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Chapter 18: Toxic Responses of the Heart and Vascular System

Y. James Kang

  • Introduction

  • Overview of the Heart

    • Overview of Cardiac Structural and Physiological Features

      • Review of Cardiac Structure

      • Electrophysiology

      • Contractility

      • Electrotonic Cell-to-Cell Coupling

      • Electrocardiograph

      • Neurohormonal Regulation

    • Overview of Cardiac Energy Metabolism and Biochemistry

      • ATP and the Heart

      • Phosphocreatine and the Heart

      • Metabolic Pathways

      • Calcium and Calcineurin

      • AMP-Activated Protein Kinase

      • Mitogen-Activated Protein Kinases

      • Protein Kinase C

      • Transcription Factors

  • Cardiac Toxic Responses

    • Basic Concepts and Definitions

      • Cardiac Arrhythmia

      • Cardiac Hypertrophy

      • Heart Failure

      • Acute Cardiac Toxicity

      • Chronic Cardiac Toxicity

    • Myocardial Degeneration and Regeneration

      • Myocardial Degenerative Responses

      • Toxic Effect on Myocardial Regeneration

      • Reversible and Irreversible Toxic Responses

    • Myocardial Cell Death and Signaling Pathways

      • Apoptosis and Necrosis

      • Mitochondrial Control of Cell Death

      • Death Receptors and Signaling Pathways

    • Mitochondrial Dynamics and Autophagy

      • Mitochondrial Dynamics

      • Autophagy

    • Cardiac Hypertrophy and Heart Failure

      • Adaptive and Maladaptive Responses

      • Hypertrophic Signaling Pathways

      • Transition from Cardiac Hypertrophy to Heart Failure

    • QT Prolongation and Sudden Cardiac Death

      • Definition of QT Prolongation

      • Molecular Basis of QT Prolongation

      • Torsade De Pointes and Sudden Cardiac Death

      • Parameters Affecting QT Prolongation and Torsadogen-esis

    • Biomarkers for Cardiac Toxicity

      • Validation of Biomarkers

      • Availability of Biomarkers

      • Biomarker Applications and Limitations

  • Cardiac Toxic Chemicals

    • Alcohol and Alcoholic Cardiomyopathy

    • Pharmaceutical Chemicals

      • Antiarrhythmic Agents

      • Inotropic Drugs

      • Central Nervous System Acting Drugs

      • Local Anesthetics

      • Anthracyclines and Other Antineoplastic Agents

      • Antimicrobial and Antiviral Agents

      • Anti-Inflammatory Agents

      • Antihistamines

      • Immunosuppressants

      • Miscellaneous Drugs

    • Natural Products

      • Catecholamines

      • Steroids and Related Hormones

      • Cytokines

      • Animal and Plant Toxins

    • Environmental Pollutants and Industrial Chemicals

      • Particulate Matters

      • Solvents

      • Alcohols and Aldehydes

      • Halogenated Alkanes

      • Metals and Metalloids

  • Overview of Vascular System

    • Vascular Physiology and Structural Features

      • Arterial System and Physiological Function

      • Capillaries and Microcirculation

      • Venous System and Physiological Function

      • Lymphatic System and Physiological Function

    • Regulatory Mechanisms of the Vascular System

      • Neurohormonal Regulation

      • Local Metabolic Regulation

  • Vascular System Toxic Responses

    • Mechanisms of Vascular Toxicity

      • Responses of Vascular Endothelial Cells to Toxic Insults

      • Responses of Smooth Muscle Cells to Toxic Insults

      • Oxidative Stress and Vascular Injury

      • Inflammatory Lesions

    • Toxic Responses of Blood Vessels

      • Hypertension and Hypotension

      • Atherosclerosis

      • Hemorrhage

      • Edema

  • Vascular System Toxic Chemicals

    • Pharmaceutical Chemicals

      • Sympathomimetic Amines

      • Nicotine

      • Cocaine

      • Psychotropic Agents

      • Antineoplastic Agents

      • Analgesics and Nonsteroidal Anti-Inflammatory Agents

      • Oral Contraceptives

    • Natural Products

      • Bacterial Endotoxins

      • Homocysteine

      • Hydrazinobenzoic Acid

      • T-2 Toxin

      • Vitamin D

      • β-Amyloid

    • Environmental Pollutants and Industrial Chemicals

      • Carbon Monoxide

      • Carbon Disulfide

      • 1,3-Butadiene

      • Metals and Metalloids

      • Aromatic Hydrocarbons

      • Particulate Air Pollution

Introduction

Cardiovascular toxicology is concerned with the adverse effects of extrinsic and intrinsic stresses on the heart and vascular system. Extrinsic stress involves exposure to therapeutic drugs, natural products, and environmental toxicants. Intrinsic stress refers to exposure to toxic metabolites derived from nontoxic compounds such as those found in food additives and supplements. The intrinsic exposures also include secondary neurohormonal disturbance such as overproduction of inflammatory cytokines derived from pressure overload of the heart and counter-regulatory responses to hypertension. These toxic exposures result in alterations in biochemical pathways, defects in cellular structure and function, and pathogenesis of the affected cardiovascular system. The manifestations of toxicological response of the heart include cardiac arrhythmia, hypertrophy, and overt heart failure. ...

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