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AOP: 554
Title
β-adrenergic receptor agonists 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 09:30
Revision dates for related pages
Page | Revision Date/Time |
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Activation, beta-2 adrenergic receptor | September 16, 2017 10:17 |
Increased Intracellular cAMP Levels | November 21, 2024 11:40 |
Increased the delayed and early afterdepolarizations | November 26, 2024 12:35 |
Occurrence, cardiac arrhythmia | September 16, 2017 10:17 |
Activation, beta-2 adrenergic receptor leads to Intracellular cAMP | November 21, 2024 11:45 |
Intracellular cAMP leads to the delayed and early afterdepolarizations | November 21, 2024 11:45 |
the delayed and early afterdepolarizations leads to Occurrence, cardiac arrhythmia | November 21, 2024 11:46 |
Isoproterenol | November 21, 2024 11:48 |
Epinephrine | November 21, 2024 11:49 |
Norepinephrine | November 21, 2024 11:49 |
Theophylline | November 21, 2024 11:49 |
Milrinone | November 21, 2024 11:50 |
Bisphenol A | December 29, 2019 18:38 |
Abstract
Excessive β-adrenergic receptor (β-AR) activation leading to arrhythmias is a well-recognized mechanism in cardiovascular toxicology and has been studied within the framework of Adverse Outcome Pathways (AOPs). This AOP outlines the biological and mechanistic processes involved in the development of arrhythmias due to excessive β-AR stimulation. The molecular initiating event (MIE) involves overstimulation of β-ARs, which activates the G-protein-mediated adenylate cyclase pathway, increasing intracellular cyclic AMP (cAMP) levels. The subsequent key events (KEs) include increased cAMP levels, altered calcium handling in cardiomyocytes, electrical instability in cardiomyocytes, and triggered activity in the heart. These events lead to the adverse outcome (AO) of cardiac arrhythmias, clinically manifesting as tachyarrhythmias or bradyarrhythmias in severe cases. Key event relationships (KERs) provide mechanistic links between each KE, supported by strong experimental evidence. Overactivation of β-ARs leads to increased cAMP levels, which, through protein kinase A (PKA)-mediated phosphorylation, alters calcium cycling, impacting the function of L-type calcium channels and ryanodine receptors (RyR2). This disrupts excitation-contraction coupling, creating electrical instability, which generates afterdepolarizations (EADs and DADs) and ultimately results in arrhythmogenic events. Modulating factors such as genetic predisposition, pre-existing cardiovascular conditions, and environmental stressors can influence susceptibility to these events. This AOP is significant for risk assessment, particularly in evaluating the pro-arrhythmic potential of β-AR agonists and understanding the cardiotoxic effects of environmental and psychological stressors. It also has applications in drug development, facilitating the identification of compounds that modulate β-AR or calcium handling with minimal arrhythmogenic risk. Additionally, key events such as altered calcium handling or increased cAMP levels can serve as biomarkers for early detection of arrhythmogenic risk. This framework organizes existing knowledge, prioritizes research needs, and guides risk management strategies related to β-AR-mediated arrhythmias.
AOP Development Strategy
Context
Excessive activation of β-adrenergic receptors (β-ARs) is a key mechanism underlying stress-induced or drug-induced cardiac arrhythmias, a leading cause of morbidity and mortality worldwide. β-ARs, primarily located in cardiac tissues, play a central role in regulating heart rate, contractility, and rhythm under normal physiological conditions. However, overstimulation of β-ARs, caused by elevated catecholamine levels (e.g., during stress or drug administration) or exogenous β-AR agonists, disrupts this balance, initiating a cascade of molecular and cellular events that increase susceptibility to arrhythmias. This AOP is especially relevant for assessing the cardiac safety of pharmaceuticals, understanding the impacts of environmental stressors, and addressing genetic or disease-related predispositions to arrhythmias. Developing this AOP framework is critical for supporting regulatory decision-making, guiding preclinical safety testing, and identifying early biomarkers of cardiac arrhythmias. By capturing the mechanistic details of β-AR overactivation and its downstream effects, the AOP enhances our ability to predict and mitigate risks associated with pro-arrhythmic compounds and conditions. It also emphasizes the interplay of modulating factors, such as genetic mutations, pre-existing cardiovascular conditions, and environmental influences, in determining the overall risk of arrhythmias.
Strategy
1. Problem Formulation
Define the adverse outcome (AO): Development of cardiac arrhythmias resulting from excessive β-AR activation.
