Pitfalls of therapies targeting the nitric oxide signaling pathway in heart failure with preserved ejection fraction

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  FIGURE 1.. Drug targets in the nitric oxide signaling pathway. By the conventional pathway, endothelial nitric oxide synthase (eNOS) produces nitric oxide—which may also be pharmacologically supplemented by nitrate or nitrite—in endothelial cells from substrates, l-arginine and oxygen. Nitric oxide diffuses to neighboring vascular smooth muscle or cardiac myocytes and binds its receptor, soluble guanylyl cyclase (sGC), to produce cyclic guanosine monophosphate (cGMP). cGMP activates protein kinase G (PKG), promoting signaling involved in smooth muscle relaxation and cardiac compliance and suppressing hypertrophic signaling in cardiac myocytes. To boost cGMP levels, sGC stimulators can be used as well as inhibitors of phosphodiesterase 5 (PDE5), which negatively regulates nitric oxide signaling by degrading cGMP. Figure produced using BioRender.com.

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  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)…