ARNIs: balancing “the good and the bad” of neuroendocrine response to HF

Background A new class of drugs—angiotensin receptor, neprylisin inhibitors, ARNI—has shown to be prognostic superior in HFrEF to the sole inhibition of the renin–angiotensin axes with enalapril. The ultimate mechanism of action of ARNIs is unknown. Aim We have considered that ARNI exerts a positive modulation of the neuroendocrine balance, with enhancement of the physiological diuresis and dilatation due to neprylisin inhibition by sacubitril. This represents a shift in HF medical therapy always directed to counteract (with inhibitors of the renin–angiotensin system, beta blockers or inhibitors of aldosterone) the so-called “bad” neuroendocrine response. Development of ARNI, on the contrary, has led to consider the neuroendocrine response to HFrEF from a different angle, which is to say that the activation is not always deleterious, but it could also be beneficial. This concept is highlighted by the enhancement of the activity of atrial natriuretic peptide, induced by sacubitril/valsartan in the PARADIGM trial, and found as proof from early studies on untreated patients with constrictive pericarditis. The possibility that sacubitril inhibition of neprylisin acts by enhancing substance P and gene-related calcitonin peptide is also considered, as well as the negative effect of neprylisin inhibition. Conclusions The beneficial effects of ARNI are related, in part at least, to a positive modulation of the neuroendocrine response to the disease, resulting in an increase of physiological diuresis and dilatation.