Direct comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure

doi:10.1054/jcaf.2000.8833

Journal of Cardiac Failure

Volume 6, Issue 3, September 2000, Pages 201-207

https://doi.org/10.1054/jcaf.2000.8833 Get rights and content

Abstract

Background: Endothelin-1 (ET-1) and cardiac natriuretic peptide plasma concentrations have prognostic significance in congestive heart failure (CHF). However, their respective prognostic values in this setting have never been directly compared. Methods and Results: We studied the prognostic performances of ET-1, N-terminal proatrial natriuretic factor (N-proANF), and brain natriuretic peptide (BNP) to predict the long-term cardiac mortality in fully treated patients with CHF. Peripheral plasma concentrations of the 3 peptides were measured in 109 patients (left ventricular ejection fraction [LVEF] < 35%) in New York Heart Association (NYHA) functional classes II (n = 65) or III to IV (n = 44). The outcome of the patients was evaluated 3 years after the beginning of the study, and a Cox regression model was used to identify predictors of death. Plasma concentrations of the 3 peptides increased with the severity of heart failure. By univariate analysis, 6 parameters were significantly associated with death during follow-up: ET-1 level, NYHA classes III to IV, N-proANF level, BNP level, LVEF, and age (all P <.01). By multivariate analysis, only ET-1 level and, to a lesser extent, N-proANF level contributed significantly and independently to risk stratification (X² = 53.4 and 12.8; P <.0001 and P <.001, respectively). Conclusion: In a group of patients in whom the vast majority were administered angiotensin-converting enzyme inhibitor therapy, plasma ET-1 and N-proANF concentrations identify better than several clinical markers a very high-risk group, fairly amenable to heart transplantation or new therapies.

Section snippets

Patients

Plasma samples were obtained from 109 patients with CHF (91 men, 18 women) with a left ventricular ejection fraction (LVEF) less than 35% (by radionuclide or angiographic technique) and classified according to the New York Heart Association (NYHA) into mild (class II; 57 men, 8 women) and moderate to severe (classes III to IV; 34 men, 10 women) CHF. Eighty-eight percent of our study population had ischemic cardiomyopathy, 11% had idiopathic dilated cardiomyopathy, and 1% had valvular disease.

Results

Peptide concentrations measured in our patients were in the expected range according to the literature, listed in Table 1.

. Baseline Clinical and Neurohumoral Characteristics

No. of Patients	Age (y)	NYHA Class	LVEF (%)	N-proANF (pg/mL)	BNP (pg/mL)	ET-1 (pg/mL)
65	62 ± 7	II	29 ± 5	478 [1.8]	44 [1.8]	2.9 [1.6]
44	65 ± 10	III-IV	21 ± 6	1,653 [1.8]	145 [1.8]	13.0 [1.5]

Values expressed as mean ± SD. Neurohumoral values represent geometric mean [deviation].

NYHA, New York Heart Association functional class; LVEF, left

Discussion

Plasma concentrations of ET-1 and the natriuretic peptides increase in chronic heart failure. In our study, we showed that these neurohumoral markers can be used to predict the prognosis of patients, particularly ET-1 and N-proANF, which are able to identify a subgroup of patients with CHF with a very high mortality risk.

Only a few studies have previously investigated the prognostic value of peptidic neurohumoral markers in fully treated patients with CHF despite evidence for their interest in

References (28)

W Kiowski et al.
Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure
Lancet
(1995)
SD Anker et al.
Metabolic, functional, and haemodynamic staging for CHF?
Lancet
(1996)
TA McDonagh et al.
Biochemical detection of left-ventricular systolic dysfunction
Lancet
(1998)
JL Rouleau et al.
Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: Effect of captopril
J Am Coll Cardiol
(1994)
T Omland et al.
Neurohumoral measurements as indicators of long-term prognosis after acute myocardial infarction
Am J Cardiol
(1995)
N Arakawa et al.
Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction
J Am Coll Cardiol
(1996)
SS Gottlieb et al.
Prognostic importance of atrial natriuretic peptide in patients with chronic heart failure
J Am Coll Cardiol
(1989)
T Tsutamoto et al.
Prognostic value of plasma soluble intercellular adhesion molecule-1 and endothelin-1 in patients with chronic congestive heart failure
Am J Cardiol
(1995)
S Galatius-Jensen et al.
Plasma endothelin in congestive heart failure: a predictor of cardiac death?
J Card Fail
(1996)
M Hülsmann et al.
Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure
J Am Coll Cardiol
(1998)

B Stanek et al.

