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Active Investigation

Several drugs and interventions are under active evaluation in long-term large-scale trials because they showed promise in pilot studies that involved small numbers of patients. Until the results of definitive trials are available, none of these interventions can be recommended for use in patients with HF.

Vasopeptidase Inhibitors

As previously stated, ACEIs can exert beneficial effects in heart failure not only blocking the conversion of angiotensin I in angiotensin II, with subsequent reduction of peripheral vasoconstriction, but also prevent the cleavage of bradykinin and kallidin, potentiating their vasodilatory effects. However, besides the angiotensin-converting enzyme, kinins are also cleaved and therefore inactivated by neutral endopeptidase. Hence, there has been interest in the development of vasopeptidase inhibitors that block not only the ACE, but also the neutral endopeptidase, which leads to enhanced activity of endogenous vasodilators. One vasopeptidase inhibitor, omapatrilat, is being developed for the treatment of hypertension and for the treatment of HF. In experimental and small-scale clinical studies, omapatrilat produced an improvement in cardiac performance and a reduction in the risk of death and worsening HF to a greater degree than a conventional ACE inhibitor. The possibility that omapatrilat may be superior to an ACE inhibitor is now being evaluated in a large-scale trial.

Cytokine Antagonists

Patients with HF have elevated levels of the cytokine, tumor necrosis factor, which can exert cardiodepressant and cardiotoxic effects in experimental models. The major source of tumor necrosis factor may be the heart itself, which appears to synthesize the cytokine in response to hemodynamic stresses. Two types of tumor necrosis factor antagonists are commercially available: a soluble receptor (etanercept) and a chimeric antibody (infliximab). Both are available for use in the management of non-cardiovascular disorders and are undergoing evaluation for use in the treatment of HF. In a short-term pilot study, etanercept produced dose-dependent increases in ejection fraction, decreases in left ventricular chamber size, and improvement in clinical status. However, a largescale trial with etanercept in HF was stopped early because of the low likelihood that the drug would show favorable effects. Alternative approaches to cytokine inhibition are being evaluated at the present time, but until definitive studies with these newer agents are completed, cytokine antagonists cannot be recommended for the treatment of HF.

Endothelin Antagonists

Endothelin is a potent vasoconstrictor that can adversely affect the structure and function of the heart and peripheral blood vessels. Circulating levels of endothelin-1 are elevated in patients with HF, and endothelin antagonism can produce favorable hemodynamic and

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