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The Value of the Nitric Oxide Pathway and its Importance in African-American Patients with Heart Failure

Jaydeep Patel Pharm D Candidate
USF College of Pharmacy

The vascular system of human anatomy made up of blood vessels is composed of endothelial cells. These endothelial cells are surrounded by smooth muscles, which aid in regulating optimal circulation. Nitric oxide is a natural gas produced by the endothelial cells, and when it is produced, it relaxes the smooth muscles of the vascular system to enable blood vessels to dilate. This effect is known as vasodilation, which allows optimal blood flow to and from tissues, which carry oxygen and other key nutrients.

To detail, nitric oxide is produced by enzymes called nitric oxide synthase (NOS). These NOS enzymes convert amino acid L-Arginine into nitric oxide. The African-American Heart Failure Trial (A-HeFT) was conducted with the thought that augmenting nitric oxide may be a different approach to slow or reverse progressive heart failure.

However, studies in heart failure and hypertension have shown that people who identify themselves as black may have a less active renin-angiotensin system and a lower bioavailability of nitric oxide. The A-HeFT study was conducted to determine if a fixed dose of isosorbide dinitrate (ISDN) and hydralazine would provide additional benefit in black patients with heart failure.

Investigators suggested that ISDN and hydralazine might act as a nitric oxide donor, with hydralazine protecting against nitric oxide degradation. In heart failure patients, production of superoxide is increased and nitric oxide synthesis is disrupted. This leads to cellular dysfunction and ultimately cell death. ISDN stimulates the nitric oxide pathway and hydralazine inhibits superoxide synthesis. Together, this combination has the potential to prevent cardiac remodeling. The A-HeFT trial was stopped early due to significantly higher mortality rates in the placebo group compared to ISDN and hydralazine group. This large, prospective clinical trial conducted in the United States has for the first time demonstrated efficacy of a heart failure therapy in an all African-American population.

Gupta, Divya, et al. “Nitrate therapy for heart failure: benefits and strategies to overcome tolerance.” JACC: Heart Failure 1.3 (2013): 183-191.
Franciosa, Joseph A., et al. “African-American heart failure trial (A-HeFT): rationale, design, and methodology.” Journal of cardiac failure 8.3 (2002): 128-135.