FIGURE 2.

Pitfalls of therapies targeted to nitric oxide signaling in heart failure with preserved ejection fraction. NO signaling–based therapies have shown inconsistent impacts on patients with HFpEF. The deleterious outcomes of treating patients with HFpEF with organic nitrates have been attributed to nitrate tolerance and associated reactive oxygen–nitrogen species (RONS). Inorganic nitrates have conversely shown mixed efficacy, with the neutral outcomes potentially being due to impaired drug conversion from nitrate to nitrite, therapeutic dosing, and/or sex of the patient population. Inconsistent efficacy of nitrite therapy may be explained by impaired drug delivery, comorbidity status of the patient population (more specifically, whether the patients are recruited based on the presence of pulmonary hypertension), and/or the short half-life (30–40 minutes) of nitrite therapy. Soluble guanylyl cyclase (sGC) stimulators may be ineffective due to the heme status of sGC. sGC stimulators require ferrous heme to be functional, though, with oxidative stress (like in HFpEF), sGC heme can become oxidized or lost, preventing drug activity. sGC stimulators and phosphodiesterase 5 (PDE5) inhibitors may also not be more effective as they only target cardiac and vascular muscle cells, but not endothelial cells. Furthermore, PDE5 inhibitors may only show minimal benefit as a result of comorbidity status (specifically, the presence or absence of combined pre- and post-capillary [Cpc] pulmonary hypertension), inability to prevent cyclic guanosine monophosphate (cGMP) breakdown, and reliance on upstream nodes of the NO signaling pathway, which have already been shown to be dysfunctional during disease. All of the aforementioned drugs are also sensitive to the oxidative environment in HFpEF, which may be preventing NO supplementation, sGC stimulation, and subsequent increases in the cGMP pool, which PDE5 inhibitors work to maintain. Figure produced using BioRender.com.