Validation of big endothelin plasma levels compared with established neurohumoral markers in patients with severe chronic heart failure

Transplant Proc

(1997)

T Tsutamoto et al.

Relationship between endothelin-1 extraction in the peripheral circulation and systemic vascular resistance in patients with severe congestive heart failure

J Am Coll Cardiol

(1999)

RO Bonow

New insights into the cardiac natriuretic peptides

Circulation

(1996)

GS Francis et al.

Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure

Circulation

(1990)

Cited by (51)

Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study
2017, International Journal of Cardiology
Increased levels of neuro-hormonal biomarkers predict poor prognosis in patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD). The predictive value of repeated (one-month interval) brain natriuretic peptides (BNP) and big-endothelin 1 (BigET-1) measurements were investigated in patients with LVSD after AMI.
In a sub-study of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS trial), BNP and BigET-1 were measured at baseline and at 1 month in 476 patients.
When included in the same Cox regression model, baseline BNP (p = 0.0003) and BigET-1 (p = 0.026) as well as the relative changes (after 1 month) from baseline in BNP (p = 0.049) and BigET-1 (p = 0.045) were predictive of the composite of cardiovascular death or hospitalization for worsening heart failure. Adding baseline and changes in BigET-1 to baseline and changes in BNP led to a significant increase in prognostic reclassification as assessed by integrated discrimination improvement index (5.0%, p = 0.01 for the primary endpoint).
Both increased baseline and changes after one month in BigET-1 concentrations were shown to be associated with adverse clinical outcomes, independently from BNP baseline levels and one month changes, in patients after recent AMI complicated with LVSD. This novel result may be of clinical interest since such combined biomarker assessment could improve risk stratification and open new avenues for biomarker-guided targeted therapies.
In the present study, we report for the first time in a population of patients with reduced LVEF after AMI and signs or symptoms of congestive HF, that increased baseline values of BNP and BigET-1 as well as a further rise of these markers over the first month after AMI, were independently predictive of future cardiovascular events. This approach may therefore be of clinical interest with the potential of improving risk stratification after AMI with reduced LVEF while further opening new avenues for biomarker-guided targeted therapies.
Prognostic significance of active and modified forms of endothelin 1 in patients with heart failure with reduced ejection fraction
2015, Clinical Biochemistry
Citation Excerpt :
Val-HeFT, a study of 2359 patients, showed that big ET1 was prognostic of morbidity and mortality, but BNP was more prognostic [2]. In contrast, ET1 was more prognostic of death than BNP and N-proANP in univariate and multivariate regression analyses in another study of 109 patients [3] and only big ET1 and ET1 independently predicted death in 47 patients [1]. Similarly, chromogranin A and C-terminal endothelin precursor fragments were shown to add prognostic information to NTproBNP in 127 patients [4].
Concentrations of endothelin I (ET1) are elevated in CHF patients and, like other biomarkers that reflect hemodynamic status and cardiac pathophysiology, are prognostic. The Singulex assay (Sgx-ET1) measures the active form of ET1, with a short in vivo half-life and the Brahms assay measures C-terminal endothelin-1 (CT-ET1), a modified (degraded) product with longer half-life. We aimed to determine the prognostic importance of active and modified forms of endothelin 1 (Singulex and Brahms assays) in comparison with other commonly measured biomarkers of inflammation, hemodynamic status and cardiac physiology in CHF.
Plasma biomarkers (Sgx-ET1, CT-ET1, NTproBNP, IL-6, TNFα, cTnI, VEGF, hs-CRP, Galectin-3, ST2) were measured in 134 NYHA class II and III CHF patients with systolic dysfunction. Prognostic importance of biomarkers for hospitalization or death were calculated by both logistic regression and Kaplan–Meier survival analyses.
