. Molecules (Basel, Switzerland). 25(11). doi:10.3390/molecules25112615

2. Robert M. Lester & Joy Olbertz (2016) Early drug development: assessment of proarrhythmic risk and cardiovascular safety, Expert Review of Clinical Pharmacology, 9:12, 1611-1618, DOI: 10.1080/17512433.2016.1245142

3.Hancox JC, McPate MJ, El Harchi A, Zhang Y hong. The hERG potassium channel and hERG screening for drug-induced torsades de pointes. Pharmacology and Therapeutics. 2008;119(2):118-132. doi:10.1016/j.pharmthera.2008.05.009

4.Chen WH, Wang WY, Zhang J, Yang D, Wang YP. State-dependent blockade of human ether-a-go-go-related gene (hERG) K(+) channels by changrolin in stably transfected HEK293 cells. Acta Pharmacol Sin. 2010 Aug;31(8):915-22. doi: 10.1038/aps.2010.84. PMID: 20686516; PMCID: PMC4007811.

5.Yao X, Anderson DL, Ross SA, et al. Predicting QT prolongation in humans during early drug development using hERG inhibition and an anaesthetized guinea-pig model. Br J Pharmacol. 2008;154(7):1446-1456. doi:10.1038/bjp.2008.267

6.Aronov AM. Predictive in silico modeling for hERG channel blockers. Drug Discovery Today. 2005;10(2):149-155. doi:10.1016/S1359-6446(04)03278-7.

7.Yang, P.-C. ( 1 ) et al. (no date) ‘A Computational Pipeline to Predict Cardiotoxicity: From the Atom to the Rhythm’, Circulation Research, pp. 947–964. doi: 10.1161/CIRCRESAHA.119.316404.

8.Braga RC, Alves VM, Silva MF, Muratov E, Fourches D, Tropsha A, Andrade CH. Tuning HERG out: antitarget QSAR models for drug development. Curr Top Med Chem. 2014;14(11):1399-415. doi: 10.2174/1568026614666140506124442. PMID: 24805060; PMCID: PMC4593700.

9.Mamoshina P, Rodriguez B, Bueno-Orovio A. Toward a broader view of mechanisms of drug cardiotoxicity. Cell Reports Medicine. 2021;2(3). doi:10.1016/j.xcrm.2021.100216

10.Dennis A, Wang L, Wan X, Ficker E. hERG channel trafficking: novel targets in drug-induced long QT syndrome. Biochem Soc Trans. 2007 Nov;35(Pt 5):1060-3. doi: 10.1042/BST0351060. PMID: 17956279.

11.Calderone V, Testai L, Martinotti E, Del Tacca M, Breschi M. Drug-induced block of cardiac HERG potassium channels and development of torsade de pointes arrhythmias: the case of antipsychotics. JOURNAL OF PHARMACY AND PHARMACOLOGY. 2005;57(2):151-161. doi:10.1211/0022357055272

12.Yu Z, IJzerman AP, Heitman LH. Kv 11.1 (hERG)-induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv 11.1 (hERG) inhibitors. Br J Pharmacol. 2015 Feb;172(3):940-55. doi: 10.1111/bph.12967. Epub 2014 Dec 15. PMID: 25296617; PMCID: PMC4301700.

13.Mladěnka P, Applová L, Patočka J, Costa VM, Remiao F, Pourová J, Mladěnka A, Karlíčková J, Jahodář L, Vopršalová M, Varner KJ, Štěrba M; TOX-OER and CARDIOTOX Hradec Králové Researchers and Collaborators. Comprehensive review of cardiovascular toxicity of drugs and related agents. Med Res Rev. 2018 Jul;38(4):1332-1403. doi: 10.1002/med.21476. Epub 2018 Jan 5. PMID: 29315692; PMCID: PMC6033155.

14.Jing Y, Easter A, Peters D, Kim N, Enyedy IJ. In silico prediction of hERG inhibition. Future Med Chem. 2015;7(5):571-86. doi: 10.4155/fmc.15.18. PMID: 25921399.

15.Tsujimae K, Suzuki S, Murakami S, Kurachi Y. Frequency-dependent effects of various IKr blockers on cardiac action potential duration in a human atrial model. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H660-9. doi: 10.1152/ajpheart.01083.2006. Epub 2007 Jan 12. PMID: 17220183.

16.Aronov AM. Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers. J Med Chem. 2006 Nov 16;49(23):6917-21. doi: 10.1021/jm060500o. PMID: 17154521.

17.Yu HB, Zou BY, Wang XL, Li M. Investigation of miscellaneous hERG inhibition in large diverse compound collection using automated patch-clamp assay. Acta Pharmacol Sin. 2016 Jan;37(1):111-23. doi: 10.1038/aps.2015.143. PMID: 26725739; PMCID: PMC4722980.

18.Di Veroli GY, Davies MR, Zhang H, Abi-Gerges N, Boyett MR. High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment. Am J Physiol Heart Circ Physiol. 2013 Jan 1;304(1):H104-17. doi: 10.1152/ajpheart.00511.2012. Epub 2012 Oct 26. PMID: 23103500.

19.Thomas D, Kiehn J, Katus HA, Karle CA. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res. 2003 Nov 1;60(2):235-41. doi: 10.1016/j.cardiores.2003.08.002. PMID: 14613852.

20.Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006 Mar 23;440(7083):463-9. doi: 10.1038/nature04710. PMID: 16554806.

21.Hoffmann P, Warner B. Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends. J Pharmacol Toxicol Methods. 2006 Mar-Apr;53(2):87-105. doi: 10.1016/j.vascn.2005.07.003. Epub 2005 Nov 11. PMID: 16289936.

22.Traebert M, Dumotier B, Meister L, Hoffmann P, Dominguez-Estevez M, Suter W. Inhibition of hERG K+ currents by antimalarial drugs in stably transfected HEK293 cells. Eur J Pharmacol. 2004 Jan 19;484(1):41-8. doi: 10.1016/j.ejphar.2003.11.003. PMID: 14729380.

23.Tse G, Chan YW, Keung W, Yan BP. Electrophysiological mechanisms of long and short QT syndromes. Int J Cardiol Heart Vasc. 2016 Nov 26;14:8-13. doi: 10.1016/j.ijcha.2016.11.006. PMID: 28382321; PMCID: PMC5368285.

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