Decreased Na/K ATPase activity leading to heart failure

• Young Jun Kim

Revision dates for related pages

1. Taxonomic Applicability

Highly Relevant Taxa

• Humans (Homo sapiens):
  • Direct relevance due to clinical evidence of cardiomyopathy resulting from cardiac glycosides (e.g., digoxin), genetic conditions, and environmental exposures affecting Na⁺/K⁺-ATPase function.
• Canines (Canis lupus familiaris):
  • Common model for cardiac electrophysiology and drug safety testing due to similarities to human cardiac ionic currents and myocardial structure.
• Guinea Pigs (Cavia porcellus):
  • Cardiomyocyte action potential and ion channel dynamics closely resemble human hearts, making them suitable for studies of Na⁺/K⁺-ATPase dysfunction.
• Rats (Rattus norvegicus) and Mice (Mus musculus):
  • Widely used in preclinical studies. While rodents exhibit some differences in cardiac electrophysiology, they provide valuable insights into ionic homeostasis and calcium dynamics.
• Rabbits (Oryctolagus cuniculus):
  • Used in QT prolongation and contractility studies due to similarities to human cardiac repolarization.

Moderately Relevant Taxa

• Zebrafish (Danio rerio):
  • Suitable for genetic and developmental studies of Na⁺/K⁺-ATPase function, though their cardiac electrophysiology differs significantly from mammals.
• Non-Mammalian Species:
  • Amphibians and reptiles rely less on Na⁺/K⁺-ATPase for cardiac repolarization, limiting direct applicability.

2. Life Stage Applicability

Highly Applicable Life Stages

• Adults:
  • Most relevant for toxicological and clinical studies, as the heart's Na⁺/K⁺-ATPase activity is critical for maintaining contractility and ionic homeostasis under stress or pharmacological interventions.
• Elderly Individuals:
  • Aging-related reductions in Na⁺/K⁺-ATPase efficiency and comorbidities (e.g., heart failure, arrhythmias) increase susceptibility to cardiomyopathy.

Moderately Applicable Life Stages

• Neonates and Infants:
  • Immature Na⁺/K⁺-ATPase activity may exacerbate vulnerability to ionic imbalances, though data are more limited.
• Pediatric Populations:
  • Less studied but relevant in cases of genetic mutations affecting Na⁺/K⁺-ATPase function.

3. Sex Applicability

Relevant to Both Sexes

• Both males and females are susceptible to cardiomyopathy caused by Na⁺/K⁺-ATPase inhibition.
• Sex-Specific Differences:
  • Hormonal differences may modulate ionic homeostasis:
    • Estrogen may enhance calcium handling, potentially mitigating early-stage events like calcium overload.
    • Testosterone has been linked to increased susceptibility to certain types of cardiomyopathy.

4. Molecular and Cellular Context

• Na⁺/K⁺-ATPase Isoforms:
  • Different isoforms (e.g., α1, α2, α3, and α4) exhibit tissue-specific expression, with the α1 isoform predominant in cardiac tissue.
  • This AOP primarily focuses on cardiac Na⁺/K⁺-ATPase isoforms involved in maintaining ionic gradients.
• Cardiomyocyte Specificity:
  • The pathway is specific to cardiac cells, where ionic dysregulation leads to excitation-contraction uncoupling, oxidative stress, and mitochondrial damage.

5. Stressor Applicability

• Chemical Stressors:
  • Cardiac glycosides (e.g., digoxin, ouabain).
  • Environmental toxins (e.g., heavy metals like lead and mercury).
• Physical Stressors:
  • Ischemia-reperfusion injury indirectly affects Na⁺/K⁺-ATPase activity.
• Biological Stressors:
  • Genetic mutations in Na⁺/K⁺-ATPase subunits.

1. MIE: Inhibition of Na⁺/K⁺-ATPase

• Essentiality: High
  • The Na⁺/K⁺-ATPase pump is fundamental for maintaining ionic gradients. Its inhibition directly initiates the cascade of events leading to cardiomyopathy.
• Evidence:
  • Cardiac glycosides (e.g., digoxin, ouabain) inhibit Na⁺/K⁺-ATPase and reliably increase intracellular sodium, impair NCX, and induce calcium overload.
  • Genetic modifications or pharmacological inhibition of Na⁺/K⁺-ATPase in animal models consistently reproduce downstream effects.

