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European Journal of Heart Failure 2007 9(8):776-786; doi:10.1016/j.ejheart.2007.05.007
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© 2007 European Society of Cardiology

The role of plasma biomarkers in acute heart failure. Serial changes and independent prognostic value of NT-proBNP and cardiac troponin-T

Marco Metraa,*, Savina Nodaria, Giovanni Parrinellob, Claudia Specchiab, Loretta Brentanaa, Patrizia Roccaa, Francesco Fracassia, Tania Bordonalia, Patrizia Milania, Rossella Danesia, Giulia Verzuraa, Ermanna Chiaria and Livio Dei Casa

a Section on Cardiovascular Diseases, Department of Experimental and Applied Medicine, University of Brescia Italy
b Section of Medical Statistics, Department of Medical Sciences and Biotechnology, University of Brescia Italy

* Corresponding author. Cattedra di Cardiologia, c/o Spedali Civili, Piazza Spedali Civili, 25100 Brescia, Italy. Tel.: +39 030 3995573; fax: +39 030 3700359. E-mail address: metramarco{at}libero.it


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Aims: Brain natriuretic peptide (BNP), NT-proBNP and troponins are useful for the assessment of patients with heart failure. Few data exist about their serial changes and their prognostic value in patients with acute heart failure (AHF).

Methods and results: NT-proBNP and troponin-T plasma levels were measured at baseline, after 6, 12, 24, 48 h and at discharge in 116 consecutive patients with AHF and no evidence of acute coronary syndrome. NT-proBNP levels were 4421 pg/mL at baseline, declined after 24 h and reached their nadir at 48 h (2703 pg/mL). Troponin-T was detectable in 48% of patients. During a median follow-up of 184 days, 52 patients died or had a non-fatal cardiovascular hospitalisation. At a multivariable analysis including clinical and echo-Doppler variables, NT-proBNP plasma levels at discharge, detectable troponin-T plasma levels, and NYHA class at discharge were the only independent prognostic factors.

Conclusion: In patients with AHF, NT-proBNP levels decline 24 h after the initiation of intravenous therapy and troponin-T is detectable in 48% of cases. NT-proBNP levels at discharge, detectable troponin-T levels, NYHA class and serum sodium have independent prognostic value.

Key Words: Acute heart failure • Prognosis

Received May 5, 2006; Revised March 22, 2007; Accepted May 8, 2007


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Acute heart failure (AHF) is the most common cause of hospitalisation for patients aged >65 years [1,2]. It is associated with a poor prognosis and with a risk of death or rehospitalisation of 30 to 60% in subsequent months [2,3,4]. These patients, therefore, warrant an accurate prognostic assessment. From this perspective, plasma biomarkers are particularly attractive as they are easier to measure and less operator dependent than clinical and instrumental parameters. In previous studies, brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) serum levels [5-14] and cardiac troponins [15-20] have been shown to be related to the severity and prognosis of patients with heart failure (HF). However, there are several limitations to the data obtained in these studies. Firstly, most of these studies were performed in outpatients with chronic HF [7,15,17,18]. Secondly, these studies were often based only on measurements taken either at admission and/or at discharge [8,10,11,13] with different results about which had the greatest prognostic value [8-11,14]. Thirdly, only a few studies have compared the prognostic value of plasma biomarkers with standard clinical, laboratory and echo-Doppler parameters [7,9,17]. Lastly, controversial results have been obtained with respect to serial changes in plasma biomarkers [9,14,19,21-25]; with some studies showing a tight relation between these changes and left ventricular (LV) filling pressures [21,23] while others did not confirm these findings [24,25]. To date, only one study [19] has assessed serial troponin changes.

In the present study, we therefore assessed changes in NT-proBNP and cardiac troponin-T (cTnT) plasma levels over time, the prognostic value of measurements taken on admission and at discharge, as well as absolute and percentage changes, and compared them to standard clinical, laboratory and echocardiographic variables, in consecutive patients hospitalised for AHF.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Patients
We prospectively recruited patients admitted to our hospital with a diagnosis of AHF between September 2003 and September 2005. Patients had to satisfy the European Society of Cardiology diagnostic criteria for AHF [2] and to need treatment with intravenous agents, namely furosemide. All patients gave written informed consent and the study was approved by the local Ethics Committee. We excluded patients who were unable to give informed consent and those with symptoms and/or electrocardiographic signs suggestive of myocardial ischaemia, acute arrhythmia, myocarditis, valve stenosis, cardiac tamponade, aortic dissection, high output syndrome or evidence of non cardiovascular factors as the main cause of symptoms. Patients who underwent coronary revascularisation procedures (CABG or PCI) during the current admission or with planned revascularisation were also excluded.

