Plasma Neprilysin Concentrations: A New Prognostic Marker in Heart Failure?

Abstract

Neprilysin, also known as neutral endopeptidase (NEP), endopeptidase 24.11, CD10, enkephalinase, and common acute lymphoblastic leukemia antigen (CALLA), is a membrane-bound metalloendopeptidase (EC 3.4.24.11) that has recently sprung to renewed prominence as a target in cardiovascular therapeutics. Numbered among the many substrates to NEP are multiple vasoactive peptides, including the cardiac natriuretic peptides, with important roles in regulating pressure and volume status in health and disease. In the 1990s, NEP inhibitors were combined with angiotensin converting enzyme inhibitor (ACEI) therapy with the hope of adding the expected multifaceted benefits of enhanced plasma and tissue natriuretic peptide levels to the proven benefits of ACEI-related suppression of adverse renin-angiotensin-aldosterone system activation. After initial promise from trials in hypertension and heart failure, drug development was halted due to an unacceptable incidence of angioneurotic edema. The current renewed interest in NEP reflects the recent success of a new combination, that of inhibition of NEP plus angiotensin II type 1 receptor blockade. The PARADIGM trial tested the NEP inhibitor sacubitril combined with the angiotensin receptor blocker valsartan (LCZ696) in chronic heart failure with reduced ejection fraction. The new treatment was significantly beneficial with respect to all important clinical endpoints and was associated with no excess of important adverse effects and in fact caused less renal failure and hyperkalemia than established evidence-based treatment with the ACEI enalapril. The results point to this strategy being the greatest advance in the pharmacotherapy of chronic heart failure in the last 20 years. In addition to its widespread tissue-based, membrane-bound form, NEP exists in a circulating nonbound form that retains catalytic activity. In the article published in Revista Espanola de Cardiologia, Bayes-Genis et al build on previous work to confirm their original finding that plasma NEP concentrations have