Di Filippo There is no evidence that digoxin may improve survival in patients with chronic HF (Shaddy 2001). Low dose to achieve levels ranging from 0.5 to 0.8 ng/mL might, however, be beneﬁcial (Clark 2000; Hoch and Netz 2005). Conversely, the inotropic effect of digoxin is likely to have a deleterious effect by increasing myocardial demand (Ross 2001). New advances in the treatment of chronic HF in adults have highlighted the advantages of beta-blockade strategy to improve prognosis (Quaife et al 1997; Lowes et al 1999). It is currently accepted that third-generation beta-blocker agents like the non-selective carvedilol can affect morbidity and mortality in the adult population (Colucci et al 1996; Packer et al 1996; Lechat et al 1998). Experience in the pediatric population is still limited and drawn from reported research on adults. Recent reports have brought divergent insights into the beneﬁcial effects of beta-blockade strategy in pediatric HF patients (Shaddy 2000, 2001). Beta-blocker agents in chronic congestive HF Mechanisms of action The mechanisms of action of beta-blockers agents are not yet clearly deﬁned and probably impact on the neurohormonal component of HF, mainly on the sympathetic activation of chronic HF. Through decreasing the sympathetic activation of chronic HF, they enable a decrease in heart rate and lower myocardial demand. Studies in adults have demonstrated reversal myocardial remodeling (decreased ventricular volumes and spherical shape) with concurrent improved ejection fraction and shortening fraction (Sackner-Bernstein and Mancini 1995; Bristow 1997). Not all the beta-receptor antagonists enable reversal of neurohormonal stimulation. The third-generation non-selective carvedilol can achieve this. It provides an additional α-adrenergic receptor blockade responsible for beneficial afterload lowering. From the COMET rand- omized double-blind trial results, carvedilol had superior hemodynamic effects and reduction of all-cause mortality compared with metoprolol. These data support the advantage of α-adrenergic receptor blockade (Poole-Wilson et al 2003; Metra et al 2005) and were conﬁrmed by experimental study (Nikolaidis et al 2006). The primary mechanism of these agents is to prevent and reverse adrenergically mediated myocardial dysfunc- tion and remodeling (chamber dilation and assumption of a more spherical shape) (Sackner-Bernstein and Mancini 850 1995; Bristow 1997; Sabbah 1999). Other mechanisms of action have been proposed for the beneﬁcial effects of third- generation beta-blockers in HF, including upregulation of beta-receptors, decreased stimulation of other neurohormo- nal systems, antiarrhythmic effects, coronary vasodilation, negative chronotropic effects, antioxidant effects, and improved myocardial energetics. In particular, carvedilol has an antioxidative effect that may inhibit catecholamine ability to generate oxygen free radicals in the myocardium (Feuerstein et al 1997; Kaye et al 2001; Nakamura et al 2002). Both carvedilol and metoprolol have antioxydant and antiapoptotic actions, which are likely to be impor- tant in the treatment of HF (Kawai et al 2004). However, carvedilol but not metoprolol was found to inhibit the calcium-dependent toxic oxidant species and to increase oxygen consumption (Kametani et al 2006). Moreover, the chronotopic effect of beta-blockade was shown to be one of the major determinants of the restoration of con- tractile function, as demonstrated in an experimental study (Nagatsu et al 2000). The impact of beta-blockers on calcium release channel function may also play a signiﬁcant role in improving myocardial performance (Reiken et al 2003). Lastly, carvedilol may inhibit endothelin-1 synthesis in vitro and prevent vascular smooth muscle cell prolifera- tion and intimal migration after vascular injury. Experience in adults Most knowledge about beta-blockers efﬁcacy in chronic HF is drawn from randomized trials performed in adults. The Metoprolol in Dilated Cardiomyopathy (MDC) trial was the ﬁrst major multicenter, randomized trial of beta- blockers in patients with HF (Waagstein et al 1993). In this study, 383 patients with idiopathic dilated cardiomyopathy were randomized to receive either metoprolol or a placebo. Patients who received metoprolol had increased ejection fractions and exercise times compared with placebo. The Cardiac Insufﬁciency Bisoprolol Study (CIBIS) compared the effects of bisoprolol with placebo in 641 adults with ischemic and non-ischemic left ventricular dysfunction (CIBIS Investigators and Committees 1994), and showed a 20% reduction in mortality in the bisoprolol group. In 1996, one study demonstrated a 65% reduction in mortality in the carvedilol group compared with placebo (Packer et al 1996). The Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA) randomized patients with HF to receive placebo or carvedilol (Bristow et al 1996). In this study, carvedilol was associated with dose-related improvements in left ven- tricular function and survival. Therapeutics and Clinical Risk Management 2007:3(5)