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AOP: 551
Title
Increased Muscarinic M2 Receptor leading to Arrhythmia
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 09:32
Revision dates for related pages
Page | Revision Date/Time |
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Occurrence, cardiac arrhythmia | September 16, 2017 10:17 |
Increased Muscarinic Acetylcholine Receptors | December 02, 2024 03:35 |
Increased, blood potassium concentration | September 16, 2017 10:16 |
Disruption, action potential generation | July 24, 2024 22:48 |
Increased delay in heart electrical conduction | November 26, 2024 12:31 |
Activation, Muscarinic Acetylcholine Receptors leads to Increased, blood potassium concentration | November 20, 2024 11:13 |
Increased, blood potassium concentration leads to Disruption in action potential generation | November 20, 2024 11:14 |
Disruption in action potential generation leads to Prolonged atrioventricular (AV) | November 20, 2024 11:15 |
Prolonged atrioventricular (AV) leads to Occurrence, cardiac arrhythmia | November 20, 2024 11:15 |
Malathion | March 30, 2020 15:59 |
Carbamate pesticides | November 20, 2024 10:40 |
Cholinergic drugs | November 20, 2024 10:40 |
Abstract
This AOP focuses on the pathophysiological changes induced by heightened parasympathetic activity that culminate in the disruption of normal cardiac rhythm. excessive stimulation of the parasympathetic nervous system (PNS) can lead to arrhythmias through its profound effects on cardiac electrical activity. The PNS, primarily mediated by the vagus nerve and acetylcholine release, activates muscarinic M2 receptors in the sinoatrial (SA) node, atrioventricular (AV) node, and atrial myocardium. This results in decreased SA node firing, slowed AV conduction, and increased refractoriness, predisposing to bradyarrhythmias such as sinus bradycardia, sinus arrest, and AV block. Parasympathetic overactivity can also promote atrial arrhythmias, including atrial fibrillation (AF) and atrial flutter, by creating heterogeneous refractoriness and slowed atrial conduction. Reflex-mediated vagal hyperactivity, such as in carotid sinus hypersensitivity, vasovagal syncope, or the Bezold-Jarisch reflex, exacerbates these effects. Additionally, prolonged parasympathetic activity can lead to early afterdepolarizations, increasing susceptibility to Torsades de Pointes (TdP) in susceptible individuals. Clinical conditions such as athlete’s heart, sleep apnea, inferior myocardial infarction, and neurological disorders highlight the arrhythmogenic potential of parasympathetic overstimulation. While moderate PNS activity provides cardioprotection, excessive vagal stimulation can disrupt cardiac rhythm, understanding parasympathetic influences on cardiac electrophysiology is critical for managing related arrhythmias and preventing adverse outcomes.
AOP Development Strategy
Context
This AOP provides a mechanistic framework linking excessive parasympathetic stimulation to arrhythmia. It is well-supported by experimental and clinical evidence and can be used for assessing the cardiotoxicity of neurotoxicants and developing therapeutic interventions for arrhythmias.
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Biological Basis:
- The parasympathetic nervous system (PNS), primarily mediated by the vagus nerve and acetylcholine, regulates cardiac function through its influence on the sinoatrial (SA) and atrioventricular (AV) nodes.
- Excessive parasympathetic stimulation can lead to bradycardia, conduction block, and arrhythmias such as atrial fibrillation or sinus arrest.
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Regulatory Context:
- This AOP is relevant for assessing risks associated with chemical exposures (e.g., organophosphates, cholinergic agonists) and diseases (e.g., neurodegenerative conditions, vagal hyperactivity) that overstimulate the PNS.
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Target Applications:
- Risk assessment of neurotoxicants.
- Identification of therapeutic targets for parasympathetic overstimulation-related arrhythmias.
Strategy
Identification of Relevant Data
- Molecular Data:
- Studies on acetylcholine dynamics, muscarinic receptor activation, and IK,ACh channel function.
- Cellular Data:
- Electrophysiological recordings of pacemaker activity and conduction velocity in SA/AV node cells.
