ABSTRACT
The heart possesses at least (i) three electrophysiological properties (chronotropy
or automaticity, dromotropy or conductivity, bathmotropy or irritability) (1,2);
(ii) 9 tissues or electrophysiological phenotypes (atrial myocardium, ventricular
myocardium [epicardial, midmyocardial (“M”), and endocardial tissues]),
His-Purkinje fibers, sinoatrial (SA) node, atrioventricular (AV) node, atrio-AV
nodal junctional fibers, and internodal pathways]; (iii) 15 or more voltage-or
ligand-gated ion channels, pumps, and exchangers (3); and (iv) 6 or more relatively
large signaling molecules [ryanodine, sarco/endoplasmic reticulum Caþþ ATPase
(SERCA), phospholambam, protein kinase A and C, calcineurin, sarcoplasmic
calcium buffers] that may be potential targets for therapeutic or toxic effects of
drugs. Because of the potential subtlety of toxic effects [e.g., small changes in heart
rate, minor lengthening of corrected QT (QTc)], and because they may not be
manifested for years (e.g., doxorubicin,mercury, arsenic), ormay require high doses
or concomitant provocateurs (e.g., hypertrophy, diabetes, heart failure, metabolites,
electrolyte disturbances), it is sometimes difficult to ascertain the potential for
toxicity. Acute toxic cardiovascular effects (as with strychnine or supratherapeutic
concentrations of dofetilide) may be easily identified, but subtle effects [as with
rofecoxib (4)] of arsenic, mercury, lead, phentermine-fenfluramine (5), 5-hydroxy-
tryptamine 2B (5-HT2B) agonists may be difficult to identify, yet result in far greater
morbidity and mortality. Notably, a leading cause of recent removals of drugs from
the market is toxicity due to electrophysiological effects on the heart, specifically
delayed repolarization, and the ventricular arrhythmia, torsades de pointes (TdP)
(6). This chapter will review proarrhythmic electrophysiological actions, provide
examples of how such effects are manifest, and discuss methods of identifying
potential toxic signals (7-14).
