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AOP: 551

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Increased Muscarinic M2 Receptor leading to Arrhythmia

Short name
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Increased M2 receptor leading to Arrhythmia
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

Coaches

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OECD Information Table

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OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:32

Revision dates for related pages

Page Revision Date/Time
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

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

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

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

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.

  • 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.
  • 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.
  • Target Applications:

    • Risk assessment of neurotoxicants.
    • Identification of therapeutic targets for parasympathetic overstimulation-related arrhythmias.

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

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.
  • 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.

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 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)

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 Moderate

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, mouse, rat human, mouse, rat Moderate NCBI

Sex Applicability

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

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
  • MIE → KE1 (Acetylcholine Overload → Muscarinic Receptor Activation):

    • Strongly supported by experimental evidence showing that acetylcholine overload increases M2 receptor activation.
  • KE1 → KE2 (Muscarinic Receptor Activation → Hyperpolarization):

    • Direct relationship through the activation of muscarinic potassium channels (IK,ACh), leading to reduced pacemaker activity.
  • KE2 → KE3 (Hyperpolarization → Prolonged AV Conduction Time):

    • Increased potassium efflux disrupts action potential propagation, particularly in the AV node.
  • KE3 → AO (Prolonged Conduction Time → Arrhythmia):

    • Slowed conduction creates conditions for reentrant circuits or ectopic pacemaker activity, leading to arrhythmias.

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
  • 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

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

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)

  1. 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.
  2. 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.
  3. Prolonged AV Conduction Time:

    • Excessive vagal stimulation slows conduction through the AV node, leading to atrioventricular block or bradyarrhythmia.
  4. 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

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

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 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

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

  • Excessive acetylcholine overstimulates M2 muscarinic receptors in the heart, particularly in the SA and AV nodes.
  • Directly influenced by factors such as acetylcholinesterase inhibition or heightened vagal nerve activity.

KE2: Hyperpolarization of Cardiac Pacemaker Cells

  • Activation of muscarinic potassium channels (IK,ACh) leads to an efflux of potassium ions, hyperpolarizing the cardiac pacemaker cells.
  • This results in a decreased firing rate of the SA node and slows action potential conduction in the AV node.

KE3: Prolonged AV Conduction Time

  • Excessive parasympathetic stimulation reduces conduction velocity in the AV node, causing a delay in ventricular activation.
  • This prolongation creates conditions conducive to conduction block and arrhythmogenesis.

AO: Disruption of Normal Sinus Rhythm (arrhythmia)

  • The combination of bradycardia, conduction block, and ectopic pacemaker activation leads to the development of arrhythmias such as atrial fibrillation or sinus arrest.

Quantitative Understanding

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

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)

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

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.

References

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