Heart failure

7439-92-1

WABPQHHGFIMREM-UHFFFAOYSA-N

Lead

Pb Blei in massiver form(nicht pulver) Blei(pulver) C.I. Pigment Metal 4 Lead element Lead Flake LEAD INGOT Lead metal Plomb(poudre) Plumbum Rough lead bullion

DTXSID2024161

7439-97-6

QSHDDOUJBYECFT-UHFFFAOYSA-N

Mercury

Liquid silver Mercure MERCURIC METAL TRIPLE DISTILLED mercurio Mercury element Quecksilber Quicksilver UN 2024 UN 2809

DTXSID1024172

56-38-2

LCCNCVORNKJIRZ-UHFFFAOYSA-N

Parathion

Diethyl O-p-nitrophenyl phosphorothioate Phosphorothioic acid, O,O-diethylO-(4-nitrophenyl) ester Alleron American Cyanamid 3422 Aphamite Bayer E-605 Bladan F Diethyl 4-nitrophenyl phosphorothioate Diethyl parathion Diethyl p-nitrophenyl phosphorothionate Diethyl p-nitrophenyl thionophosphate Ethyl parathion Folidol Folidol E Folidol E-605 Folidol oil Fosferno Gearphos Lirothion Nitrostigmine Nourithion NSC 8933 O,O-Diethyl O-(4-nitrophenyl) phosphorothioate O,O-Diethyl O-(p-nitrophenyl) phosphorothioate O,O-Diethyl O-p-nitrophenyl thiophosphate O,O-Diethyl-O-(4-nitrophenyl)phosphorothioate Oleoparathene Oleoparathion Paraphos Parathene Parathion [Phosphorothioic acid, O,O-diethyl-O-(4-nitrophenyl)ester] Parathion A Parathion-ethyl paration Penncap E Phosphorothioic acid O,O-diethyl O-(4-nitrophenyl)ester Phosphorothioic acid, O,O-diethyl O-(4-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl) ester Phosphorothioic acid, O,O-diethyl O-(p-nitrophenyl)ester Rhodiasol Rhodiatox Selephos Super Rodiatox Thiomex Thiophos Thiophos 3422 Ethylparathion

DTXSID7021100

96-64-0

GRXKLBBBQUKJJZ-UHFFFAOYNA-N

GRXKLBBBQUKJJZ-UHFFFAOYSA-N

Soman

Soman Phosphonofluoridic acid, methyl-, 1,2,2-trimethylpropyl ester 1,2,2-Trimethylpropoxyfluorophosphine oxide 1,2,2-Trimethylpropyl methylphosphonofluoridate 3,3-Dimethyl-n-but-2-yl methylphosphonofluoridate Methyl pinacolyl phosphonofluoridate Methyl pinacolyloxy phosphorylfluoride Methylphosphonofluoridic acid 1,2,2-trimethylpropyl ester Phosphine oxide, fluoromethyl(1,2,2-trimethylpropoxy)- Phosphonofluoridic acid, P-methyl-, 1,2,2-trimethylpropyl ester Pinacoloxymethylphosphoryl fluoride Pinacolyl methylfluorophosphonate

DTXSID2031906

UBERON:0000948

UBERON heart

CHEBI:39124

CHEBI calcium ion

GO:0005890

GO sodium:potassium-exchanging ATPase complex

HP:0001695

HP Cardiac arrest

GO:0006816

GO calcium ion transport

GO:0005391

GO sodium:potassium-exchanging ATPase activity

WIKI occurrence

WIKI increased

WIKI decreased

Digoxin

2024-11-21T14:41:58

Ouabain

2024-11-21T14:42:24

Lead

2016-11-29T18:42:26

Mercury

2016-11-29T18:42:19

Polycyclic aromatic hydrocarbons (PAHs)

2017-02-09T15:43:00

Organophosphates Organophosphate

repeated exposure

2016-11-29T18:42:20

2016-11-29T21:20:01

Thapsigargin

2024-11-21T14:44:36

E-4031

2024-11-21T13:15:12

33208

NCBI Animals

WCS_7955

common ecological species zebrafish

WikiUser_4

Wikiuser: Blandesmann Human, rat, mouse

Heart failure

Organ

Heart failure, also known as cardiac arrest, refers to the heart ceasing to pump blood through the circulatory system.