Establish the relevance of this AOP for risk assessment, particularly in evaluating drug-induced arrhythmias, environmental stressors, or pre-existing cardiovascular risks.
Identify potential applications for pharmaceutical safety testing, regulatory decision-making, and biomarker development.
2. Identify and Define Key Elements
Molecular Initiating Event (MIE):
Overactivation of β-adrenergic receptors by endogenous (e.g., stress-induced catecholamines) or exogenous (e.g., β-AR agonists) agents.
Key Events (KEs):
Increased intracellular cyclic AMP (cAMP) levels.
Altered calcium handling in cardiomyocytes (e.g., increased calcium influx, sarcoplasmic reticulum dysfunction).
Electrical instability in cardiomyocytes (e.g., afterdepolarizations and action potential prolongation).
Triggered activity in the heart (e.g., ectopic beats or reentry circuits).
3. Conduct Literature Review and Data Collection
Perform a systematic review of relevant studies on β-AR signaling, calcium dynamics, and arrhythmias.
Collect data from:
In vitro and in vivo studies on β-AR activation and downstream effects.
Clinical case reports and epidemiological studies linking stress, drug exposure, or genetic predisposition to arrhythmias.
High-throughput screening data to identify potential modulators or triggers.
3. Conduct Literature Review and Data Collection
Perform a systematic review of relevant studies on β-AR signaling, calcium dynamics, and arrhythmias.
Collect data from:
In vitro and in vivo studies on β-AR activation and downstream effects.
Clinical case reports and epidemiological studies linking stress, drug exposure, or genetic predisposition to arrhythmias.
High-throughput screening data to identify potential modulators or triggers.
4. Evidence Integration
Use a weight-of-evidence (WoE) framework to evaluate:
Biological Plausibility: Mechanistic understanding of β-AR activation and its role in arrhythmogenesis.
Empirical Evidence: Dose-response and temporal concordance of KEs and KERs.
Quantitative Understanding: Thresholds and magnitude of changes required to progress through the pathway.
5. Validation of Key Events and Relationships
Experimental Validation:
Conduct experiments in cardiomyocyte models to confirm the relationship between β-AR activation, calcium handling, and electrical instability.
Use genetically modified models (e.g., RyR2 mutations) to study predisposition to arrhythmias.
Computational Modeling:
Develop models to simulate β-AR signaling, calcium dynamics, and the progression of electrical instability to arrhythmias.
Predict dose-response relationships and temporal progression across KEs.
Biomarker Identification:
Validate biomarkers (e.g., cAMP levels, calcium flux) for early detection of arrhythmogenic risks.
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 | 1038 | Activation, beta-2 adrenergic receptor | Activation, beta-2 adrenergic receptor |
KE | 2284 | Increased Intracellular cAMP Levels | Intracellular cAMP |
KE | 2285 | Increased the delayed and early afterdepolarizations | the delayed and early afterdepolarizations |
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, beta-2 adrenergic receptor leads to Intracellular cAMP | adjacent | High | High |
Intracellular cAMP leads to the delayed and early afterdepolarizations | adjacent | High | Moderate |
the delayed and early afterdepolarizations leads to Occurrence, cardiac arrhythmia | adjacent | High | High |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
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Not Otherwise Specified | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
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Mixed | Moderate |
Overall Assessment of the AOP
Molecular Initiating Event (MIE): Numerous studies demonstrate that excessive β-AR activation by catecholamines, stress, or β-AR agonists directly leads to increased cAMP levels.
Key Events (KEs): Experimental data from in vitro and in vivo studies confirm:
Elevated cAMP levels increase protein kinase A (PKA) activity, driving calcium influx and sarcoplasmic reticulum (SR) calcium release.
Calcium overload causes delayed afterdepolarizations (DADs) and early afterdepolarizations (EADs), leading to electrical instability.
Adverse Outcome (AO): Clinical and animal studies link triggered electrical activity to various forms of cardiac arrhythmias, such as ventricular tachycardia and atrial fibrillation.
Domain of Applicability
Species Applicability:
Mammalian species: The AOP is highly applicable to mammals, including humans, rodents (e.g., rats and mice), and larger animals (e.g., dogs and pigs) commonly used in cardiovascular research.
Human relevance: β-AR signaling and calcium handling pathways are highly conserved across mammals, making the AOP directly applicable to human risk assessment.
