Augmentation of natriuretic peptide (NP) receptor A and B (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) signalling as a therapeutic strategy in heart failure

ABSTRACT

Introduction

Heart failure is a complex, debilitating condition and despite advances in treatment, it remains a significant cause of morbidity and mortality worldwide. Therefore, the need for alternative treatment strategies is essential. In this review, we explore the therapeutic strategies of augmenting natriuretic peptide receptors (NPR-A and NPR-B) and cyclic guanosine monophosphate (cGMP) in heart failure.

Areas covered

We aim to provide an overview of the evidence of preclinical and clinical studies on novel heart failure treatment strategies. Papers collected in this review have been filtered and screened following PubMed searches. This includes epigenetics, modulating enzyme activity in natriuretic peptide (NP) synthesis, gene therapy, modulation of downstream signaling by augmenting soluble guanylate cyclase (sGC) and phosphodiesterase (PDE) inhibition, nitrates, c-GMP-dependent protein kinase, synthetic and designer NP and RNA therapy.

Expert opinion

The novel treatment strategies mentioned above have shown great potential, however, large randomized controlled trials are still lacking. The biggest challenge is translating the results seen in preclinical trials into clinical trials. We recommend a multi-disciplinary team approach with cardiologists, geneticist, pharmacologists, bioengineers, researchers, regulators, and patients to improve heart failure outcomes. Future management can involve telemedicine, remote monitoring, and artificial intelligence to optimize patient care.

KEYWORDS:

• Natriuretic peptide
• cyclic guanosine monophosphate
• heart failure
• epigenetic
• downstream signaling
• gene therapy
• RNA based therapy
• modulating enzyme activity

Article highlights

• Heart failure is a complex syndrome modulated by angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), and natriuretic peptide system (NPS).

• Despite advances in heart failure treatment, the prognosis of heart failure remains poor.

• Novel therapies are being developed to target natriuretic peptide receptors (NPR-A and NPR-B) and cGMP.

• Epigenetics involve modulating chromatin and the use of histone deacetylase (HDAC) inhibitor has shown to improve NPR1 promoter levels and cGMP in preclinical studies

• Modulating enzyme activity is mainly by targeting neprilysin, corin and endothelin converting enzyme.

• Gene therapy using viral vectors has shown to be beneficial in pre-clinical studies to improve cardiac function and survival, however the results could not be translated into clinical practice (CUPID-2 trial).

• Modulating downstream signaling with sGC simulators and phosphodiesterase inhibitors helps to increase cGMP. Vericiguat, a sGC stimulator has shown benefit in the VICTORIA study and is approved in the treatment for HFrEF.

• Three main designer NPs have moved from preclinical study into clinical trials: Cenderitide, MANP and ANX042.

• RNA therapy lacks clinical trials but has shown improvement of cardiac function in animal models.

• Moving from preclinical studies to clinical application is challenging as several treatments that were promising in preclinical trials do not always translate in human patients.

• Future of heart failure treatment is promising with the development of these novel treatment agents.

Declarations of interest

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.