Physicians' Academy for Cardiovascular Education

Serum endothelin-1 levels as prognostic biomarker in patients with HFrEF

Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin: Findings From DAPA-HF

Literature - Yeoh SE, Docherty KF, Campbell RT, et al. - Circulation. 2023 Apr 11. [Online ahead of print]. doi: 10.1161/CIRCULATIONAHA.122.063327

Introduction and methods


Endothelin-1 (ET-1) functions as a local paracrine and autocrine mediator [1]. The effects of ET-1 are mediated by endothelin A and B (ETA and ETB) receptors. These receptors have opposing effects. ETA receptors promote vasoconstriction and inflammation, whereas ETB receptors promote vasodilation and natriuresis and inhibit inflammation. There is an association between the level of ET-1 in the circulation with severity of HF, and the risk of HF hospitalization and mortality [2-5]. Moreover, it was shown that the SGLT2 inhibitor empagliflozin regulates ET-1 expression in cultured human proximal tubular cells [6]. It may therefore be plausible that there is an interaction between the endothelin system and SGLT2 inhibitors in patients with HF.

Aim of the study

The study objectives were to determine whether: (1) serum ET-1 levels are a prognostic biomarker in patients with HFrEF; (2) there is a relationship between serum ET-1 and decline in kidney function in patients with HFrEF; and (3) ET-1 modifies the effects of SGLT2 inhibitor dapagliflozin.


For these analyses, data of the DAPA-HF trial were used. DAPA-HF was a prospective, randomized, double-blind, controlled trial that included a total of 4744 adult patients with HFrEF (NYHA classes II to IV, LVEF ≤40%, elevated NT-proBNP, and optimally treated with HF pharmacological and device therapy). The effects of 10 mg dapagliflozin once daily were compared with placebo. Venous blood samples were taken at randomization (n=3048) and at month 12 (n=2436). For this analysis, patients were stratified in groups according to baseline serum ET-1 levels (tertile 1: ≤3.28 pg/mL, tertile 2: >3.28-4.41 pg/mL, and tertile 3: >4.41 pg/mL).


The primary outcome was the composite of worsening HF (HF hospitalization or urgent HF visit) or CV mortality. Secondary outcomes were: HF hospitalization or CV mortality; all-cause mortality; and change in KCCQ-TSS from baseline to 8 months.

Main results

ET-1 concentration as prognostic biomarker

ET-1 concentration and kidney decline

ET-1 concentration and dapagliflozin


Using data from DAPA-HF, it was shown that elevated serum ET-1 levels are associated with worse clinical outcomes and more rapid decline in kidney function in patients with HFrEF. Dapagliflozin had beneficial effects on clinical outcomes across the range of ET-1 concentrations, and reduced ET-1 levels at month 12 in a small degree.


Show references

Find this article online at Circulation.

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