Heart failure can be measured by electrocardiograms to assess heart electrical activity across a wide variety of animal taxa to determine when heart rate falls to zero (Hauser et al. 2012).

Life Stage: Applies to all life stages with developed heart; not specific to any life stage. Sex: Applies to both males and females; not sex-specific. Taxonomic: Present broadly in animals that have a heart.

High Unspecific

High

All life stages

High

Houser, S.R., Margulies, K.B., Murphy, A.M., Spinale, F.G., Francis, G.S., Prabu, S.D., Rockman, H.A., Kass, D.A., Mokentin, J.D., Sussman, M.A., and Koch, W.J.  2012.  Animal models of heart failure: a statement from the American Heart Association.  Circulation Research 11: 131-150. NOTE: Italics indicate edits from John Frisch September 2024 AOPWiki 2018-06-19T14:04:03

2024-12-03T10:15:46

Increased, intracellular sodium (Na+)

Molecular

AOPWiki 2017-04-13T14:21:05

2017-04-13T14:21:05

Impaired Sodium-Calcium Exchange

Cellular

AOPWiki 2024-11-21T14:36:12

2024-11-21T14:36:12

Increased, Intracellular Calcium overload

Cellular

NMDAR agonist binding results in increased intracellular calcium, whereas NMDAR antagonist binding results in decreased intracellular calcium levels. For the relevant paragraphs below please see AOP entitled Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities. Biological state: KE <a href="/wiki/index.php/Event:52" title="Event:52"> Calcium influx, Decreased</a> Biological compartments: KE <a href="/wiki/index.php/Event:52" title="Event:52"> Calcium influx, Decreased</a> General role in biology: KE <a href="/wiki/index.php/Event:52" title="Event:52"> Calcium influx, Decreased</a> The text specific for the AOP "ionotropic glutamatergic receptors and cognition” and “Acetylcholinesterase inhibition leading to neurodegeneration”: It is now well accepted that modest activation of NMDARs leading to modest increases in postsynaptic calcium are optimal for triggering LTD (Lledo et al. 1998; Bloodgood and Sabatin, 2007; Bloodgood et al. 2009), whereas much stronger activation of NMDARs leading to much larger increases in postsynaptic calcium are required to trigger LTP (Luscher and Malenka, 2012; Malenka 1994). Indeed, high-frequency stimulation causes a strong temporal summation of the excitatory postsynaptic potentials (EPSPs), and depolarization of the postsynaptic cell is sufficient to relieve the Mg2+ block of the NMDAR and allow a large amount of calcium to enter into the postsynaptic cells. Therefore, intra-cellular calcium is measured as a readout for evaluation NMDAR stimulation.

Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible? Please see KE <a href="/wiki/index.php/Event:52" title="Event:52"> Calcium influx, Decreasedin</a> the AOP entitled: Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities.

Please see KE <a href="/wiki/index.php/Event:52" title="Event:52"> Calcium influx, Decreasedin</a> the AOP entitled Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities.   Additional text, specific for the AOP “Acetylcholinesterase Inhibition leading to Neurodegeneration”: Zebrafish have shown dysregulation in intracellular calcium ion levels following exposure to organophosphate compounds through similar mechanisms demonstrated in mammals (Faria et al. 2015).

CL:0000255

CL eukaryotic cell

Not Specified Mixed

High

During brain development, adulthood and aging

High High

Bloodgood BL, Sabatini BL., Nonlinear regulation of unitary synaptic signals by CaV2.3 voltage-sensitive calcium channels located in dendritic spines. Neuron, 2007, 53:249–260. Bloodgood BL, Giessel AJ, Sabatini BL., Biphasic synaptic Ca influx arising from compartmentalized electrical signals in dendritic spines. PLoS Biol., 2009, 7: e1000190. Faria, M., N. Garcia-Reyero, F. Padrós, P. J. Babin, D. Sebastián, J. Cachot, E. Prats, M. Arick Ii, E. Rial, A. Knoll-Gellida, G. Mathieu, F. Le Bihanic, B. L. Escalon, A. Zorzano, A. M. Soares and D. Raldúa (2015), "Zebrafish Models for Human Acute Organophosphorus Poisoning.” Sci Rep 5. DOI: 10.1038/srep15591. Lledo PM, Zhang X, Sudhof TC, Malenka RC, Nicoll RA., Postsynaptic membrane fusion and long-term potentiation. Science, 1998, 279: 399–403. Malenka RC. Synaptic plasticity in the hippocampus: LTP and LTD. Cell, 1994, 78: 535–538. Luscher C. and Robert C. Malenka. NMDA Receptor-Dependent Long-Term Potentiation and Long-Term Depression (LTP/LTD). Cold Spring Harb Perspect Biol., 2012, 4: a005710. AOPWiki 2016-11-29T18:41:24

