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

ahajournals.org
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

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.

Main results

ET-1 concentration as prognostic biomarker

  • The incidence of the primary outcome increased with increasing ET-1 tertile (adjusted HR: 1.38; 95%CI: 1.06-1.75; adjusted HR: 1.95; 95%CI: 1.53-2.50; for tertile 2 and 3, respectively). This was mainly driven by risk of worsening HF (adjusted HR: 1.54; 95%CI: 1.10-2.18; adjusted HR: 2.54; 95%CI: 1.82-3.53; for tertile 2 and 3, respectively).
  • The risk of the primary and secondary outcomes was increased from the ET-1 concentration of >4 pg/mL as shown with restricted cubic spine models.
  • The addition of ET-1 as biomarker together with NT-proBNP or hs-TnT showed additive prognostic value. Patients in tertile 3 for ET-1 and in tertile 3 for hs-TnT or NT-proBNP had an increased risk of the primary outcome (>8-fold higher risk for hs-Tnt; >6-fold higher risk for NT-proBNP) than patients in tertile 1 for ET-1 and hs-TnT or NT-proBNP.

ET-1 concentration and kidney decline

  • The largest decline in eGFR (in mL/min/1.73 m² per year) occurred in patients in ET-1 tertile 3 (change in eGFR of -2.35 [95%CI: -2.79 to -1.91] in tertile 1; -2.08 [95%CI:-2.52 to -1.63] in tertile 2; and -3.19 [95%CI: -3.66 to 2.72] in tertile 3; P=0.002).

ET-1 concentration and dapagliflozin

  • The beneficial effects of dapagliflozin on the primary outcome were not modified by ET-1 concentration as analyzed according to tertiles (P for interaction=0.47) or as continuous variable (P for interaction=0.10).
  • The effects of dapagliflozin on secondary outcomes or the slope of eGFR were not modified by baseline ET-1 tertiles.
  • Dapagliflozin reduced ET-1 level at month 12 compared with placebo (difference -0.13 pg/mL; 95%CI: -0.25 to -0.01; P=0.029).

Conclusion

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.

References

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.

Find this article online at Circulation.

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