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AOP: 555

Title

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Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure

Short name
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Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

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Authors

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Sun-Woong Kanga, Myeong Hwa Song,Do-Sun Lim b and Kim Young Jun

aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea

bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea

cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany 

Point of Contact

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Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:29

Revision dates for related pages

Page Revision Date/Time
Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel December 03, 2016 16:33
Prolongation of Action Potential Duration January 29, 2023 11:26
Prolongation of QT interval December 13, 2021 05:03
Increased the early premature depolarizations during repolarization November 26, 2024 12:57
Heart failure December 03, 2024 10:15
Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel leads to Prolongation of Action Potential November 21, 2024 13:08
Prolongation of Action Potential leads to Prolongation of QT interval December 13, 2021 05:14
Prolongation of QT interval leads to Early premature depolarizations November 21, 2024 13:09
Early premature depolarizations leads to Heart failure November 21, 2024 13:09
Sotalol November 21, 2024 13:11
Dofetilide November 21, 2024 13:12
Amiodarone November 29, 2016 18:42
Haloperidol November 29, 2016 18:42
ziprasidone November 21, 2024 13:12
Fluoroquinolones: December 21, 2016 09:45
Terfenadine December 13, 2021 06:55
Cadmium October 25, 2017 08:33
Lead November 29, 2016 18:42
Organophosphates November 29, 2016 21:20
E-4031 November 21, 2024 13:15
Cisapride December 13, 2021 06:56

Abstract

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Potassium ion channel dysfunctions are indirectly associated with the development of cardiomyopathy through their critical role in maintaining cardiac electrical stability and repolarization. Abnormalities in potassium channels, including the IKr, IKs, and IK1 currents, disrupt action potential repolarization, leading to arrhythmias such as Torsades de Pointes and ventricular fibrillation. These electrical instabilities place chronic stress on the myocardium, promoting calcium overload, cellular apoptosis, and fibrotic remodeling, which are hallmarks of cardiomyopathy. Genetic mutations, such as those in the KCNH2, KCNQ1, and KCNJ2 genes, cause inherited channelopathies like Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), and Andersen-Tawil Syndrome, which predispose to structural and functional cardiac remodeling. Additionally, acquired conditions, including drug-induced channelopathies, electrolyte imbalances, and ischemia, exacerbate potassium channel dysfunction, further increasing the risk of cardiomyopathy. The resulting cardiomyopathies include dilated, hypertrophic, and arrhythmogenic forms, characterized by ventricular remodeling and systolic dysfunction. This highlights the critical interplay between potassium channel abnormalities and the pathogenesis of cardiomyopathy.

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

The Adverse Outcome Pathway (AOP) for dysfunction of potassium ion channels leading to cardiomyopathy describes the mechanistic progression from impaired potassium ion channel function to structural and functional deterioration of the heart. Potassium ion channels, such as HERG (KCNH2), KCNQ1, and Kir2.x, are critical for cardiac repolarization. Dysfunction caused by genetic mutations, pharmacological blockade, or environmental stressors disrupts potassium efflux, initiating a cascade of adverse effects. The molecular initiating event (MIE), dysfunction of potassium ion channels, leads to prolonged action potential duration (APD), which manifests as QT interval prolongation on the electrocardiogram (ECG). Prolonged QT intervals increase susceptibility to early afterdepolarizations (EADs), which trigger arrhythmias such as ventricular tachycardia, Torsades de Pointes (TdP), and ventricular fibrillation (VF). This AOP is supported by robust empirical evidence linking potassium channel dysfunction to each key event (KE) and adverse outcome (AO). Prototypical stressors include genetic mutations (e.g., KCNH2 in Long QT Syndrome), pharmacological agents (e.g., sotalol, amiodarone, and dofetilide), and environmental factors such as hypokalemia and oxidative stress. Sex, age, and comorbidities act as modulating factors, with females and individuals with pre-existing cardiac conditions at higher risk. Life stage and taxonomic applicability extend across humans and preclinical animal models such as canines, guinea pigs, and rabbits, which share similar cardiac repolarization mechanisms. Understanding this AOP provides critical insights for toxicological risk assessment, drug safety evaluations, and therapeutic interventions targeting potassium ion channel dysfunction. It highlights the need for personalized approaches to mitigate the risk of cardiomyopathy in vulnerable populations.