2020-06-26T04:45:09

Decrease, Cardiac contractility

Organ

AOPWiki 2018-06-19T14:01:46

2018-06-19T14:02:04

Decreased Na/K ATPase activity

Cellular

The sodium/potassium (Na/K) ATPase is an active pump that consumes ATP to transport 3 sodium ions (Na + ) out of the cell against its electrochemical gradient, in exchange for 2 potassium ions (K + ). A decrease in Na/K activity can come from a decrease in ATP available to perform this reaction or direct blocking of the pump at the catalytic binding domain and/or the Mg binding site of the enzyme.

Na/K ATPase activity can be measured in cell lysates preserving enzymatic activity, and corresponds to the difference between total ATPase activity and ouabain-sensitive ATPase activity. The measurement can use the leftover ATP or inorganic phosphate produced during ATP hydrolysis as its primary substrate, followed by coupling to colorimetric or fluorimetric dye (Baginski, Foa, and Zak 1967; Nowak 2002) (NovusBio kit 601-0120).   Generally Na/K ATPase activity is measured via immunoblots or spectrophotometry; historically electrophysiology measurements of charge changes was more common (Moyes et al. 2021).

Life Stage: Applies to all life stages; not specific to any life stage. Sex: Applies to both males and females; not sex-specific. Taxonomic: Present broadly in animals as evolutionarily conserved across taxa.

High Unspecific

High

All life stages

High

Baginski, E. S., P. P. Foa, and B. Zak. 1967. “Determination of Phosphate: Study of Labile Organic Phosphate Interference.” Clinica Chimica Acta 15(1):155–58. Retrieved December 6, 2017 Moyes, C.D.  Dastjerdi, S.H., Robertson, R.M.  2021.  Measuring enzyme activities in crude homogenates: Na+/K+-ATPase as a case study in optimizing assays.  Comparative Biochemistry and Physiology, Part B 255: 110577. Nowak, Grazyna. 2002. “Protein Kinase C-Alpha and ERK1/2 Mediate Mitochondrial Dysfunction, Decreases in Active Na+ Transport, and Cisplatin-Induced Apoptosis in Renal Cells.” The Journal of Biological Chemistry 277(45):43377–88. Retrieved December 5, 2017 (http://www.ncbi.nlm.nih.gov/pubmed/12218054). NOTE: Italics indicate edits from John Frisch September 2024   AOPWiki 2018-12-20T09:55:11

2024-12-03T10:12:08

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AOPWiki 2024-11-21T14:39:10

2024-11-21T14:39:10

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AOPWiki 2024-11-21T14:39:40

2024-11-21T14:39:40

<upstream-id>583d736d-878c-4512-b016-d6b83d9e9071</upstream-id> <downstream-id>bc165698-4384-4af0-977d-e3ea648acc29</downstream-id>

AOPWiki 2024-11-21T14:40:11

2024-11-21T14:40:11

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AOPWiki 2023-01-05T07:48:05

2023-01-05T07:48:05

<upstream-id>368fd787-1833-4211-aee6-002ccb87d438</upstream-id> <downstream-id>f44df2ef-06ea-4b2c-b1ac-948c2f70af8e</downstream-id>

AOPWiki 2024-11-26T12:40:39

2024-11-26T12:40:39

Decreased Na/K ATPase activity leading to heart failure

Inhibition of the sodium-potassium-ATP pump

Young Jun Kim

Sun-Woong Kanga, Myeong Hwa Songb  ,Do-Sun Lim b and Kim Young Junc  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