Non-mammalian species: Limited evidence exists for applicability to non-mammalian species, but similar calcium signaling pathways in some vertebrates suggest potential relevance.
Life Stages:
Adults: The AOP is most applicable to adult individuals where β-AR signaling is fully functional.
Pediatrics and elderly: While the AOP is relevant, differences in β-AR density, calcium cycling efficiency, and cardiac remodeling may modulate susceptibility in these populations.
Essentiality of the Key Events
Key Events (KEs) and Their Essentiality
Molecular Initiating Event (MIE): Excessive Activation of β-Adrenergic Receptors (β-ARs)
Essentiality Rating: High
Rationale: β-AR overstimulation is the trigger for the entire pathway. Pharmacological studies show that β-AR antagonists (e.g., propranolol) prevent the subsequent cascade of events, including cAMP elevation, altered calcium handling, and arrhythmias. Without excessive β-AR activation, the downstream effects are absent.
Evidence: Inhibition of β-AR activity eliminates the arrhythmogenic effects of stress or β-AR agonists in both in vitro and in vivo models.
KE1: Increased Intracellular cAMP Levels
Essentiality Rating: High
Rationale: Elevated cAMP is a direct consequence of β-AR activation and a critical signaling molecule in activating downstream targets like protein kinase A (PKA). Blocking cAMP synthesis (e.g., via adenylate cyclase inhibitors) prevents subsequent effects on calcium handling and electrical stability.
Evidence: Studies demonstrate that manipulating cAMP levels directly alters the phosphorylation of calcium-handling proteins and cardiac excitability. Pharmacological inhibitors of adenylate cyclase reduce arrhythmias in experimental models.
3. KE2: Electrical Instability in Cardiomyocytes
Essentiality Rating: High
Rationale: Electrical instability, characterized by early or delayed afterdepolarizations (EADs or DADs), is a necessary precursor for triggered activity and arrhythmias. Preventing these depolarizations (e.g., through ion channel blockers or PKA inhibitors) effectively reduces the likelihood of arrhythmias.
Evidence: Experimental and computational studies confirm that suppressing electrical instability eliminates ectopic beats and reentrant circuits, directly preventing arrhythmogenesis.
4. Adverse Outcome (AO): Cardiac Arrhythmias
Essentiality Rating: Outcome
Rationale: The AO is the ultimate manifestation of the pathway and does not influence upstream KEs. Preventing the AO is the goal of intervention strategies.
Evidence Assessment
1. Molecular Initiating Event (MIE): Excessive β-Adrenergic Receptor Activation
Biological Plausibility: High. β-Adrenergic receptor (β-AR) activation is a well-documented mechanism initiating sympathetic responses. Excessive stimulation by agonists (e.g., isoproterenol) or catecholamine surges is strongly linked to cardiac stress and arrhythmias.
Empirical Evidence: Robust experimental data show that β-AR activation leads to increased cyclic AMP (cAMP) and downstream signaling. Studies using β-blockers (e.g., propranolol) effectively prevent the cascade.
Temporal and Dose Concordance: High. The extent of β-AR activation correlates with the magnitude of downstream events and the severity of arrhythmias.
Uncertainties or Inconsistencies: Limited to rare cases of receptor desensitization or individual variability in β-AR expression.
2. KE1: Increased Intracellular cAMP Levels
Biological Plausibility: High. β-AR signaling is directly coupled to adenylate cyclase activation, leading to cAMP synthesis. Elevated cAMP is a central mediator in the pathway.
Empirical Evidence: Strong evidence from in vitro and in vivo studies demonstrates that excessive cAMP triggers protein kinase A (PKA) activation, altering downstream calcium dynamics. Inhibitors of adenylate cyclase attenuate these effects.
3. KE2: Electrical Instability in Cardiomyocytes
Biological Plausibility: High. Electrical instability is a direct consequence of calcium overload, manifesting as delayed afterdepolarizations (DADs) and early afterdepolarizations (EADs). These abnormalities disrupt normal cardiac excitation-contraction coupling.
Empirical Evidence: Robust. Studies using ion channel blockers or stabilizers (e.g., flecainide) demonstrate the importance of electrical stability in preventing triggered activity.
Temporal and Dose Concordance: High. Electrical instability arises after calcium dysregulation and is directly correlated with arrhythmic risk.
4. Adverse Outcome (AO): Cardiac Arrhythmias
Biological Plausibility: High. The link between triggered activity and clinically observed arrhythmias is direct and well-documented in humans and animal models.
