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AOP: 562
Title
HCN Channel Inhibition leading to Arrhythmias
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 09:27
Revision dates for related pages
Page | Revision Date/Time |
---|---|
HCN Channel Inhibition | November 24, 2024 11:24 |
Reduced Pacemaker Activity in SA Node | November 25, 2024 03:38 |
Slowed Heart Rate | November 25, 2024 04:13 |
Altered Cardiac Electrical Conduction | November 22, 2024 11:12 |
Occurrence, cardiac arrhythmia | September 16, 2017 10:17 |
HCN Channel Inhibition leads to Reduced Pacemaker Activity in SA Node | November 24, 2024 11:28 |
Reduced Pacemaker Activity in SA Node leads to Bradycardia | November 24, 2024 11:29 |
Bradycardia leads to Altered Cardiac Electrical Conduction | November 22, 2024 11:13 |
Altered Cardiac Electrical Conduction leads to Occurrence, cardiac arrhythmia | November 22, 2024 11:14 |
Zatebradine | November 22, 2024 11:16 |
Ivabradine | November 22, 2024 11:15 |
Cilobradine | November 24, 2024 11:33 |
Organophosphates | November 29, 2016 21:20 |
4-bromo-2-(methylamino)-benzimidazole | November 24, 2024 11:35 |
Abstract
The Adverse Outcome Pathway (AOP) for HCN Channel Inhibition Leading to Arrhythmias describes a mechanistic sequence linking the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate the Funny Current (If), to the adverse outcome of cardiac arrhythmias. HCN channels are critical for maintaining diastolic depolarization in pacemaker cells of the sinoatrial (SA) node, and their inhibition disrupts cardiac pacemaker activity, leading to bradycardia, conduction abnormalities, and arrhythmias.
The pathway begins with the Molecular Initiating Event (MIE) leading to Key Event 1 (KE1): reduced pacemaker activity in the SA node, which slows heart rate (KE2: Bradycardia). Bradycardia disrupts cardiac electrical conduction (KE3: Altered Cardiac Electrical Conduction), increasing the risk of arrhythmias (Adverse Outcome). This sequence is strongly supported by experimental and clinical evidence, including dose-dependent reductions in pacemaker activity and heart rate following pharmacological HCN channel inhibition. Clinical and preclinical studies, particularly with selective If inhibitors like ivabradine, demonstrate the consistent progression from HCN inhibition to arrhythmias. Prototypical stressors include pharmacological agents such as ivabradine and zatebradine, which selectively inhibit If and are associated with bradycardia and conduction delays. Genetic mutations, such as HCN4 mutations, impair channel function and predispose individuals to arrhythmias. Environmental stressors and indirect modulators, such as electrolyte imbalances or autonomic stress, can amplify the progression of key events. This AOP provides strong biological plausibility and empirical support for early key events, though further research is needed to refine dose-response relationships and explore long-term effects of HCN inhibition. By integrating mechanistic insights with practical applications, this AOP advances understanding and assessment of cardiac arrhythmias linked to HCN channel inhibition
AOP Development Strategy
Context
The AOP for HCN Channel Inhibition Leading to Arrhythmias provides a mechanistic framework to understand how the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels disrupts cardiac pacemaker function and culminates in arrhythmias. HCN channels mediate the Funny Current (If), which plays a vital role in the automaticity of sinoatrial (SA) node pacemaker cells. This current is crucial for initiating diastolic depolarization and maintaining the rhythmic contraction of the heart. Any disruption in HCN channel activity can profoundly affect cardiac electrical stability, leading to life-threatening arrhythmias. HCN channel inhibition is most commonly studied in the context of pharmacological agents, such as selective If inhibitors used to treat cardiovascular conditions. However, the pathway is also relevant to genetic mutations affecting HCN channels, indirect modulation by autonomic imbalances, and environmental factors that alter cardiac ionic currents. The AOP integrates evidence from molecular to organismal levels, providing a comprehensive framework to assess cardiotoxic risks. The pathway's applications span regulatory toxicology, drug safety evaluation, and therapeutic development. It enables the identification of cardiotoxic chemicals, informs the design of safer HCN modulators, and supports the development of diagnostic tools to predict arrhythmogenic risks. Additionally, it highlights the importance of personalized medicine approaches, such as genetic screening for HCN4 mutations, to tailor therapies and mitigate adverse outcomes.