2.7

The inhibition of the sodium-potassium ATPase pump (Na⁺/K⁺-ATPase) is a critical molecular initiating event (MIE) that disrupts ionic homeostasis, triggering a cascade of adverse effects culminating in cardiomyopathy. The Na⁺/K⁺-ATPase actively maintains intracellular sodium and potassium gradients essential for cardiac function. Its inhibition leads to increased intracellular sodium levels (Key Event 1, KE1), which impair the sodium-calcium exchanger (NCX), resulting in calcium overload (KE2) in cardiomyocytes. Elevated intracellular calcium disrupts excitation-contraction coupling, impairs contractility (KE3). Chronic contractile dysfunction induces compensatory mechanisms such as myocardial hypertrophy and fibrosis (KE4). Over time, these structural changes impair cardiac elasticity and efficiency, progressing to cardiomyopathy, characterized by reduced cardiac output and heart failure. This AOP is supported by strong biological plausibility, empirical evidence, and moderate quantitative understanding, with well-characterized relationships between Na⁺/K⁺-ATPase inhibition and calcium overload, impaired contractility, and myocardial remodeling. Its applications span chemical safety assessment, environmental risk evaluation, and therapeutic development, offering a robust framework for understanding the cardiotoxic effects of Na⁺/K⁺-ATPase inhibition and guiding regulatory decisions. The AOP for inhibition of Na⁺/K⁺-ATPase leading to cardiomyopathy addresses a critical pathway by which molecular disruption at the sodium-potassium ATPase pump impacts cardiac function and structure. The Na⁺/K⁺-ATPase is a fundamental membrane protein that maintains ionic gradients across the plasma membrane by actively exchanging three sodium ions (Na⁺) for two potassium ions (K⁺) during each cycle. This process is vital for cellular homeostasis, electrical excitability, and myocardial contractility. This AOP provides a mechanistic framework to explain how inhibition of Na⁺/K⁺-ATPase contributes to cardiotoxicity, integrating molecular, cellular, and organ-level effects. It is relevant to toxicology, pharmacology, and risk assessment, offering insights into the cardiotoxic potential of drugs, chemicals, and environmental pollutants. The pathway also identifies modulating factors, such as genetic predispositions, electrolyte imbalances, and pre-existing cardiovascular conditions, that may influence individual susceptibility to adverse outcomes. Understanding this AOP supports the development of targeted interventions to mitigate cardiotoxic risks and informs regulatory guidelines for safer by design.

<h3>1. Problem Formulation</h3> <h4>Objective</h4> To map the mechanistic progression from molecular inhibition of Na⁺/K⁺-ATPase to cardiomyopathy. To identify key events (KEs), key event relationships (KERs), and stressors that modulate the pathway. To apply the AOP in toxicological risk assessment, drug safety evaluation, and environmental risk mitigation. <h4>Relevance</h4> Na⁺/K⁺-ATPase is critical for maintaining ionic homeostasis in cardiac cells. Inhibition by drugs (e.g., cardiac glycosides), environmental toxins, or pathological conditions disrupts ionic gradients, leading to calcium overload, contractile dysfunction, and myocardial remodeling. <h3>2. Identification of Key Events (KEs)</h3> The pathway begins with the Molecular Initiating Event (MIE) of Na⁺/K⁺-ATPase inhibition and progresses through a series of KEs leading to cardiomyopathy: MIE: Inhibition of Na⁺/K⁺-ATPase Disruption of sodium and potassium transport across the membrane. KE1: Increased Intracellular Sodium Levels Accumulation of intracellular sodium due to reduced Na⁺ extrusion. KE2: Impaired Sodium-Calcium Exchange Reduced NCX activity leading to decreased calcium extrusion. KE3: Calcium Overload in Cardiomyocytes Cytosolic and sarcoplasmic calcium accumulation disrupting excitation-contraction coupling. KE4: Impaired Cardiac Contractility Reduced myocardial efficiency due to calcium dysregulation. Adverse Outcome: Cardiomyopathy Functional and structural heart failure characterized by reduced cardiac output and arrhythmias. 3.Validation and Refinement Validate the AOP using multiple lines of evidence, including experimental, computational, and clinical data. Regularly update the AOP with new research findings to refine key events, relationships, and quantitative models.

