Natriuretic Peptides and Volume Handling in Heart Failure: The Paradigm of a New Treatment

This article refers to ‘Chronic subcutaneous brain natriuretic peptide therapy in asymptomatic systolic heart failure’†, by PM McKie et al., published in this issue on pages 433–441. Despite recent advances in the treatment of heart failure (HF), its morbidity and mortality remain unacceptably high. Indeed, HF continues to represent the most common cause of hospitalization and the 5-year mortality is still approximately 50%—worse than that of many cancers.1, 2 The reasons for this trend are largely linked to ageing of the population, survival after myocardial infarction, and the long-term effects of hypertension. At the same time, the standard medical therapy for HF aimed at antagonizing the renin–angiotensin–aldosterone system (RAAS), through angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and mineralocorticoid receptor antagonists, and inhibiting the sympathetic nervous system (SNS) through β-blockers, may be insufficient to target all neurohormonal abnormalities that contribute to pathophysiological dysregulation and disease progression. Since its discovery more than 30 years ago, the natriuretic peptide (NP) system has been viewed as a potentially therapeutic tool for a better management of HF. The NP system is, in fact, intimately involved in cardiorenal homeostasis in health, and its dysregulation appears to play an important role in the pathophysiology of HF.3, 4 Natriuretic peptides, acting mostly through the NP receptors linked to the guanylate cyclase pathway with the production of cyclic guanosine monophosphate (cGMP), can induce a balanced vasodilation, decreasing preload and afterload when cardiac function is impaired. Furthermore, they promote the renal excretion of salt and water and reduce renal renin secretion and aldosterone production in both the heart and adrenal cortex, thus qualifying as an ideal counter-regulatory hormone, designed to antagonize the effects of the RAAS and the SNS under conditions of volume overload and cardiac load mismatch and remodelling.5 The importance of these NP-related compensatory actions in slowing the progression of HF has been suggested by experimental studies demonstrating that transition from asymptomatic left ventricular dysfunction to severe chronic HF can be accelerated using NP receptor antagonists. In a canine model of early left ventricular dysfunction, pharmacological inhibition of the NP receptor resulted in activation of the RAAS, premature sodium retention, impaired renal response to volume expansion, and further increases in cardiac filling pressures.6 Based on this and other evidence,3, 4 HF has also been regarded as a state of NP deficiency, in which NP overproduction by myocytes is an insufficient response overridden by the activation of RAAS and SNS. Plasma levels of ANP and BNP are indeed markedly elevated in HF and positively correlated with the severity of the disease. Moreover, it is also known that a large proportion of measured ANP and BNP in HF patients is biologically inactive, being unable to bind cGMP linked receptors and activate the intracellular signalling pathway.7 In both symptomatic and asymptomatic HF it has been demonstrated that impairment of the NP system in response to acute volume overload or chronic salt loading is associated with blunted natriuretic, vasodilator and RAAS-suppressing actions.8, 9 This abnormal hormonal response is supposed to have a role in the progression of sodium retention and vasoconstriction in HF. It is attractive to note that pretreatment with ACE inhibitors may partly restore the ANP secretagogue response to volume expansion in patients with asymptomatic HF8 and that pretreatment with an ARB may preserve the natriuretic and renal vasodilating capacity of ANP in the same patients.10 The fact that the NP system plays a favourable role in HF, counteracting the adverse effects of sodium-retaining and vasoconstrictive hormonal systems, provides a rationale for the use of these peptides as a therapeutic tool. The first strategy was based on exogenous NP or NP analogue administration. In 2001, exogenous BNP (nesiritide) was approved by the Food and Drug Administration (FDA) for intravenous administration in the treatment of patients with acute decompensated congestive HF, as it was demonstrated that it provides arterial and venous dilation. This produces a significant reduction in both cardiac preload and afterload, and a consequent improvement of clinical symptoms. However, subsequent reports of an increased risk of worsening renal function and death compared with control therapy raised doubts on the safety of this approach.11 Moreover, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial showed that nesiritide does not, however, improve mortality or hospital