2. KE1: Increased Intracellular Sodium Levels

• Essentiality: High
  • Sodium accumulation is a prerequisite for downstream ionic dysregulation, including impaired NCX activity and calcium overload.
• Evidence:
  • Experimental models demonstrate that sodium accumulation occurs immediately after Na⁺/K⁺-ATPase inhibition.
  • Interventions reducing sodium accumulation (e.g., enhanced sodium extrusion via alternative pathways) mitigate calcium overload and subsequent events.
• Intervention Studies:
  • Modulation of intracellular sodium levels through pharmacological agents (e.g., sodium channel inhibitors) prevents calcium overload and contractile dysfunction.

3. KE2: Impaired Sodium-Calcium Exchange

• Essentiality: High
  • The sodium-calcium exchanger (NCX) is critical for calcium extrusion in cardiomyocytes. Sodium imbalance impairs NCX, resulting in calcium retention.
• Evidence:
  • Experimental studies show that NCX activity is directly influenced by intracellular sodium levels, and its dysfunction leads to calcium overload.
  • Pharmacological enhancement of NCX activity (e.g., through NCX activators) reduces calcium overload and subsequent events.
• Intervention Studies:
  • Stimulating NCX reduces calcium accumulation and prevents impaired contractility and myocardial remodeling.

4. KE3: Calcium Overload in Cardiomyocytes

• Essentiality: High
  • Calcium overload is a critical driver of excitation-contraction uncoupling, oxidative stress, and mitochondrial dysfunction, leading to impaired contractility and cell damage.
• Evidence:
  • Calcium imaging studies demonstrate that Na⁺/K⁺-ATPase inhibition induces significant calcium accumulation.
  • Interventions targeting calcium overload (e.g., calcium channel blockers or inhibitors of SR calcium release) reduce contractile dysfunction and myocardial remodeling.
• Intervention Studies:
  • Calcium chelators and SERCA activators mitigate contractile dysfunction and prevent fibrosis.

5. KE4: Impaired Cardiac Contractility

• Essentiality: Moderate to High
  • Impaired contractility increases myocardial workload and oxygen demand, initiating compensatory remodeling. However, interventions targeting earlier KEs can prevent contractility impairment.
• Evidence:
  • Reduced ejection fraction and cardiac output are directly observed following Na⁺/K⁺-ATPase inhibition and calcium overload.
  • Pharmacological improvement of contractility (e.g., inotropic agents) mitigates myocardial stress and delays remodeling.
• Intervention Studies:
  • Inotropic support improves acute cardiac function but does not fully prevent myocardial remodeling if earlier KEs persist.

6. Adverse Outcome (AO): Cardiomyopathy

• Essentiality: Defined as the final outcome
  • Cardiomyopathy is the endpoint of the pathway and results from the cumulative effects of earlier KEs.
• Evidence:
  • Clinical and preclinical data consistently show progression from myocardial remodeling to cardiomyopathy when earlier KEs are unresolved.
  • Addressing earlier KEs (e.g., calcium overload or remodeling) can prevent the development of cardiomyopathy.

1. Molecular Initiating Event (MIE): Inhibition of Na⁺/K⁺-ATPase

Biological Plausibility:

The Na⁺/K⁺-ATPase is well-established as essential for ionic homeostasis, maintaining transmembrane sodium and potassium gradients.

Inhibition directly disrupts this balance, initiating cellular ionic dysregulation.

Empirical Evidence:

Cardiac glycosides (e.g., digoxin, ouabain) are potent inhibitors of Na⁺/K⁺-ATPase and show dose-dependent effects on sodium and potassium gradients.

Inhibition of Na⁺/K⁺-ATPase leads to increased intracellular sodium levels in both in vitro and in vivo models.

Quantitative Understanding:

IC50 values for cardiac glycosides in Na⁺/K⁺-ATPase inhibition range from nanomolar to micromolar concentrations, depending on the isoform and species.

