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AOP: 553
Title
Inhibition of Voltage-gated sodium channels (Na⁺ channels) 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 09:31
Revision dates for related pages
Page | Revision Date/Time |
---|---|
Inhibition, sodium channel | September 16, 2017 10:15 |
Altered, Action Potential | March 31, 2022 06:49 |
Decrease, Cardiac contractility | June 19, 2018 14:02 |
Heart failure | December 03, 2024 10:15 |
Inhibition, sodium channel leads to Altered, Action Potential | November 21, 2024 09:58 |
Altered, Action Potential leads to Decrease, Cardiac contractility | November 21, 2024 09:58 |
Decrease, Cardiac contractility leads to Heart failure | January 05, 2023 07:48 |
Lidocaine | November 29, 2016 18:42 |
Flecainide | November 21, 2024 09:40 |
Bupivacaine | November 21, 2024 09:40 |
Tetracaine | November 21, 2024 09:40 |
Tetrodotoxin | November 29, 2016 18:42 |
Saxitoxin | November 21, 2024 09:41 |
Pyrethrins and Pyrethroids | November 29, 2016 18:42 |
p,p'-DDT | December 20, 2018 07:53 |
Tetrodotoxin derivatives | November 21, 2024 09:42 |
Abstract
Voltage-gated sodium channels (Na⁺ channels) are critical for initiating and propagating action potentials in cardiac myocytes. Their inhibition can trigger a cascade of biological events culminating in heart failure, which can be conceptualized within an Adverse Outcome Pathway (AOP) framework. The molecular initiating event (MIE) of Na⁺ channel inhibition reduces sodium ion influx, impairing the depolarization phase of cardiac action potentials. This leads to key events (KEs) such as reduced action potential amplitude, disrupted cardiac electrical conductance, decreased cardiac contractility, and compromised cardiac output. Prolonged dysfunction triggers maladaptive stress responses, including fibrosis, hypertrophy, and apoptosis, ultimately resulting in heart failure as the adverse outcome (AO). Key event relationships (KERs) provide mechanistic insights into this progression, linking reduced Na⁺ influx to impaired electrical and mechanical function through calcium dysregulation and myocardial remodeling. Developing this AOP requires robust empirical evidence, biological plausibility, and an understanding of modulating factors such as genetic predisposition and comorbidities. Quantitative modeling of the dose-response and temporal relationships between KEs and the AO will enhance predictive capability and inform risk assessment. This AOP framework offers a structured approach for studying the cardiotoxic effects of Na⁺ channel inhibitors, identifying potential biomarkers, and guiding therapeutic interventions to mitigate heart failure.
AOP Development Strategy
Context
Inhibition of sodium channel conductance can contribute to the development of cardiomyopathy through its impact on cardiac electrophysiology, ion homeostasis, and mechanical function. Voltage-gated sodium channels, primarily Nav1.5 (encoded by SCN5A), are essential for rapid depolarization during the cardiac action potential. Inhibition of sodium channel conductance reduces the inward sodium current (INa), leading to slowed conduction velocity, conduction blocks, and increased susceptibility to arrhythmias. These electrical abnormalities impose hemodynamic stress on the myocardium, promoting maladaptive remodeling. Sodium channel inhibition also disrupts the sodium gradient, impairing the sodium-calcium exchanger (NCX) and causing calcium overload, oxidative stress, mitochondrial dysfunction, and myocyte apoptosis. Chronic electromechanical dysfunction can lead to ventricular dilation and the progression of dilated cardiomyopathy (DCM). Conditions associated with sodium channel inhibition include genetic mutations, such as SCN5A mutations in Brugada syndrome and Lenègre disease, drug-induced sodium channel blockade from Class I antiarrhythmics, and ischemia-induced sodium channel dysfunction. These pathologies manifest as arrhythmias, heart failure, and an increased risk of sudden cardiac death. Understanding the role of sodium channel inhibition in cardiomyopathy highlights the need for targeted interventions to prevent the progression of sodium channel-related cardiac dysfunction.
