Heart Failure With Reduced Ejection Fraction Is Characterized by Systemic NEP Downregulation

Area of Science:

• Biochemistry
• Cardiology
• Physiology

Background:

• Neprilysin (NEP) plays a role in cardiovascular regulation.
• Understanding NEP's role in chronic heart failure (HF) is crucial for developing targeted therapies.
• Current therapeutic strategies involving NEP inhibition lack a complete understanding of the enzyme's systemic regulation.

Purpose of the Study:

• To investigate the regulation of neprilysin (NEP) in a translational porcine model of chronic heart failure (HF).
• To elucidate the role of different organs, particularly the kidneys, in systemic NEP regulation under HF conditions.
• To assess the potential of plasma NEP concentrations and activity as biomarkers for HF.

Main Methods:

• Utilized a translational porcine model to simulate chronic heart failure.
• Quantified NEP content and activity across various organs.
• Measured plasma NEP concentrations and activity in the context of HF.

Main Results:

• Kidneys exhibit significantly higher NEP content and/or activity (20-100x) compared to other organs, suggesting a pivotal role in systemic NEP regulation.
• NEP expression and/or activity were found to be downregulated under chronic heart failure conditions.
• Plasma NEP concentrations and activity showed questionable value as reliable biomarkers for HF.

Conclusions:

• The kidneys are identified as a major contributor to systemic neprilysin regulation.
• Neprilysin activity is diminished in the pathophysiology of chronic heart failure.
• The findings provide foundational insights into HF-related alterations of the NEP system and aid in understanding the mechanism of action for angiotensin-receptor neprilysin-inhibitors.