CT-ET1 (OR = 5.2, 95% CI = 1.7–15.7) and Sgx-ET1 (OR = 2.9, CI = 1.1–7.7) were independent predictors of hospitalization and death and additively predicted events after adjusting for age, sex, and other significant biomarkers. Other biomarkers did not improve the model. Similarly, in Cox regression analysis, only CT-ET1 (HR 3.4, 95% CI = 1.4–8.4), VEGF (2.7, 95% CI = 1.3–5.4), and Sgx-ET1 (HR 2.6, 95% CI = 1.2–5.6) were independently prognostic.
Elevated concentrations of endothelin 1 predict mortality and hospitalizations in HF patients. Endothelin 1 was more prognostic than commonly obtained hemodynamic, inflammatory, and fibrotic biomarkers. Two different assays of endothelin 1 independently and synergistically were prognostic, suggesting either complementary information or extreme prognostic importance.
Mineralocorticoid receptor antagonism in acutely decompensated chronic heart failure
2014, European Journal of Internal Medicine
Citation Excerpt :
Consistent with the faster resolution of congestive signs and with the preservation of the renal function discussed above, we documented a significant reduction in NTproBNP within the spironolactone group. This is a notable finding since natriuretic peptides have shown to correlate with changes in ventricular wall stress, are inversely related to the severity of left ventricular dysfunction, and are robust prognostic predictors in HF [22–26]. Despite no significant differences were found, patients in the treatment group had greater albuminuria reduction during the treatment period.
Mineralocorticoid receptor antagonist (MRA) use in acutely decompensated chronic heart failure (ADCHF) may improve congestion through diuretic effect and prevent neurohormonal activation. We aimed to evaluate the clinical effect and safety of spironolactone in ADCHF.
Prospective, experimental, single-center, and single-blinded trial. Patients were treated with: standard ADCHF therapy or oral spironolactone 50–100 mg/d plus standard ADCHF therapy.
During a 1 year period, 100 patients were enrolled, 50 included in the treatment group. Mean (SD) spironolactone dose (mg) at day 1 was 94.5 ± 23.3 and at day 3 was 62.7 ± 24.3. Worsening renal function (increase in pCr ≥ 0.3 mg/dL from day 1 to day 3) was more likely to occur in control group (20% vs. 4%; p = 0.038), serum potassium did not differ between groups, and plasma NTproBNP had a significant decrease in spironolactone group at day 3 (median [IQR], 2488 [4579] vs. 1555 [1832]; p = 0.05). Furthermore, a greater proportion of patients in the treatment group were free of congestion at day 3: less edema, rales, jugular venous pressure (JVP) and orthopnea (all, p < 0.05). In addition, a significantly higher proportion of patients were on oral furosemide at day 3 (44% vs. 82%; p < 0.001).
Our study supports the safety of high dose spironolactone in ADCHF and suggests a positive impact in the resolution of congestion. The important findings of our pilot study need to be confirmed in larger trials.
Determination of endothelin-1 in rats using a high-performance liquid chromatography coupled to electrospray tandem mass spectrometry
2010, Talanta
A sensitive and specific liquid chromatography tandem mass spectrometry method with electrospray ionization for the determination of endothelin-1 in rat plasma and lung effluents has been developed and validated. Detection was achieved by an Applied Biosystems MDS Sciex API 2000 triple quadrupole mass spectrometer coupled to an Agilent 1100 LC system. The limit of detection and the limit of the quantification of ET-1 in matrix buffer was estimated at 40 pM and 1 nM, respectively. The precision and accuracy for both intra- and inter-day determination of the analyte ranged from 2.5% to 14.7% and from 104.2% to 113.3%, respectively. No significant relative matrix effect was observed. Stability of ET-1 established in a bench-top, autosampler, long-term storage stability as well as freeze/thaw cycles shown no significant degradation products in the samples. The results of the method validation indicated that this method is applicable for the determination of the ET-1 concentration in an effluent from the isolated lung preparation as well as in vivo in plasma samples to evaluate ET-1 as a potential biomarker of the progression of pulmonary endothelial dysfunction and pulmonary hypertension in rats induced by a monocrotaline injection.
Biomarkers in cardiovascular disease: Beyond natriuretic peptides
2009, Journal of Veterinary Cardiology
Citation Excerpt :
