Neprilysin Inhibitors as a New Approach in the Treatment of Right Heart Failure in the Course of Chronic Obstructive Pulmonary Disease

Abstract

The aim of the study was to find out scientific evidence on the possible use of the combined angiotensin II receptor antagonist and neprilysin inhibitors (ARNI) in patients with right heart failure (RHF) in the course of chronic obstructive pulmonary disease (COPD). It has been proven that a lack of neprilysin or its reduced expression in hypoxia leads to exacerbation of pulmonary arterial remodelling (PAR) or pulmonary hypertension (PH) in the mechanism related to the platelet-derived growth factor (PDGF) resulting in the proliferation and migration of pulmonary artery smooth muscle cells and endothelial-to-mesenchymal transition. Such action in the course of COPD can lead to RHF, which would signify noxious effect of this group of drugs. However, the inhibition of neprilysin also inhibits natriuretic peptide metabolism. The representative of this group - brain natriuretic peptide (BNP) - acts as a vasodilator and also exerts an anti-proliferative activity through the cGMP-dependent protein kinase G pathway. Additionally, it causes bronchodilation by inducing the release of acetylcholine from bronchial epithelial cells. This suggests that natriuretic peptides may appear to be a potential treatment agent in patients with cardiac complications and COPD. Their effects associated with the immunosuppression capacity by reducing the release of inflammatory mediators - IL-6, IL-1β, and TNF-α can bring benefits to patients with acute lung injury caused by pulmonary inflammation during COPD exacerbations. Considering the potentially positive effect of natriuretic peptides in this group of patients, further research is required in this area, which can provide strong scientific data demonstrating the need for introducing ARNI drugs to the treatment of patients with COPD.

Acute pulmonary pressure change after transition to sacubitril/valsartan in patients with heart failure reduced ejection fraction

“…Natriuretic peptides are secreted and degraded in the lungs, and a number of studies have shown that their concentration is increased in the setting of PH. 12 In a study using a rodent model of hypoxemia-induced PH, sacubitril/valsartan was shown to significantly reduce right ventricular pressure and right ventricular dilatation. 13 Zern et al described five inotrope-dependent HFrEF patients listed for heart transplant in whom sacubitril/valsartan initiation resulted in reduced PVR within 24 h. 14 A proof of concept trial of acute neprilysin inhibition for PAH demonstrated a swift 14% fall in PVR.…”

Additive protective effects of sacubitril/valsartan and bosentan on vascular remodelling in experimental pulmonary hypertension

“…In contrast to our results obtained in adult rats with the combined use of a neprilysin inhibitor and an angiotensin receptor blocker, mice deficient in neprilysin from birth are more prone to remodel their pulmonary vessels in response to chronic hypoxia compared to their littermate controls 28 . While some of this difference could be explained by interspecies differences, or by the effects of knockout versus pharmacological inhibition, the pleiotropic functions of ANP and other natriuretic peptides in the heart and in the vascular system that are independent of blood pressure regulation could also explain this discrepancy 29 .…”

Neprilysin Inhibitors as a New Approach in the Treatment of Right Heart Failure in the Course of Chronic Obstructive Pulmonary Disease. Response to the Letter of Siniorakis et al.

“…Therefore, there is a reasonable concern that neprilysin inhibitors may increase the level of bradykinin in the lungs and exacerbate symptoms in patients suffering from asthma or COPD. On the other hand, neutral endopeptidase 24.11 causes an increase in the level of natriuretic peptides having bronchodilatory and immunosuppressive properties, which could lessen the effect of bradykinin action [5]. Moreover, there are studies suggesting that natriuretic peptides, as natural antagonists of B 2 R signaling pathway may decrease the harmful consequences of BK activity [6].…”