Hingorany S et al. – Derangements of the cascade may play an important role in the pathophysiology of heart failure (HF) and other diseases. Organic nitrates, which derive their action from their metabolic conversion to nitric oxide, exploit this pathway therapeutically. They are a mainstay of treatment for acute HF, but the development of tolerance with chronic administration limits their long–term efficacy. The development of a novel class of soluble guanylate cyclase (sGC) activators has shown in both animal and preliminary clinical trials to improve hemodynamics without tolerance, while preserving renal function in patients with HF. A phase II clinical program using the sGC activator cinaciguat is now in progress in patients with symptomatic HF to further evaluate the efficacy and safety of this treatment approach.