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AOP: 558

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

Phosphodiesterase inhibition leading to heart failure

Short name
A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help
Phosphodiesterase inhibition leading to cardiomyopathy
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

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

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  • 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
Phosphodiesterase inhibition November 22, 2024 07:57
Hyperphosphorylation of ryanodine receptor (RyR2) November 22, 2024 08:00
Increased, Intracellular Calcium overload June 26, 2020 04:45
Decrease, Cardiac contractility June 19, 2018 14:02
Heart failure December 03, 2024 10:15
Increased, cyclic adenosine monophosphate December 03, 2016 16:37
RyR2 hyperphosphorylation leads to Increased, Intracellular Calcium overload November 22, 2024 08:04
Decrease, Cardiac contractility leads to Heart failure January 05, 2023 07:48
Increased, Intracellular Calcium overload leads to Decrease, Cardiac contractility November 21, 2024 14:40
Phosphodiesterase (PDE) leads to Increased, cyclic adenosine monophosphate November 26, 2024 12:45
Increased, cyclic adenosine monophosphate leads to RyR2 hyperphosphorylation November 26, 2024 12:46
Milrinone November 21, 2024 11:50
Enoximone November 22, 2024 08:11
Roflumilast November 22, 2024 08:11
Catecholamines November 22, 2024 08:12
Isoproterenol November 21, 2024 11:48
Forskolin November 22, 2024 08:13
Lead November 29, 2016 18:42
Mercury November 29, 2016 18:42

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

The inhibition of phosphodiesterase (PDE) enzymes in cardiomyocytes disrupts cyclic nucleotide signaling, leading to maladaptive cellular responses and the development of cardiomyopathy. PDEs play a critical role in regulating cyclic AMP (cAMP) and cyclic GMP (cGMP) levels, which are essential for maintaining calcium homeostasis and cardiac function. Phosphodiesterase inhibition results in the accumulation of cAMP, leading to the activation of protein kinase A (PKA) and hyperphosphorylation of key regulatory proteins such as ryanodine receptors (RyR2) and phospholamban (PLN). This process triggers calcium dysregulation, characterized by increased cytosolic calcium levels and sarcoplasmic reticulum (SR) calcium leakage. The resulting calcium overload causes excitation-contraction coupling dysfunction, mitochondrial calcium accumulation, and reactive oxygen species (ROS) generation, leading to oxidative stress and mitochondrial dysfunction. Chronic calcium dysregulation and oxidative damage impair cardiac contractility and initiate pathological myocardial remodeling, including fibrosis and hypertrophy. These structural changes reduce cardiac compliance and output, culminating in cardiomyopathy characterized by reduced ejection fraction, arrhythmias, and heart failure. It offers applications in drug safety evaluation, regulatory toxicology, and therapeutic development by targeting intermediate key events to mitigate cardiomyopathy progression.

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

The AOP: Phosphodiesterase (PDE) Inhibition Leading to Cardiomyopathy provides a mechanistic understanding of how disruption of cyclic nucleotide signaling in cardiomyocytes contributes to cardiac dysfunction and structural damage. Phosphodiesterases (PDEs) are critical enzymes that regulate the levels of cyclic AMP (cAMP) and cyclic GMP (cGMP), key secondary messengers involved in the modulation of cardiac function, particularly calcium handling and excitation-contraction coupling. Inhibition of PDEs, particularly PDE3 and PDE4 isoforms, results in the accumulation of cAMP, which activates protein kinase A (PKA). PKA hyperphosphorylates important regulatory proteins in cardiomyocytes, including ryanodine receptors (RyR2) and phospholamban (PLN). This hyperphosphorylation disrupts calcium homeostasis by increasing calcium leakage from the sarcoplasmic reticulum (SR) into the cytosol, a condition known as calcium dysregulation. Dysregulated calcium cycling leads to cytosolic calcium overload, impairing myocardial contraction and relaxation. Furthermore, excessive calcium influx into mitochondria promotes the generation of reactive oxygen species (ROS), triggering oxidative stress and mitochondrial dysfunction.

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

Objective

To describe the mechanistic progression from the inhibition of PDE enzymes to cardiomyopathy.

To identify key events (KEs), key event relationships (KERs), and modulating factors influencing the pathway.

To enable regulatory applications such as chemical risk assessment, drug safety evaluation, and therapeutic development.

2. Identification of Key Events (KEs)

The pathway starts with the Molecular Initiating Event (MIE) of PDE inhibition and progresses through several KEs to the adverse outcome (AO)

3. Identification of Prototypical Stressors

Pharmacological PDE Inhibitors:

PDE3 inhibitors (e.g., milrinone, enoximone).

PDE4 inhibitors (e.g., roflumilast).

