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CARDIAC TOXICOLOGY

CARDIAC TOXICOLOGY. James Swenberg University of North Carolina. Basic Cardiovascular Function:. The heart, in concert with elastic blood vessels, maintains precise control of blood pressure and critical tissue perfusion. Basic Myocardial Structure. Cardiac Myofilaments. Cardiac Tissue.

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CARDIAC TOXICOLOGY

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  1. CARDIAC TOXICOLOGY James Swenberg University of North Carolina

  2. Basic Cardiovascular Function: The heart, in concert with elastic blood vessels, maintains precise control of blood pressure and critical tissue perfusion

  3. Basic Myocardial Structure Cardiac Myofilaments Cardiac Tissue Cardiac Myofibril Cardiac Myocyte

  4. Basic Myocardial Structure • Cardiac muscle is striated, BUT : • single nucleus • under autonomic control • all cardiac cells contract together (skeletal - selective recruitment of motor units) • high oxygen demand • structure permits coordinated contraction (acts as a syncytium) • Cardiac myocytes do not regenerate

  5. Superior Vena Cava Left Atrium Bundle of His Bundle Branches Sinoatrial Node Left Ventricle Right Atrium Purkinje Fibers Atrioventricular Node Papillary Muscle Right Ventricle Purkinje Fibers Basic Cardiac Electrophysiology

  6. Ion Channels and Transporters in Cardiac Myocytes Decrease in voltage triggers Ca2+ in, K+ out, and Na+ out Ca2+ in slow mitochondrion K+ out fast Na+ in fast

  7. Cellular Adaptation Adapted Cell (hypertrophy) Reversible Cell Injury Cell Hypoxia Normal Cardiac Myocyte Cell Death Irreversible Cell Injury Figure adapted from Robbins Pathologic Basis of Disease, Cotran, et al.

  8. Cardiac Myocyte Adaptation Normal myocardium Myocardial degeneration Cardiomyopathy Myocardial necrosis

  9. Hypertrophic Cardiomyopathy

  10. Ischemic Injury

  11. Manifestations of Cardiac Dysfunction • Arrhythmias (flutters, fibrillations) • Cardiomyopathies • Organism effects • poor tissue oxygenation/perfusion (heart, other) • accumulation of body fluids in inappropriate locations (lungs, abdominal cavity, legs) • organ failure (kidney, liver, lungs) • in the extreme …….death

  12. Measures of Toxicity:Alterations in Cardiovascular Function • Physiologic function • Electrocardiograms (EKG) • most sensitive early indicator of cardiac toxicity • Heart rate • tail cuff method with photosensor (noninvasive) • implanted telemetry devices • Systemic arterial blood pressure/blood flow • electromagnetic or doppler ultrasonic techniques • Cardiac output • transthoracic echocardiography

  13. Measures of Toxicity:Alterations in Cardiovascular Function • Clinical Chemistry • Electrolyte disturbances/imbalances • sodium, potassium, calcium, magnesium, zinc • Blood gas (acid/base balance) • Proteins • plasma albumin, myoglobin, fibrinogen • Lipids • plasma total cholesterol and triglycerides • plasma lipoproteins, total lipids, phospholipids

  14. Measures of Toxicity:Alterations in Cardiovascular Structure • Clinical Chemistry • enzyme release (short half-life) • creatine phosphokinase (CPK) • hybrid dimer specific for cardiac muscle (CPK-MB) • lactate dehydrogenase (LDH) • -hydroxybutyrate dehydrogenase (-HBDH) • serum glutamic-oxaloacetic transaminase (SGOT, AST)

  15. Measures of Toxicity:Alterations in Cardiovascular Function • Anatomic Pathology • Direct cardiotoxicity • Thrombosis & infarction • Inflammation (myositis, endocarditis, vasculitis) • Downstream tissue/organ effects

  16. Compound-Induced Toxicity • Toxicants that alter aerobic metabolism • Toxicants that alter myocardial conduction • Toxicants that alter cell membrane function • Toxicants that directly damage myocardium • Toxicants that induce vascular changes

  17. Toxicants That Interfere With Aerobic Metabolism • High energy demands of the heart make it susceptible to toxicants that interfere with: • oxygen availability (e.g., nitrite, carbon monoxide) • carbohydrate metabolism (e.g., fluoroacetate), or • oxidative phosphorylation (e.g., dinitrophenols) • rotenone • antimycin A • cyanide and carbon monoxide • Toxicity may result in myocardial necrosis