All patients underwent a complete clinical and laboratory examination at the time of hospital admission, on an at least a daily basis thereafter, and at the time of hospital discharge. Doppler-echocardiography was performed at baseline, <12 h after the initiation of intravenous therapy, and before discharge. Discharge was always planned on the basis of improvement in the patient's symptoms and resolution of the clinical signs of congestion, with no knowledge of the echo-Doppler measurements at discharge or of the NT-proBNP and cTnT measurements.

2.2. Laboratory exams
NT-proBNP and cTnT plasma levels were measured at the time of initiation of intravenous therapy (baseline), after 6, 12, 24 and 48 h and at the time of discharge from hospital. Blood samples were taken with 10-mL EDTA syringes. Plasma was separated and stored at –80 °C until assay, which was performed using a third-generation electrochemiluminescent immunoassay for cTnT and a first generation assay with an Elecsys automatic analyzer for NT-proBNP (Elecsys pro-BNP® and Elecsys Troponin-T®, Roche Diagnostics GmbH). The lower detection limit for cTnT was 0.010 ng/mL. Values >0.010 ng/mL were considered abnormal. At the time of blood collection, the physicians were unaware of the NT-proBNP and cTnT results. Blood analyses for plasma NT-proBNP and cTnT concentrations were performed after patients' discharge by personnel from an independent laboratory.

Glomerular filtration rate was calculated by the Modification of Diet in Renal Disease (MDRD) equations [26].

2.3. Echocardiography
Each patient underwent standard Doppler-echocardiography at baseline (within 24 h of admission) and before discharge. Echo-Doppler measurements were performed according to standard protocols. Mitral inflow pattern was considered as restrictive when the early to late peak velocity ratio was >1 and/or the deceleration half time was <130 ms [27,28]. Similarly to previous studies [9,27], the patients were categorized on the basis of the evidence of increased filling pressures. Namely, we considered as evidence of increased ventricular filling pressures, the presence of either a restrictive left ventricular (LV) filling pattern and/or of inferior vena cava congestion at Doppler-echocardiography.

2.4. Statistical analysis
Continuous variables with a normal distribution were expressed as mean±standard deviation. Skewed variables, namely NT-proBNP and cTnT plasma levels, were reported as median values with their 25th and 75th percentiles (interquartile range, IQR). Categorical variables are presented as percentages and compared by chi-square test or Fisher exact test. The measurement of abnormal cTnT levels was entered as a categorical variable with patients subdivided into those with or without detectable cTnT levels in any of the 6 measurements performed during the initial hospitalisation. NT-proBNP and cTnT changes from baseline during the initial hospitalisation were evaluated by generalized linear mixed model for NT-proBNP and descriptive analysis given the relatively small number of data.

Two end-points were used to assess the outcome: all-cause mortality and the combined end-point of all-cause mortality or cardiovascular hospitalisation. Cumulative survival estimates were calculated using the Kaplan-Meier method. Patients were censored at the time of transplantation or of any cardiac surgical procedure. NT-proBNP levels were analyzed as continuous variables and were log transformed to take into account their skewed distribution. To compare the prognostic value of NT-proBNP measurements obtained at different intervals during the hospitalisation and to compare the prognostic value of absolute NT-proBNP plasma levels with their percent changes we performed a ROC analysis of the relation between NT-proBNP levels and events.

To assess the relative prognostic value of NT-proBNP compared to standard variables, variables related to outcome at univariable analysis (Table 1) were entered into a multivariable Cox regression model [29-32]. The variables entered into this model were the following: age and gender, amongst the demographic variables, body mass index, systolic blood pressure, heart rate, NYHA class, serum haemoglobin, serum sodium, LV ejection fraction (EF) and echo-Doppler evidence of increased ventricular filling pressures, amongst the variables assessed at the time of discharge, treatment with inotropic agents during the hospitalisation, furosemide dose at discharge and digoxin prescription at discharge. For descriptive purposes, we showed the hazard ratio (HR) and 95% confidence intervals (CI) associated with the presence of categorical variables as well as with having values above or below the median values of the continuous variables selected by the multivariable survival analysis.