Strategy
1. Identify and Characterize Key Events (KEs)
1.1 Molecular Initiating Event (MIE)
Focus: Establish the inhibition of HCN channels as the molecular initiating event (MIE).
Approach:
Use in vitro electrophysiological assays (e.g., patch-clamp) to quantify HCN channel activity and the Funny Current (If).
Validate with selective HCN inhibitors (e.g., ivabradine) and their dose-dependent effects on If.
Outcome:
Define thresholds for HCN inhibition and the onset of reduced pacemaker activity.
1.2 Downstream KEs
Focus: Characterize how reduced pacemaker activity progresses to bradycardia, conduction abnormalities, and arrhythmias.
Approach:
Employ in vivo animal models and clinical data to measure:
Firing rates of sinoatrial (SA) node pacemaker cells.
Heart rate (bradycardia) using telemetry or ECG.
Electrical conduction parameters (e.g., PR interval, QRS duration).
Correlate changes in these metrics with HCN inhibition.
Outcome:
Provide mechanistic and temporal links between KEs.
2. Define Key Event Relationships (KERs)
2.1 Biological Plausibility
Focus: Establish the mechanistic rationale for each KER.
Approach:
Use computational models of cardiac electrophysiology to simulate the effects of HCN inhibition on pacemaker activity and electrical conduction.
Compare model predictions with experimental and clinical findings.
Outcome:
Support biological plausibility with experimental and modeling data.
2.2 Empirical Support
Focus: Strengthen empirical evidence for KERs through dose-response and temporal data.
Approach:
Analyze dose-response relationships between HCN inhibition, pacemaker activity, heart rate, and arrhythmias.
Document temporal concordance between the onset of KEs and the progression to arrhythmias.
Outcome:
Provide quantitative and temporal evidence for each KER.
2.3 Quantitative Understanding
Focus: Quantify relationships between KEs to predict the likelihood of the adverse outcome (AO).
Approach:
Develop dose-response curves for HCN inhibition and the severity of downstream events.
Identify thresholds for arrhythmic risk based on changes in heart rate and conduction parameters.
Outcome:
Enable predictive modeling of arrhythmias.
3. Address Modulating Factors
Focus: Evaluate how modulating factors influence the progression and severity of KEs.
Approach:
Investigate the effects of age, genetic mutations (e.g., HCN4 variants), comorbidities (e.g., heart failure), electrolyte imbalances, and sex differences.
Use subgroup analyses in preclinical and clinical studies to identify populations at higher risk.
Outcome:
Incorporate modulating factors into risk assessments and predictive models.
4. Expand Domain of Applicability
4.1 Taxonomic Applicability
Focus: Confirm the conservation of HCN channel function across species.
Approach:
Test the effects of HCN inhibition in humans, rodents, dogs, and other species using in vitro and in vivo models.
Outcome:
Establish cross-species relevance of the AOP.
4.2 Life Stage and Sex Applicability
Focus: Assess the AOP’s relevance to different life stages and sexes.
Approach:
Include juvenile, adult, and elderly models in preclinical studies.
Evaluate hormonal influences on cardiac responses to HCN inhibition.