It has also been suggested that in dogs an increasing concentration of a circulating marker of endothelin activity, Big ET-1, may be indicative of a worse outcome in dogs with dilated cardiomyopathy.72 In human patients elevated endothelin concentrations have been shown to be strong independent predictors of a poor outcome that provide information in addition to that given by natriuretic peptide concentrations.73 What can be drawn from the bewildering and still incomplete list of biomarkers that has been discussed above?
Currently natriuretic peptides are justifiably regarded as the most promising circulating markers of cardiovascular disease in dogs and cats, but there are many other markers that can be used in the evaluation of such patients. There are markers of myocyte injury typified by troponins I and T; markers of myocyte stress including adrenomedullin and ST2; markers of remodeling including matrix metalloproteinases, tissue inhibitors of metalloproteinases and collagen molecules (PIIINP); markers of endothelial function including dimethylarginines and nitric oxide metabolites; markers of inflammation including C-reactive protein, several interleukins and tumor necrosis factor alpha; and finally neurohormonal markers. The potential of many of these markers has at best been only partially explored in veterinary patients. Evidence emerging from studies of human and in some cases veterinary patients suggests that using multiple markers may be superior to using single markers alone. As well as evaluating markers for their diagnostic value they should be considered as methods of identification of patients at increased risk of experiencing complications or death. Future areas of research in this field could include improved characterization of the clinical utility of multi-marker evaluation in veterinary patients and using markers to identify patients that may benefit from particular interventions.
Introduction of an NT-proBNP assay to an acute admission unit - A 2-year audit
2009, European Journal of Internal Medicine
The differential diagnosis of dyspnoea is difficult due to the low predictive value of clinical and laboratory parameters. The elevated levels of NT-proBNP in congestive heart failure may improve diagnostic accuracy. We have evaluated the effect of the introduction of an NT-proBNP assay on hospital length of stay (LOS) and mortality.
There were 11,853 AMAU patient episodes in the 22 months study period (March 2005–Dec 2006). An NT-proBNP assay was requested in 657 (5.5%) of these. Comparison between categorical variables such as diagnosis, NT-proBNP testing, LOS, and in-hospital mortality was made using Chi-square tests. Literature review suggested that an NT-proBNP cut-off ≥ 5000 ng/L should predict acute in-patient mortality. Logistic regression analysis was used to examine the association between such an elevated NT-proBNP level and outcomes.
Of the 396 patients with NT-proBNP < 5000 ng/L, 8.1% died compared with 22.5% of the 178 patients dying with values ≥ 5000 ng/L (p < 0.0001). An NT-proBNP ≥ 5000 ng/L was predictive of both LOS ≥ 9 days (odds ratios (OR) 1.54 (95% CI 1.06, 2.24: p = 0.02) and LOS ≥ 14 days (OR = 1.87 (95% CI 1.29, 2.71: p = 0.0009). NT-proBNP requests increased over time, from 2.6% to 8.2% of all patients; the result fell in the diagnostic range for CHF in 60% of requests.
The introduction of an NT-proBNP was reflected in an appropriate but rapidly increasing pattern of requests from clinicians. High NT-proBNP levels predicted in-hospital mortality and longer LOS in an acute medical population.

View all citing articles on Scopus

^*: Supported in part by grant no. 3,4572.96 from the Fonds National de la Recherche Scientifique, Brussels, Belgium.

^**: P.L.S. was Aspirant of the Fonds National Belge de la Recherche Scientifique.

^★: Reprint requests: Michel F. Rousseau, MD, PhD, University of Louvain, Division of Cardiology, Ave Hippocrate 10/2800, B-1200 Brussels, Belgium.

View full text

Clinical InvestigationsDirect comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure*,**,★

Abstract

Section snippets

Patients

Results

Discussion

Lancet

Lancet

Lancet

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Am J Cardiol

J Card Fail

J Am Coll Cardiol

Transplant Proc

J Am Coll Cardiol

New insights into the cardiac natriuretic peptides

Circulation

Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure

Circulation

Clinical Investigations
Direct comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure*,**,★