Empirical Evidence: Strong. Numerous studies demonstrate that interventions preventing upstream KEs significantly reduce the incidence and severity of arrhythmias.
Temporal and Dose Concordance: High. Arrhythmias occur after upstream events in a dose- and time-dependent manner.
Key Event Relationships (KERs)
The relationships between KEs are well-supported by empirical evidence:
MIE → KE1: β-AR activation directly leads to increased cAMP levels
KE1 → KE2: cAMP elevation drives PKA activation, induced electrical instability triggers ectopic activity; antiarrhythmic drugs targeting this stage effectively block arrhythmias.
KE2 →AO: Electrical instability triggers leads to arrhythmias; suppressing ectopic beats prevents adverse outcomes.
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
Genetic Variability Environmental Stressors Age Electrolyte Imbalances |
Amplifies or attenuates calcium mishandling and electrical instability Acute stress amplifies β-AR activation; chronic stress alters receptor responsivenes Age-related cardiac changes exacerbate calcium handling issues and electrical instability Disrupts action potentials and calcium cycling, increasing instability |
MIE → KE1, KE1 → KE2 KE1 → KE2, KE2 → AO MIE → AO |
Quantitative Understanding
Quantitative data exist for several components of the AOP:
Dose-response relationships for β-AR agonists and their effects on cAMP production and calcium handling have been quantified in cardiac cells.
Time-course studies show the progression from β-AR activation to calcium overload and arrhythmogenesis.
Mathematical models of cardiac electrophysiology further quantify the thresholds for afterdepolarizations and triggered activity, supporting the pathway’s predictive capabilities.
In Vitro Models:
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for studying β-AR signaling and calcium handling.
Isolated cardiac tissue preparations from animals to assess electrical instability and arrhythmogenic potential.
In Vivo Models:
Rodent and large-animal models for evaluating the progression from molecular initiating events to arrhythmias.
Use of genetic models (e.g., RyR2 mutations) to investigate modulating factors.
However, gaps remain in fully quantifying the transition between certain key events, particularly the dose-dependent progression from calcium handling alterations to electrical instability.
Considerations for Potential Applications of the AOP (optional)
The AOP for excessive β-adrenergic receptor (β-AR) activation leading to arrhythmias provides a mechanistic framework for understanding the progression from molecular initiating events to adverse cardiac outcomes. This AOP has significant potential applications across regulatory, research, and risk assessment domains. In risk assessment, it can evaluate the potential of chemicals, drugs, or stressors to induce arrhythmias by identifying β-AR agonists or compounds that indirectly activate β-ARs as potential arrhythmogenic agents. The AOP supports the establishment of dose-response relationships and the consideration of population susceptibilities, such as age, genetic predisposition, and pre-existing cardiovascular conditions. For regulatory decision-making, it informs guidelines for cardiovascular safety evaluation under frameworks like OECD guidelines or REACH. It can also integrate into computational models for high-throughput screening of cardiovascular risks the AOP also plays an educational role, serving as a training tool for stakeholders in toxicology and regulatory science, with workshops and case studies demonstrating its practical applications. Despite its broad applicability, challenges remain, including data gaps in some key event relationships, species variability, and the multifactorial nature of arrhythmias, requiring integration with other models or AOPs. Addressing these challenges will enhance its utility and reliability. This AOP provides a valuable framework for risk management and regulatory decision-making, contributing to safer by design.
References
Yi-Hsin et al. CD44 regulates Epac1-mediated β-adrenergic-receptor-induced Ca²⁺-handling abnormalities: implication in cardiac arrhythmias. Journal of Biomedical Science. 2023;30(55).
Lefkowitz RS, Kobilka BK. Mechanisms of β-adrenergic receptor signaling and regulation. Molecular Pharmacology. 1990;38(6):801-808.
Bers RS. Cardiac excitation-contraction coupling. Nature. 2002;415(6868):198-205.
Glukhov CE, Salazar C. Arrhythmogenesis in heart failure: altered electrical conduction. Circulation Research. 2016;119(6):807-819.
Rosen MR, Efimov IR. Mechanisms of triggered activity in arrhythmias. Heart Rhythm. 2014;11(12):2017-2026.
Zipes DP, Jalife J. Cardiac electrophysiology: from cell to bedside. Cardiology Clinics. 2007;25(3):447-457.