Therapeutic achievements of phosphodiesterase inhibitors and the future.

Heart failure remains a major therapeutic problem with a poor prognosis despite therapy with digitalis, diuretics and vasodilator drugs. Because impaired myocardial contractility is a principal feature of persistent heart failure, the development of phosphodiesterase inhibitors, e.g. milrinone, has presented important therapeutic possibilities. Milrinone exerts both positive inotropic and vasodilator activity, and improves systemic haemodynamics by increasing left ventricular stroke volume and decreasing left ventricular filling pressure and systemic vascular resistance. In addition to improving systolic pump function, milrinone has also been shown to improve impaired diastolic relaxation of the failing heart. Importantly, treatment with milrinone does not significantly increase myocardial oxygen consumption. In moderate to severe heart failure (NYHA class III and IV), intravenous and oral milrinone have been shown not only to produce acute haemodynamic improvement but also to relieve the associated symptom of breathlessness, with improvement in quality-of-life indices. In placebo-controlled, double-blind studies oral milrinone has enhanced exercise tolerance and increased total body oxygen consumption in mild (class II), moderate and severe heart failure. There is no evidence of a substantial pro-arrhythmic effect or other significant non-cardiovascular side-effects associated with the use of milrinone. The possibility of improved survival, which is still the ultimate goal of therapy with phosphodiesterase inhibitors, remains to the studied. Similarly, the role of these agents in the management of mild heart failure, alone or in addition to therapy with diuretics and angiotensin-converting enzyme (ACE) inhibitors, warrants further evaluation.