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  		Table 1 Clinical characteristics of the patients discharged after their first hospitalisation

 
The selection of the significant parameters in the multivariable Cox model was performed by the Akaike Information Criterion. The Harrell's c-index was calculated to validate our models. The c-index is the proportion of all usable subjects pairs in which predictions and outcomes are concordant. This index was calculated after having applied resampling validation of our models by ‘bootstrap’. [33,34]

We also applied the classification and regression tree (CART) model. This model involves repeated subdivisions of patients on the basis of the choice of the optimal cut-point of covariates which may maximize a certain split criterion. CART model was chosen as it is closer to the clinical reasoning and as it classifies patients into homogenous groups of which the actual observed incidences of the events may be calculated [29,35]. Moreover it allowed confirming multivariable results previously obtained by Cox regression analysis. However, as the number of end-points was relatively low, we did not use the CART model to obtain cut-off values for prognostic assessment but only as an exploratory analysis to assess potential interactions between variables and the robustness of our results.

A two-tailed p value <0.05 was considered significant. Statistical analysis was performed using the open source "R language" statistical package. [36]

The size of the study group was calculated with the primary aim of assessing the power of NT-proBNP plasma levels to predict the incidence of major cardiovascular events (death or hospitalisation). Assuming a 6-month incidence of major cardiovascular events of 50% we calculated that a sample size of 120 patients (114 patients plus 6 in-hospital deaths, 5%) would have allowed an 80% power, with an alpha value of 0.05, to detect an HR of 0.50 with respect of the risk of events in the patients with NT-proBNP plasma levels below or above cut-off levels.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Follow-up
Of the 121 patients originally enrolled, 5 were excluded because their symptoms were subsequently diagnosed as being of non-cardiac origin. None of these patients had detectable plasma cTnT levels, and their median NT-proBNP levels were 274 pg/mL (IQR 10-487 pg/mL), at admission. The remaining 116 patients had a diagnosis of AHF confirmed by echocardiography. The median duration of hospitalisation was 11 days (IQR, 2-20 days). During the initial hospitalisation, seven of these patients (6%) died due to worsening HF and two underwent urgent surgery (mitral valve repair for acute mitral regurgitation and heart transplantation for severe HF). The remaining 107 patients were discharged alive from hospital and were followed for 247±183 days (median, 184 days; IQR, 7-444 days). Twenty-one of these patients died during follow-up. Of these, three deaths were sudden, and the other 18 were caused by worsening HF and were preceded by a hospitalisation. Thirty-one other patients had a non-fatal hospitalisation for cardiovascular causes (unstable angina in two cases, stroke in other two and worsening HF in the other 27).

3.2. Baseline clinical characteristics
The characteristics of the patients discharged alive are shown in Table 1. Compared to patients who survived, those who died after their initial hospitalisation had more severe symptoms, lower body weight and LVEF, higher serum BUN and creatinine, more severe mitral regurgitation and were more likely to have a restrictive pattern of LV filling. All these differences were significant both at the time of admission and at discharge. Compared to the others, patients who died or were rehospitalised had also lower systolic blood pressure, serum haemoglobin and serum sodium levels at discharge, were more likely to be treated with an intravenous inotropic agent during the hospitalisation and less likely to receive a renin-angiotensin inhibitor at discharge.

3.3. Serial NT-proBNP changes
In the whole study group, serum NT-proBNP levels remained constant during the first 12 h, started to decline at 24 h (p=0.003), reached their nadir after 48 h and remained stable thereafter. Plasma NT-proBNP levels were significantly higher in the patients who subsequently died, compared to the survivors; and in the patients who died or had a cardiovascular hospitalisation, compared to those with no events (Table 2, Fig. 1).


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  		Table 2 Serum NT-proBNP and troponin-T levels during the initial hospitalisation

 


Figure 01
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  		Fig. 1 Absolute values (median and interquartile range) of NT-proBNP plasma levels of patients subdivided on the basis of their clinical course. Abbreviations, bs = baseline; ds = discharge.