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

1. Problem Formulation

Biological Context:

Potassium ion channels (e.g., HERG/KCNH2, KCNQ1, Kir2.x) regulate cardiac action potential repolarization and electrical stability. Dysfunction, whether through mutations, pharmacological agents, or environmental stressors, disrupts repolarization, leading to electrophysiological instability, arrhythmias, and myocardial remodeling.

The AOP focuses on the progression from potassium ion channel dysfunction to cardiomyopathy, a structural and functional deterioration of the myocardium.

Regulatory Relevance:

The AOP addresses risks associated with:

QT-prolonging drugs and environmental toxins.

Genetic mutations in potassium channels.

Electrolyte imbalances exacerbating ion channel dysfunction.

2. Key Components of the AOP

Molecular Initiating Event (MIE)

Dysfunction of Potassium Ion Channels:

Loss-of-function mutations (e.g., in KCNH2, KCNQ1) or pharmacological inhibition reduces potassium efflux during cardiac repolarization.

Key Events (KEs)

Prolonged Action Potential Duration (APD):

Reduced potassium currents delay ventricular repolarization.

QT Interval Prolongation:

Prolonged repolarization translates to a longer QT interval on ECG.

Early Afterdepolarizations (EADs):

Abnormal depolarizations during repolarization phases.

Arrhythmias:

EADs and repolarization heterogeneity trigger arrhythmias, such as Torsades de Pointes (TdP) and ventricular fibrillation (VF).

Increased Cardiac Workload:

Chronic arrhythmias elevate myocardial stress and workload.

Myocardial Remodeling:

Structural changes such as fibrosis and hypertrophy reduce myocardial function.

Adverse Outcome (AO)

Cardiomyopathy:

Characterized by contractile dysfunction, reduced cardiac output, and risk of heart failure or sudden cardiac death.

3. Evidence Gathering and Assessment

Identification of Evidence

Molecular-Level Evidence:

Studies on potassium channel mutations (e.g., HERG/KCNH2 in Long QT Syndrome).

Pharmacological studies of QT-prolonging drugs (e.g., sotalol, amiodarone).

Cellular-Level Evidence:

Electrophysiological studies measuring APD, EADs, and arrhythmias in isolated cardiomyocytes.

Organ-Level Evidence:

Animal models and clinical studies linking QT prolongation and arrhythmias to cardiomyopathy.

Screening and Prioritization

Identify studies demonstrating:

Temporal concordance (e.g., APD prolongation preceding arrhythmias).

Dose-response relationships (e.g., drug concentration vs. QT prolongation).

Consistency across species and models.

Evidence Quality and Weight

Apply weight-of-evidence frameworks to:

Assess biological plausibility for each KE and KER.

Evaluate empirical support (e.g., reproducibility, coherence, consistency).

Quantify dose-response relationships for predictive modeling.

Regulatory Relevance:

The AOP addresses risks associated with:

QT-prolonging drugs and environmental toxins.

Genetic mutations in potassium channels.

Electrolyte imbalances exacerbating ion channel dysfunction.

