Physicians' Academy for Cardiovascular Education

Early increase ANP after ARNI initiation associated with reverse cardiac remodeling in HFrEF

Atrial Natriuretic Peptide and Treatment With Sacubitril/Valsartan in Heart Failure With Reduced Ejection Fraction

Literature - Murphy SP, Prescott MF, Camachoet A et al., - JACC Heart Fail. 2020,

Introduction and methods

Binding of atrial natriuretic peptide (ANP) and the related B-type natriuretic peptide (BNP) to the NP receptor A leads to cyclic guanosine monophosphate (cGMP) activation resulting in natriuresis, diuresis, and vasodilation. This counterbalances activation of the RAS and sympathetic nervous system in heart failure. Other effects mediated by this cGMP pathway are antihypertrophic, antifibrotic and positive lusitropic effects, suggesting that this pathway may be a therapeutic target in heart failure [1]. Inhibition of neprilysin partially blocks the clearance of ANP and BNP.

Sacubitril/valsartan is an angiotensin receptor blocker/neprilysin inhibitor (ARNI) and has demonstrated to reduce mortality and HF hospitalization in patients with HFrEF [2,3]. The PROVE-HF study showed that sacubitril/valsartan induced changes in measures of cardiac reverse remodeling (increase in LVEF and improvements in left atrial volume index [LAVI]), which were associated with reductions in NT-proBNP. It is unknown whether changes in ANP are associated with improvement in measures of cardiac remodeling.

This pre-specified substudy of PROVE-HF assessed multivariate associations between changes in ANP, cGMP, LVEF and LAVI over a 12-month period.

The PROVE-HF study was a 52-week, multicenter, open-label, single-arm study that enrolled 794 patients with HFrEF who were started on sacubitril/valsartan [4,5]. Echocardiographic assessments were performed at baseline, and at 6 and 12 months. In addition to blood and urine collection at each study visit, blood was collected in tubes with protease inhibitors at 9 additional visits in the biomarker substudy. After implementing restrictions on missing data, 111 patients were included.

Main results


This pre-specified analysis using data of the PROVE-HF trial showed that after initiation of sacubitril/valsartan in HFrEF patients, a rapid significant rise in ANP was associated with greater improvements in LVEF and reduction of LAVI, measures of cardiac remodeling. These results suggest a role of ANP as a mechanism of benefit by sacubitril/valsartan.


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Find this article online at JACC Heart Fail Watch a video by Sean Murphy on this study

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