The role of phosphodiesterase 9A inhibitors in heart failure

ABSTRACT

Introduction

There are currently limited effective treatments available to improve lusitropy in patients suffering from heart failure with preserved ejection fraction. The role of PDE9A in diastolic dysfunction has been well-studied over recent years, with a special focus on its association with myocardial hypertrophy. Recent insights into PDE9A inhibition have brought to light the potential for reversal of cardiac remodeling, with multiple studies showing promising results in preclinical data.

Areas covered

This expert opinion provides an overview of the role of PDE9A in diastolic heart dysfunction along with the efficacy of PDE9A inhibitors in laboratory models of heart failure with preserved ejection fraction.

Expert opinion

The available data on PDE9A inhibition in preclinical studies suggest that there is potential for reversal of diastolic dysfunction and myocardial hypertrophy, however, conflicting data suggests that further studies are required before progressing to clinical trials.

KEYWORDS:

• cGMP
• diastolic dysfunction
• HFpEF
• heart failure with preserved ejection fraction
• myocardium
• PDE9A inhibition

Article highlights

• Phosphodiesterases (PDEs) are a diverse family of enzymes involved in hydrolyzing phosphodiester bonds in cGMP and cAMP.

• With over 100 isoforms across 11 families, PDE inhibitors targeting specific isoforms like PDE3 and PDE5 are established treatments for heart failure and pulmonary hypertension.

• PDE9A differs from PDE5A via a NO-independent mechanism mediated by natriuretic peptide and is upregulated in cardiac hypertrophy.

• Mouse models treated with PF-9613, a selective PDE9A inhibitor, showed significant reversal of cardiac hypertrophy.

• Various studies using novel PDE9A inhibitors such as C33(S), CRD-733, and PF04447943 demonstrate promising results in preventing hypertrophy, reversing cardiac remodeling, and improving hemodynamics.

• PDE9A inhibition showcases potential benefits, including reduced LV stiffness, improved endothelial and cardiomyocyte function, and restoration of natriuretic peptide activity.

• Some studies, like Methawasin’s, present conflicting evidence regarding PDE9A inhibition, suggesting potential limitations due to impairment of systolic function with chronic usage.

• Blanton’s response acknowledges limitations but suggests a longer duration of PDE9A inhibition might yield more encouraging results.

• PDE9A inhibition in HFpEF treatment is an emerging field with increasingly growing preclinical support, showcasing potential for future clinical trials.

• Current evidence highlights the urgent need for therapies in HFpEF, as no existing medications reduce mortality, emphasizing the significance of further research in potentially reversing cardiac remodeling and improving patient outcomes.

Declaration of interest

GM Lanier is associated with the Merck Speakers’ Bureau. This disclosure is made in accordance with the journal’s policy on conflicts of interest. We wish to emphasize that this association does not influence the content or findings presented in the manuscript, and we are committed to maintaining the highest standards of transparency and integrity.

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.