P5449Neurohumoral regulation of the low-, medium- and high-renin HFrEF phenotypes
Authors: Prausmueller S , Arfsten H , Spinka G , Novak J F , Cho A , Goliasch G , Bartko P E , Huelsmann M 
Published: October 2019

Abstract

Background
Previous investigations of plasma Renin-Angiotensin-System (RAS) fingerprints of patients with heart failure with reduced ejection fraction (HFrEF) revealed the existence of low, medium and high renin phenotypes independently of disease severity. Plasma renin serves as an excellent surrogate for angiotensin levels. The different renin phenotypes could not only hypothetically respond differently to RAS blockade but associated alterations of other vasoactive peptide systems could elucidate disease mechanisms and novel targets for heart failure therapy. The study aimed to investigate the relation between RAS regulation and pathophysiologically relevant vasoactive peptide systems based on different renin phenotypes.

Methods
We prospectively enrolled 369 patients with stable HFrEF. Laboratory markers including NT-proBNP and active renin concentration (ARC) were assessed. Plasma NEP levels (sNEP), bioactive adrenomedullin (bio-ADM) and big-endothelin1 (bigET-1) were measured by ELISA (R&D systems, UK; Sphingotec GmbH, Germany and Eagle Biosciences, Austria). NEP activity was determined by a fluorimetric peptide cleavage assay. The correlation between biomarkers and association with all-cause mortality was assessed. sNEP, bio-ADM and bigET-1 levels as well as NEP activity between the different renin phenotypes (i.e. <15. percentile, 15.-85. percentile and >85. percentile of ARC) was compared.

Results
Median age was 65 (IQR 53–73) years, 75% of patients were male. Median NT-proBNP levels were 1936 (IQR 855–4126) pg/mL. Median ARC was 155 (29–569) μIE/mL, the low, medium and high renin HFrEF phenotypes showed median ARC levels of 4.2μIE/mL (IQR 2.0–7.8), 155.1μIE/mL (IQR 43.3–353.5) and 2360μIE/mL (IQR 1483–3250) μIE/mL. Median bigET-1 was 0.62pmol/L (IQR 0.42–1.10), bio-ADM 26.0pg/mL (IQR 16.1–46.7), sNEP 413pg/mL (IQR 0–4111) and NEP activity 2.36nmol/mL/min (IQR 1.16–4.59). There was no correlation between sNEP and NEP activity [r=0.09, p=0.088]. ARC did not show a meaningful correlation with any of the four biomarkers [p=ns for sNEP, NEP activity and bigET-1; r=0.13, p=0.018 for bio-ADM]. In the univariate analysis ARC, bigET-1, bio-ADM but not sNEP and NEP activity, were associated with outcome. This association remained significant after adjustment for age, gender and kidney function for all three markers and for ARC after adding NT-proBNP [adj. HR per 1-IQR increase of ARC 1.27 (95% CI 1.04–1.22), p=0.003]. There were no differences in bigET-1, bio-ADM and sNEP or NEP activity stratified by the different renin phenotypes (Figure1).
Figure 1

Conclusions
ARC is a risk factor for mortality in HFrEF patients, independently of NT-proBNP. Plasma NEP levels and activity neither correlated with each other nor were associated with outcome. Bio-ADM and bigET-1 were strong risk factors for all-cause mortality. Interestingly, neither NEP nor bio-ADM or bigET-1 were related to RAS-activation, suggesting that there is no direct relationship with RAS regulation.