Strategy
This AOP describes the sequence of biological events triggered by Na⁺ channel inhibition, beginning with the molecular initiating event (MIE) and culminating in cardiomyopathy as the adverse outcome (AO). Key events (KEs) include impaired action potential propagation, disrupted calcium homeostasis, reduced cardiac contractility, and maladaptive remodeling of cardiac tissue. These events are supported by empirical and mechanistic evidence, with temporal and dose-response concordance observed in experimental studies. This AOP provides a structured framework for assessing the cardiotoxicity of compounds targeting Na⁺ channels and identifying biomarkers and intervention points to mitigate the risk of cardiomyopathy.
1. Problem Formulation
Define the Scope and Purpose:
Clearly outline the biological context, regulatory application, and the specific chemical, biological, or environmental perturbation under investigation (e.g., Na⁺ channel inhibitors leading to heart failure).
Identify Stakeholders:
Engage stakeholders from academia, industry, and regulatory agencies to align the AOP objectives with practical needs, such as risk assessment or prioritization of chemical testing.
2. Identification of Key Events (KEs)
Molecular Initiating Event (MIE):
Pinpoint the initial perturbation at the molecular level (e.g., inhibition of Na⁺ channels). This is the starting point of the AOP.
Intermediate Biological Events:
Identify key biological responses at the cellular, tissue, organ, and organism levels. For example:
Reduced action potential amplitude.
Disrupted electrical conductance in cardiomyocytes.
Decreased cardiac contractility and output.
Adverse Outcome (AO):
Define the final negative impact on health, such as heart failure.
3. Establish Key Event Relationships (KERs)
Mechanistic Linkages:
Define how each KE leads to the next. For example:
Reduced Na⁺ influx → Reduced action potential amplitude.
Disrupted electrical signaling → Decreased cardiac output.
Empirical Evidence:
Gather and analyze data to support the strength, consistency, and specificity of the relationships between KEs.
Temporal and Dose-Response Concordance:
Ensure that the sequence and intensity of events align logically with biological plausibility and experimental data.
4. Data Gathering and Analysis
Literature Review:
Perform a systematic review to collate existing studies on the MIE, KEs, and AO.
Experimental Data:
Use in vitro, in vivo, or computational models to fill knowledge gaps, focusing on dose-response, time-course studies, and species-specific effects.
Data Integration Tools:
Leverage tools like AOP-Wiki for organizing data and mapping KEs and KERs.
Summary of the AOP
Events:
Molecular Initiating Events (MIE)
Key Events (KE)
Adverse Outcomes (AO)
Type | Event ID | Title | Short name |
---|
MIE | 584 | Inhibition, sodium channel | Inhibition, sodium channel |
KE | 698 | Altered, Action Potential | Altered, Action Potential |
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 |
---|
Inhibition, sodium channel leads to Altered, Action Potential | adjacent | High | High |
Altered, Action Potential leads to Decrease, Cardiac contractility | adjacent | High | High |
Decrease, Cardiac contractility leads to Heart failure | adjacent | High | Moderate |
Network View
Prototypical Stressors
Life Stage Applicability
Life stage | Evidence |
---|---|
Not Otherwise Specified | Moderate |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Overall Assessment of the AOP
1. Molecular Initiating Event (MIE)
Inhibition of Voltage-Gated Sodium Channels (Na⁺ Channels): Reduced Na⁺ influx due to channel inhibition disrupts the depolarization phase of the cardiac action potential, impairing electrical activity in cardiomyocytes.
2. Key Events (KEs)
KE1: Reduced Action Potential Propagation
Decreased Na⁺ influx reduces the amplitude and speed of action potential propagation in cardiac cells. This leads to electrical conduction delays, arrhythmias, and asynchronous contraction of the myocardium.
Voltage-gated Na⁺ channel dysfunction affects downstream ion exchange mechanisms, particularly the Na⁺/Ca²⁺ exchanger. This disrupts intracellular calcium levels, which are essential for excitation-contraction coupling.
