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AOP: 554

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

β-adrenergic receptor agonists leading to arrhythmias.

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
β-adrenergic receptor agonists leading to arrhythmias.
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

A graphical representation of the AOP.This graphic should list all KEs in sequence, including the MIE (if known) and AO, and the pair-wise relationships (links or KERs) between those KEs. More help
Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

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

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Young Jun Kim   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Young Jun Kim

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:30

Revision dates for related pages

Page Revision Date/Time
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

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

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

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

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

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

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

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 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)

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 and other cells in culture human and other cells in culture High NCBI
rodents rodents High NCBI
Macaca mulatta Macaca mulatta High NCBI
zebrafish Danio rerio Moderate NCBI
Gallus gallus Gallus gallus 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

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

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

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

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

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

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

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 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

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

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

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)

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

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

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

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.