Phosphodiesterase III inhibitors: Long-term risks and short-term benefits

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Abstract
Heart failure is now viewed as a disorder of the circulation, not merely the heart, which becomes manifest only when certain compensatory mechanisms break down. After treatment with diuretics, the two main strategies in treating heart failure involve decreasing the work of the heart by vasodilatation or increasing ventricular contractility by positive inotropic agents. It is now apparent, however, that the resulting hemodynamic benefit need not equate with long-term clinical improvement or increased longevity; indeed, the reverse can be true. Inhibitors of phosphodiesterase III, which is specific for the breakdown of cyclic adenosine monophosphate (cAMP), produce useful hemodynamic effects following intravenous and oral dosing, but have not fulfilled their initial promise in the chronic oral treatment of heart failure patients. The reason for reduced survival in the long-term studies of milrinone is not clear, but cardiac arrhythmias, possibly resulting from the increased intracellular levels of cAMP, may be responsible. However, intravenous usage may not suffer from the same limitations as chronic oral dosing. Short-term intravenous administration produces the expected beneficial hemodynamic effects of positive inotropism and vasodilatation. Though infusions of milrinone have been shown to enhance atrioventricular conduction in some, but not all, studies, there appears to be no significant increase in ventricular premature contractions, or ventricular or sustained tachyarrhythmias. Because milrinone does not have a significant adverse effect on His-Purkinje conduction, its use should be well tolerated in patients with intraventricular conduction disturbances. However, accurate assessment of the mortality risk and benefit of short-term intravenous treatment remains to be made in sufficiently powerful prospective, randomized controlled studies. In the meantime, PDE III inhibitors may be suitable for short-term intravenous administration in carefully selected and monitored heart failure patients requiring short-term inotropic support, including potential cardiac transplant patients awaiting surgery.