adjacent

Moderate

High adjacent

Moderate

High adjacent

Moderate

High adjacent

Moderate

Moderate adjacent

High

Moderate Mixed

Moderate

Not Otherwise Specified

<h3>Biological Plausibility</h3> <ul> <li>Strength: <ul> <li>The mechanistic role of Na⁺/K⁺-ATPase in maintaining ionic gradients is well-established in physiology.</li> <li>Key events (KEs) such as intracellular sodium accumulation, impaired sodium-calcium exchange, calcium overload, and myocardial remodeling are consistent with fundamental cardiac biology.</li> </ul> </li> <li>Supportive Evidence: <ul> <li>Cardiac glycosides (e.g., digoxin, ouabain) directly inhibit Na⁺/K⁺-ATPase, initiating downstream ionic disturbances.</li> <li>Experimental and clinical studies link calcium overload and excitation-contraction coupling dysfunction to myocardial damage and remodeling.</li> </ul> </li> </ul> <h3>1. Taxonomic Applicability</h3> <h4>Highly Relevant Taxa</h4> <ul> <li>Humans (Homo sapiens): <ul> <li>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.</li> </ul> </li> <li>Canines (Canis lupus familiaris): <ul> <li>Common model for cardiac electrophysiology and drug safety testing due to similarities to human cardiac ionic currents and myocardial structure.</li> </ul> </li> <li>Guinea Pigs (Cavia porcellus): <ul> <li>Cardiomyocyte action potential and ion channel dynamics closely resemble human hearts, making them suitable for studies of Na⁺/K⁺-ATPase dysfunction.</li> </ul> </li> <li>Rats (Rattus norvegicus) and Mice (Mus musculus): <ul> <li>Widely used in preclinical studies. While rodents exhibit some differences in cardiac electrophysiology, they provide valuable insights into ionic homeostasis and calcium dynamics.</li> </ul> </li> <li>Rabbits (Oryctolagus cuniculus): <ul> <li>Used in QT prolongation and contractility studies due to similarities to human cardiac repolarization.</li> </ul> </li> </ul> <h4>Moderately Relevant Taxa</h4> <ul> <li>Zebrafish (Danio rerio): <ul> <li>Suitable for genetic and developmental studies of Na⁺/K⁺-ATPase function, though their cardiac electrophysiology differs significantly from mammals.</li> </ul> </li> <li>Non-Mammalian Species: <ul> <li>Amphibians and reptiles rely less on Na⁺/K⁺-ATPase for cardiac repolarization, limiting direct applicability.</li> </ul> </li> </ul> <h3>2. Life Stage Applicability</h3> <h4>Highly Applicable Life Stages</h4> <ul> <li>Adults: <ul> <li>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.</li> </ul> </li> <li>Elderly Individuals: <ul> <li>Aging-related reductions in Na⁺/K⁺-ATPase efficiency and comorbidities (e.g., heart failure, arrhythmias) increase susceptibility to cardiomyopathy.</li> </ul> </li> </ul> <h4>Moderately Applicable Life Stages</h4> <ul> <li>Neonates and Infants: <ul> <li>Immature Na⁺/K⁺-ATPase activity may exacerbate vulnerability to ionic imbalances, though data are more limited.</li> </ul> </li> <li>Pediatric Populations: <ul> <li>Less studied but relevant in cases of genetic mutations affecting Na⁺/K⁺-ATPase function.</li> </ul> </li> </ul> <h3>3. Sex Applicability</h3> <h4>Relevant to Both Sexes</h4> <ul> <li>Both males and females are susceptible to cardiomyopathy caused by Na⁺/K⁺-ATPase inhibition.</li> <li>Sex-Specific Differences: <ul> <li>Hormonal differences may modulate ionic homeostasis: <ul> <li>Estrogen may enhance calcium handling, potentially mitigating early-stage events like calcium overload.</li> <li>Testosterone has been linked to increased susceptibility to certain types of cardiomyopathy.</li> </ul> </li> </ul> </li> </ul> <h3>4. Molecular and Cellular Context</h3> <ul> <li>Na⁺/K⁺-ATPase Isoforms: <ul> <li>Different isoforms (e.g., α1, α2, α3, and α4) exhibit tissue-specific expression, with the α1 isoform predominant in cardiac tissue.</li> <li>This AOP primarily focuses on cardiac Na⁺/K⁺-ATPase isoforms involved in maintaining ionic gradients.</li> </ul> </li> <li>Cardiomyocyte Specificity: <ul> <li>The pathway is specific to cardiac cells, where ionic dysregulation leads to excitation-contraction uncoupling, oxidative stress, and mitochondrial damage.</li> </ul> </li> </ul> <h3>5. Stressor Applicability</h3> <ul> <li>Chemical Stressors: <ul> <li>Cardiac glycosides (e.g., digoxin, ouabain).</li> <li>Environmental toxins (e.g., heavy metals like lead and mercury).</li> </ul> </li> <li>Physical Stressors: <ul> <li>Ischemia-reperfusion injury indirectly affects Na⁺/K⁺-ATPase activity.</li> </ul> </li> <li>Biological Stressors: <ul> <li>Genetic mutations in Na⁺/K⁺-ATPase subunits.</li> </ul> </li> </ul>