- Tissue and Organ Data:
- ECG recordings showing bradycardia, conduction block, or arrhythmias in animal and human models.
Screening of Data
- Filter studies based on their relevance to the pathway, including chemical stressors (e.g., acetylcholinesterase inhibitors) and conditions mimicking excessive parasympathetic activity.
Quality Assessment
- Use weight-of-evidence frameworks to evaluate biological plausibility, empirical support, and consistency across species.
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Empirical Evidence:
- Experimental studies demonstrating acetylcholine-induced bradycardia and arrhythmias.
- Data showing the dose-response relationship between parasympathetic stimulation and arrhythmias.
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Mechanistic Plausibility:
- Supported by well-characterized roles of muscarinic receptors, IK,ACh channels, and cardiac pacemaker cells.
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Quantitative Understanding:
- Quantitative relationships between acetylcholine levels, receptor activation, and arrhythmia onset are well-defined in many models.
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 | 1602 | Increased Muscarinic Acetylcholine Receptors | Activation, Muscarinic Acetylcholine Receptors |
KE | 1098 | Increased, blood potassium concentration | Increased, blood potassium concentration |
KE | 1983 | Disruption, action potential generation | Disruption in action potential generation |
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 |
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Activation, Muscarinic Acetylcholine Receptors leads to Increased, blood potassium concentration | adjacent | High | Moderate |
Increased, blood potassium concentration leads to Disruption in action potential generation | adjacent | High | Moderate |
Disruption in action potential generation leads to Prolonged atrioventricular (AV) | adjacent | High | Moderate |
Prolonged atrioventricular (AV) leads to Occurrence, cardiac arrhythmia | adjacent | High | Moderate |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
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Not Otherwise Specified | Moderate |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
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human, mouse, rat | human, mouse, rat | Moderate | NCBI |
Sex Applicability
Sex | Evidence |
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Mixed | Moderate |
Overall Assessment of the AOP
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MIE → KE1 (Acetylcholine Overload → Muscarinic Receptor Activation):
- Strongly supported by experimental evidence showing that acetylcholine overload increases M2 receptor activation.
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KE1 → KE2 (Muscarinic Receptor Activation → Hyperpolarization):
- Direct relationship through the activation of muscarinic potassium channels (IK,ACh), leading to reduced pacemaker activity.
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KE2 → KE3 (Hyperpolarization → Prolonged AV Conduction Time):
- Increased potassium efflux disrupts action potential propagation, particularly in the AV node.
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KE3 → AO (Prolonged Conduction Time → Arrhythmia):
- Slowed conduction creates conditions for reentrant circuits or ectopic pacemaker activity, leading to arrhythmias.
Domain of Applicability
- Species:
- Humans, as well as mammalian models (e.g., rodents, canines) used for studying cardiac physiology.
- Life Stage:
- Adults are primarily affected, but neonates and older individuals may exhibit heightened sensitivity to parasympathetic overstimulation.
- Sex:
- No significant sex differences reported, though hormonal influences on autonomic regulation may exist.
- Exposure:
- Relevant for chemicals like organophosphates, carbamates, and other cholinergic agonists.
Essentiality of the Key Events
Molecular Initiating Event (MIE)
- Excessive Release or Accumulation of Acetylcholine:
- Caused by overstimulation of parasympathetic nerves, acetylcholinesterase inhibition (e.g., by organophosphates), or excessive activation of muscarinic receptors.
Key Events (KEs)
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Increased Muscarinic Receptor Activation:
- Excess acetylcholine binds to M2 muscarinic receptors in cardiac tissue, primarily in the SA and AV nodes, leading to decreased heart rate and altered conduction velocity.
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Hyperpolarization of Cardiac Cells:
- Activation of muscarinic potassium channels (IK,ACh) increases potassium efflux, hyperpolarizing cardiac pacemaker cells and reducing the likelihood of action potential generation.
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Prolonged AV Conduction Time:
- Excessive vagal stimulation slows conduction through the AV node, leading to atrioventricular block or bradyarrhythmia.