 
3.4. Troponin-T levels
Amongst the 107 patients discharged alive from hospital, serum cTnT was detectable in 41 cases (38%) at baseline with similar percentages thereafter. Overall, 51 patients (48%) had detectable cTnT levels in at least one measurement.

Seven patients (6.5%) had only one abnormal cTnT measurement. Troponin-T was undetectable at baseline but abnormal in subsequent samples in 10 patients (9%). Twenty-six patients (24%) had detectable cTnT levels in all the measurements. In these patients, serum cTnT levels tended to increase during the first 48 h of hospitalisation (Table 2).

The percentage of patients with ischaemic heart disease tended to be higher amongst those with abnormal cTnT levels (31 patients, 61%) compared to those with undetectable cTnT levels (25 patients, 45%; p=0.119). Fourteen patients (27%) with detectable cTnT levels had idiopathic dilated cardiomyopathy. The patients with abnormal cTnT levels had, compared to the others, higher serum BUN (110±58 versus 72±48 gm/dL, p=0.003 at baseline, and 118±62 versus 74±51 gm/dL, p=0.002, at discharge) and higher serum creatinine concentrations, (2.05±0.82 versus 1.50±0.72 mg/dL, p=0.003, at baseline and 2.02±0.95 versus 1.48±0.71 mg/dL, p=0.006, at discharge), with a lower GFR (50±24 versus 64±31 mL/min, p=0.011, at baseline, and 51±24 versus 64±30 mL/min, p=0.015, at discharge). No significant difference was found with respect to any other variable. Patients with detectable cTnT levels during hospitalisation had a worse outcome. Their subsequent mortality was 16/52 patients (31%), compared to 5/55 patients (9%) in those with normal results (p<0.001). Similarly, their death or rehospitalisation rate was 32/52 patients (62%), compared to 20/55 patients (36%) amongst those with normal cTnT results (p<0.001). No difference in outcome was found between the patients with all abnormal cTnT measurements versus those with only one or more abnormal measurement.

3.5. Multivariable analysis
The prognostic value of NT-proBNP levels measured both as absolute values at different time intervals and as percentage or absolute changes from baseline, was assessed by ROC analysis (Table 3). NT-proBNP levels at discharge had the greatest prognostic power (area under curve [AUC], 0.85; 95% CIs, 0.77-0.94 for death and AUC, 0.78; 95%CI, 0.69-0.87 for death or hospitalisations; p<0.001 in both cases). Discharge NT-proBNP levels and detectable cTnT levels were entered into a Cox multivariable model including all the variables significant at univariable analysis and listed in Table 1. The only variables selected by multivariable survival analysis, both for mortality and for mortality or CV hospitalisations, were NT-proBNP at discharge, NYHA class at discharge and presence of detectable cTnT levels. The HR and 95%CIs for cardiac death and death or cardiovascular hospitalisation are shown in Table 4. CART analysis yielded similar results (Fig. 2).


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  		Table 3 Prognostic value of NT-proBNP at different times:area under the ROC curve

 


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  		Table 4 Hazard ratios and 95% confidence intervals for variables selected by multivariable survival analysis

 


Figure 02
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  		Fig. 2 Risk stratification tree for mortality (A), and mortality or cardiovascular hospitalisation (B). Variables and cut-points were chosen on the basis of CART analysis.

 
Kaplan-Meier survival curves for the patients subdivided on the basis of the median NT-proBNP values at discharge, cTnT detection and on the basis of NT-proBNP combined with cTnT or NYHA class are shown in Figs. 3-6GoGoGo.


Figure 03
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  		Fig. 3 Kaplan-Meier all-cause mortality and all-cause mortality and cardiovascular hospitalisation free survival curves for the patients subdivided on the basis of their median NT-proBNP levels at discharge.

 


Figure 04
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  		Fig. 4 Kaplan-Meier all-cause mortality and all-cause mortality and cardiovascular hospitalisation free survival curves for the patients subdivided on the basis of the detection of cTnT levels during hospitalisation.

 


Figure 05
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  		Fig. 5 Kaplan-Meier all-cause mortality and cardiovascular hospitalisation free survival curves for the patients subdivided on the basis of their NT-proBNP levels combined with the detection of cTnT.

