Impact of prolonged utilization of neprilysin inhibition on the cognitive function of heart failure patients

One of the most important pharmacological therapies in patients with chronic heart failure and reduced ejection fraction (HFrEF) is to administer agents that modulate the renin–angiotensin–aldosterone system (RAAS), such as angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs) and mineralocorticoid antagonists (MRAs). These drugs limit the effects of hormones that cause the body to constrict blood vessels as well as to retain sodium. On the other hand, vasoactive substances such as bradykinin and adrenomedullin, counteract vasoconstriction by promoting vasodilation of blood vessels. Neprilysin, formerly called neutral endopeptidase (NEP), is a circulating protease that is responsible for the breakdown of these vasoactive peptides including natriuretic peptides (NPs), neuropeptides (e.g. substance P, enkephalins) and the amyloid-β (Aβ) peptides.1,2 Due to these degradation properties, NEP has emerged as a pharmaceutical target of interest in the management of cardiovascular disease (CVD) and Alzheimer’s disease (AD). It has been hypothesized that inhibiting NEP may elevate levels of these beneficial peptides and thus counteract systemic overactivity which generally leads to heart failure (HF) symptoms.