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 593 Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel
KE 1961 Prolongation of Action Potential Duration Prolongation of Action Potential
KE 1962 Prolongation of QT interval Prolongation of QT interval
KE 2283 Increased the early premature depolarizations during repolarization Early premature depolarizations
AO 1535 Heart failure Heart failure

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
Not Otherwise Specified 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 and other cells in culture human and other cells in culture High NCBI
dogs Canis lupus familiaris High NCBI
zebrafish Danio rerio Moderate NCBI
rat Rattus norvegicus High NCBI
guinea pig Cavia porcellus High NCBI
rabbits Oryctolagus cuniculus High NCBI

Sex Applicability

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

1. Biological Plausibility

  • Strength:
    • The biological mechanisms underlying the AOP are well-understood and supported by decades of research in cardiac electrophysiology.
    • Dysfunction in potassium ion channels (HERG/KCNH2, KCNQ1, Kir2.x) disrupts potassium efflux during cardiac repolarization, delaying action potential duration (APD). This leads to prolonged QT intervals, early afterdepolarizations (EADs), arrhythmias, and myocardial remodeling—culminating in cardiomyopathy.
  • Supporting Evidence:
    • Potassium channel function is critical for maintaining electrical stability in the heart. Loss-of-function mutations (e.g., in KCNH2) or pharmacological blockade (e.g., by sotalol) result in predictable downstream effects.
    • The sequence of key events (KEs) aligns with known pathophysiological processes in cardiac diseases.

Key Event Relationships (KERs)

  • MIE → KE1 (Potassium Channel Dysfunction → Prolonged APD):

    • Strong evidence from patch-clamp studies and genetic models demonstrates that potassium current reduction prolongs APD.
    • Dose-response relationships between potassium channel blockade and APD prolongation are well-characterized.

KE1 → KE2 (Prolonged APD → QT Interval Prolongation):

  • APD prolongation in ventricular myocytes translates directly to QT interval prolongation in ECG measurements.
  • Clinical data from patients with Long QT Syndrome and animal studies consistently confirm this relationship.

KE2 → KE3 (QT Interval Prolongation → EADs):

  • Prolonged repolarization increases susceptibility to EADs due to reactivation of calcium and sodium currents.
  • Experimental models demonstrate that QT prolongation >500 ms correlates with EAD formation.

KE3 → AO (EADs → Cardiomyopathy):

  • Myocardial fibrosis and hypertrophy directly impair contractile function, leading to cardiomyopathy.
  • EADs are a well-established trigger for arrhythmias, including ventricular tachycardia (VT), Torsades de Pointes (TdP), and ventricular fibrillation (VF).
  • Clinical observations and animal models confirm the progression from remodeling to heart failure.

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
Domain Applicability
Taxonomy High: Humans, rodents, canines, guinea pigs. Moderate: Rabbits, zebrafish.
Life Stage High: Neonates, infants, elderly. Moderate: Children, adolescents, adults.
Sex High for both, but females more susceptible due to hormonal influences.
Molecular/Cellular Broad: Conserved potassium ion channels across mammals.

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

1. Molecular Initiating Event (MIE): Dysfunction of Potassium Ion Channels

  • Essentiality:
    • Potassium ion channels (HERG/KCNH2, KCNQ1, Kir2.x) are critical for maintaining cardiac repolarization. Dysfunction impairs potassium efflux, delaying repolarization and initiating the cascade of key events.
  • Evidence:
    • Genetic mutations (e.g., KCNH2 in Long QT Syndrome) directly cause prolonged action potentials, QT prolongation, and arrhythmias.
    • Pharmacological inhibition of potassium channels (e.g., sotalol, dofetilide) reliably induces these effects in vitro and in vivo.

2. KE1: Prolonged Action Potential Duration (APD)

  • Essentiality:
    • Prolonged APD is a prerequisite for QT interval prolongation and the development of early afterdepolarizations (EADs).
    • Shortening the APD (e.g., with potassium channel activators or pacing) prevents downstream arrhythmic events.
  • Evidence:
    • Patch-clamp studies show that reduced potassium currents prolong the action potential in isolated cardiomyocytes.
    • Pharmacological studies demonstrate that restoring APD with drugs or genetic rescue techniques reduces arrhythmia risk.