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Disruption of Normal Sinus Rhythm:
- Bradycardia or pauses in pacemaker activity can result in ectopic pacemaker activation or reentrant circuits, leading to arrhythmias such as atrial fibrillation.
Evidence Assessment
Empirical Evidence:
Experimental studies demonstrating acetylcholine-induced bradycardia and arrhythmias.
Data showing the dose-response relationship between parasympathetic stimulation and arrhythmias.
Mechanistic Plausibility:
Supported by well-characterized roles of muscarinic receptors, IK,ACh channels, and cardiac pacemaker cells.
Quantitative Understanding:
Quantitative relationships between acetylcholine levels, receptor activation, and arrhythmia onset are well-defined in many models.
Techniques:
Molecular Level:
Enzymatic assays for acetylcholine levels.
Binding assays for muscarinic receptor activation.
Cellular Level:
Patch-clamp recordings to assess IK,ACh activity and hyperpolarization.
Tissue and Organ Level:
ECG and electrophysiological studies for arrhythmia detection.
Known Modulating Factors
Modulating Factor (MF) |
Influence or Outcome |
KER(s) involved |
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Muscarinic receptors (e.g., CHRM2) or potassium channel function (e.g., KCNJ3 encoding IK,ACh) Cholinergic Agents: Drugs (e.g., pilocarpine, bethanechol) and toxins (e.g., organophosphates, carbamates) can amplify parasympathetic stimulation by i ncreasing acetylcholine levels or directly activating muscarinic receptors. |
Sinus Bradycardia: |
MIE: Increased Muscarinic Receptor Activation
KE2: Hyperpolarization of Cardiac Pacemaker Cells
KE3: Prolonged AV Conduction Time
AO: Disruption of Normal Sinus Rhythm (arrhythmia)
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Quantitative Understanding
1. Molecular Initiating Event (MIE): Muscarinic Receptor Activation via Excessive Acetylcholine Release or Accumulation
Quantifiable Metrics:
Acetylcholine Concentration:
Measured in plasma or cardiac tissue using biochemical assays (e.g., high-performance liquid chromatography).
Inhibition of Acetylcholinesterase (AChE):
Degree of AChE inhibition is quantified as a percentage of enzyme activity reduction. A >50% reduction in AChE activity is typically associated with significant acetylcholine accumulation.
Dose-Response Relationship:
Studies show a strong correlation between the concentration of acetylcholine or AChE inhibitors (e.g., organophosphates) and parasympathetic overstimulation.
Example: Increased acetylcholine levels of 10–50 µM can lead to significant M2 receptor activation.
2. KE1: Increased Muscarinic Receptor Activation
Quantifiable Metrics:
Receptor Binding Affinity:
Measured as the dissociation constant (Kd) or half-maximal effective concentration (EC50) for acetylcholine binding to M2 muscarinic receptors.
Receptor Activation:
Quantified by downstream signaling responses, such as increased cAMP inhibition or IK,ACh activation.
Dose-Response Relationship:
EC50 values for acetylcholine binding to M2 receptors in cardiac tissue are typically in the range of 1–10 µM.
Higher acetylcholine concentrations lead to saturable receptor activation, with receptor desensitization occurring at extremely high levels.
3. KE2: Hyperpolarization of Cardiac Pacemaker Cells
Quantifiable Metrics:
Potassium Channel Activation (IK,ACh):
Measured using patch-clamp electrophysiology to quantify potassium current density (e.g., pA/pF).
Resting Membrane Potential:
Hyperpolarization is quantified as a shift in resting membrane potential (e.g., from −60 mV to −75 mV).
Dose-Response Relationship:
Potassium efflux increases in proportion to M2 receptor activation. A >20% increase in IK,ACh activity is associated with significant hyperpolarization.
Hyperpolarization beyond −75 mV reduces action potential firing in the SA node.
4. KE3: Prolonged AV Conduction Time
Quantifiable Metrics:
PR Interval on Electrocardiogram (ECG):
The PR interval, representing AV conduction time, is measured in milliseconds (ms). Normal PR interval: 120–200 ms.