  18. Direct Cardiotoxicity: Myocardial Degeneration & Myocytolysis

  19. Toxicant Interference With Oxidative Phosphorylation Rotenone X Antimycin A X Cyanide and carbon monoxide X

  20. Toxicants That Alter Myocardial Conduction • Alter impulse formation and cause arrhythmias • Toxicants that cause acidosis and hyperkalemia (e.g., ethylene glycol) • enhance slow current activity • increase automaticity and promote arrhythmia • Cardiotoxic divalent ions (e.g., barium, strontium) • replace calcium in slow-current channels • alter efflux of potassium from myocardial cells  hypokalemia and arrhythmias

  21. R T P U Q S Toxicants That Alter Myocardial Conduction • Alter impulse formation and cause arrhythmias • Toxicants that cause prolongation of the QT interval (e.g., seldane) • Blockage of multiple ionic channels that may lead to syncope and ventricular fibrillation (torsade de pointes) QT Interval

  22. Toxicants That Cause Prolongation of the QT Interval • Over 100 marketed pharmaceutical agents cause interference in ventricular repolarization • QT prolongation is mentioned in the FDA-approved labeling as a known action of the drug • e.g. Terfenadine (Seldane®) – antihistamine/removed in 1997 Chlorpromazine (Thorazine®) – anti-psychotic Arsenic trioxide (Trisenox®) – anti-cancer/leukemia Erythromycin (Erythrocin®) – antibiotic Fluoxetine (Prozac®, Sarafem®) – anti-depressant Haloperidol (Haldol®) – anti-psychotic/schizophrenia

  23. Toxicants That Alter Myocardial Conduction • Alter impulse formation and cause arrhythmias • Halogenated hydrocarbons (e.g., chloroform) • suppress SA node (AV node becomes pacemaker) • sensitizes myocardium to arrhythmogenic effects of sympathomimetic amines (catecholamines) • Cardiac glycosides (e.g., digitalis) • inhibit the sodium-potassium exchange mechanism  decreased intracellular potassium, increased intracellular sodium  catecholamine sensitivity • increase refractory period of the AV node

  24. Toxicants That Alter Cell Membrane Function • Alter cell membrane control of ion movement and affect cardiac contraction • Cardiac glycosides and catecholamines • Chemical ionophores (e.g., monensin) • facilitates the passage of sodium, potassium, or calcium • monensin: alters Ca2+ and Na+ transport  increased intracellular calcium  changes myocardial contractility • excessive calcium accumulation impairs mitochondrial oxidative phosphorylation  myocardial necrosis

  25. Toxicants That Alter Cell Membrane Function • Alter cell membrane control of ion movement and affect cardiac contraction • Toxicants that bind to phospholipids (e.g., gossypol) • effect potassium transport  hyperkalemia  arrhythmias • Toxicants that selectively block sodium channels • tetrodotoxin, saxitoxin • decreased intracellular Na+  depression of normal pacemaker function and conduction  arrhythmias

  26. Toxicants That Directly Damage Myocardium • Damage the pumping effectiveness by reducing the number of active myocytes • Toxicants that cause oxidative damage and lipid peroxidation (e.g., doxorubicin, ethanol) • redox cycling of doxorubicin  semiquinone and superoxide radicals • ethanol metabolism  lipid peroxidation of myocytes • results in cell swelling, altered Ca2+ homeostasis, and irreversible myocyte injury

  27. Toxicants That Directly Damage Myocardium • Damage the pumping effectiveness by reducing the number of active myocytes • Toxicants that cause sarcolemmal injury and calcium alterations (e.g., catecholamines) • endogenous: epinephrine and norepinephrine • exogenous: isoproterenol (> toxicity than above) • sarcolemmal damage through lipid peroxidation • increased calcium uptake  impaired mitochondrial function and activation of neutral proteases and phospholipases  myocyte dysfunction and toxicity

  28. Cardiovascular changes following chronic rodent exposure to dioxin-like compounds Reference: Jokinen MP, Walker NJ, Brix AE, Sells DM , Haseman JK, Nyska A (2003). Cardiovascular Pathology in Female Sprague-Dawley Rats Following Chronic Treatment with Dioxin-like Compounds. Cardiovascular Toxicology.; 3(4): 299-310

  29. Cardiomyopathy • Myocardial fiber degeneration/necrosis, inflammation, fibrosis • Common spontaneous degenerative change of myocardium in old rats • Cause unknown but is affected by diet and stress

  30. Incidences of Cardiomyopathy • TCDD • PCB126

  31. Normal heart

  32. Cardiomyopathy

  33. Cardiac Toxicity observed in90-days exposure to Bis(2-chloroethoxy)methane in rats and mice Bis (2-chloroethoxy)methane (CEM) is a synthetic organic compound used as the starting compound to produce polysulfide elastomers used extensively in a variety of sealant applications.

