P1661The myocardial tissue Renin-Angiotensin-System (RAS) of the failing heart
Authors: Pavo N , Arfsten H , Wurm R , Prausmueller S , Spinka G , Goliasch G , Bartko E P , Poglitsch M , Zuckermann A , Huelsmann M 
Published: October 2019

Abstract

Background
Prognosis of patients with HFrEF remains poor despite recent advances in pharmacologic therapy as the introduction of the angiotensin-receptor neprilysin-inhibitor (ARNI). The Renin-Angiotensin-System (RAS) is dysregulated in HF with elevated AngII levels as a central driver of disease progression. The myocardium is capable of synthesizing all RAS components resulting in tissue specific angiotensin levels. Neprilysin (NEP) catalyzes the generation of Ang1–7 which counteracts the deleterious effects of AngII. Myocardial tissue angiotensins of the failing heart and the role of long-lasting RAS-inhibitor therapy and particularly NEP inhibition on tissue RAS have not been investigated yet.

Methods
Concentrations of AngI, AngII, Ang1–7, AngIII, Ang1–5 and AngIV (RAS-fingerprints) were investigated in myocardial samples of end-stage HFrEF patients undergoing heart transplantation with a mass-spectrometry based method. Patients were stratified according to background therapy with RAS-inhibitors and variables were compared by a non-parametrical test.

Results
A total of 30 patients were included (n=6 without RAS-blockade, n=16 with ACE-I, n=6 with ARB and n=2 with ARNI). Median age was 55 (IQR 45–63) years and 87% of patients were male. 40% of patients had an ischemic etiology of HF, median NT-proBNP levels were 3498pg/ml (IQR 1761–8400). Tissue RAS patterns were visually similar between all groups (Figure 1). Myocardial AngI, Ang1–7, Ang1–5 and AngIV levels were below the detection limit for all samples. Median tissue AngII and AngIII concentrations across all samples were 83.1pg/ml (IQR 29.3–196.6) and 26.4pg/ml (IQR 5.0–64.5). Despite different background RAS-inhibitor therapy, AngII and AngIII levels were comparable between all groups [median (IQR) in pg/ml – AngII: 51.5 (41.5–123.8) vs. 72.4 (28.5–177.6) vs. 176.1 (22.4–286.8) vs. 266.0 (108.2–423.8); p=ns and 26.4 (5.0–89.2) vs. 23.2 (5.0–59.3) vs. 39.4 (5.0–94.3) vs. 105.9 (46.5–165.3); p=ns for no therapy, ACE-I, ARB and ARNI respectively].
Figure 1. RAS-fingerprints of the failing heart according to RAS-inhibiton. Numbers in brackets indicate the specific angiotensin peptides. Side of spheres and numbers beside represent absolute concentrations of angiotensins (pg/ml, median value).

Conclusions
Although in the plasma of HFrEF patients only AngI and AngII are detectable at substantial concentrations, the predominant angiotensins of the failing heart are AngII and AngIII. AngII levels are high in the failing heart supporting the hypothesis that excess AngII is involved in disease progression. AngIII similarly increases cardiac sympathetic activity assumedly potentiating further deteoriation. The modality of long established RAS-inhibitor therapy in end-stage HF, particularly the inhibition of NEP, seems to have no (more) influence on myocardial tissue RAS regulation. The impact of NEP inhibition by ARNI on tissue RAS enzymes and mechanism of action need to be further investigated.