Why Your Heart's Natural Protective Peptides Stop Working in Heart Failure — and How Sacubitril/Valsartan Helps

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).

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.

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.

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.