KE2: Decreased Cardiac Contractility
Impaired calcium handling reduces myocyte contractile force. This weakens overall cardiac output and increases stress on the myocardium.
3. Adverse Outcome (AO)
Cardiomyopathy:
Chronic mechanical and oxidative stress from reduced contractility initiates maladaptive remodeling, including:
Fibrosis: Excessive deposition of extracellular matrix proteins.
Hypertrophy: Enlargement of cardiomyocytes.
Apoptosis: Programmed cell death of cardiac cells.
A progressive disorder characterized by structural abnormalities (e.g., fibrosis, hypertrophy) and functional impairments (e.g., reduced ejection fraction), ultimately compromising cardiac performance and increasing the risk of heart failure.
4. Key Event Relationships (KERs)
KER1: Na⁺ Channel Inhibition → Reduced Action Potential Propagation
Strong mechanistic evidence supports the role of Na⁺ channels in driving the depolarization phase of action potentials. Their inhibition disrupts electrical signaling in cardiomyocytes.
KER2: Reduced Action Potential Propagation → Decreased Cardiac Contractility
Altered electrical activity impacts calcium cycling, particularly through voltage-gated calcium channels and Na⁺/Ca²⁺ exchangers, leading to imbalanced intracellular calcium.
Calcium is a critical regulator of cardiomyocyte contraction. Disrupted calcium homeostasis diminishes excitation-contraction coupling, leading to weaker contractions.
KER3: Decreased Cardiac Contractility → Cardiomyopathy
Fibrosis, hypertrophy, and cell death reduce myocardial efficiency and elasticity, resulting in the structural and functional impairments characteristic of cardiomyopathy.
5. Biological Plausibility
The role of Na⁺ channels in cardiac electrophysiology and their influence on calcium cycling is well-established.
Chronic impairments in contractility and stress response are known drivers of maladaptive remodeling and cardiomyopathy.
6. Empirical Evidence
Temporal Concordance: Studies show a stepwise progression from Na⁺ channel inhibition to structural and functional myocardial changes.
Dose-Response Relationship: Increasing levels of Na⁺ channel inhibitors correlate with more severe effects on electrical and mechanical function.
Species Relevance: Evidence exists across multiple species, including humans, rodents, and non-human primates.
7. Modulating Factors
Intrinsic Factors: Genetic mutations in Na⁺ channel genes (e.g., SCN5A) can exacerbate susceptibility.
Extrinsic Factors: Co-exposure to other cardiotoxic agents, ischemia, or oxidative stress may influence pathway progression.
8. Regulatory and Practical Utility
Chemical Risk Assessment: This AOP can help identify and prioritize chemicals with potential cardiotoxic effects for further testing.
Biomarker Development: Intermediate KEs, such as impaired calcium homeostasis, can serve as early indicators of cardiomyopathy.
Alternative Testing Methods: The AOP provides a framework for in vitro and computational models to evaluate cardiotoxicity without relying on animal testing.
Domain of Applicability
- High Relevance Across Vertebrates:
- Voltage-gated Na⁺ channels are evolutionarily conserved across vertebrate species, including humans, rodents, and non-human primates.
- Cardiomyopathy-related structural and functional responses, such as fibrosis and hypertrophy, are also conserved, supporting broad taxonomic applicability.
- Empirical Evidence:
- Studies in humans and animal models (e.g., mice, rats, dogs) demonstrate similar pathological responses to Na⁺ channel inhibition.
- Specific Na⁺ channel subtypes (e.g., SCN5A) are well-characterized in these species, with functional roles and perturbations largely consistent.
Essentiality of the Key Events
Key Events (KEs) and Their Essentiality
1. Molecular Initiating Event (MIE): Inhibition of Voltage-Gated Sodium Channels (Na⁺ Channels)
Essentiality: High
Voltage-gated sodium channels are fundamental to cardiac electrophysiology. Their inhibition initiates the cascade of downstream effects.
Experimental evidence: Pharmacological or genetic inhibition of Na⁺ channels results in immediate effects on action potential generation and propagation in cardiomyocytes.
