Multiple Avenues of Modulating the Nitric Oxide Pathway in Heart Failure Clinical Trials

This review discusses the integral role of the nitric oxide (NO) pathway in the pathophysiology of heart failure (HF). We emphasize potential therapeutic targets in the NO pathway and review contemporary clinical trials evaluating these novel therapeutic options.

Nitrates, neprilysin inhibitors, and phosphodiesterase (PDE) inhibitors have all proven to be efficacious in HF patients with systolic dysfunction, with the former two classes of medications producing a net mortality benefit. However, neither PDE inhibitors nor nitrates have demonstrated significant clinical benefit in patients with HF with preserved ejection fraction (HFpEF), and neprilysin inhibitors have yet to be evaluated in this population. Soluble guanylate cyclase (sGC) stimulators have shown significant promise in all HF patients, leading to improvements in both quality of life scores and exercise capacity. Conversely, sGC activators have limited clinical utility in HF, owing largely to safety concerns of hypotension. Inorganic nitrates and nitrites, meanwhile, may be emerging as potential therapies for the HFpEF population. The advent of novel therapies targeting the NO pathway is beginning to create a paradigm shift in the treatment of the HF patient. These therapies offer a promising outlook for the future, with hopes of reducing HF-associated morbidity and mortality.