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European Journal of Heart Failure 2005 7(2):253-260; doi:10.1016/j.ejheart.2004.06.002
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© 2005 European Society of Cardiology

N-terminal brain natriuretic peptide is a more powerful predictor of mortality than endothelin-1, adrenomedullin and tumour necrosis factor-{alpha} in patients referred for consideration of cardiac transplantation

Roy S. Gardnera,*, Victor Chonga, Iain Mortonb and Theresa A. McDonaghc

a The Scottish Cardiopulmonary Transplant Unit, Glasgow Royal Infirmary UK
b Division of Cardiovascular and Medical Sciences, Western Infirmary Glasgow, UK
c Department of Cardiology, Royal Brompton Hospital London, UK

* Corresponding author. The Scottish Cardiopulmonary Transplant Unit, Glasgow Royal Infirmary, 10 Alexandra Parade, Glasgow G31 2ER, UK. Tel.: +44 141 943 2310; fax: +44 141 211 4950. E-mail address: rsgardner{at}doctors.org.uk


   Abstract
Top
 Abstract
1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The selection of patients for cardiac transplantation is notoriously difficult. We have demonstrated that N-terminal brain natriuretic peptide (NT-proBNP) is a powerful predictor of mortality in advanced heart failure and is superior to the traditional markers of chronic heart failure (CHF) severity. However, the comparative prognostic power of endothelin-1 (Et-1), adrenomedullin (Adm) and tumour necrosis factor-alpha (TNF-{alpha}) in this patient group is unknown.

Methods and results: We prospectively studied 150 consecutive patients with advanced CHF referred for consideration of cardiac transplantation. Blood samples for NT-proBNP, Et-1, Adm and TNF-{alpha} analysis were taken at recruitment and patients followed up for a median of 666 days. The primary endpoint of all-cause mortality was reached in 25 patients and the secondary endpoint of all-cause mortality or urgent cardiac transplantation in 29 patients. The median values for NT-proBNP, Et-1, Adm and TNF-{alpha} were 1494 pg/ml [interquartile range 530–3930], 0.39 fmol/ml [0.10–1.24], 94 pg/ml [54–207] and 2.0 pg/ml [0–18.5] respectively. The only univariate and multivariate predictor of all-cause mortality ({chi}2=26.95, p<0.0001), or the secondary endpoint of all-cause mortality or urgent transplantation ({chi}2=31.23, p<0.0001), was an NT-proBNP concentration above the median value.

Conclusion: A single measurement of NT-proBNP in patients with advanced CHF can help identify patients at the highest risk of death, and is a better prognostic marker than Et-1, Adm and TNF-{alpha}.

Key Words: Chronic heart failure • Prognosis • Neurohormones • Natriuretic peptides • Cardiac transplantation

Received April 12, 2004; Revised May 12, 2004; Accepted June 10, 2004


   1. Background
Top
 Abstract
 1. Background
2. Methods
 3. Results
 4. Discussion
 References
 
The treatment of chronic heart failure (CHF) has been revolutionized over the last two decades, with ACE inhibitors, [1,2] beta-blockers, [3–5] aldosterone antagonists, [6] and more recently, devices [7]. However, identifying patients who have failed to respond to disease modifying therapy and therefore those that would benefit most from cardiac transplantation (CTx) is notoriously difficult.

Many studies have been performed to identify markers of prognosis in such a population. Traditional markers of outcome include the left ventricular ejection fraction (LVEF), [8,9] maximum oxygen uptake (pkVO2) [10] and heart failure survival score (HFSS) [11]. However, we have recently shown that N-terminal brain natriuretic peptide (NT-proBNP) is an independent predictor of all-cause mortality, and death or urgent transplantation patients with advanced heart failure and is far superior to the LVEF, pkVO2 and HFSS [12].

