In this issue of the Journal, Taylor and colleagues report the results of the African-American Heart Failure Trial (A-HeFT), a double-blind, randomized trial that evaluated the effect of the addition of isosorbide dinitrate and hydralazine to the best conventional therapy in patients with symptomatic congestive heart failure who identified themselves as black. 1 The results with the combination therapy were markedly positive, meeting the composite end point of the trial, which included death from any cause, a first hospitalization for heart failure, and quality-oflife measures. In addition, there was an impressive reduction in the rate of death from any cause of approximately 45 percent, leading to an early termination of the study.

This trial raises fascinating issues regarding heart-failure therapeutics and variations in drug susceptibility among populations. Attempting to understand these issues requires insight into the pharmacologic and biologic underpinnings of any drug combination that may enhance nitric oxide availability. This regimen of isosorbide dinitrate and hydralazine (which are available individually as inexpensive, generic formulations), initially selected for its vasodilatory properties in the Veterans Administration Heart Failure Trials (V-Heft) I and II, 2 turns out to be one of the most fortuitous combination therapies in cardiovascular medicine. Isosorbide dinitrate is an organic nitrate that stimulates nitric oxide signaling, 3 and hydralazine is a vasodilator and antioxidant that inhibits the enzymatic formation of reactive oxygen species such as superoxide (O2¡) by NADH and NADPH oxidases. 4 The success of this therapy now brings to the forefront the need to understand the underlying biochemistry of nitric oxide and superoxide and their interaction, since these molecules are key determinants of cellular redox balance.