Angiotensin-Neprilysin Inhibition Strategies in Heart Failure Management

Heart failure remains a leading cause of morbidity and mortality worldwide, driven by maladaptive neurohormonal activation and adverse myocardial remodelling. Dual inhibition of the renin-angiotensin system and neprilysin offers a novel approach by simultaneously blocking angiotensin II–mediated vasoconstriction, sodium retention and fibrosis, while preserving beneficial natriuretic peptides that promote vasodilation, natriuresis and inhibition of hypertrophy. The prototypical agent in this class combines an angiotensin receptor blocker with a neprilysin inhibitor, creating synergistic effects on haemodynamics, neurohormonal balance and tissue remodelling. Clinical adoption has accelerated following trials demonstrating superior reductions in cardiovascular death and hospitalisation compared with standard therapy. Ongoing studies continue to refine patient selection, optimal timing of initiation and long-term effects on cardiac structure, renal function and exercise capacity.

Research from Nature Portfolio

Experimental studies in post-infarction heart failure models have delineated how combined angiotensin receptor and neprilysin inhibition exerts multi-compartment benefits. In rodent infarction experiments, dual inhibition limited left ventricular dilation more effectively than angiotensin blockade alone, prevented interstitial fibrosis in remote myocardium and reduced cardiomyocyte hypertrophy in border zones. Notably, the therapy promoted early angiogenesis within the infarct, improving perfusion as detected by advanced imaging tracers. These mechanistic insights underpin the pronounced improvements in global left ventricular function observed clinically and strengthen the rationale for targeting both pathways in concert.

Angiotensin-Neprilysin Inhibition Strategies in Heart Failure Management publication trend

The graph below shows the total number of articles in angiotensin-neprilysin inhibition strategies in heart failure management across all publications each year (not limited to Nature Index journals).

Technical terms

Neprilysin: A ubiquitous endopeptidase responsible for degrading natriuretic peptides, bradykinin and other vasoactive substances.

Natriuretic peptides: Hormones released by the heart under stress that induce vasodilation, natriuresis and inhibition of cardiac remodelling.

Renin-angiotensin-aldosterone system: A hormonal cascade that regulates blood pressure and fluid balance, often overactivated in heart failure.

Angiotensin receptor-neprilysin inhibitor: A dual-action therapeutic combining blockade of angiotensin II receptors with inhibition of neprilysin to enhance natriuretic peptide activity.

Reverse remodelling: Structural improvements in myocardial geometry and function, including reductions in chamber size and fibrotic burden.

References

1. Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction. Circulation (2021).
2. Sacubitril/Valsartan Induces Global Cardiac Reverse Remodeling in Long-Lasting Heart Failure with Reduced Ejection Fraction: Standard and Advanced Echocardiographic Evidences. Journal of Clinical Medicine (2020).
3. Angiotensin Receptor Neprilysin Inhibitor Attenuates Myocardial Remodeling and Improves Infarct Perfusion in Experimental Heart Failure. Scientific Reports (2019).