IMPROVEMENT OF POSTRECEPTOR EVENTS BY METOPROLOL TREATMENT IN PATIENTS WITH CHRONIC HEART-FAILURE

Objectives. This study tested the hypothesis that metoprolol restores the reduction of the inotropic effect of the cyclic adenosine monophos phate (cAMP)-phosphodiesterase inhibitor milrinone, which is cAMP depe ndent but beta-adrenoceptor independent. Background. Treatment with be ta-adrenergic blocking agents has been shown to lessen symptoms and im prove submaximal exercise performance and left ventricular ejection fr action in patients with heart failure. Restoration of the number of do wn-regulated beta-adrenoceptors has been suggested to be one mechanism of beta-blocker effectiveness. However, the reversal of postreceptor events, namely, an increase in inhibitory G-protein alpha-subunit conc entrations, could also play a role. Methods. Fifteen patients with hea rt failure due to dilated cardiomyopathy (left ventricular ejection fr action 24.6 +/- 1.5% [mean +/- SD], New York Heart Association functio nal class II or III) were treated with metoprolol (maximal dose 50 mg three times daily) for 6 months. Before and after metoprolol treatment , inotropic responses to milrinone (5 to 10 mu g/kg body weight per mi n) were measured echocardiographically. For comparison, responses to m ilrinone were determined under control conditions and after accelerate d application of 150 mg of metoprolol to inactivate beta adrenoceptors in subjects with normal left ventricular function. Results. In subjec ts with normal left ventricular function, treatment with metoprolol di d not alter the increase in fractional shortening or pressure/dimensio n ratio of circumferential fiber shortening after application of milri none. In patients with heart failure, treatment with metoprolol signif icantly increased left ventricular ejection fraction, fractional short ening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations and functional class. After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blacker treatment. Conclusions. Milrinone increases inotr opic performance independently of beta-adrenoceptors in vivo. Metoprol ol treatment restores the blunted inotropic response to milrinone in p atients with heart failure, indicating that postreceptor events (e.g., increase in inhibitory G-proteins) are favorably influenced. This mec hanism could contribute to the beneficial effects observed in the stud y patients and represents an important mechanism of how beta blocker t reatment influences the performance of the failing heart. (C) 1997 by the American College of Cardiology.