Credit: Artville/Russell Thurston

It is thought that heart failure with preserved ejection fraction (HFPEF) could be treated by promoting intracellular signalling by the secondary messenger cyclic GMP, which has cardioprotective effects. However, blocking cGMP breakdown with the phosphodiesterase 5A (PDE5A) inhibitor sildenafil was not successful in clinical trials for HFPEF, despite showing preclinical promise. Kass and colleagues now provide an explanation for this observation, and show that inhibition of PDE9A could be more effective.

Increases in cGMP levels are triggered by two independent factors: nitric oxide (NO) and atrial natriuretic peptide (ANP). PDE5A hydrolyses NO-coupled cGMP, but NO signalling is downregulated in heart disease, which might help to explain the lack of efficacy of PDE5A inhibition. Which PDEs are responsible for degrading cGMP resulting from ANP stimulation was not clear, and so the authors investigated the activity of the other cGMP-selective PDE, PDE9A, in the heart.

The authors found that PDE9A was expressed in myocardial tissue from mice and from humans, and was increased in the myocardium of patients with various forms of heart failure, especially HFPEF. Interestingly, PDE9A and PDE5A were localized in different compartments of the sarcomere in myocytes, suggesting that they may have distinct functions.

To determine how the function of PDE9A might differ to that of PDE5A, the authors measured levels of cGMP in rat neonatal cardiomyocytes (RNCMs) that expressed a fluorescent cGMP indicator. cGMP levels increased in RNCMs stimulated with ANP or an NO donor. Interestingly, after stimulation with ANP, but not after stimulation with the NO donor, cGMP levels were further increased by the selective PDE9A antagonist PF-9613, indicating that PDE9A degrades ANP-dependent cGMP but not NO-dependent cGMP.

In the transverse aortic constriction (TAC) model of heart failure, Pde9a−/− mice showed less cardiac hypertrophy, lower expression of genes associated with myocardial pathology and better ventricular function at 3 weeks after TAC surgery than did wild-type TAC controls. Wild-type TAC mice exhibited heart hypertrophy and ventricular dysfunction 8 days after the surgery, and these symptoms were improved by 4 weeks of treatment with PF-9613 or the selective PDE5A antagonist sildenafil.

PDE5A and PDE9A target cGMP in the NO- and ANP-signalling pathways, respectively

However, TAC mice given the NO synthase inhibitor L-NAME — to mimic the clinical scenario in HFPEF in which NO production is suppressed — showed improvements in heart function and increases in myocardial cGMP levels and downstream PKG activity only in response to PF-9613, and not sildenafil. Together, these findings confirm that PDE5A and PDE9A target cGMP in the NO- and ANP-signalling pathways, respectively.

Overall, this study shows that PDE9A, unlike PDE5A, specifically hydrolyses NO-independent, ANP-coupled cGMP. So, selective PDE9A inhibitors such as PF-9613 could have greater effectiveness than PDE5A inhibitors for treating cases of HFPEF in which NO production is lower.