Background
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.
Methods
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).
Outcomes
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.
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.
1. Eroglu E, Kocyigit I, Lindholm B. The endothelin system as target for therapeutic interventions in cardiovascular and renal disease. Clin Chim Acta. 2020;506:92-106.
2. Tsutamoto T, Hisanaga T, Fukai D, et al. Prognostic value of plasma soluble intercellular adhesion molecule-1 and endothelin-1 concentration in patients with chronic congestive heart failure. Am J Cardiol. 1995;76(11):803-808.
3. Pousset F, Isnard R, Lechat P, et al. Prognostic value of plasma endothelin-1 in patients with chronic heart failure. Eur Heart J. 1997;18(2):254-258.
4. Gottlieb SS, Harris K, Todd J, et al. Prognostic significance of active and modified forms of endothelin 1 in patients with heart failure with reduced ejection fraction. Clin Biochem. 2015;48(4-5):292-296.
5. Perez AL, Grodin JL, Wu Y, et al. Increased mortality with elevated plasma endothelin-1 in acute heart failure: an ASCEND-HF biomarker substudy. Eur J Heart Fail. 2016;18(3):290-297.
6. Pirklbauer M, Bernd M, Fuchs L, et al. Empagliflozin inhibits basal and IL-1β-mediated MCP-1/CCL2 and endothelin-1 expression in human proximal tubular cells. Int J Mol Sci. 2020;21(21):8189.
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