Prognostic Value of Plasma Big Endothelin-1 in Patients Hospitalized for Heart Failure

Abstract

Background and objectives: Endothelin-1 (ET-1) is a potent vasoconstrictor and multifunctional neuroendocrine hormone that is closely associated with the pathophysiology of heart failure (HF). Currently, the evidence about the predictive value of big ET-1 in HF remains insufficient. This study aims to investigate the prognostic importance of big ET-1 in HF.

Methods: We examined the incidence of cardiovascular death in a single-center retrospective cohort of HF (de novo, worsening, or chronic included).

Results: The 4,368 hospitalized HF patients were enrolled. During the median follow-up of 875 (365-1,400) days, 851 (19.5%) patients had primary outcome events. Big ET-1 was independently associated with cardiovascular death as a continuous variable (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21; p<0.001) and by tertiles (HR, 1.35; 95% CI, 1.06-1.72; p=0.017 for tertile 2 and HR, 1.70; 95% CI, 1.32-2.19; p<0.001 for tertile 3). This pattern of risk was maintained after further adjustment for NT-proBNP (HR, 1.11; 95% CI, 1.03-1.19; p=0.006 for continuous variable, HR, 1.30; 95% CI, 1.02-1.67; p=0.035 for tertile 2, and HR, 1.69; 95% CI, 1.23-2.05; p=0.034 for tertile 3). Net reclassification index (NRI) and integrated discrimination improvement (IDI) analysis showed that big ET-1 provided additional predictive power in combination with NT-proBNP (NRI, 0.11; 95% CI, 0.04-0.17; p=0.012 and IDI, 0.012; 95% CI, 0.003-0.017; p<0.001).

Conclusions: Elevated big ET-1 was independently associated with cardiovascular death in patients with HF. Big ET-1 may be a promising indicator of HF prognosis. In combination with NT-proBNP, big ET-1 may provide incremental predictive information.

Keywords: Big endothelin-1; Biomarkers; Heart failure; Prognosis.

Figure 1. Kaplan-Meier curves of cardiovascular death and secondary outcomes stratified by baseline big endothelin-1 tertile.

(A) Cardiovascular death, (B) HHF, and (C) all-cause mortality. HHF = hospitalization for heart failure.

Figure 2. Association between baseline big ET-1 as a continuous variable and unadjusted risk of cardiovascular death by restricted cubic splines.

CI = confidence interval; ET-1 = endothelin-1; HR = hazard ratio.

Figure 3. The time-dependent ROC curves of big ET-1 and NT-proBNP in predicting the primary outcome of heart failure.

AUC = area under the curve; ET-1 = endothelin-1; NT-proBNP = N-terminal pro-B-type natriuretic peptide; ROC, receiver operating characteristic.

Figure 4. Event rates of cardiovascular death and all-cause mortality according to baseline big ET-1 tertile and NT-proBNP tertile.

(A) Cardiovascular death and (B) all-cause mortality. CI = confidence interval; ET-1 = endothelin-1; HR = hazard ratio; NT-proBNP = N-terminal pro-B-type natriuretic peptide; T = tertile.