Neprilysin: Function and Role in Heart Failure
Neprilysin is a zinc-dependent metalloprotease that inactivates several vasoactive peptides crucial in heart failure pathophysiology, including natriuretic peptides, adrenomedullin, bradykinin, and substance P. 1
Structure and Function
Neprilysin, also known as neutral endopeptidase, is an integral membrane-bound enzyme with widespread distribution throughout the body. Its primary function involves the enzymatic breakdown of multiple biologically active peptides that play important roles in:
- Cardiovascular regulation
- Renal function
- Neurological processes
- Immune response
- Cell proliferation
The enzyme has over 50 potential peptide substrates, making it remarkably versatile in its biological effects 2. Its activity is particularly important in the heart failure setting, where it contributes to the degradation of beneficial peptides that would otherwise promote vasodilation, natriuresis, and other compensatory responses.
Role in Heart Failure Pathophysiology
In heart failure, neprilysin's degradation of natriuretic peptides is especially significant because:
- It reduces the beneficial effects of endogenous natriuretic peptides that would promote vasodilation and sodium excretion
- It contributes to fluid retention and vasoconstriction
- It limits the body's natural compensatory mechanisms against heart failure progression
Importantly, angiotensin II is also a substrate for neprilysin, which explains why neprilysin inhibitors are combined with angiotensin receptor blockers (ARBs) rather than ACE inhibitors 1. This combination prevents the undesirable increase in angiotensin II levels that would occur with neprilysin inhibition alone.
Clinical Applications: Angiotensin Receptor-Neprilysin Inhibitors (ARNIs)
The understanding of neprilysin's role led to the development of ARNIs, which combine:
- Sacubitril - a neprilysin inhibitor (prodrug converted to active metabolite LBQ657)
- Valsartan - an angiotensin receptor blocker
This combination:
- Increases levels of beneficial peptides degraded by neprilysin
- Blocks the harmful effects of angiotensin II
- Provides superior outcomes compared to ACE inhibitors alone in heart failure with reduced ejection fraction (HFrEF)
The cardiovascular and renal effects of ARNIs are attributed to increased levels of peptides that would normally be degraded by neprilysin, combined with simultaneous inhibition of angiotensin II effects 3.
Important Clinical Considerations
When using ARNIs in clinical practice, several precautions must be observed:
- Never combine with ACE inhibitors due to increased risk of angioedema 1
- Must wait 36 hours after discontinuing ACE inhibitors before starting an ARNI 1
- Contraindicated in patients with history of angioedema 1
- Associated with hypotension as a common side effect 1
Biomarker Effects
ARNIs have notable effects on cardiac biomarkers:
- Decrease NT-proBNP levels (not a neprilysin substrate)
- Increase BNP levels (a neprilysin substrate) due to reduced degradation
- Increase urinary cGMP levels 3
These biomarker changes can complicate the interpretation of BNP levels in patients on ARNI therapy, making NT-proBNP the preferred biomarker for monitoring these patients 1.
Limitations and Future Directions
Despite the benefits of neprilysin inhibition in heart failure with reduced ejection fraction, studies have shown limitations:
- Less effective in advanced heart failure
- No significant benefit in post-myocardial infarction patients without established heart failure 4
- Potential long-term effects on albuminuria, glycemic control, and cognitive function require further study
The complex and widespread actions of neprilysin throughout multiple body systems suggest that our understanding of its full therapeutic potential and possible adverse effects continues to evolve.