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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 channel blockade leading to sudden cardiac death

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

From hERG blockade to death

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

Authors

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

Egemen Bilgin

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

Evgeniia Kazymova (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
Evgeniia Kazymova

Coaches

This field is used to identify coaches who supported the development of the AOP. Each coach selected must be a registered author. More help

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

Handbook Version	OECD status	OECD project
v2.0

This AOP was last modified on April 29, 2023 13:02

Revision dates for related pages

Page	Revision Date/Time
hERG channel blockade	January 29, 2023 11:22
Inhibition of rapid delayed rectifying potassium current	January 29, 2023 11:24
Prolongation of Action Potential Duration	January 29, 2023 11:26
Prolongation of QT interval	December 13, 2021 05:03
Torsades de Pointes	January 29, 2023 11:28
Sudden cardiac death	December 13, 2021 05:05
hERG channel blockade leads to Inhibition of rapid delayed rectifying potassium current	January 29, 2023 11:39
Inhibition of rapid delayed rectifying potassium current leads to Prolongation of Action Potential	January 29, 2023 11:39
Prolongation of Action Potential leads to Prolongation of QT interval	December 13, 2021 05:14
Prolongation of QT interval leads to Torsades de Pointes	December 13, 2021 05:15
Torsades 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

Adverse Outcome Pathways aim to give a precise mechanistic description of relevant toxicological effects. In the current study, an AOP framework is used for increased mortality triggered by drug-mediated blockade of human ether-a-gogo-related gene (hERG) channel. An extensive review of the related scientific literature was conducted for this purpose in order to figure out key events (KEs). The KEs include the inhibition of rapid delayed rectifying potassium current, prolongation of action potential duration, prolongation of QT interval and Torsades de Pointes. Overall, all these steps clearly indicate that there has been a distruption in cardiac electrophysiology, leading to sudden cardiac death on individual level.

AOP development was performed in parallel with OECD guideline. The postulated AOP is expected to serve as the basis for the development of novel drugs with less risk of sudden cardiac death mainly triggered by hERG channel blockade.

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

2099

hERG channel blockade

KE	2100	Inhibition of rapid delayed rectifying potassium current	Inhibition of rapid delayed rectifying potassium current
KE	1961	Prolongation of Action Potential Duration	Prolongation of Action Potential
KE	1962	Prolongation of QT interval	Prolongation of QT interval
KE	1963	Torsades de Pointes	Torsades de Pointes

1964

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

Title	Adjacency	Evidence	Quantitative Understanding

hERG channel blockade leads to Inhibition of rapid delayed rectifying potassium current	adjacent	High
Inhibition of rapid delayed rectifying potassium current leads to Prolongation of Action Potential	adjacent	High
Prolongation of Action Potential leads to Prolongation of QT interval	adjacent	High
Prolongation of QT interval leads to Torsades de Pointes	adjacent	Low
Torsades de Pointes leads to Sudden cardiac death	adjacent	Low

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	Not Specified

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
Female	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

Evidence Assessment

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

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

Modulating Factor (MF)	Influence or Outcome	KER(s) involved

Quantitative Understanding

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

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 hERG blockade 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.

24.Foo B, Williamson B, Young JC, Lukacs G, Shrier A. hERG quality control and the long QT syndrome. J Physiol. 2016 May 1;594(9):2469-81. doi: 10.1113/JP270531. Epub 2016 Feb 9. PMID: 26718903; PMCID: PMC4850197.

25.Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced QT Prolongation and Torsades de Pointes. J Am Coll Cardiol. 2016 Apr 5;67(13):1639-1650. doi: 10.1016/j.jacc.2015.12.063. PMID: 27150690.

26.Cohagan B, Brandis D. Torsade de Pointes. 2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–. PMID: 29083738.

27.Konstantinos P. LETSAS . 2010 . İlaca Bağlı Qt İnterval Uzaması ve Torsade de Pointes: Risk Faktörlerinin Saptanması . Balkan Medical Journal