Outcome:
Broaden the applicability of the AOP to diverse populations.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 2295 | HCN Channel Inhibition | HCN Channel Inhibition |
KE | 2296 | Reduced Pacemaker Activity in SA Node | Reduced Pacemaker Activity in SA Node |
KE | 2291 | Slowed Heart Rate | Bradycardia |
KE | 2292 | Altered Cardiac Electrical Conduction | Altered Cardiac Electrical Conduction |
AO | 1106 | Occurrence, cardiac arrhythmia | Occurrence, cardiac arrhythmia |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
HCN Channel Inhibition leads to Reduced Pacemaker Activity in SA Node | adjacent | Moderate | Moderate |
Reduced Pacemaker Activity in SA Node leads to Bradycardia | adjacent | High | Moderate |
Bradycardia leads to Altered Cardiac Electrical Conduction | adjacent | Moderate | Low |
Altered Cardiac Electrical Conduction leads to Occurrence, cardiac arrhythmia | adjacent | Low | Low |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Not Otherwise Specified | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | Moderate |
Overall Assessment of the AOP
The AOP for HCN Channel Inhibition Leading to Arrhythmias describes a mechanistic sequence linking HCN channel inhibition to cardiac arrhythmias. It is supported by strong biological plausibility and robust empirical evidence for early key events (KEs), such as reduced pacemaker activity and bradycardia, while downstream events like conduction abnormalities and arrhythmias require further quantitative refinement. This AOP provides a robust framework for understanding and predicting arrhythmic risks due to HCN channel inhibition. While early events are well-supported, further research on later events and modulating factors will enhance its utility in regulatory applications.
Domain of Applicability
Domain | Relevance | Evidence |
Taxonomic Relevance | Humans, rodents, dogs, pigs | Clinical evidence and experimental models demonstrate conservation of HCN channel function. |
Life Stage | Adults, elderly | Strong relevance to adult populations; some relevance in pediatric cases with congenital mutations. |
Sex | Both sexes | Minimal sex differences observed; slight modulation by hormonal factors possible. |
Molecular/Cellular Level | HCN channels in SA node | Primary focus on HCN4 and its role in pacemaker activity and cardiac rhythm regulation. |
Stressors | Ivabradine, HCN4 mutations | Prototypical stressors include pharmacological agents, genetic mutations, and environmental factors. |
Essentiality of the Key Events
Key Event (KE) | Essentiality | Rationale and Evidence |
MIE: HCN Channel Inhibition | Strong | Primary initiating event; inhibition directly impacts pacemaker activity and heart rate. |
KE1: Reduced Pacemaker Activity | Strong | Essential for maintaining normal rhythm; reduced activity leads to bradycardia and conduction issues. |
KE2: Slowed Heart Rate | Moderate | Critical intermediate step, though compensatory mechanisms may prevent progression to arrhythmias. |
KE3: Altered Electrical Conduction | Strong | Directly linked to arrhythmias; correcting conduction abnormalities prevents downstream adverse outcomes. |
AO: Arrhythmias | Outcome | Resulting adverse outcome of upstream disruptions; dependent on progression through earlier key events. |
Evidence Assessment
1. Molecular Initiating Event (MIE): HCN Channel Inhibition
- Biological Plausibility: Strong
- HCN channels mediate the Funny Current (If), essential for diastolic depolarization in pacemaker cells.
- HCN channel inhibition directly reduces If, slowing pacemaker activity.
- Empirical Support: Strong
- Ivabradine and other selective If inhibitors show dose-dependent reductions in pacemaker activity and heart rate in humans and animal models.
- Genetic mutations in HCN4 reduce channel function and are associated with bradycardia and arrhythmias.
2. KE1: Reduced Pacemaker Activity in SA Node
- Biological Plausibility: Strong
- The Funny Current (If) drives diastolic depolarization; reducing If slows pacemaker firing.
- Pacemaker activity directly influences heart rate and rhythm.
- Empirical Support: Strong
- Electrophysiological studies confirm reduced firing rates in SA node cells following HCN inhibition.
- HCN4 knockout models demonstrate reduced pacemaker activity and increased susceptibility to arrhythmias.
3. KE2: Slowed Heart Rate (Bradycardia)
- Biological Plausibility: Strong
- Reduced pacemaker activity slows heart rate (bradycardia), increasing the risk of conduction delays and arrhythmias.
- Empirical Support: Strong
- Ivabradine-induced bradycardia is observed consistently in humans, dogs, and rodents.
- ECG recordings show heart rate reductions that correlate with If inhibition.
4. KE3: Altered Cardiac Electrical Conduction
- Biological Plausibility: Strong
- Bradycardia increases the likelihood of conduction delays, leading to asynchronous electrical activity and reentrant circuits.
