Biochemical Principles of Cardiac Toxicology
Cardiovascular disease is the number one cause of disability and premature death in industrial societies, and an enormous amount of time, effort, and money has been spent trying to alleviate this affliction. A great deal of emphasis has been put into the development of remedies that prolong life and eliminate suffering due to diseases of the heart and vasculature. Naturally, drugs that correct cardiovascular problems also produce undesirable results when given in excess amounts. Nearly as often, substances that were first perceived as toxic have proved to be quite beneficial either clinically or for research when titrated properly. As a result, the literature abounds with an overwhelming amount of information on variations in the normal physiology and biochemistry of the heart produced by xenobiotics, independent of whether they are perceived as medicinal or hazardous. Therefore, even a cursory review of every biochemical perturbation of the myocardium is beyond the scope of this chapter. Instead, a brief overview of the general biochemistry of the heart is provided and a small number of extensively studied cardiac toxicants and toxins are discussed in an attempt to demonstrate the various ways xenobiotics can interfere with subcellular processes. This chapter only considers specific cardiac effects and not effects of substances on the vascular system. For the most part, specific details of experiments such as animal species, doses or concentrations of chemicals, and temporal factors are not
included. Four major areas of cardiac biochemistry are emphasized: energy metabolism and oxidative phosphorylation, ion balance, excitation contraction, and catecholamine regulation. In addition, gap junctions are discussed because halogenated hydrocarbons block gap junctional intercellular communication in cardiomyocytes, and this action may be the basis of the arrhythmogenicity of halocarbon solvents and aerosols.