Cyclic nucleotide phosphodiesterase (PDE) are a regulatory hydrolase enzyme which play a crucial role in modulating the levels of second messengers, the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These messengers are involved in maintaining physiologic cardiac contractility and integrity, as well as mediating natriuretic peptides (NPs). To date, eleven different PDE families have been identified, categorized based on the homology of the amino acid sequence in their C-terminal catalytic domains, and distinguished by variations in their N-terminal regulatory regions.

In heart failure (HF), the expression and activity of multiple PDEs are altered, leading to disruptions in cyclic nucleoside levels and contributing cardiac dysfunction. PDE 3 inhibitors, such as milrinone, are used to increase intracellular cAMP content in cardiac muscle, exerting inotropic effects. While these drugs may be effective in acute settings, chronic therapy has been associated with increased morbidity and mortality compared with placebo in patients with HF. PDE5 inhibitors are most often used in the management of pulmonary artery hypertension, and have been studied for HF treatment due to their vasodilating and other pleiotropic effects, with potential benefits on cardiovascular function. However, in randomized trials, there was no clear hemodynamic or clinical benefit of treatment with PDE 5 inhibitor in HF patients.

PDE 9 inhibitors are currently being investigated for the treatment of not only HF but also non-HF conditions, such as obesity, hepatic fibrosis, Alzheimer’s disease, psychotic disorders, and sickle cell anemia. PDE9 has the highest affinity for cGMP and specific affinity for the NP-associated cGMP signaling pathway, unlike PDE5, which regulates the nitric oxide(NO)-associated cGMP pathway. Elevated levels of PDE9 have been observed in patients with HF and preclinical models of myocardial hypertrophy. Inhibition of PDE9 increases a signaling through the NP/cGMP pathway, which also can enhance the beneficial natriuretic, diuretic, arterial and venous vasodilatory, and antifibrotic effects of NP. This, in turn, has the potential to improve cardiac function and alleviate symptoms in HF patients.

Prior animal studies have shown that PDE9 inhibitors can elevate cGMP levels, reduce myocardial fibrosis, improve cardiac function, and decreased ventricular stiffness independently of NO activity, suggesting that these effects are mediated through the NP-cGMP pathway. These results indicated favorable effects on hemodynamics and renal function.

Consequently, there is growing interest in evaluating PDE9 inhibitors, particularly in HF. Studies involving a novel PDE9 inhibitor, tovinontrine, are being planned to assess the safety and efficacy of PDE9 inhibition in patients with HF with either preserved or reduced left ventricular ejection fraction. These studies are expected to provide more robust data regarding the potential benefits and risks of PDE9 inhibitors in HF patients. The results of ongoing and future clinical trials will be critical in determining whether PDE9 inhibitors can become an integral component of HF therapy.