4. Development of Quantitative Models

Build dose-response models linking PDE inhibition to downstream events such as cAMP accumulation, calcium dysregulation, and myocardial remodeling.

Use computational simulations to predict thresholds and time courses for KEs.

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 2288 Phosphodiesterase inhibition Phosphodiesterase (PDE)
KE 693 Increased, cyclic adenosine monophosphate Increased, cyclic adenosine monophosphate
KE 2289 Hyperphosphorylation of ryanodine receptor (RyR2) RyR2 hyperphosphorylation
KE 389 Increased, Intracellular Calcium overload Increased, Intracellular Calcium overload
KE 1532 Decrease, Cardiac contractility Decrease, Cardiac contractility
AO 1535 Heart failure Heart failure

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
dog Canis lupus familiaris High NCBI
Pig Pig Moderate NCBI
zebrafish Danio rerio 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
Aspect Evaluation
Biological Plausibility Strong: Mechanisms are well-established and consistent with cardiac physiology.
Empirical Evidence Robust: Extensive data support most KEs and KERs, particularly early events.
Quantitative Understanding Moderate: Dose-response relationships are documented for early events; later stages need further refinement.
Modulating Factors Identified: Genetic predispositions, age, comorbidities, and drug interactions influence progression.
Regulatory Relevance High: Applicable for assessing  environmental risks, and therapeutic strategies.

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
Domain  Description
Taxonomy Highly applicable to humans, rodents, canines, and pigs; moderately relevant to zebrafish.
Life Stage Most relevant to adults and elderly; moderately applicable to neonates and pediatric populations.
Sex Relevant to both sexes, with potential hormonal modulation influencing outcomes.
Molecular Context Focuses on cardiac PDE isoforms (PDE3, PDE4) and their role in cyclic nucleotide signaling.
Stressors Pharmacological PDE inhibitors, catecholamine surges, and potentially environmental PDE-disrupting agents.

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 Event Essentiality Supporting Evidence
MIE: PDE Inhibition High Directly initiates the cascade leading to cAMP accumulation and downstream effects.
KE1: Increased cAMP Levels High Required for PKA activation and subsequent signaling events.
KE2:  Hyperphosphorylation of ryanodine receptor RyR2 High Necessary for RyR2 and PLN hyperphosphorylation, leading to calcium dysregulation.
KE3: Increased cytosolic Calcium level High Central to contractile dysfunction, oxidative stress, and mitochondrial damage.
KE5: Impaired Contractility Moderate Critical for initiating remodeling but reversible with early intervention.
AO: Cardiomyopathy Endpoint Final outcome of sustained structural and functional deterioration.

Evidence Assessment

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

1. MIE: Inhibition of PDE Enzymes

Essentiality: High

PDEs are crucial for degrading cyclic AMP (cAMP) and cyclic GMP (cGMP), which regulate signaling pathways in cardiomyocytes. Their inhibition directly initiates the cascade of events leading to cardiomyopathy.

Evidence:

PDE inhibitors (e.g., milrinone, roflumilast) consistently increase cAMP levels in a dose-dependent manner.

Genetic or pharmacological PDE knockouts in experimental models reproduce the downstream effects of calcium dysregulation and myocardial remodeling.

2. KE1: Increased cAMP Levels

Essentiality: High

Elevated cAMP is necessary for activating protein kinase A (PKA), which mediates the phosphorylation of key calcium-handling proteins.

Evidence:

Experimental studies show that increases in cAMP levels correlate with PKA activation and RyR2 hyperphosphorylation.

Pharmacological reduction of cAMP (e.g., through PDE overexpression or cAMP inhibitors) prevents downstream events such as cytosolic calcium increases

3. KE2:  Hyperphosphorylation of ryanodine receptor RyR2

Essentiality: High

PKA-mediated hyperphosphorylation of RyR2 and phospholamban (PLN) disrupts calcium handling, leading to calcium leakage from the sarcoplasmic reticulum (SR).

Evidence:

RyR2 hyperphosphorylation causes SR calcium leakage in cardiomyocytes treated with PDE inhibitors.

Blocking PKA activation (e.g., with PKA inhibitors) prevents calcium dysregulation and improves cardiac contractility in experimental models.

4. KE3: Increased Cytosolic Calcium Level

Essentiality: High

Calcium dysregulation is a central event that disrupts excitation-contraction coupling, impairs myocardial contractility, and induces oxidative stress.

Evidence:

Calcium imaging studies confirm that PDE inhibitors increase cytosolic calcium levels and impair calcium cycling.

Pharmacological interventions that stabilize calcium handling (e.g., RyR2 stabilizers, SERCA activators) mitigate downstream effects, including mitochondrial dysfunction and contractile impairment.