readmission rates in the absence of untoward effects on renal function.12 Based on these results and on those of the renal optimization strategies evaluation (ROSE) study,13 the routine use of intravenous nesiritide in the acute decompensated HF patient is no longer guideline-recommended.14 Subsequently, the group led by Burnett15, 16 suggested that many of the beneficial cardiorenal effects of NPs in HF may not be fully optimized with intravenous administration, as it was adopted in ASCEND-HF, and hypothesized that subcutaneous chronic NP administration might improve HF outcomes. In a first study, Chen and colleagues15 tested this hypothesis in symptomatic HF in the NICE study, in which patients with ejection fraction <35% and New York Heart Association functional class II to III HF were given either subcutaneous (SQ) BNP (10 µg/kg twice daily) or placebo, in addition to standard of care, for 8 weeks. It was found that SQ BNP was associated with improved left ventricular remodelling and filling pressures, improved functional class, and greater RAAS suppression than standard of care alone.15 Moreover, Burnett and colleagues16 showed that the cardiorenal response to volume expansion improves even with a single administration of SQ BNP, compared with placebo, without affecting renal function. In the work presented in this issue of the journal, McKie et al.17 from the same group extend their previous work and show that in asymptomatic systolic HF patients, the chronic administration of SQ BNP for 12 weeks, associated with subcutaneous administration 15 min before volume expansion, improves cardiorenal function in response to acute volume expansion. They also observed a trend for a greater reduction of LV mass index with SQ BNP whereas systemic blood pressure and heart rate, LV ejection fraction, E/e′, right ventricular systolic pressure, and stroke volume index were not significantly altered by chronic SQ BNP. Moreover, they found that renal function was preserved. Although the population is small and the study is relatively short-term, this work provides an interesting proof of concept that chronic BNP therapy may represent a potential and safe therapy to improve cardiorenal function in the earlier stages of systolic HF.17 It could be speculated that the effects of NP reported in this study could contribute to explain recent exciting data on morbidity and mortality with the clinical use of LCZ696 (sacubitril/valsartan), an orally available compound which provides, in a 1:1 ratio, blockade of the angiotensin type 1 receptor (AT1R) with a valsartan moiety and the neprilysin (NEP) inhibitor prodrug sacubitril (AHU377), which is soon metabolized to the active moiety LBQ657. This later action preserves NPs from catabolism, thus increasing bioavailability of NPs. This approach thus combines increases of endogenous NP levels through NEP inhibition, while ARB attenuates the effects of angiotensin II increases seen with NEP inhibitors alone.4, 5, 18 The promotion of the activity of NPs by inhibiting their degradation may lead to a better balance of neurohormones in HF. In particular, an improved handling of volume overload may reasonably contribute, at least in part, to the benefits observed in recent clinical trials. In the first trial, the Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT),19 administration of LCZ696 to patients with chronic HF and preserved ejection fraction (HFpEF) was associated with a greater reduction in N-terminal pro-brain natriuretic peptide (NT-proBNP) compared with valsartan. Moreover, in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial, LCZ696 was demonstrated to be largely and significantly superior to ACE inhibitor-based optimal therapy in reducing the risks of death and hospitalization for HF.20 The extent of clinical benefits obtained with LCZ696 was somewhat unexpected, at least for the observed size, and, beyond the obvious biological plausibility of the effects of LCZ969 on the NP system and RAAS in HF, the favourable effect produced by NP on volume handling and increased cardiac load in HF may explain the beneficial clinical findings. Further investigations are required to elucidate these aspects in greater detail. In conclusion, HF is a complex syndrome characterized by the activation of different neurohormonal systems such as SNS, RAAS, and NP. Recently, there has been a conceptual shift in the target treatment of HF, moving from the inhibition of RAAS and SNS to a concomitant enhancement of counterbalancing mechanism, such as NPs. This work by McKie et al.17 helps to explain the role of NPs in the pathophysiology of cardiorenal impairment in HF and gives support to the validity of this new therapeutic approach, which has recently shown outstanding results in the treatment of chronic HF. Conflict of interest: none declared.