This review explains why natriuretic peptides — the heart's natural defense against fluid overload — become ineffective as heart failure progresses, and why sacubitril/valsartan works by restoring their function.
3 reasons NPs failReduced active BNP, diminished organ response, and overwhelming counter-regulatory hormones explain why the heart's protective peptides stop working in advanced failure
What the researchers found
The review identifies three major mechanisms for natriuretic peptide system failure in chronic heart failure: (1) reduced availability of biologically active BNP due to increased processing into inactive forms, (2) diminished target organ responsiveness to NPs, and (3) overstimulation of counter-regulatory systems (RAAS, sympathetic nervous system, and endothelin-1) that overpower NP effects.
Sacubitril/valsartan addresses this by simultaneously inhibiting neprilysin (the enzyme that degrades NPs) and blocking angiotensin receptors (countering RAAS activation). Clinical data show this combination increases NP levels and their intracellular mediator cGMP, suggesting genuine restoration of NP system effectiveness — translating into reduced mortality and morbidity.
Why it matters
Heart failure affects over 60 million people worldwide and remains a leading cause of death. Understanding why the body's own protective peptide system fails in advanced heart failure is crucial for developing better treatments. This review provides the mechanistic rationale for sacubitril/valsartan (Entresto), which has become a standard-of-care treatment — explaining not just that it works, but why it works at the peptide level.
How the study worked
This is a narrative review synthesizing evidence from clinical studies of exogenous NP administration in heart failure patients, mechanistic research on NP metabolism and receptor function, and clinical trial data on neprilysin inhibitors and sacubitril/valsartan (particularly the PARADIGM-HF trial).
What this study cannot tell us
As a single-author narrative review, there is no systematic search methodology or formal quality assessment of cited studies. The review was published in 2017, before long-term real-world data on sacubitril/valsartan fully matured. Some of the mechanistic explanations for NP system failure remain partially theoretical, particularly regarding BNP processing abnormalities.
How to read the evidence
This is a narrative review by a single expert author, synthesizing clinical and preclinical evidence. While it draws on data from major RCTs (including PARADIGM-HF), the review itself does not generate new evidence or use systematic methodology.
When this study was published
Published in 2017 in the European Journal of Heart Failure. The core mechanistic concepts remain valid, though sacubitril/valsartan now has substantially more real-world outcome data supporting its use.
The bigger picture
The natriuretic peptide system is one of the body's most important cardiovascular defense mechanisms, but heart failure essentially overwhelms it. The success of sacubitril/valsartan has validated the concept of 'neurohormonal rebalancing' — rather than just blocking harmful systems (RAAS, SNS), modern heart failure treatment also enhances protective ones (NPS). This dual approach represents a paradigm shift in how cardiologists think about heart failure therapy.
Questions still open
- Could even more effective ways to boost natriuretic peptide signaling further improve heart failure outcomes beyond what sacubitril/valsartan achieves?
- At what stage of heart failure does the natriuretic peptide system become irreversibly impaired?
- Would combining NP system enhancement with newer therapies like SGLT2 inhibitors produce additive cardiovascular protection?
Common questions
What are natriuretic peptides and why do they matter in heart failure?
How does sacubitril/valsartan help restore natriuretic peptide function?
Read the original research
Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy.
European journal of heart failure, 19(2), 167-176
Citation
Díez, Javier. (2017). Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy.. European journal of heart failure, 19(2), 167-176. https://doi.org/10.1002/ejhf.656