Pitfalls of Therapies Targeting the Nitric Oxide Signaling Pathway in Heart Failure With Preserved Ejection Fraction

Over 30 million individuals globally are afflicted with heart failure with preserved ejection fraction (HFpEF). Despite this substantial figure, treatment options for HFpEF remain limited. This is largely attributed to the variability in disease features and comorbidities with which patients present in the clinic. A common feature among patients with HFpEF is reduced nitric oxide (NO) bioavailability-a finding which prompted the use of therapeutics targeting the NO signaling pathway in HFpEF preclinical and clinical trials. Although many of these therapeutics were successful in animal models, clinical trials have yielded neutral, negative, or contradictory results. In this review, we will summarize the outcomes of HFpEF clinical trials investigating drugs that target the NO signaling pathway (nitrates, nitrites, soluble guanylyl cyclase stimulators, and phosphodiesterase 5 inhibitors) and discuss potential pitfalls underlying the neutral or negative results, as well as considerations for the design of future studies.