Conduction Velocity:
Measured as the speed of action potential propagation through the AV node (e.g., cm/s).
Dose-Response Relationship:
Increased parasympathetic activity correlates with PR interval prolongation. A 50% increase in acetylcholine levels can extend the PR interval by >30 ms.
Extreme vagal stimulation may result in second-degree or third-degree AV block.
5. KE4: Disruption of Normal Sinus Rhythm
Quantifiable Metrics:
Heart Rate:
Bradycardia is defined as a heart rate <60 beats per minute (bpm) in humans.
Arrhythmia Incidence:
Measured as the frequency of arrhythmic events (e.g., atrial fibrillation episodes) in a given time frame.
Dose-Response Relationship:
High acetylcholine concentrations (>50 µM) can cause sinus pauses, ectopic pacemaker activation, or atrial fibrillation.
Quantitative relationships between IK,ACh activation and arrhythmia onset show that >30% increase in IK,ACh activity correlates with significant arrhythmogenesis.
6. Adverse Outcome (AO): Arrhythmia
Quantifiable Metrics:
ECG Parameters:
Bradycardia: Heart rate <60 bpm.
AV Block: Prolonged PR interval >200 ms or dropped beats.
Atrial Fibrillation: Irregular R-R intervals and absence of P waves.
Cardiac Output:
Measured in liters per minute, reduced due to arrhythmia-related inefficiency.
Dose-Response Relationship:
Strong correlation between prolonged vagal stimulation and arrhythmia severity.
Studies in animal models show that >50% vagal nerve stimulation induces sustained arrhythmias, including atrial fibrillation.
Quantitative Understanding Across KEs
Temporal Concordance:
Excessive acetylcholine release rapidly activates M2 receptors (within seconds), leading to hyperpolarization and prolonged AV conduction time (within minutes). Arrhythmias can develop in minutes to hours after excessive stimulation.
Thresholds for Activation:
Acetylcholine concentration thresholds for key events:
~5–10 µM: Significant M2 receptor activation.
30 µM: Marked hyperpolarization and bradycardia.
50 µM: Severe arrhythmias (e.g., atrial fibrillation).
Mathematical Models:
Computational models of cardiac electrophysiology can predict the likelihood of arrhythmias based on acetylcholine concentrations and IK,ACh activity.
Key Data Gaps
Limited quantitative data on the precise thresholds for arrhythmia onset in human populations.
Need for dose-response models that integrate multi-level interactions (e.g., molecular, cellular, tissue-level effects).
Variability in thresholds across species and individual susceptibilities.
Considerations for Potential Applications of the AOP (optional)
In hazard identification, this AOP helps identify chemicals, drugs, and environmental agents (e.g., cholinergic agonists, acetylcholinesterase inhibitors) that overstimulate the parasympathetic nervous system, including neurotoxicants such as organophosphates and carbamates that induce vagal hyperactivity. High-throughput screening platforms like ToxCast and Tox21 can evaluate the potential of chemicals to trigger molecular initiating events (MIEs) such as excessive acetylcholine release or muscarinic receptor activation, while computational models incorporating dose-response data for key events (KEs) can prioritize compounds for further evaluation. Additionally, the AOP facilitates read-across approaches for chemicals with similar structures or mechanisms of action, enabling efficient identification of risks.
In risk assessment, quantitative relationships between KEs (e.g., acetylcholine concentration, IK,ACh activation) and the adverse outcome (arrhythmia) support the development of dose-response models to establish acceptable exposure limits for neurotoxicants. The AOP framework also allows for cumulative risk assessment by evaluating the combined effects of multiple stressors influencing parasympathetic activity, such as concurrent exposure to organophosphates and emotional stressors. Moreover, the framework accounts for variability in susceptible populations, including age, genetic differences, and pre-existing health conditions that increase sensitivity to parasympathetic overstimulation. This AOP enables the identification and management of risks associated with parasympathetic overstimulation and provides a robust basis for regulatory decisions and research into cardiotoxic effects.