  34. Histopathologic definitions of cardiac lesions Myocyte vacuolization - Widespread accumulation of multiple, round, variably sized, primarily small, and clear vacuoles, located within the myocyte sarcoplasm - Vacuoles, often similar in appearance, present in the interstitium are interpreted as a background change

  35. Histopathologic definitions of cardiac lesions (Cont.) Myocyte necrosis - Small areas containing fragmented, angular, brightly eosinophilic myofibers with dark, shrunken nuclei Atrial thrombosis - A mature, antemortem blood clot present within the lumen of the atrium, consisting of alternating areas of fibrin and layered cellular elements

  36. Histopathological findings in the heart in rats treated for 3 months with CEM (n=10). ( ) severity * all male and female animals treated with the 600 mg/kg/day and two females treated with the 400 mg/kg/day died before the end of the study.

  37. Atrial thrombosis

  38. Heart of a female rat treated with 600 mg/kg of CEM (R-right ventricle; M-interventricular septa; L- left ventricle) L M R

  39. Myofiber vavuolation and mononuclear cell infitration

  40. Myofiber cytoplasmic vacuolization

  41. 16-day cardiac toxicity of bis(2-chlorethoxy)methane H&E staining Control 2-D 3-D 5-D

  42. 16-day cardiac toxicity of bis(2-chloroethoxy)methane masson’s trichrome staining Control 2-D 3-D 5-D

  43. 16-day cardiac toxicity of bis(2-chlorethoxy)methane troponin immunostaining Control 2-D 3-D 5-D

  44. 16-day cardiac toxicity of bis(2-chlorethoxy)methane TUNEL immunostaining Control 2-D 3-D 5-D

  45. Proposed Mechanism of Heart Toxicity CI – CH2 – CH2 –O – CH2 – O – CH2 – CH2 – CI Bis(2-chloroethoxy)methane HOOC – CH2 – S – CH2 – COOH Mitochondrial damage Thiodiglycolic acid Apoptotic signals Damage to myocytes - apoptosis Cell death

  46. MITOCHONDRIAL CARDIOMYOPATHY IN 3'AZIDO-3'DEOXYTHYMIDINE (AZT)/ 3TC MULTIGENERATIONAL REPRODUCTIVE ASSESSMENT BY CONTINUOUS BREEDING WHEN ADMINISTERED TO CD-1® MICE BY GAVAGE AZT (Zidovudine) and 3TC (Lamivudine) – are nucleoside reverse transcriptase inhibitors for HIV-1 infection and AIDS -

  47. AZT - Introduction • AZT is known to cause mitochondrial myopathy in human and animals • The mechanism of cardiomyopathy from AZT is not completely understood, but suggested to be related to depletion mtDNA replication, resulting in impaired synthesis of mitochondrial enzymes that generate ATP - The enzyme responsible for mtDNA replication is DNA polymerase gamma, and it was found to be inhibited by AZT

  48. Pathological changes in the heart • Light microscopy – not commonly seen. Using masson’s trichrome – granular cytoplasm of myofibers, but no interstitial inflammation or fibrosis • EM – Mitochondrial swelling, with fractured, dissolution and disrupted cristae (abnormal mitochondria is defined when there is loss or dissolution of more than 25% of the cristae area) • Clinical chemistry – increased plasma lactate (lactic acidosis - indicating disturbed oxidative metabolism)

  49. Changes in the heart of rats exposed to Ephedrine + Caffeine Nyska A, Murphy E, Foley JF, Collins BJ, Petranka J, Howden R, Hanlon P, Dunnick JK. Acute Hemorrhagic Myocardial Necrosis and Sudden Death of Rats Exposed to a Combination of Ephedrine and Caffeine. Toxicol Sci. 2004 Nov 10

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