2. KE1: Reduced Action Potential Propagation
Essentiality: High
Sodium channels drive the depolarization phase of cardiac action potentials, which is crucial for electrical signal propagation.
Perturbation of action potential propagation disrupts the coordinated contraction of the heart.
Supporting evidence: Experimental blockade of Na⁺ channels leads to reduced action potential amplitude and conduction velocity in vitro and in vivo.
3. KE2: Decreased Cardiac Contractility
Essentiality: High
Reduced contractility directly impacts cardiac output and places mechanical stress on the myocardium, driving compensatory and maladaptive responses.
This KE represents a critical tipping point for the transition from functional impairment to pathological remodeling.
Supporting evidence: Cardiac-specific suppression of contractility in animal models induces myocardial remodeling and dysfunction.
Adverse Outcome (AO): Cardiomyopathy
Essentiality: Outcome
Cardiomyopathy represents the ultimate pathological state resulting from the preceding key events.
Fibrosis, hypertrophy, and apoptosis are central to the structural changes observed in cardiomyopathy. However, the extent of remodeling may vary depending on compensatory mechanisms and external factors.
Supporting evidence: Chronic stress on the myocardium (e.g., due to reduced contractility or electrical dysfunction) induces remodeling in experimental models. Reversing the stress (e.g., unloading the heart) reduces remodeling severity.
Supporting Evidence for Essentiality
Chemical Inhibition Studies:
Selective inhibitors of Na⁺ channels produce predictable downstream effects, from electrical dysfunction to structural remodeling and cardiomyopathy.
Genetic Models:
Knockout or knockdown of Na⁺ channel genes (e.g., SCN5A) in animal models recapitulates the AOP, demonstrating the essentiality of upstream events.
Rescue Studies:
Interventions targeting specific KEs (e.g., restoring calcium homeostasis or contractility) prevent or reverse downstream events, confirming the necessity of the targeted KE.
Temporal Concordance:
The progression of events aligns temporally, with perturbation of upstream KEs preceding and enabling downstream effects.
Evidence Assessment
- Empirical Evidence:
- Na⁺ channel blockers (e.g., tetrodotoxin, lidocaine) reduce action potential amplitude and conduction velocity in cardiomyocytes in vitro and in vivo.
- Temporal and dose-response concordance is well-documented.
- Calcium dysregulation observed in experiments using Na⁺ channel inhibitors.
- Perturbations in calcium transients measured in isolated cardiomyocytes following Na⁺ channel blockade.
- Reduction in contractility observed in animal models treated with Na⁺ channel inhibitors.
- Evidence from chronic studies shows structural changes (e.g., increased collagen deposition) in response to Na⁺ channel inhibitors.
- Observations of hypertrophy and fibrosis in genetic models of Na⁺ channel dysfunction.
- Dose-dependent reduction in action potential amplitude with Na⁺ channel inhibitors.
Known Modulating Factors
Modulating Factor (MF) | Influence or Outcome | KER(s) involved |
---|---|---|
co-exposure to ion channel modulators NCX functionality, electrolyte imbalances, cardiac load Collagen turnover, chronic stress, anti-fibrotic therapies |
Variations in the expression of auxiliary ion channels (e.g., potassium or calcium channels) may buffer or enhance the effects of Na⁺ channel inhibition. Increased or decreased conduction delays Altered calcium cycling efficiency or partially mitigate contractility. Increased fibrosis, hypertrophy, or apoptosis |
KER1 KER2 KER3 |
Quantitative Understanding
MIE: Na⁺ Channel Inhibition
Quantitative Data:
IC50 values for Na⁺ channel blockers (e.g., tetrodotoxin, lidocaine) are well-established, indicating concentrations required for 50% inhibition of Na⁺ channels.
Example: Lidocaine IC50 for Nav1.5 channels in cardiomyocytes ~40 µM.
Key Metrics:
Degree of channel inhibition (e.g., 25%, 50%, 75%) correlates with the reduction in action potential amplitude.