Although brain natriuretic peptide (BNP) and the N-terminal fragment of its prohormone (NT-proBNP) are now well established in the diagnosis and assigning of prognosis in all stages of CHF, other neurohormones and cytokines have also been studied in this regard: Adrenomedullin (Adm), a potent vasodilating and natriuretic 52-amino-acid peptide, has previously been shown to be an independent predictor of prognosis in mild to moderate CHF [13]. Endothelin-1 (Et-1) is a potent vasoconstrictive peptide which has also been shown to be associated with a poor prognosis in mild to moderate heart failure [14]. Tumour necrosis factor-alpha (TNF-{alpha}), a pro-inflammatory cytokine, has also been linked to outcome in such a population [15,16]. However, to date, there are no published data comparing the prognostic ability of NT-proBNP with other neurohormones and cytokines in patients with advanced heart failure and, therefore, their potential role in patient selection for cardiac transplantation.

The aim of this study was to compare the prognostic ability of NT-proBNP to that of the adrenomedullin, endothelin-1 and tumour necrosis factor-{alpha} in patients with advanced heart failure referred for consideration of cardiac transplantation.


   2. Methods
Top
 Abstract
 1. Background
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patient selection
We recruited 150 consecutive patients with advanced heart failure referred to the Scottish Cardiopulmonary Transplant Unit for cardiac transplant assessment between April 2001 and April 2003. Patients with chronic heart failure secondary to left ventricular systolic dysfunction (LVEF≤35% by radionuclide ventriculography) in New York Heart Association functional class II–IV were included. No patients fulfilled the exclusion criteria of age less than 16 years, pregnancy or known concurrent malignancy. The local research ethics committee approved the study protocol and all patients gave written informed consent. The study complies with the Declaration of Helsinki.

At baseline screening, patients had a full medical history taken, clinical examination performed and NYHA class assigned. All patients had an LVEF measured by RNVG and, where possible, a progressive exercise test to quantify their peak VO2. A baseline HFSS was calculated for each patient [17] Patients were followed up every three months or more frequently as required.

2.2. Measurement of neurohormones and cytokines
Venous blood samples were collected in ethylenediamine–tetraacetic acid-containing tubes. The samples were spun at 3000 rpm for 10 min at 0 °C and the plasma extracted and frozen in aliquots at –70 °C until analysis. NT-proBNP was measured using a chemiluminescent immunoassay kit (Röche Diagnostics) on an Elecsys 2010 analyser. Adrenomedullin was measured, after prior plasma extraction on reverse phase C18 columns, using a radioimmunoassay kit supplied by Phoenix Pharmaceuticals of Belmont, California, USA. Human TNF was measured directly by enzyme immunoassay using a kit supplied by Quidel (UK), Oxford, UK. Human endothelin (1–21) was measured directly in plasma using a Biomedica enzyme immunoassay kit supplied by Cozart Bioscience, Abingdon, Oxfordshire. NT-proBNP, ADM, TNF and Et-1 have a within- and between-assay coefficients of variation of up to a maximum of 6%, 15%, 11% and 8%, respectively. The clinicians involved with the patients' care were blinded to the neurohormone concentrations obtained.

2.3. Follow-up
The primary end point was all-cause mortality. The secondary endpoint was all-cause mortality or urgent transplantation. Urgent transplantation is considered in suitable inotrope dependent patients with end-stage heart failure who have an anticipated life expectancy of less than 1 week. Patients were followed up until the endpoints were reached or 22nd February 2004. The median follow-up was 666 days (range: 1–1047). No patients were lost to follow-up.

2.4. Statistical analysis
All data analysis was performed using the Statistical Package for Social Sciences (SPSS 9.0) software (SPSS, Chicago, Illinois). Normally distributed, continuous data, unless otherwise stated, are expressed as mean values (±S.D.). Non-normally distributed continuous data are expressed as medians [25th and 75th percentile].

