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
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 . 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.
- There was an early and significant increase in ANP; from a geometric mean of 99 pg/mL at baseline to 157 pg/mL at day 14 (P<0.001). From day 30 to day 45 there was a trend for a subsequent rise (P=0.07). Highest ANP was observed at month 3 (203 pg/mL).
- Age and ANP were positively associated (P=0.04) and ANP and eGFR were negatively associated (P=0.04). ANP was lower in patients without a history of AF than in patients with AF.
- Early change in ANP was correlated with later change in urinary cGMP, especially between baseline and month 2.
- Changes in ANP and cGMP were associated at all timepoints (linear slope: r=0.734, P<0.001, quadratic slope: r=0.605, P<0.001).
- Baseline values for ANP and LVEF were negatively associated (r=-0.333, P<0.001). After initiation of sacubitril/valsartan, the rise in ANP was positively associated with improvement in LVEF (r=0.237, P<0.001).
- Baseline values for ANP and LAVI were strongly associated (r=0.6999, P<0.001), and after initiation of sacubitril/valsartan changes in ANP were associated with reductions in LAVI, even more strongly than with LVEF.
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.