Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy

Abstract

Natriuretic peptides (NPs) promote diuresis, natriuresis and vasodilation in early chronic heart failure (CHF), countering renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) overstimulation. Despite dramatic increases in circulating NP concentrations as CHF progresses, their effects become blunted. Increases in diuresis, natriuresis, and vasodilation after administration of exogenous atrial (ANP) or brain (BNP) natriuretic peptides are attenuated in patients with advanced CHF compared with controls. Several major factors may account for the reduced effectiveness of the natriuretic peptide system (NPS) in CHF. First, there is reduced availability of active forms of NPs, namely BNP. Second, target organ responsiveness becomes diminished. Third, the counter-regulatory hormones of the RAAS and SNS, and endothelin-1 become over-activated. Therefore, pharmacological approaches to enhance the functional effectiveness of the NPS in CHF have been explored in recent years. In terms of clinical outcomes, studies of synthetic BNP, or of neprilysin inhibitors alone or associated with an angiotensin converting enzyme inhibitor, have been controversial for several reasons. Recently, however, encouraging results have been obtained with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan. The available data show that treatment with sacubitril/valsartan is associated with increased levels of NPs and their intracellular mediator cyclic guanosine monophosphate, suggesting improved functional effectiveness of the NPS, in addition to beneficial effects on mortality and morbidity outcomes. Therefore, combined targeting of the NPS and RAAS with sacubitril/valsartan emerges as the current optimal approach for redressing the neurohormonal imbalance in CHF.

Keywords: Atrial natriuretic peptide; Brain natriuretic peptide; Heart failure; Natriuretic peptide; Neprilysin.

Figure 1

Mechanisms of action and main effects of natriuretic peptides (NPs). AC, adenylyl cyclase; ANP, atrial natriuretic peptide; AVP, arginine–vasopressin; BNP, brain natriuretic peptide; cGMP, cyclic guanosine monophosphate; CNP, C‐type natriuretic peptide; GTP, guanosine triphosphate; NPR, natriuretic peptide receptor; PKG, protein kinase G; PLC, phospholipase C; sGC, soluble guanylate cyclase.

Figure 2

Overview of the main pathophysiological consequences of reduced effectiveness of natriuretic peptides (NPs) in chronic heart failure.

Figure 3

Net change in urinary sodium excretion in response to infusion of atrial natriuretic peptide (ANP) or placebo (P) in seven patients with chronic heart failure (CHF) and seven healthy controls. Open and closed circles indicate individual and mean values, respectively, for controls. Asterisk indicates that the mean value with the highest dose of ANP was higher (P < 0.05) than with P. Triangles indicate individual values for CHF patients with the highest dose of ANP.(Reproduced from Cody et al. 11 with permission.)

Figure 4

Changes in forearm blood flow response to infusion of atrial natriuretic peptide (ANP) in 53 patients with chronic heart failure (closed squares) and 11 healthy controls (open circles). Changes were assessed in the infused and non‐infused arms and changes in the former were also expressed as a ratio of those in the latter. The first value corresponds to the baseline measurements. **P < 0.01, ***P < 0.001; these refer to within‐group comparison. P < 0.01 refers to area under curve comparison between both groups. (Reproduced from Schmitt et al. 16 with permission.)

Figure 5

Neprilysin (NEP) messenger RNA (mRNA) and activity in left ventricular myocardial samples from patients with chronic heart failure (CHF) caused by dilated cardiomyopathy and controls. The NEP mRNA was quantified by real‐time polymerase chain reaction assay and NEP activity was measured by an enzymatic assay. Results are expressed as mean ± SEM. (Reproduced from Fielitz et al. 34 with permission.)

Figure 6

Association of plasma levels of atrial natriuretic peptide (ANP) with cyclic guanosine monophosphate (cGMP) in 43 patients with mild chronic heart failure (closed circles) and acute heart failure (open circles) (left panel), and 45 patients with moderate‐to‐severe CHF (right panel). NYHA, New York Heart Association. (Reproduced from Tsutamoto et al. 37 with permission.)