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AOP: 559
Title
Inhibition of acetylcholinesterase (AChE) 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 09:29
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Acetylcholinesterase (AchE) Inhibition | April 29, 2020 17:21 |
Increased Muscarinic Acetylcholine Receptors | December 02, 2024 03:35 |
Altered, Action Potential | March 31, 2022 06:49 |
Increased delay in heart electrical conduction | November 26, 2024 12:31 |
Occurrence, cardiac arrhythmia | September 16, 2017 10:17 |
AchE Inhibition leads to Activation, Muscarinic Acetylcholine Receptors | November 22, 2024 09:45 |
Activation, Muscarinic Acetylcholine Receptors leads to Altered, Action Potential | November 22, 2024 09:45 |
Altered, Action Potential leads to Prolonged atrioventricular (AV) | November 22, 2024 09:46 |
Prolonged atrioventricular (AV) leads to Occurrence, cardiac arrhythmia | November 20, 2024 11:15 |
Donepezil | November 22, 2024 11:21 |
Neostigmine | November 22, 2024 11:21 |
Pyridostigmine | November 22, 2024 11:21 |
Parathion | November 29, 2016 18:42 |
Malathion | March 30, 2020 15:59 |
Chlorpyrifos | July 27, 2022 04:02 |
Diazinon | November 22, 2024 11:22 |
Sarin | November 22, 2024 11:22 |
Tabun | November 22, 2024 11:23 |
Carbaryl | November 22, 2024 11:23 |
Aldicarb | November 22, 2024 11:23 |
Physostigmine | November 22, 2024 11:23 |
Ciprofloxacin | December 04, 2018 04:26 |
Carbofuran | November 22, 2024 11:24 |
Pilocarpine | November 22, 2024 11:24 |
Bethanechol | November 22, 2024 11:24 |
Abstract
Inhibition of acetylcholinesterase (AChE) can lead to arrhythmias by disrupting parasympathetic regulation of cardiac activity. AChE normally terminates the action of acetylcholine (ACh) at muscarinic M2 receptors in the heart, maintaining a balance in autonomic control. Inhibition of AChE, such as in organophosphate poisoning or carbamate toxicity, results in excessive ACh accumulation, causing prolonged parasympathetic stimulation. This leads to bradyarrhythmias, including sinus bradycardia, atrioventricular (AV) block, and in severe cases, asystole. Excessive vagal stimulation also contributes to electrical instability through early and delayed afterdepolarizations, increasing the risk of polymorphic ventricular tachycardia, such as Torsades de Pointes (TdP), and ventricular fibrillation (VF). Additionally, autonomic imbalance caused by prolonged parasympathetic overdrive may predispose to alternating bradyarrhythmias and tachyarrhythmias. Clinical scenarios such as organophosphate poisoning and the therapeutic use of cholinesterase inhibitors in myasthenia gravis or Alzheimer’s disease illustrate the potential cardiac effects of AChE inhibition. While mild bradycardia is manageable in controlled settings, severe AChE inhibition can cause life-threatening arrhythmias, emphasizing the importance of understanding these mechanisms for effective management of AChE-related cardiac dysfunction.
AOP Development Strategy
Context
AOP: Inhibition of Acetylcholinesterase (AChE) Leading to Arrhythmias provides a mechanistic framework linking the disruption of acetylcholine (ACh) regulation at synapses to the development of cardiac arrhythmias. AChE is a critical enzyme responsible for breaking down ACh, a neurotransmitter that mediates parasympathetic signaling in the autonomic nervous system. When AChE is inhibited, ACh accumulates excessively at synaptic junctions, particularly within the cardiac parasympathetic system, leading to overstimulation of muscarinic acetylcholine receptors (M2 receptors) in the heart. The overstimulation of M2 receptors triggers potassium efflux through G-protein-coupled inwardly rectifying potassium channels (IK,ACh), resulting in hyperpolarization of cardiac cells. This disrupts the normal electrical activity of the heart by prolonging or destabilizing cardiac action potentials. The altered electrical signaling can cause conduction delays, reentrant circuits, and early afterdepolarizations (EADs), which ultimately manifest as bradyarrhythmias, tachyarrhythmias, or fibrillation. This AOP has applications in regulatory toxicology, where it can be used to screen for cardiotoxic effects of environmental toxins and pharmaceuticals, and in therapeutic development, where targeting intermediate key events (e.g., using muscarinic receptor antagonists) can help mitigate arrhythmias. It also provides a framework for assessing combined risks from multiple stressors affecting AChE activity or parasympathetic signaling.
