Hemodynamic effects of antiarrhythmic compounds: intrinsic effects and autonomic modulation

Besides their proarrhythmic side-effects, most antiarrhythmic drugs exert varying degrees of depressant action on hemodynamics, which may limit their utility, especially in patients with compromised left ventricular function. Antiarrhythmic drugs have not only myocardial inotropic effects but also act on the coronary and peripheral circulation and the heart rate. Thus, sophisticated and appropriate experimental conditions are necessary to define the effect of their direct negative inotropic actions versus their circulatory effects and the impact of drug-induced autonomic modulation. This study describes an extended comparison of amiodarone, d-sotalol, d,l-sotalol, and dofetilide as class III antiarrhythmic drugs with the actions of several class I antiarrhythmic drugs in an open-chest model. The experimental model permits not only measurements in the intact circulation but also measurements of isovolumic indexes of contractility, which are independent of drug-induced changes in ventricular preload and afterload. Furthermore, after autonomic blockade, hemodynamic effects can be measured independently of modulatory adrenergic effects in such a model. d-Sotalol and amiodarone had cardiodepressant effects only at doses significantly higher than the highest doses used clinically. Dofetilide did not have a negative inotropic effect at doses up to 40 ng/kg. However, these results might be modified in experimental models with severely compromised left ventricular function, as was shown for class I antiarrhythmic drugs and for d,l- and d-sotalol. The sensitivity to a drug's negative inotropic action is markedly increased in functionally impaired myocardium. Furthermore, in a model of postischemic myocardial dysfunction, the depressant effect of d-sotalol could largely be avoided by previous autonomic blockade, indicating the importance of the residual beta-blocking potency of d-sotalol in the doses used in our experiments. Thus, in clinically relevant doses amiodarone, d-sotalol, and dofetilide were found to be devoid of negative inotropic actions in the setting of normal left ventricular myocardium. In failing hearts, such effects become more readily evident than they do in normal hearts after high doses of amiodarone and d-sotalol. From beta-blocking experiments in hearts with left ventricular dysfunction, it could be inferred that residual beta-blocking and other negative inotropic mechanisms may produce a net negative inotropic action, thus masking the minor positive class III effects postulated from in vitro experiments. These observations may have significant clinical implications, because they suggest that the intrinsic myocardial effects of antiarrhythmic drugs may be modified by autonomic effects, the status of ventricular function, and changes in preload and afterload.