Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides.
The autonomic nervous system, the renin-angiotensin-aldosterone system, and the natriuretic peptide system represent critical regulatory pathways in heart failure and as such have been the major targets of pharmacological development. The introduction and approval of angiotensin receptor neprilysin inhibitors (ARNi) have broadened the available drug treatments of patients with chronic heart failure with reduced ejection fraction. Neprilysin catalyses the degradation of a number of vasodilator peptides, including the natriuretic peptides, bradykinin, substance P, and adrenomedullin, as well as vasoconstrictor peptides, including endothelin-1 and angiotensin I and II. We review the multiple, potentially competing, substrates for neprilysin inhibition, and the resultant composite clinical effects of ARNi therapy. A mechanistic understanding of this novel therapeutic class may provide important insights into the expected on-target and off-target effects when this agent is more widely prescribed.
Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy.
Emilia
E
D'Elia
Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy.
Attilio
A
Iacovoni
Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School, Boston, MA, USA.
Muthiah
M
Vaduganathan
Anesthesiology Department, Hospital Papa Giovanni XXIII, Bergamo, Italy.
Ferdinando L
FL
Lorini
Internal Medicine Department, IRCCS Polyclinic San Matteo, University of Pavia, Pavia, Italy.
Stefano
S
Perlini
Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy.
Michele
M
Senni
D001341:Autonomic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D045265:Natriuretic Peptides / Q000378:metabolism*; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*
D045265:Natriuretic Peptides; D015260:Neprilysin
Biomarkers; Heart failure; Neprilysin; Neurohormonal activation; Pharmacology