Strategy
1. Problem Formulation
Objective
To describe the mechanistic progression from AChE inhibition to arrhythmias.
To identify key events (KEs), key event relationships (KERs), and modulating factors influencing this pathway.
To enable applications in toxicology, pharmacology, and therapeutic development.
Relevance
AChE inhibitors, such as organophosphates and carbamates, are widely used pesticides and chemical warfare agents, posing risks of cardiac arrhythmias.
Therapeutic agents like donepezil for Alzheimer's disease also inhibit AChE and may induce adverse cardiac effects.
2. Identification of Key Events (KEs)
The pathway begins with the Molecular Initiating Event (MIE) of AChE inhibition and progresses through several KEs to the adverse outcome (AO):
MIE: Inhibition of AChE
Prevents the breakdown of acetylcholine (ACh), leading to its accumulation at synaptic junctions.
KE1: Increased ACh Levels
Accumulated ACh overstimulates parasympathetic signaling.
KE2: Overactivation of Muscarinic Receptors
Activation of M2 receptors in the heart disrupts ionic balance and electrical signaling.
KE3: Altered Cardiac Action Potential
Hyperpolarization and increased potassium efflux through IK,ACh channels impair excitation-contraction coupling.
KE4: Prolonged atrioventricular (AV) conduction time
Conduction blocks and reentrant circuits emerge, causing electrical instability.
AO: Arrhythmias
Sustained electrical instability leads to bradyarrhythmias, tachyarrhythmias, or fibrillation.
3. Evidence Collection and Screening
Data Sources
In Vitro Studies:
Cardiac cell models assessing ACh accumulation, muscarinic receptor activation, and ionic currents.
In Vivo Studies:
Animal models exposed to AChE inhibitors to monitor cardiac electrophysiology and arrhythmic patterns.
Clinical Data:
Observations of arrhythmias in patients exposed to pesticides or receiving therapeutic AChE inhibitors.
Computational Models:
Simulations of parasympathetic signaling and cardiac action potential dynamics.
Screening Criteria
Relevance: Data must address the MIE or KEs in the pathway.
Quality: Prioritize studies with robust experimental designs and reproducibility.
Consistency: Focus on findings that align with the proposed mechanistic progression.
4. Validation and Refinement
Validate the AOP using experimental, computational, and clinical data.
Refine KERs and quantitative models based on emerging evidence.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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MIE | 12 | Acetylcholinesterase (AchE) Inhibition | AchE Inhibition |
KE | 1602 | Increased Muscarinic Acetylcholine Receptors | Activation, Muscarinic Acetylcholine Receptors |
KE | 698 | Altered, Action Potential | Altered, Action Potential |
KE | 2280 | Increased delay in heart electrical conduction | Prolonged atrioventricular (AV) |
AO | 1106 | Occurrence, cardiac arrhythmia | Occurrence, cardiac arrhythmia |
Relationships Between Two Key Events (Including MIEs and AOs)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
AchE Inhibition leads to Activation, Muscarinic Acetylcholine Receptors | adjacent | High | High |
Activation, Muscarinic Acetylcholine Receptors leads to Altered, Action Potential | adjacent | High | High |
Altered, Action Potential leads to Prolonged atrioventricular (AV) | adjacent | High | Moderate |
Prolonged atrioventricular (AV) leads to Occurrence, cardiac arrhythmia | adjacent | High | Low |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Not Otherwise Specified | Moderate |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
human and other cells in culture | human and other cells in culture | High | NCBI |
Rattus norvegicus | Rattus norvegicus | High | NCBI |
dogs | Canis lupus familiaris | High | NCBI |
Sus scrofa | Sus scrofa | Moderate | NCBI |
zebrafish | Danio rerio | Moderate | NCBI |
Insecta sp. BOLD:AAN5199 | Insecta sp. BOLD:AAN5199 | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Mixed | Moderate |
Overall Assessment of the AOP
Contents | Evaluation |
Biological Plausibility | Strong: Mechanisms linking AChE inhibition to arrhythmias are well-established. |
Empirical Evidence | Robust: Consistent support across experimental and clinical studies. |
Quantitative Understanding | Moderate: Well-characterized for early events; limited for late-stage effects. |
