Cardiology Letters 2021, 30(1):23-30

Dual inhibition of neprilysin and angiotensin II type 1 receptor in light of clinical studies

Baka T^{1, *}, Stanko P^{1, *}, Hrenák J^{1, 2}, Dukát A³, Šimko F^{1, 4, 5}

¹ Ústav patologickej fyziológie, Lekárska fakulta, Univerzita Komenského v Bratislave

² Department of Cardiovascular Surgery, Inselspital - University Hospital of Bern, Switzerland

³ V. interná kliniky, Lekárska fakulta a Univerzitná nemocnica, Univerzita Komenského v Bratislave

⁴ III. interná kliniky, Lekárska fakulta a Univerzitná nemocnica, Univerzita Komenského v Bratislave

⁵ Ústav experimentálnej endokrinológie, Biomedicínske centrum, Slovenská akadémia vied v Bratislave, Slovenská republika

^* Tomáš Baka a Peter Stanko prispeli k tejto práci rovnakou mierou, a preto zdieľajú prvoautorstvo

Despite advances in heart failure (HF) pharmacotherapy over the last three decades, the residual mortality with HF remains high. The antipode to the drug-induced inhibition of vasoconstrictive and proliferative substances could be an increase of vasodilative and antiproliferative humoral substances, including the natriuretic peptides (NPs). NPs are secreted by the distended myocardium and stimulate diuresis and vasodilation, exert antiproliferative effects, and inhibit both the sympathetic and renin-angiotensin systems (RAS). The proteolytic enzyme neprilysin cleaves NPs and thus limits their effects. However, this non-specific protease degrades a variety of other proteins, including angiotensin II (Ang II). Therefore, neprilysin inhibition increases the level of both NPs and Ang II. Sacubitril/valsartan, a representative of the new drug class: angiotensin receptor-neprilysin inhibitors (ARNi), contains one molecule of Ang II type 1 receptor blocker (valsartan) and one molecule of neprilysin inhibitor (sacubitril). The interaction of these substances, ensuing potential increase of NPs without RAS activation, brings an additive morbidity and mortality benefit in the management of HF with reduced ejection fraction (HFrEF), as compared to RAS inhibition alone. Yet, the hope for ARNi's benefit in HF with preserved ejection fraction (HFpEF) remains is unmet. Preliminary studies suggest a potential benefit by ARNi in hypertensive heart disease, kidney protection and post-myocardial infarction cardiac remodelling.

Keywords: natriuretic peptides; neprilysin; ARNi; sacubitril, valsartan; heart failure

Published: January 1, 2021  Show citation