Cumulative univariate adverse event rates were compared by use of {chi}2 tests with risk ratios and 95% confidence intervals quoted. Kaplan–Meier survival curves were calculated with the data dichotomised at the mean or median values for each parameter as appropriate. The mean values of clinical variables for patients with and without the primary or secondary endpoints were compared by the use of independent t tests and median values by the Mann–Whitney U-test.

To compare the predictive value of NT-proBNP, endothelin-1, adrenomedullin and TNF{alpha}, receiver operating characteristic (ROC) analysis was performed and the area under the curves calculated [18]. To identify predictors of death, Cox proportional hazards analysis was used and variables achieving p<0.10 on univariate analysis were then tested in a stepwise (forward) multiple Cox regression survival model to determine the independent predictors of both the primary and secondary endpoints. A p<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Background
 2. Methods
 3. Results
4. Discussion
 References
 
The baseline clinical and demographic features of the patients are described in Table 1. The population were predominantly male (82.7%). Over 85% of patients were in NYHA classes III and IV, the mean LVEF was 14.9% and the mean peak VO2 was 11.7 ml/kg/min. The NT-proBNP values were skewed with the median concentration being 1494 [530–3930] pg/ml.


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  		Table 1 General patient characteristics in 150 patients with advanced heart failure

 
Of the 150 patients, 25 (16.7%) reached the primary endpoint of death (13.5% 1-year mortality) and 4 (2.7%) were urgently transplanted. The secondary endpoint of death or urgent CTx occurred in 29 (19.3%). A further 29 patients (19.3%) were transplanted during the study, but these subjects were considered survivors.

3.1. Neurohormonal markers of prognosis in advanced heart failure
Table 2 shows the odds ratios for NT-proBNP, endothelin-1, TNF{alpha} and adrenomedullin (dichotomised about their median values) for the prediction of the primary and secondary endpoints. The only significant univariate predictor of all-cause mortality was an NT-proBNP level above the median value (OR=6.9 [2.2–21.3], p<0.001)—out of 25 deaths, 21 (84%) had an NT-proBNP concentration above the median, compared with four deaths below the median level. Also, 86% of patients who reached the combined endpoint of death or urgent transplantation had an NT-proBNP level above the median value.


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  		Table 2 Cumulative all-cause mortality and combined endpoint of all-cause mortality or urgent transplantation

 
Table 3 describes the mean and median values of various clinical parameters, as well as the mean concentrations of NT-proBNP, endothelin-1, TNF{alpha} and adrenomedullin in survivors, non-survivors and in those who died or were urgently transplanted. The median NT-proBNP concentration in patients who died was 2645 pg/ml, compared to that of survivors of 1031 pg/ml (p<0.001) and the median NT-proBNP concentration in patients who died or required urgent transplantation was 4325 pg/ml, compared to that of survivors of 1017 pg/ml (p<0.001).


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  		Table 3 Mean values of variables (*Median values [interquartile range]) for patients incurring or spared primary and secondary endpoints

 
The areas under the curve on ROC analysis for NT-proBNP, Et-1, TNF{alpha} and Adm, for the prediction of the primary and secondary endpoints are shown in Figs. 1 and 2. The greatest area under the curve for both endpoints was NT-proBNP (AUC=0.785 and 0.822, respectively, p<0.001).


Figure 1
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  		Fig. 1 ROC curves for NT-proBNP, endothelin-1, tumour necrosis factor-{alpha} and adrenomedullin against all-cause mortality in 150 patients with advanced heart failure.

 


Figure 2
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  		Fig. 2 ROC curves for NT-proBNP, endothelin-1, tumour necrosis factor-{alpha} and adrenomedullin against all-cause mortality and urgent transplantation in 150 patients with advanced heart failure.

 
Multiple Cox proportional hazards regression analysis was performed using the above univariate predictors (NT-proBNP, Et-1, TNF{alpha} and Adm). The analysis was first conducted with variables dichotomised about their median value and then repeated using continuous variables with similar results. NT-proBNP remained the only independent predictor of all-cause mortality ({chi}2=26.95, p<0.0001). For the combined endpoint of all-cause mortality or urgent cardiac transplantation, the only independent predictor was again an NT-proBNP value above the median ({chi}2=31.23, p<0.0001). Endothelin-1, Adm and TNF{alpha} were not independently predictive of mortality or need for urgent transplantation.

