Bioactive Signaling in Next-Generation Pharmacotherapies for Heart Failure: A Review

Importance: The standard pharmacotherapy for heart failure (HF), particularly HF with reduced ejection fraction (HFrEF), is primarily through the use of receptor antagonists, notably inhibition of the renin-angiotensin system by either angiotensin-converting enzyme inhibition or angiotensin II receptor blockade (ARB). However, the completed Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial identified that the use of a single molecule (sacubitril/valsartan), which is an ARB and the neutral endopeptidase inhibitor (NEPi) neprilysin, yielded improved clinical outcomes in HFrEF compared with angiotensin-converting enzyme inhibition alone. Observations: This review examined specific bioactive signaling pathways that would be potentiated by NEPi and how these would affect key cardiovascular processes relevant to HFrEF. It also addressed potential additive/synergistic effects of ARB. A number of biological signaling pathways that may be potentiated by sacubitril/valsartan were identified, including some novel candidate molecules, which will act in a synergistic manner to favorably alter the natural history of HFrEF. Conclusions and Relevance: This review identified that activation rather than inhibition of specific receptor pathways provided favorable cardiovascular effects that cannot be achieved by renin-angiotensin system inhibition alone. Thus, an entirely new avenue of translational and clinical research lies ahead in which HF pharmacotherapies will move beyond receptor antagonist strategies.