<h3>1. MIE: Inhibition of Na⁺/K⁺-ATPase</h3> <ul> <li>Essentiality: High <ul> <li>The Na⁺/K⁺-ATPase pump is fundamental for maintaining ionic gradients. Its inhibition directly initiates the cascade of events leading to cardiomyopathy.</li> </ul> </li> <li>Evidence: <ul> <li>Cardiac glycosides (e.g., digoxin, ouabain) inhibit Na⁺/K⁺-ATPase and reliably increase intracellular sodium, impair NCX, and induce calcium overload.</li> <li>Genetic modifications or pharmacological inhibition of Na⁺/K⁺-ATPase in animal models consistently reproduce downstream effects.</li> </ul> </li> </ul> <h3>2. KE1: Increased Intracellular Sodium Levels</h3> <ul> <li>Essentiality: High <ul> <li>Sodium accumulation is a prerequisite for downstream ionic dysregulation, including impaired NCX activity and calcium overload.</li> </ul> </li> <li>Evidence: <ul> <li>Experimental models demonstrate that sodium accumulation occurs immediately after Na⁺/K⁺-ATPase inhibition.</li> <li>Interventions reducing sodium accumulation (e.g., enhanced sodium extrusion via alternative pathways) mitigate calcium overload and subsequent events.</li> </ul> </li> <li>Intervention Studies: <ul> <li>Modulation of intracellular sodium levels through pharmacological agents (e.g., sodium channel inhibitors) prevents calcium overload and contractile dysfunction.</li> </ul> </li> </ul> <h3>3. KE2: Impaired Sodium-Calcium Exchange</h3> <ul> <li>Essentiality: High <ul> <li>The sodium-calcium exchanger (NCX) is critical for calcium extrusion in cardiomyocytes. Sodium imbalance impairs NCX, resulting in calcium retention.</li> </ul> </li> <li>Evidence: <ul> <li>Experimental studies show that NCX activity is directly influenced by intracellular sodium levels, and its dysfunction leads to calcium overload.</li> <li>Pharmacological enhancement of NCX activity (e.g., through NCX activators) reduces calcium overload and subsequent events.</li> </ul> </li> <li>Intervention Studies: <ul> <li>Stimulating NCX reduces calcium accumulation and prevents impaired contractility and myocardial remodeling.</li> </ul> </li> </ul> <h3>4. KE3: Calcium Overload in Cardiomyocytes</h3> <ul> <li>Essentiality: High <ul> <li>Calcium overload is a critical driver of excitation-contraction uncoupling, oxidative stress, and mitochondrial dysfunction, leading to impaired contractility and cell damage.</li> </ul> </li> <li>Evidence: <ul> <li>Calcium imaging studies demonstrate that Na⁺/K⁺-ATPase inhibition induces significant calcium accumulation.</li> <li>Interventions targeting calcium overload (e.g., calcium channel blockers or inhibitors of SR calcium release) reduce contractile dysfunction and myocardial remodeling.</li> </ul> </li> <li>Intervention Studies: <ul> <li>Calcium chelators and SERCA activators mitigate contractile dysfunction and prevent fibrosis.</li> </ul> </li> </ul> <h3>5. KE4: Impaired Cardiac Contractility</h3> <ul> <li>Essentiality: Moderate to High <ul> <li>Impaired contractility increases myocardial workload and oxygen demand, initiating compensatory remodeling. However, interventions targeting earlier KEs can prevent contractility impairment.</li> </ul> </li> <li>Evidence: <ul> <li>Reduced ejection fraction and cardiac output are directly observed following Na⁺/K⁺-ATPase inhibition and calcium overload.</li> <li>Pharmacological improvement of contractility (e.g., inotropic agents) mitigates myocardial stress and delays remodeling.</li> </ul> </li> <li>Intervention Studies: <ul> <li>Inotropic support improves acute cardiac function but does not fully prevent myocardial remodeling if earlier KEs persist.</li> </ul> </li> </ul> <h3>6. Adverse Outcome (AO): Cardiomyopathy</h3> <ul> <li>Essentiality: Defined as the final outcome <ul> <li>Cardiomyopathy is the endpoint of the pathway and results from the cumulative effects of earlier KEs.</li> </ul> </li> <li>Evidence: <ul> <li>Clinical and preclinical data consistently show progression from myocardial remodeling to cardiomyopathy when earlier KEs are unresolved.</li> <li>Addressing earlier KEs (e.g., calcium overload or remodeling) can prevent the development of cardiomyopathy.</li> </ul> </li> </ul>