Modulating Factors | Identified: Age, genetics, comorbidities, and stress influence outcomes. |
Regulatory Relevance | High: Applicable to toxicology, drug safety, and therapeutic development. |
Domain of Applicability
Domain | Description |
Taxonomic Relevance | Humans, rodents, and dogs are most relevant; pigs and zebrafish are moderately applicable. |
Life Stage | Highly relevant to adults and elderly; moderately applicable to neonates and children. |
Sex | Applicable to both sexes, with potential hormonal modulation of outcomes. |
Molecular/Cellular Level | Focuses on AChE, M2 muscarinic receptors, and cardiac myocytes. |
Stressors | Includes organophosphates, carbamates, therapeutic AChE inhibitors, and physiological vagal activation. |
Essentiality of the Key Events
Key Event | Essentiality | Evidence |
MIE: AChE Inhibition | High | Directly causes ACh accumulation, initiating downstream effects. |
KE1: Overactivation of M2 Receptors | High | Necessary for potassium efflux and action potential disruption. |
KE2: Altered Cardiac Action Potential | High | Central to the development of conduction blocks and arrhythmic activity. |
KE3: Prolonged atrioventricular (AV) conduction time | Moderate-High | Directly leads to arrhythmias but can be modulated by other factors. |
AO: Arrhythmias | Endpoint | Result of sustained electrical instability. |
Evidence Assessment
Key Event | Biological Plausibility | Evidence Assessment |
MIE: AChE Inhibition | Strong | Numerous studies have demonstrated that exposure to AChE inhibitors, such as organophosphates and carbamates, results in dose-dependent increases in ACh levels. Measurement tools such as Ellman’s assay provide reliable quantification of AChE activity. |
KE1: Overactivation of M2 Receptors | Strong | Electrophysiological studies in isolated cardiac myocytes demonstrate M2 receptor-mediated activation of inwardly rectifying potassium channels (IK,ACh). Muscarinic agonists mimic the effects of AChE inhibitors, supporting the role of receptor overactivation. |
KE2: Altered Cardiac Action Potential | Strong | Patch-clamp recordings show alterations in action potential duration and repolarization under conditions of muscarinic receptor overstimulation. Clinical ECG data from organophosphate poisoning cases reveal bradyarrhythmias and conduction delays. |
KE3: Prolonged atrioventricular (AV) conduction time | Moderate | In vivo studies in animal models exposed to organophosphates demonstrate conduction blocks and reentrant arrhythmias. Human clinical reports support associations between AChE inhibitor exposure and conduction disturbances. |
AO: Arrhythmias | Strong | Extensive clinical documentation links AChE inhibitor exposure to arrhythmias. Animal studies confirm dose-dependent progression from conduction disturbances to arrhythmias. |
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Age Genetic Variants Electrolyte Imbalances Chemical Interactions |
Older individuals are more susceptible to arrhythmias due to reduced cardiac plasticity and slower compensatory responses to parasympathetic overstimulation. Variants in muscarinic receptors or ion channels can affect the sensitivity of key cellular processes, amplifying or reducing responses to AChE inhibitors. Hypokalemia (low potassium) and hypercalcemia (high calcium) exacerbate ionic imbalances caused by AChE inhibition, worsening conduction abnormalities and arrhythmias. Co-administration of β-adrenergic agonists (e.g., isoproterenol) or other parasympathomimetic agents exacerbates the effects of AChE inhibitors. Conversely, muscarinic antagonists (e.g., atropine) can mitigate these effects |
Inhibition of AChE → Prolonged atrioventricular (AV) conduction time Increased ACh → Overactivation of Muscarinic Receptors Overactivation of Muscarinic Receptors → Altered Action Potential Overactivation of Muscarinic Receptors → Altered Action Potential Overactivation of Muscarinic Receptors → Altered Action Potential |
Quantitative Understanding
MIE: Inhibition of AChE
Quantitative Relationship:
AChE inhibition is directly proportional to the dose of the stressor (e.g., organophosphates, carbamates).
IC50 values for AChE inhibition are well-established for various chemicals, ranging from nanomolar to micromolar concentrations depending on the compound.
Measurement:
AChE activity can be quantified using Ellman’s assay or biosensor-based techniques.