- Conduction abnormalities (e.g., prolonged PR intervals) are precursors to arrhythmias.
- Empirical Support: Moderate
- ECG studies in animals and humans show conduction delays following HCN inhibition, though secondary factors (e.g., autonomic tone) may modulate effects.
5. Adverse Outcome (AO): Arrhythmias
- Biological Plausibility: Strong
- Arrhythmias result from electrical instability caused by conduction abnormalities, bradycardia, or asynchronous depolarization.
- Empirical Support: Moderate
- Clinical case reports and experimental studies link HCN inhibition and bradycardia to increased arrhythmogenic risks.
- Arrhythmias observed in patients with HCN4 mutations provide indirect evidence.
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Age Genetic Variants Electrolyte Imbalances Chemical Interactions |
Increased susceptibility to bradycardia and conduction delays. HCN4 mutations amplify pacemaker dysfunction and arrhythmias. Hypokalemia worsens bradycardia; hypercalcemia modulates risks. β-blockers amplify bradycardia; atropine mitigates it. |
HCN Inhibition → Reduced Pacemaker Activity; Reduced Activity → HR HCN Inhibition → Reduced Pacemaker Activity; HR → Conduction Changes Reduced Activity → HR; HR → Conduction Changes Reduced Activity → HR; Conduction Changes → Arrhythmias |
Quantitative Understanding
Key Event/Relationship | Quantitative Evidence | Thresholds | Temporal Concordance |
HCN Channel Inhibition (MIE) | IC50 ~ 2–3 µM for If inhibition. | 50% If inhibition for pacemaker effects. | Seconds to minutes. |
Reduced Pacemaker Activity (KE1) | 50% If inhibition → 30–50% reduced activity. | >40–50% If inhibition significant. | Seconds to minutes. |
Slowed Heart Rate (KE2) | 50% If inhibition → 20–30% heart rate decrease. | <50 bpm clinically significant. | Minutes. |
Altered Electrical Conduction (KE3) | 30% HR reduction → 10–15% PR prolongation. | PR > 200 ms significant. | Seconds to minutes. |
Arrhythmias (AO) | HR < 40 bpm or PR > 250 ms → arrhythmias. | Depends on heart rate and conduction. | Minutes to hours. |
Considerations for Potential Applications of the AOP (optional)
The Adverse Outcome Pathway (AOP) for HCN Channel Inhibition Leading to Arrhythmias provides a mechanistic framework linking the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate the Funny Current (If), to the adverse outcome of cardiac arrhythmias. HCN channels are critical for initiating diastolic depolarization in pacemaker cells of the sinoatrial (SA) node. Inhibition of these channels reduces pacemaker activity, leading to bradycardia, altered cardiac conduction, and arrhythmias. This AOP is supported by strong biological plausibility and robust experimental and clinical evidence. The pathway begins with the Molecular Initiating Event (MIE): HCN channel inhibition. This leads to reduced pacemaker activity in the SA node, resulting in slowed heart rate (bradycardia). Bradycardia disrupts cardiac electrical conduction, causing conduction abnormalities that increase susceptibility to arrhythmias, such as atrioventricular (AV) blocks or ventricular tachyarrhythmias. Prototypical stressors include pharmacological agents such as ivabradine and zatebradine, genetic mutations like HCN4 variants, and environmental chemicals that indirectly affect HCN channel function. This AOP has significant applications in various domains. In regulatory toxicology, it facilitates chemical screening, prioritization, and hazard identification for compounds with HCN inhibitory properties. It supports read-across approaches, enabling predictions of cardiotoxic effects in structurally or mechanistically similar chemicals. In drug development, the AOP informs preclinical safety testing, therapeutic design of HCN-targeting agents, and clinical monitoring for arrhythmic risks. Personalized medicine applications include genetic screening for HCN4 mutations and risk stratification based on individual susceptibilities. In environmental risk assessment, the AOP aids in evaluating the impact of HCN channel-inhibiting contaminants on human health and non-human species.
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