<h3>1. Molecular Initiating Event (MIE): Inhibition of Na⁺/K⁺-ATPase</h3> 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. <h3>2. KE1: Increased Intracellular Sodium Levels</h3> 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. <h3>3. KE2: Impaired Sodium-Calcium Exchange</h3> 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. <h3>4. KE3: Impaired Cardiac Contractility</h3> 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. <h3>5. Adverse Outcome (AO): Cardiomyopathy</h3> 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. <h4>KER1: Na⁺/K⁺-ATPase Inhibition → Increased Intracellular Sodium Levels</h4> 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. <h4>KER2: Increased Intracellular Sodium → Impaired NCX Activity</h4> 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. <h4>KER3: Impaired NCX Activity → Impaired Contractility</h4> 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. <h4>KER4: Impaired Contractility → Cardiomyopathy</h4> 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.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> Electrolyte Imbalances Drug Interactions Age Stress </td> <td> Hypokalemia increases sodium accumulation and calcium retention. Co-administration of Na⁺/K⁺-ATPase or NCX inhibitors amplifies ionic dysregulation. Aging reduces compensatory mechanisms, accelerating progression to cardiomyopathy. Adrenergic stimulation amplifies calcium overload and contractile dysfunction. </td> <td> MIE → KE1, KE1 → KE2 MIE → KE1, KE2 → KE3 KE1 → KE2, KE4→ AO KE2 → KE4, KE3 →AO </td> </tr> </tbody> </table> </div>

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

The inhibition of the sodium-potassium ATPase pump (Na⁺/K⁺-ATPase) is a critical molecular initiating event (MIE) that disrupts ionic homeostasis in cardiac cells, triggering a cascade of adverse effects culminating in cardiomyopathy. This Adverse Outcome Pathway (AOP) details the mechanistic progression from Na⁺/K⁺-ATPase inhibition to structural and functional deterioration of the heart. Inhibition of Na⁺/K⁺-ATPase leads to increased intracellular sodium levels, impairing sodium-calcium exchanger (NCX) activity and causing calcium overload in cardiomyocytes. Excess calcium disrupts excitation-contraction coupling, impairs contractility, and activates pathological signaling pathways, leading to myocardial remodeling, including fibrosis and hypertrophy. Chronic remodeling ultimately results in cardiomyopathy, characterized by reduced cardiac output, arrhythmias, and heart failure. This AOP is supported by strong biological plausibility, robust empirical evidence from in vitro, in vivo, and clinical studies, and moderate quantitative understanding of key event relationships (KERs). Prototypical stressors, such as cardiac glycosides (e.g., digoxin, ouabain), heavy metals (e.g., lead, mercury), and environmental pollutants, are well-characterized for their ability to disrupt Na⁺/K⁺-ATPase activity and trigger downstream events. Modulating factors, including genetic mutations, electrolyte imbalances, and pre-existing cardiovascular conditions, influence the progression and severity of the pathway. this AOP has significant applications across regulatory toxicology, drug safety evaluation, and environmental risk assessment. It can guide the identification and prioritization of chemicals and drugs for further testing, support the development of therapeutic interventions targeting intermediate key events (e.g., calcium overload or myocardial remodeling), and enable personalized medicine approaches for individuals at greater risk. This mechanistic framework provides a valuable tool for understanding the cardiotoxic potential of Na⁺/K⁺-ATPase inhibitors and informs regulatory decision-making and research strategies.

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