Thresholds:
Substantial ACh accumulation occurs when AChE activity is reduced by >50%.
Time Course:
AChE inhibition is rapid, occurring within minutes to hours following exposure.
KE1: Overactivation of Muscarinic Receptors
Quantitative Relationship:
Muscarinic receptor activation depends on the concentration of ACh. EC50 for M2 receptor activation by ACh is approximately 1 µM.
Overactivation occurs when ACh levels exceed the physiological range (e.g., >10 µM).
Measurement:
Muscarinic receptor activity is assessed using radioligand binding assays or electrophysiological recordings of IK,ACh currents.
Thresholds:
Overactivation of M2 receptors is correlated with prolonged IK,ACh channel opening and increased potassium efflux.
Time Course:
Receptor activation occurs within seconds to minutes after ACh levels rise.
KE2: Altered Cardiac Action Potential
Quantitative Relationship:
The degree of action potential alteration (e.g., prolongation, amplitude reduction) is proportional to M2 receptor activation and potassium efflux through IK,ACh.
Dose-response studies demonstrate significant changes in action potential duration at ACh concentrations >10 µM.
Measurement:
Patch-clamp techniques are used to measure action potential duration (APD) and ionic currents in cardiac myocytes.
ECG analysis provides indirect measurements of action potential changes (e.g., QT prolongation).
Thresholds:
A >20% change in APD is associated with electrical instability.
Time Course:
Action potential alterations manifest within minutes to hours of AChE inhibition.
KE3: Prolonged atrioventricular (AV) conduction time
Quantitative Relationship:
Electrical conduction delays increase with the degree of action potential alteration and ionic imbalance.
Conduction blocks are observed at higher ACh concentrations (>50 µM) or prolonged receptor overstimulation.
Measurement:
ECG analysis detects conduction blocks, PR interval prolongation, and QRS widening.
Thresholds:
Prolonged PR intervals (>200 ms) and QRS widening (>120 ms) are indicative of conduction delays.
Time Course:
Conduction disruptions are observed shortly after action potential changes, often within hours.
AO: Arrhythmias
Quantitative Relationship:
The likelihood of arrhythmias increases with the severity of conduction disruption and action potential instability.
Dose-response studies in animal models link higher AChE inhibitor concentrations with increased incidence of bradyarrhythmias, tachyarrhythmias, or fibrillation.
Measurement:
Arrhythmias are diagnosed using ECG, measuring irregularities in heart rate, rhythm, and intervals (e.g., bradycardia, tachycardia, QT prolongation).
Thresholds:
Severe arrhythmias typically occur when ACh levels are >10-fold above physiological levels.
Time Course:
Arrhythmias can occur within hours of exposure, depending on the dose and stressor.
Key Event or Relationship | Quantitative Relationship | Measurement Tools |
MIE: AChE Inhibition | Dose-response (IC50 well-characterized) | Ellman’s assay, LC-MS |
KE1: Increased ACh Levels | Linear relationship with AChE inhibition | LC-MS, ELISA |
KE2: Overactivation of M2 Receptors | ACh EC50 (~1 µM) for receptor activation | Radioligand binding, IK,ACh |
KE3: Altered Cardiac Action Potential | Dose-response for APD changes with ACh >10 µM | Patch-clamp, Electrocardiogram |
KE4: Prolonged atrioventricular (AV) conduction time | Conduction blocks proportional to APD changes | Electrocardiogram |
AO: Arrhythmias | Incidence correlates with severity of conduction disruptions | Electrocardiogram |
Considerations for Potential Applications of the AOP (optional)
Potential applications of this AOP include hazard identification, chemical screening, and prioritization of AChE inhibitors, as well as preclinical drug safety evaluations. In regulatory toxicology, it can assess the cardiotoxic risks of pesticides and environmental toxins. For therapeutic development, it supports the design of safer cholinesterase inhibitors and post-exposure treatments targeting intermediate key events. Personalized medicine applications include genetic risk stratification and precision therapies for at-risk populations. This AOP framework advances the understanding of how AChE inhibition leads to arrhythmias, with significant implications for toxicology, pharmacology, and regulatory science. It enables predictive risk assessments, therapeutic innovation, and enhanced regulatory decision-making to mitigate the cardiotoxic effects of AChE inhibition.
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