INTRODUCTION

The toxicological development and therapeutic utility of a number of important drugs is frequently limited by their potential for cardiotoxicity. Such side effects may develop acutely or chronically and can range from minimal electrocardiographic (ECG) changes to permanent cardiac damage, or even sudden death (Marshall and Lewis, 1973). Inevitably much time and effort has been spent investigating ways to improve the predictability of myocardial involvement. This has resulted in the proliferation of often complex animal models (Rona, 1967; Balazs et al, 1969; Osborne and Dent, 1973; Chappie et al, 1976), and highly sophisticated schemes of clinical monitoring (Lahtinen et al, 1982). The detection of cardiotoxicity nevertheless remains complicated by the large functional reserve of the heart which can mask mechanical impairment, its ability to develop resistance to further damage after certain insults (Joseph et al, 1983) and also to repair foci of myocarditis (Lehr, 1972; Bach and Cockburn, in press).

Damage to the heart generally occurs either as a consequence of direct cellular toxicity or due to remote effects on the neural, humoral and haemodynamic influences which normally control it. The latter indirect toxicity is frequently seen as a result of exaggerated pharmacological response at the high dose levels commonly used in routine toxicological studies (Herman et al, 1979).

While the toxic end point may be the same it is important to appreciate and differentiate these mechanisms when assessing the significance of cardiotoxicity.