Currently available guidelines on the treatment of heart failure clearly indicate the limitations of available inotropic therapy. The European guidelines for the Diagnosis and Treatment of Heart Failure published in September ofthis year recognize the use of positive intropes as intravenous treatment for heart failure used to limit severe episodes of heart failure or as a bridge to transplanation [1]. However, these guidelines clearly indicate thattheuse of positiveinotropes intravenously is insufficiently documented in controlled trials and the effect on prognosis unknown. Their use is associated with tachyphylaxis and increased heart rate and oxygen demand, which is particularly true for agents like dobutamine or the phosphodiesterase inhibitors. More-over, some studies indicate that treatment with these cAMP-dependent positive inotropes is associated with a high incidence of treatment-related complications, particularly atrial fibrillation and hypotension, as noted in studies with milrinone.

As regards the long-term oral use of positive inotropes, studies with cAMP-dependent agents clearly indicate a negative effect on survival [2]. Thus, studies with dobutamine, enoximone, milrinone, xamoterol, flosequinan and vesnarinone all resulted in an increase in mortality as compared to the control group. Pimobendan, a drug that is partly cAMP-dependent with phosphodiesterase-inhibiting properties, but also calcium sensitizing effects, showed a trend to a negative effect on survival [3]. The problem with these positive inotropic agents is that they either predominantly or partly increase the level of the second messenger cAMP in the cardiocyte. Of the available positive inotropes, this occurs through activation of the beta receptor complex (dobutamine, isoprenaline) or by inhibiting phosphodiesterase, the enzyme that breaks down cAMP. Agents in the latter class are milrinone and enoximone. cAMP, through activation of several protein kinases, affects the cell in different ways. It leads to an increase in flux of calcium through L-type calcium channels and an increase in uptake of calcium in the sarcoplasmatic reticulum (SR). Subsequent increased release of the calcium from the SR may lead to arrhythmias. Moreover, cAMP increases ATPase activity of the contractile protein, which results in increased energy consumption and oxygen demand. Both the enhanced arrhythmogeneity and increased energy consumption are likely to be detrimental, certainly in the cardiomypathic heart. Indeed, increased