2. KE1: Increased Intracellular Sodium Levels

Biological Plausibility:

Reduced Na⁺ efflux through the pump leads to intracellular sodium accumulation.

Elevated sodium levels impair downstream ionic transport processes, such as the sodium-calcium exchanger (NCX).

Empirical Evidence:

Experimental studies show that Na⁺/K⁺-ATPase inhibition by ouabain or digoxin increases intracellular sodium in cardiomyocytes.

Direct measurements using sodium-sensitive dyes confirm sodium accumulation following pump inhibition.

3. KE2: Impaired Sodium-Calcium Exchange

Biological Plausibility:

Elevated intracellular sodium reduces the driving force for NCX, leading to decreased calcium extrusion and cytosolic calcium accumulation.

Empirical Evidence:

Studies demonstrate a direct link between increased sodium levels and impaired NCX activity in isolated cardiomyocytes.

NCX-mediated calcium flux is reduced in the presence of high intracellular sodium concentrations.

Quantitative Understanding:

Mathematical models predict that NCX activity declines as intracellular sodium concentration exceeds 12–15 mM.

4. KE3: Impaired Cardiac Contractility

Biological Plausibility:

Calcium overload disrupts excitation-contraction coupling, impairing myocardial contractility.

Reduced contractility increases myocardial workload and triggers compensatory mechanisms such as hypertrophy.

Empirical Evidence:

Animal studies and in vitro experiments link calcium dysregulation to decreased ejection fraction and cardiac output.

Chronic Na⁺/K⁺-ATPase inhibition reduces contractile efficiency in preclinical models.

Quantitative Understanding:

A reduction in left ventricular ejection fraction (LVEF) by 10–20% is observed in response to prolonged Na⁺/K⁺-ATPase inhibition.

5. Adverse Outcome (AO): Cardiomyopathy

Biological Plausibility:

Myocardial remodeling and impaired contractility culminate in cardiomyopathy, characterized by reduced cardiac output and structural abnormalities.

Empirical Evidence:

Patients with chronic cardiac glycoside use show increased risk of cardiomyopathy and heart failure.

Animal studies confirm progression from calcium dysregulation to structural and functional heart failure.

Quantitative Understanding:

Reductions in ejection fraction below 40% and increased ventricular dilation are hallmarks of cardiomyopathy progression.

KER1: Na⁺/K⁺-ATPase Inhibition → Increased Intracellular Sodium Levels

Empirical Evidence:

Dose-dependent increases in intracellular sodium levels are observed following Na⁺/K⁺-ATPase inhibition.

Temporal Concordance:

Sodium accumulation occurs within minutes of Na⁺/K⁺-ATPase inhibition.

KER2: Increased Intracellular Sodium → Impaired NCX Activity

Empirical Evidence:

Experimental studies link elevated sodium to reduced NCX-mediated calcium extrusion.

Quantitative Understanding:

Impaired NCX activity becomes significant when sodium concentrations exceed 12–15 mM.

KER3: Impaired NCX Activity → Impaired Contractility

Empirical Evidence:

Calcium imaging studies confirm elevated cytosolic calcium following NCX impairment.

Biological Plausibility:

Impaired Contractility results from impaired extrusion, consistent with NCX dependence on sodium gradients.

KER4: Impaired Contractility → Cardiomyopathy

Empirical Evidence:

Impaired Contractility is strongly associated with functional heart failure in animal models and patients.

Biological Plausibility:

Cardiomyopathy arises from cumulative structural and functional deterioration.

• Strength:
  • Quantitative data are available for many KEs, particularly for the MIE, sodium accumulation, and calcium overload.
  • Dose-response relationships have been established for cardiac glycosides and their effects on Na⁺/K⁺-ATPase activity.
• Examples:
  • IC50 values for Na⁺/K⁺-ATPase inhibition by digoxin and ouabain.
  • Threshold levels of intracellular calcium linked to impaired contractility and oxidative stress.
• Gaps:
  • Long-term dose-response data for chronic exposure to Na⁺/K⁺-ATPase inhibitors.
  • Thresholds for transition from myocardial remodeling to cardiomyopathy.