3. KE2: QT Interval Prolongation

  • Essentiality:
    • QT prolongation reflects delayed ventricular repolarization and increases susceptibility to EADs, arrhythmias, and sudden cardiac death.
    • Interventions that reduce QT prolongation (e.g., correcting electrolyte imbalances or discontinuing QT-prolonging drugs) mitigate arrhythmic risk.
  • Evidence:
    • QT prolongation is consistently observed in patients with Long QT Syndrome and in animal models with potassium channel dysfunction.
    • Drugs that prolong the QT interval (e.g., sotalol, amiodarone) are strongly associated with arrhythmic events, such as Torsades de Pointes (TdP).

4. KE3: Early Afterdepolarizations (EADs)

  • Essentiality:
    • EADs are the primary trigger for arrhythmias by creating abnormal depolarizations and repolarization heterogeneity.
    • Suppressing EADs with drugs (e.g., late sodium current inhibitors) prevents arrhythmia onset.
  • Evidence:
    • EADs are experimentally induced in models with QT prolongation and are directly correlated with arrhythmic episodes.
    • Inhibition of the late sodium current or calcium overload effectively abolishes EADs and reduces arrhythmic events.

5. Adverse Outcome (AO): Cardiomyopathy

  • Essentiality:
    • Cardiomyopathy represents the endpoint of sustained structural and functional deterioration of the myocardium. It is the cumulative result of upstream key events.
  • Evidence:
    • Prolonged arrhythmias and remodeling are directly associated with cardiomyopathy in animal and human studies.
    • Treating earlier key events (e.g., arrhythmias, increased workload) prevents or delays the onset of cardiomyopathy.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help
Event (KE) Biological Plausibility Empirical Evidence Quantitative Understanding
MIE: Potassium Channel Dysfunction Strong Mutation and pharmacological studies (e.g., HERG block). IC50 for HERG blockers correlates with APD increase.
KE1: Prolonged APD Strong Dose-dependent APD90 prolongation in human myocytes. APD90 > 300 ms increases EAD risk significantly.
KE2: QT Prolongation Strong QT prolongation linked to arrhythmia in clinical data. QTc > 500 ms associated with 2–5x TdP risk.
KE3: EADs Strong EADs observed in models of prolonged APD/QT. >10% EAD frequency increases arrhythmia risk.
AO: Cardiomyopathy Strong Structural remodeling leads to systolic dysfunction. EF <40% correlates with severe cardiomyopathy.

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

Genetic Variants

Hormonal Influence

Electrolyte Imbalances

Age

Stress

Amplify APD and QT prolongation; increase arrhythmia risk.

Estrogen increases QT prolongation and EAD frequency; testosterone is protective.

Hypokalemia/magnesemia exacerbate APD prolongation and arrhythmias.

Neonates and elderly have reduced repolarization reserve, increasing arrhythmia risk.

Adrenergic stimulation triggers EADs and tachyarrhythmias, increasing workload.

MIE → KE1, KE1 → KE2

KE1 → KE2, KE2 → KE3

MIE → KE1, KE2 → KE3

KE1 → KE2, KE2 → KE3

KE3 → KE4,

Quantitative Understanding

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

1. Molecular Initiating Event (MIE): Dysfunction of Potassium Ion Channels

  • Key Metrics:
    • Potassium Current (IKr, IKs, IK1):
      • Reduction in potassium current density (e.g., measured in pA/pF using patch-clamp techniques).
    • IC50 for Channel Blockade:
      • Half-maximal inhibitory concentration (IC50) for drugs blocking HERG/KCNH2 or other potassium channels.
  • Quantitative Relationships:
    • Reduction in IKr by >30% correlates with significant prolongation of action potential duration (APD).
    • IC50 values for drugs like sotalol or dofetilide are typically in the nanomolar range for HERG inhibition.

