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AOP: 555
Title
Inhibition, Ether-a-go-go (ERG) Voltage-Gated Potassium Channel leading to heart failure
Short name
Graphical Representation
Point of Contact
Contributors
- Young Jun Kim
Coaches
OECD Information Table
OECD Project # | OECD Status | Reviewer's Reports | Journal-format Article | OECD iLibrary Published Version |
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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
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
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
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
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
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)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
Inhibition, Ether-a-go-go (ERG) voltage-gated potassium channel leads to Prolongation of Action Potential | adjacent | High | High |
Prolongation of Action Potential leads to Prolongation of QT interval | adjacent | High | High |
Prolongation of QT interval leads to Early premature depolarizations | adjacent | High | High |
Early premature depolarizations leads to Heart failure | adjacent | High | High |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Not Otherwise Specified | High |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Overall Assessment of the AOP
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
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
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
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 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. |
MIE → KE1, KE1 → KE2 KE1 → KE2, KE2 → KE3 MIE → KE1, KE2 → KE3 KE1 → KE2, KE2 → KE3 KE3 → KE4, |
Quantitative Understanding
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.
- Potassium Current (IKr, IKs, IK1):
- 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)
References
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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.
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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