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AOP: 558
Title
Phosphodiesterase inhibition leading to heart failure
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 |
---|---|
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
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
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
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
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
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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)
Title | Adjacency | Evidence | Quantitative Understanding |
---|
RyR2 hyperphosphorylation leads to Increased, Intracellular Calcium overload | adjacent | High | High |
Decrease, Cardiac contractility leads to Heart failure | adjacent | Moderate | Low |
Increased, Intracellular Calcium overload leads to Decrease, Cardiac contractility | adjacent | High | Moderate |
Phosphodiesterase (PDE) leads to Increased, cyclic adenosine monophosphate | adjacent | High | High |
Increased, cyclic adenosine monophosphate leads to RyR2 hyperphosphorylation | adjacent | High | Moderate |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Not Otherwise Specified | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | Moderate |
Overall Assessment of the AOP
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
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
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
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 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
- 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)
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
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