2. KE1: Prolonged Action Potential Duration (APD)

  • Key Metrics:
    • APD90: Duration of the action potential at 90% repolarization, measured in milliseconds (ms).
  • Dose-Response Relationships:
    • APD90 prolongation increases linearly with the degree of potassium current inhibition.
    • Example:
      • 25% reduction in IKr → APD90 increase by ~20 ms in human ventricular myocytes.
      • 50% reduction in IKr → APD90 increase by ~40 ms.
  • Thresholds:
    • APD90 > 300 ms in human ventricular cardiomyocytes is associated with a high risk of early afterdepolarizations (EADs).

3. KE2: QT Interval Prolongation

  • Key Metrics:
    • QT interval on ECG (measured in ms).
    • Corrected QT interval (QTc), adjusted for heart rate.
  • Dose-Response Relationships:
    • QT prolongation is directly proportional to APD prolongation.
    • Example:
      • 30 ms increase in APD90 → ~10 ms increase in QT interval.
    • QTc > 450 ms (men) or > 460 ms (women) is associated with a significant increase in arrhythmia risk.
  • Thresholds:
    • QTc > 500 ms dramatically increases the likelihood of Torsades de Pointes (TdP).
  • Quantitative Models:
    • Clinical studies show that drugs prolonging the QT interval by >10 ms have a measurable increase in arrhythmia risk.

4. KE3: Early Afterdepolarizations (EADs)

  • Key Metrics:
    • Frequency of EADs per 100 action potentials, measured in isolated cardiomyocytes or tissue slices.
  • Dose-Response Relationships:
    • APD90 prolongation beyond a critical threshold (~300 ms in human cells) increases the probability of EADs by ~60–70%.
    • Potassium current reduction >50% significantly elevates EAD occurrence.
  • Thresholds:
    • EAD frequency >10% of beats increases the likelihood of arrhythmogenic triggers.

5. Adverse Outcome (AO): Cardiomyopathy

  • Key Metrics:
    • Ejection fraction (EF, %), left ventricular end-diastolic volume (mL), and cardiac output (L/min).
  • Dose-Response Relationships:
    • Progressive myocardial remodeling (e.g., 20% fibrosis, EF <40%) leads to a 3–5x increase in heart failure incidence.
  • Thresholds:
    • EF <35% is strongly associated with symptomatic heart failure and sudden cardiac death risk.

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

References

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

Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization: insights into arrhythmogenesis. Nature Reviews Cardiology, 6(12), 975–985.

Roden DM. Drug-induced prolongation of the QT interval. New England Journal of Medicine, 350(10), 1013–1022

Splawski I, et al. Mutation in the HERG potassium channel leads to arrhythmias and sudden death. Cell, 119(1), 19–31.

Antzelevitch C, et al. Early afterdepolarizations and their role in arrhythmogenesis. Heart Rhythm, 4(3), 299–301.

Abi-Gerges N, et al. The role of QT interval prolongation in arrhythmogenicity. Journal of Pharmacological and Toxicological Methods, 61(1), 15–25.

Shah RR. The significance of QT interval prolongation in drug development. British Journal of Clinical Pharmacology, 60(4), 377–392.

Volders PG, et al. Repolarization heterogeneity and arrhythmogenesis. Circulation, 102(6), 672–678.

Surawicz B. Role of electrolyte imbalances in QT prolongation. American Heart Journal, 118(3), 687–692

Tse G, et al. Mechanisms of electrical remodeling and arrhythmogenesis in cardiomyopathy. Frontiers in Physiology, 7, 105

Heist EK, et al. Torsades de Pointes and its progression to ventricular fibrillation. Journal of the American College of Cardiology, 45(1), 115–118.

Sanguinetti MC, Tristani-Firouzi M. HERG potassium channels and cardiac arrhythmias. Nature, 440(7083), 463–469.

Zhou Q, et al. Mechanisms of cardiac arrhythmias associated with potassium channel dysfunction. Journal of Clinical Investigation, 119(11), 2757–2772