Kaplan–Meier survival curves for all-cause mortality are depicted in Fig. 3 for NT-proBNP, Et-1, Adm and TNF{alpha}. The only predictor of all-cause mortality was an NT-proBNP above the median value (log rank statistic=17.23, p<0.00001). Kaplan–Meier survival curves for all-cause mortality and urgent transplantation are shown in Fig. 4 for the same variables. The only predictor of mortality or urgent CTx was again NT-proBNP (log rank statistic=21.75, p<0.00001).


Figure 3
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  		Fig. 3 Kaplan Meier Survival curves for NT-proBNP, endothelin-1, tumour necrosis factor-{alpha} and adrenomedullin stratified above (broken line) and below (solid line) the median concentration, against all-cause mortality.

 


Figure 4
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  		Fig. 4 Kaplan–Meier Survival curves for NT-proBNP, endothelin-1, TNF-{alpha} and adrenomedullin stratified above (broken line) and below (solid line) the median value against all-cause mortality and urgent transplantation.

 

   4. Discussion
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
References
 
This study first of all highlights that advanced heart failure is associated with a poor prognosis: 16.7% of patients died and 19.3% either did not survive or were urgently transplanted in the median follow up period of 666 days. The truly advanced nature of the LVSD in this transplant referral population is also highlighted by the fact that the mean LVEF was 14.9% and the mean peak VO2 was 11.7 ml/kg/min, and 85% of patients were either in NYHA Classes III or IV.

Brain natriuretic peptide (BNP) and the N-terminal portion of pro-brain natriuretic peptide (NT-proBNP) are now well established both in the diagnosis and assigning of prognosis in all stages of CHF. These natriuretic peptides are known to be increased in both asymptomatic and symptomatic LVSD [19,20] and increase in proportion to the severity of chronic heart failure [21]. They also independently predict morbidity and mortality in asymptomatic LVSD, [22] in mild-moderate [23–25] and severe CHF [12]. In addition, BNP has also been shown to be a strong, independent predictor of sudden death in patients with CHF [26]. Similarly, NT-proBNP has been shown to be an independent marker of mortality or decompensated heart failure after myocardial infarction [27] or in those with chronic LV dysfunction of an ischaemic aetiology [28].

In this study, NT-proBNP was the only independent predictor of both all-cause mortality ({chi}2=26.95, p<0.0001) and death or urgent transplantation ({chi}2=31.23, p<0.0001) in patients with advanced heart failure referred for heart transplantation. We have shown, for the first time, that NT-proBNP is far superior to adrenomedullin, endothelin-1 and tumour necrosis factor-{alpha} in assigning a risk of mortality or the need for urgent transplantation in such a population. Indeed, Adm, Et-1 and TNF-{alpha} were not shown to be univariate predictors of prognosis in this cohort. As such, this work adds weight to our previous finding that NT-proBNP is a superior marker of prognosis than traditional markers of outcome in advanced heart failure.

Further evidence of the prognostic properties of B-type natriuretic peptides was demonstrated in a recently published substudy of the Val-HeFT trial, where BNP was compared to norepinephrine, renin activity, aldosterone and Et-1 in 4300 patients with heart failure [29]. Although all of the neurohormones were found to be univariate predictors of mortality, only the first two were found to be independent markers of prognosis. Indeed, BNP had the highest predictive value for death, as well as heart failure hospitalizations. However, this study did not assess the prognostic potential of either Adm or TNF-{alpha}.

