New and emerging pharmacologic strategies in the management of chronic heart failure.

Chronic heart failure (CHF) is a complex syndrome involving activation of multiple cellular, metabolic, and neurohumoral pathways following the initial myocardial insult. Recently, there have been considerable advances in the pharmacologic management of CHF. The current approach to treatment recognizes the need to target neurohormonal activation, and the use of angiotensin-converting enzyme (ACE) inhibitors and beta blockers should now be regarded as part of standard therapy in many patients with CHF. However, because of the complexity of the disease, blockade of additional pathways is likely to be required to maximize the therapeutic benefit of intervention. To this end, there are several agents under active late-phase clinical evaluation. The most advanced of these new strategies (beyond renin-angiotensin-aldosterone blockade) is inhibition of the endothelin system. There is a substantial body of evidence that this system is intimately involved in CHF disease progression. Early-phase clinical data are very encouraging and support the potential utility of long-term endothelin inhibition. Other novel approaches involve the use of cytokine antagonists (e.g., agents that block tumor necrosis factor-alpha activity) and the augmentation of natriuretic peptides. If all these potential agents prove to be of benefit in CHF, the question of which agent or combination of agents to use in which patients will arise. There is therefore a need to develop scientific approaches in order to be able to identify more accurately patients who will obtain benefit from specific classes or combinations of drugs.