How Stress Hormone Systems Drive Heart Failure Progression and How Peptide Biomarkers Guide Treatment | Research

The takeaway

Sustained activation of the sympathetic nervous system, renin-angiotensin system, and vasopressin system drives heart failure progression, while natriuretic peptides serve as both biomarkers and therapeutic targets.

3 neurohormonal systems drive HF
The sympathetic nervous system, renin-angiotensin-aldosterone system, and vasopressin system become chronically overactive in heart failure, worsening the disease they were meant to compensate for

What the researchers found

Sustained neurohumoral activation involving the sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), and arginine vasopressin system drives the progression of heart failure through tachycardia and increased vascular resistance.

Natriuretic peptides and catecholamines serve as biomarkers for these pathways and can help identify which patients will benefit from specific therapies. The introduction of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor, or ARNI) represents a refinement in RAAS blockade by combining RAAS inhibition with enhanced natriuretic peptide activity through neprilysin blocking.

Why it matters

Understanding why the body's own stress responses worsen heart failure is fundamental to modern cardiology. Every major class of heart failure drug — beta blockers, ACE inhibitors, ARBs, mineralocorticoid antagonists, and the newer ARNI sacubitril/valsartan — works by blocking one of these overactive neurohormonal pathways. Natriuretic peptides occupy a dual role as both diagnostic tools and therapeutic targets, making them central to personalized heart failure management.

How the study worked

This is a comprehensive narrative review examining the neurohumoral pathways activated in heart failure, their biomarkers, and the therapies directed against them. The review synthesizes published literature on the sympathetic nervous system, RAAS, vasopressin system, natriuretic peptides, and their roles in heart failure pathophysiology and treatment. Key mechanisms are illustrated pictorially.

What this study cannot tell us

As a narrative review, this paper synthesizes existing knowledge rather than presenting new data. The review covers well-established concepts alongside newer developments, and study selection reflects the authors' perspective. Some emerging neurohormonal targets and newer drugs may not be fully covered. The review focuses on pathophysiology and pharmacology rather than clinical trial outcomes.

How to read the evidence

This is a narrative review summarizing established pathophysiology and current treatment paradigms. The concepts are well-supported by decades of clinical trial evidence, but the review itself does not present new primary data.

When this study was published

Published in 2023, this review is current and includes discussion of sacubitril/valsartan and newer biomarker approaches. The underlying pathophysiology it describes has been well-established for decades.

The bigger picture

This review provides the mechanistic foundation for understanding why modern heart failure therapy is fundamentally about neurohormonal antagonism. The evolution from individual pathway blocking (beta blockers, ACE inhibitors) to multi-pathway approaches (ARNI) reflects decades of understanding how these systems interact. The natriuretic peptide system in particular has become central to both diagnosis (BNP and NT-proBNP blood tests) and treatment (neprilysin inhibition), making peptides one of the most important biomolecule classes in heart failure care.

Questions still open

Can natriuretic peptide levels be used to more precisely tailor heart failure drug regimens to individual patients?
Are there additional neurohormonal pathways beyond the classic three (SNS, RAAS, AVP) that represent viable therapeutic targets?
How do GLP-1 receptor agonists, which are showing cardiovascular benefits, interact with these established neurohormonal pathways in heart failure?

Common questions

What are natriuretic peptides and why are they important in heart failure?

Natriuretic peptides (BNP and ANP) are hormones released by the heart when it's under stress. They help the body get rid of excess salt and water and relax blood vessels. In heart failure, their levels rise as the heart struggles, making them useful blood test markers for diagnosis and monitoring. The drug sacubitril works by preventing their breakdown, enhancing their beneficial effects.

Why do the body's protective stress responses make heart failure worse?

When the heart weakens, the body activates emergency systems — speeding up the heart, constricting blood vessels, and retaining fluid — to maintain blood pressure. Short-term, this helps. But long-term, these responses overwork the already struggling heart, cause further damage, and trap the body in a vicious cycle. Heart failure drugs break this cycle by blocking these overactive systems.

Read the original research

Neurohumoral Activation in Heart Failure.

International journal of molecular sciences, 24(20)

View on PubMed ↗Publisher’s paper ↗

Citation

Manolis, Antonis A; Manolis, Theodora A; Manolis, Antonis S. (2023). Neurohumoral Activation in Heart Failure.. International journal of molecular sciences, 24(20). https://doi.org/10.3390/ijms242015472