5. KE4: Impaired Cardiac Contractility

Essentiality: Moderate

Impaired contractility places sustained stress on the myocardium, triggering remodeling processes. However, interventions targeting earlier KEs (e.g., calcium dysregulation) can prevent contractile dysfunction.

Evidence:

Echocardiographic studies in animal models of PDE inhibition show reduced cardiac output and ejection fraction as early indicators of contractile impairment.

Supportive therapies (e.g., inotropes) temporarily restore contractility but do not prevent structural remodeling.

6. AO: Cardiomyopathy

Essentiality: Endpoint

Cardiomyopathy is the cumulative result of the prior key events and represents the terminal adverse outcome in this pathway.

Evidence:

Clinical data from patients treated with PDE inhibitors (e.g., milrinone) highlight the development of heart failure and structural remodeling consistent with cardiomyopathy.

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 Variants

Age

Sex

Electrolyte Imbalances

Chemical Interactions

Exacerbate calcium dysregulation and oxidative stress through RyR2/PLN dysfunction

Reduces compensatory mechanisms, amplifying calcium and contractile dysfunction.

Hormonal differences modulate susceptibility to calcium dysregulation and remodeling.

Hypokalemia and hypercalcemia worsen calcium dysregulation and contractile impairment.

β-agonists  raises cAMP levels

Increased cAMP → PKA Activation → Calcium Dysregulation

Calcium Dysregulation → Impaired Contractility 

PKA Activation → Calcium Dysregulation

Calcium Dysregulation →  Contractility

PDE Inhibition → Increased cAMP; cAMP → PKA Activation

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help
  • Build dose-response models linking PDE inhibition to downstream events such as cAMP accumulation, calcium dysregulation, and myocardial remodeling.
  • Use computational simulations to predict thresholds and time courses for KEs.
  • In Vitro Studies:
    • Experiments using cardiomyocyte cultures to study the effects of PDE inhibitors on cAMP levels, calcium handling, and contractility.
  • In Vivo Studies:
    • Animal models of PDE inhibitor-induced cardiac dysfunction and myocardial remodeling.
  • Clinical Data:
    • Observations from patients treated with PDE inhibitors (e.g., milrinone) showing cardiotoxic effects.
  • Computational Models:
    • Simulations of cyclic nucleotide signaling and calcium dynamics under PDE inhibition.

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

This Adverse Outcome Pathway (AOP) is supported by robust biological plausibility and empirical evidence from in vitro, in vivo, and clinical studies. Modulating factors, including genetic predispositions (e.g., RyR2 mutations), aging, sex, and comorbidities (e.g., hypertension, diabetes), influence the severity and progression of cardiotoxic outcomes. This AOP offers broad applicability across regulatory toxicology, drug safety evaluation, and therapeutic development. It provides a mechanistic framework for identifying and assessing the risks of PDE inhibitors, guiding preclinical and clinical drug testing, and developing targeted therapies to mitigate cardiotoxic effects. By focusing on key events such as calcium dysregulation and oxidative stress, this AOP also supports the design of combination therapies and personalized medicine strategies to prevent the progression to cardiomyopathy.

References

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

Degerman E, Belfrage P, Manganiello VC. Structure, localization, and regulation of cAMP-specific phosphodiesterase (PDE3). Journal of Biological Chemistry. 1997;272(12):6823–6826.

Movsesian MA, Smith CJ, Krall J. PDE3 inhibitors: A review of their mechanism of action and role in heart failure therapy. Current Heart Failure Reports. 2009;6(1):6–13.

Lehnart SE, Wehrens XHT, Laitinen PJ, et al.. Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak. Circulation Research. 2004;94(12):e21–e27.

Marks AR. Calcium cycling proteins and heart failure: Mechanisms and therapeutics. Journal of Clinical Investigation. 2013;123(1):46–52.

Baillie GS, Tejeda GS, Kelly MP. Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: Inhibition and beyond. Nature Reviews Drug Discovery. 2019;18(10):770–796.

Zhou Q, Zhou Y, Chen L, et al.. Oxidative stress-induced calpain activation contributes to hyperphosphorylation of RyR2 in cardiac hypertrophy. Circulation Research. 2017;121(12):1252–1265

Hasenfuss G, Maier LS. Mechanism of action of the new inotropic drug levosimendan. European Heart Journal Supplements. 2008;10(suppl A):A2–A10.

Fukushima A, Lopaschuk GD. Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 2016;1862(10):2270–2276

Smith CJ, Teitgen AM, Movsesian MA. PDE3 inhibition in dilated cardiomyopathy: Current clinical uses and future perspectives. Current Opinion in Cardiology. 2010;25(2):151–155.

Wang SQ, Song LS, Lakatta EG, Cheng H. Ca2+ signalling between single L-type Ca2+ channels and ryanodine receptors in heart cells. Nature. 2001;410(6828):592–596.