Adrenomedullin is an endogenous vasodilating 52-amino acid peptide that was originally isolated from human phaechromocytoma cells, and has a structural homology related to calcitonin gene-related peptide [30]. It has potent natriuretic and diuretic properties [31] and is known to be increased in hypertension, heart failure and chronic renal failure in relation to the severity of disease [32,33] Richards et al. [27] first demonstrated that NT-proBNP concentrations, not Adm, were independently predictive of death and left ventricular failure following myocardial infarction. However, subsequently Pousset et al. [13] demonstrated that Adm was an independent predictor of prognosis in mild-moderate CHF.

In contrast, tumour necrosis factor-{alpha} is a pro-inflammatory cytokine that has been shown to be elevated in CHF, particularly in those with cachexia [34,35] and appears to reflect the severity of the disease [34,36,37], TNF{alpha} has also been shown to be a univariate, but not multivariate, predictor of mortality, [16,37] although in the former study, TNF{alpha} soluble receptor-1 was shown to be an independent marker of prognosis, but was not compared to the natriuretic peptides.

Endothelin-1 is a paracrine peptide with potent vasoconstricting properties. Increased plasma concentrations of Et-1 have been described in patients with CHF, [38] and several studies have shown it to be independently predictive of mortality [14] In the aforementioned study by Poussett et al. [13], Et-1 was also shown to be an independent prognostic marker in patients with mild-moderate CHF, and was found to be superior to Adm. Selvais et al. [39] evaluated the prognostic performances of Et-1, BNP, and N-terminal atrial natriuretic peptide in patients with moderate heart failure and found Et-1 to be the best predictor of cardiac death. However, only a small percentage of patients in their study were treated with a beta-blocker (9% of those in NYHA classes III/IV) and only 40% of patients were in NYHA Classes III/IV compared to 85% in this work, indicating they were not as severe a group of patients.

Although these latter factors (Adm, TNF-{alpha} and Et-1) have been previously shown to be predictive of outcome in patients with heart failure, they were largely performed in patients prior to the use of the entire armamentarium of modern disease-modifying therapies. This current study in a much more contemporary cohort and as such, is more relevant to current practice. This study has confirmed that baseline concentrations of NT-proBNP are powerful and independent predictors of an adverse outcome in patients with advanced heart failure and, for the first time, has demonstrated NT-proBNP is superior to adrenomedullin, endothelin-1 and tumour necrosis factor-{alpha} in assigning a risk of mortality or the need for urgent transplantation in a heart transplant referral population. As such, this work adds weight to our previous finding that NT-proBNP is a superior marker of prognosis than traditional markers of outcome in advanced heart failure.

It is becoming clear that natriuretic peptides, in particular BNP and NT-proBNP, have significant potential in helping to decide which of our advanced heart failure patients may benefit from the scarce resource of a cardiac transplant. Further work still needs to be done to test whether a certain concentration of NT-proBNP at referral would be used or whether a value that is rising or failing to fall with optimisation of disease-modifying therapy would be the best option.

With the 1-year mortality rate post-transplantation being in the region of 15–20% [40], it is of vital importance to try and select those for the procedure whose mortality rate exceeds this. It should be noted that in our study, the mortality rate at our median follow-up of 666 days was 28% in those with a NT-proBNP concentration greater than the median value, compared to 5.3% in those with an NT-proBNP concentration less than the median value, and 84% of the deaths and 86% of the secondary endpoints occurred in this group with an NT-proBNP above the median level for the cohort. As rapid assays for BNP and NT-proBNP are now available for the diagnosis of heart failure, it is tantalizing to think that we now may well have a simple, non-invasive marker of the severity of heart failure to help unravel the complex problem of whom to refer for cardiac transplantation.


   Acknowledgements
 
We would like to acknowledge the help and support of Dr. Roger Carter PhD and Dr. Bill Martin PhD, and the patients and staff of the Scottish Cardiopulmonary Transplant Unit. We would also like to acknowledge the financial assistance of the British Heart Foundation.


   References
Top
 Abstract
 1. Background
 2. Methods
 3. Results
 4. Discussion
 References
 

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