Neurohormonal modulation: The new paradigm of pharmacological treatment of heart failure

Sacubitril/valsartan versus angiotensin inhibitors and arrhythmia endpoints in heart failure with reduced ejection fraction

“…17,19 Neprilysin inhibition also decreases cardiomyocyte hypertrophy by promoting increased levels of atrial natriuretic peptide and brain natriuretic peptide, which inhibit the angiotensin II and endothelin 1 that are responsible for cardiomyocyte and fibroblast growth. 20 With HF progression, both mechanical and electrical remodeling are observed in the cardiomyocytes. In a normal heart, the action potential depolarizes the L-type calcium channels at the T-tubules, promoting calcium entrance.…”

Angiotensin receptor blocker neprilysin inhibitors

“…Furthermore, another study conducted in Japan reported a 23.6%–26.2% HF readmission rate within one year after discharge for HF[ 15 ]. Overall, despite the underlying pathophysiological mechanisms of HF being well understood, the disease still has significant morbidity, with three-year mortality of 30% and five-year mortality of 50%[ 1 , 3 , 16 ].…”

“…In the 2014 PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial of 8399 outpatient subjects with HFrEF, SAC/VAL was found to be more effective than enalapril for slowing disease progression by decreasing the risk of worsening HF leading to the need for hospitalization or emergency admission and the need for intensified therapy; it also reduced the rates of 30-day HF readmission, as well as all-cause readmission after HF hospitalization, HF devices, or cardiac transplantation[ 24 , 31 , 37 ]. In addition, treatment with SAC/VAL was associated with statistically important reductions in cardiovascular death, a 16% reduction in all-cause mortality, and a 20% reduction in the composite of cardiovascular-related death or HF-related hospitalization (composite primary endpoint) compared to treatment with enalapril[ 16 , 26 , 33 , 37 , 47 , 48 , 50 - 52 ].…”

“…Accordingly, in 2016, the European and American cardiology societies (ACC/ AHA/Heart Failure Society of America) simultaneously issued a class I recommendation to replace ACEI with SAC/VAL for management of patients with HFrEF NYHA II-IV[ 4 , 16 , 26 , 33 , 48 , 50 , 52 ]. The results indicate that SAC/VAL should be started from the earliest symptomatic stages of the disease[ 31 , 37 ].…”

“…The association of an angiotensin II receptor antagonist and a neprilysin inhibitor is a new actor in HF management; recently, a newer pharmacotherapy, SAC/VAL, has become available for this purpose[ 3 , 24 ]. The stimulation of counter-regulatory systems, in addition to neurohormonal blockade, constitutes a new paradigm, known as “neurohormonal modulation,” and SAC/VAL is the first example of this new approach[ 3 , 8 , 16 , 19 ]. This new pharmacological class of ARNI has prompted a substantial conceptual change in HF treatment, with a transition from only inhibition of the RAAS and SNS, to a strategy built around concomitant pharmacological enhancement of endogenous NPs[ 11 ].…”