heart and vascular system

• Typical chemical induced disturbances in cardiac function


  • Effects on heart rate (chronotropic)
  • Contractility (inotropic)
  • Conductivity (dromotropic)
  • Excitability (bathmotropic)

  
• Any xenobiotic that disrupts ion movement or homeostasis may induce a cardiotoxic reaction composed principally of disturbances in heart rhythm
• Blood flow through the heart

  Blood from superior and inferior vena cava → right atrium → (tricuspid valve) right ventricle → (pulmonary valve) pulmonary artery → lungs → pulmonary veins → left atrium → (mitral valve) left ventricle → (aortic valve) aorta → rest of the body

  
• Cardiac muscle contraction and relaxation


  The electrical impulse begins at the SA node (right atrium contracts) → AV node (between atria and ventricles – slows the electrical signal before entering the ventricles) → His-Purkinje network (electrical impulse is sent to the muscular walls of the ventricle – contraction)
• Acute cardiac toxic response


  Cardiac response to a single exposure to a cardiac toxicant – often manifested as arrhythmia, but myocardial apoptosis and necrosis may also be involved esp if the toxic insult is severe
• Chronic cardiac toxic response


  Cardiac response to long-term exposure to a cardiac toxicant – often manifested by cardiac hypertrophy and the transition to heart failure
• Hypertrophy


  Compensatory response of the heart - prolonged HTN, component of cardiac remodeling following IHD, following injury
• Heart failure


  When the hypertrophic myocardium decompensates resulting to failure – ventricular contractility is reduced
• Toxic responses of the heart


  • Cardiac arrhythmia
  • Ischemic heart disease
  • Cardiomyopathies
  • Apoptosis and oncosis
  • Mitochondrial injury
• Cardiac arrhythmia


  Interference with ion homeostasis
• Xenobiotics that can induce cardiac arrhythmia


  • 5-Fluorouracil
  • Cyclophosphamide
  • Halogenated hydrocarbons
  • Interferon – γ
  • Ketones
  • TCAs
  • Toluene
• Inhibition of Na+-K+ ATPase


  Increases Na+ and subsequently Ca++ resulting to positive inotropy
• Xenobiotics that inhibit Na+-K+ ATPase


  • Cardiac glycosides (digoxin)
• Na+ channel blockade


  Reduced cardiac excitability
• Xenobiotics that block Na+ channels


  • Amphotericin B
  • Class I antiarrhythmics
  • Cocaine
  • Local anesthetics
  • SSRIs
• K+ channel blockade


  Increases AP duration and refractoriness
• Xenobiotics that block K+ channels


  • Antihistamines
  • Cisapride
  • Class III antiarrhythmics
  • Fluoroquinolones
  • Macrolides
• Ca++ channel blockade


  Produces negative inotropy
• Xenobiotics that block Ca++ channels


  • Aminoglycosides, Tetracycline, Chloramphenicol, Amphotericin B
  • Class IV antiarrhythmics
  • Phenothiazine antipsychotics (chlorpromazine…)
  • SSRIs
• Sarcolemmal injury, sarcoplasmic reticulum dysfunction, and Ca++ overload


  Alterations of cardiac calcium homeostasis by toxicants may disturb the regulation of cellular function
• Xenobiotics that cause sarcolemmal injury, sarcoplasmic reticulum dysfunction, and Ca++ overload


  • Anthracycline antineoplastics (doxorubicin, daunorubicin…)
  • Ba, La, Mn, Ni
  • Cocaine
  • Ethanol
  • General anesthetics
  • Heavy metals (Cd, Co, Pb)
  • Immunosuppressants (rapamycin, tacrolimus)
  • Methylxanthines (theophylline…)
  • Thyroid hormone
• Ischemic heart disease


  Altered cardiac contractility and coronary blood flow. Xenobiotics that alter cardiac contractility and disturb myocardial perfusion may result to ischemia. Prolonged ischemia may lead to MI
• Xenobiotics that can cause ischemic heart disease


  • Interleukin 1β, -2, -6 (increased NO synthase expression – (-) inotrophy)
  • Toluene, halogenated hydrocarbons, ketones – decreased parasympathetic activity, and increased adrenergic sensitivity - proarrhythmogenic
• Beta-1 receptor stimulation


  Positive inotropy and chronotropy
• Xenobiotics that stimulate beta-1 receptors


  • Bronchodilators (non-selective Beta agonists - salbutamol, procaterol, terbutaline)
  • Catecholamines
• M1 receptor stimulation


  Negative chronotropy
• Xenobiotics that stimulate M1 receptors


  • Bethanecol, carbachol, pilocarpine, neostigmine, Physostigmine, galantamine, donepezil, rivastigmine
• Xenobiotics that activate M3 and M5 receptors


  • Bethanecol, carbachol, pilocarpine, neostigmine, Physostigmine, galantamine, donepezil, rivastigmine
• Xenobiotics that stimulate alpha-1 receptors


  • Catecholamines
  • Nasal decongestants (ephedrine, PPP)
  • TCAs (alpha adrenergic blockade)
• Oxidative stress – ROS are generated during myocardial ischemia and at the time of reperfusion. Toxicants may induce cardiotoxicity through the generation of ROS
• Xenobiotics that can induce oxidative stress


  • Anthracycline antineoplastics (doxorubicin, daunorubicin…)
  • Catecholamines
  • Cocaine
• Atherosclerosis – buildup of fat and cholesterol plaques in and on the walls of blood vessels – block blood flow, and may form dangerous clots
• Cardiomyopathies


  General term for diseases of the heart muscle, where the walls of the heart chambers have become stretched, thickened, or stiff. Causes: IHD, hypertrophy, infectious diseases, drug or chemical-induced, idiopathic

  
• Dilated cardiomyopathy


  Produced by progressive cardiac hypertrophy, decompensation, ventricular dilation, leading to systolic dysfunction, or impaired contractility
• Hypertrophic cardiomyopathy


  Produced by progressive cardiac hypertrophy, with impaired compliance of the ventricular walls and reduced diastolic ventricular filling
• Xenobiotics that can cause cardiomyopathies


  • Ethanol (chronic, for acute – reduced conductivity)
  • Mineralocorticoids
  • Natural and synthetic androgens
  • Natural and synthetic glucocorticoids
  • Nucleoside analog reverse transcriptase inhibitors (zidovudine…)
• Apoptosis and oncosis


  Myocyte death – peptides and cytokines directly activate apoptotic signaling pathways. Xenobiotics may induce cardiac myocyte apoptosis
• Xenobiotics that can induce apoptosis and oncosis


  • Anthracycline antineoplastics (doxorubicin, daunorubicin…)
  • Catecholamines
  • Cocaine
  • Radiocontrast agents (diatrizoate, iohexol…)
  • TNF - α
• Mitochondrial injury


  Oxidative phosphorylation of ADP to ATP in the mitochondria may be affected by xenobiotics, i.e. chemical inhibitors, and uncouplers
• Xenobiotics that can cause mitochondrial injury


  • Anthracycline antineoplastics (doxorubicin, daunorubicin…)
  • Cocaine