KE1: Reduced Action Potential Propagation
Quantitative Data:
Direct measurements of action potential amplitude and conduction velocity under Na⁺ channel inhibition:
Reduced amplitude (~30-70%) with increasing inhibitor concentrations.
Slower conduction velocity in isolated cardiomyocytes and cardiac tissue slices.
Temporal Concordance:
Immediate effects observed within milliseconds to seconds after Na⁺ channel blockade.
Predictive Models:
Hodgkin-Huxley-type models simulate the effects of Na⁺ channel inhibition on action potential propagation.
KE2: Decreased Cardiac Contractility
Quantitative Data:
Fractional shortening and ejection fraction reductions correlate with impaired calcium handling:
20-50% reduction in intracellular calcium leads to a proportional decrease in contraction force.
Dose-dependent reductions in contractility observed in vitro and in vivo with Na⁺ channel blockers.
Na⁺/Ca²⁺ exchanger (NCX) activity reduction as a function of intracellular Na⁺ accumulation:
Example: 50% reduction in NCX flux correlates with ~30% decrease in calcium transients.
Measured changes in intracellular calcium levels (amplitude and duration of calcium transients).
Temporal Concordance:
Decreased contractility occurs within minutes to hours of calcium dysregulation.
Predictive Models:
Hill-type models describe the relationship between intracellular calcium levels and contraction force.
AO: Cardiomyopathy
Quantitative Data:
Myocardial stiffness increases by ~50-100% with fibrosis.
Left ventricular ejection fraction (LVEF) reduction by ~10-20% indicates significant dysfunction.
Chronic reductions in contractility and increased wall stress drive fibrosis and hypertrophy:
Fibrosis increases collagen content by ~30-50% after weeks of stress.
Hypertrophy measured as a ~20-40% increase in cardiomyocyte cross-sectional area.
Thresholds for stress-induced remodeling vary but are typically dose- and time-dependent.
Temporal Concordance:
Myocardial dysfunction occurs over weeks to months, following sustained remodeling.
Predictive Models:
Cardiac output and pressure-volume loop models predict functional impairments based on structural and mechanical changes.
Considerations for Potential Applications of the AOP (optional)
The Adverse Outcome Pathway (AOP) describing the inhibition of voltage-gated sodium channels (Na⁺ channels) leading to cardiomyopathy provides a structured framework for understanding the mechanistic progression from a molecular initiating event (MIE) to an adverse outcome (AO). Inhibition of Na⁺ channels disrupts action potential propagation, impairs calcium homeostasis, decreases cardiac contractility, triggers maladaptive cardiac remodeling, and ultimately results in myocardial dysfunction and cardiomyopathy. This pathway is supported by strong biological plausibility, empirical evidence, and emerging quantitative models that describe dose-response relationships and temporal concordance between key events (KEs).
The AOP has significant applications in chemical risk assessment, enabling screening and prioritization of chemicals, regulatory decision-making, and weight-of-evidence evaluations. In drug development, the AOP can guide preclinical safety testing, biomarker identification, and rational drug design to minimize cardiotoxicity. Additionally, it supports the development of alternative testing strategies, including in vitro and computational models, promoting the 3Rs (replacement, reduction, refinement) in toxicology. Environmental and ecological risk assessments can also benefit from this AOP, given the conserved role of Na⁺ channels across vertebrates.
Quantitative understanding of the AOP is advancing, with predictive models emerging for early KEs, such as reduced action potential propagation and impaired calcium cycling, though further work is needed for chronic effects like cardiac remodeling. Modulating factors, including genetic predispositions, comorbidities, and co-exposures, influence the progression and severity of the pathway, emphasizing the need for context-specific risk assessment tools.
This AOP provides a versatile framework for regulatory, scientific, and industrial applications. It supports the integration of mechanistic evidence into risk prediction, fosters the development of alternative testing methods, and facilitates cross-sector collaboration. By addressing current knowledge gaps and refining quantitative models, this AOP has the potential to significantly advance cardiotoxicity assessment and risk mitigation strategies for Na⁺ channel inhibitors and related compound
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