The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan

Figures

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  Figure 1. Neuro-hormonal interactions in heart failure and their role in contributing to the progression of heart failure. Heart failure activates the SNS and the RAAS, which leads to increased sympathetic tone and vasoconstriction, thereby increasing the afterload on the failing heart. RAAS activation leads to an increase in secretion of aldosterone and ADH causing fluid retention, edema, and fibrotic changes in the failing myocardium. Together, the SNS and the RAAS result in pathophysiological and clinical worsening of HF. ACEI, ARB, MRA, and BB reduce the effects of the RAAS and the SNS. The failing heart also activates the NPS, which promotes sodium and water excretion, vasodilatation, and decreased aldosterone secretion, and inhibits fibrotic changes in the failing myocardium. The effects of the NPS are antagonistic to those of the SNS and the RAAS. LCZ696 acts by augmenting the NPS and inhibiting the RAAS, thereby improving the symptoms and inhibiting the progression of HF NPS – natriuretic peptide system, RAAS – renin-angiotensin-aldosterone system, SNS – sympathetic nervous system, ACEI – angiotensin converting enzyme inhibitor, ARB – angiotensin receptor blocker, MRA –…

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  Figure 2. Physiological mechanisms behind the failure of lone neprilysin inhibition, and combined angiotensin converting enzyme – neprilysin inhibitors, as potential therapies in the management of heart failure. The beneficial effects of augmenting endogenous natriuretic peptides with NEPI were offset by the NEP-mediated enhancement of vasoconstrictor substances, especially AT-II, which enhanced the RAAS pathway. Bradykinin is inactivated by various enzymes including ACE, NEP, and APP, all of which are inhibited by omapatrilat. The synergism of ACE inhibition with NEP inhibition led to a large increase in the levels of bradykinin, thereby causing angioedema NPS – natriuretic peptide system, ANP – A-type natriuretic peptide, BNP – B-type natriuretic peptide, CNP – C-type natriuretic peptide, RAAS – renin-angiotensin-aldosterone system, AT-I – angiotensin I, AT-II – angiotensin II, NEP – neprilysin, ACE – angiotensin converting enzyme, APP – aminopeptidase P, ACEI – angiotensin converting enzyme inhibitor, NEPI – neprilysin inhibitor, “+” indicates increase/augmentation, “–” indicates inhibition, continuous line indicates direct action, dotted line indicates indirect action.