 


Figure 06
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  		Fig. 6 Kaplan-Meier all-cause mortality and cardiovascular hospitalisation free survival curves for the patients subdivided on the basis of their NT-proBNP levels combined with NYHA class.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
Acute HF is increasing in prevalence with a high short-term morbidity and mortality [1-4]. We need simple measurements which are sensitive to the effects of treatment and may allow prognostic stratification. NT-proBNP and cTnT levels are related to LV dysfunction and ongoing myocardial damage, respectively [37]. In our study, we assessed serial changes in NT-proBNP and cTnT levels in 116 consecutive patients admitted for AHF and compared their prognostic value with the other standard clinical, laboratory and echo-Doppler variables.

4.1. Time course of NT-proBNP levels
Our patients showed a decline in NT-proBNP plasma levels during the initial hospitalisation. Similar to previous studies [22,24,25], this reduction was evident 24 h after the initiation of treatment, reached its nadir at 48 h and was maintained thereafter. This response seems to lag behind symptoms and haemodynamic changes and this must be taken into account if NT-proBNP levels are used as a surrogate of direct clinical assessment and/or haemodynamic monitoring. Other studies have reported a slightly earlier (≤24 h) decline in BNP levels [21,23]. These differences may be related to the different assay or to the characteristics of the patients and/or their treatment.

The magnitude of the NT-proBNP changes (–28% at 48 h and –29% at discharge) in our study is comparable to that measured by other authors [23-25]. In another study, the decline in natriuretic peptide plasma levels was similar at 1.4 days but greater (–53%) at a later time interval (3.4 days). However, in this study, the effects of therapy were monitored by pulmonary artery catheterisation and this may have allowed better titration of drug therapy [22].

4.2. Troponin-T
In our study, cTnT was detectable in 51/107 patients (48%). Our results confirm and extend previous findings showing that cTnT may be detected in a significant percentage (17% to 46%) of patients with HF and no signs of acute coronary syndrome [15-20]. In contrast to NT-proBNP, cTnT increased from baseline during the hospitalisation, despite ongoing clinical and haemodynamic improvement. These data agree with a recent study [19] and suggest cTnT changes may be a potential target for treatment [35].

4.3. Prognostic value of plasma biomarkers
Our study is one of the few [9,16,17,20] to assess the prognostic value of two plasma biomarkers, NT-proBNP and cTnT, and to compare them with standard clinical and echo-Doppler parameters in patients with AHF. NT-proBNP and cardiac troponins have independent prognostic value in patients with acute coronary syndrome. There are less data in patients with HF, with some [16,17], but not all [20], studies demonstrating their independent prognostic value. Our study confirms that NT-proBNP and cTnT are independent markers of increased risk. Important prognostic variables, like anaemia, renal function and the echo-Doppler signs of increased ventricular filling pressures, though significant at univariable analysis, lost their value at multivariable survival analysis. [27]

Our data are consistent with previous findings [7,9,10]. A recent systematic review of the literature [12] has shown that BNP or NT-proBNP were the most significant prognostic variables for HF patients in 23 of 35 multivariable models and were the only predictors reaching significance in 9 of these models. To our knowledge, Gackowski et al. [9] are the only investigators who, like us, compared the prognostic value of BNP with that of echo-Doppler parameters. In line with our results, they also found that the persistence of a restrictive LV filling pattern was related to mortality at univariable analysis but lost its prognostic value when BNP was entered in the multivariable model. In contrast with clinical and echocardiographic parameters, the detection of increased cTnT levels maintained an independent prognostic value in our study. These data are consistent with the hypothesis that NT-proBNP and cTnT measure different mechanisms contributing to the prognosis of AHF [16,37,38].

We performed serial measurements of NT-proBNP and cTnT during hospitalisation. This allowed the assessment of their relative prognostic value. Similar to other studies [8,9,10], we showed the greatest prognostic value of NT-proBNP levels measured at discharge, compared to those at baseline. In contrast to some previous studies [11,14], the percentage change in NT-proBNP during hospitalisation had a lower prognostic value, compared to its absolute value at discharge. This is likely related to differences in the patients studied as well as in their treatment. In the study by Bettencourt et al [11] NT-proBNP levels were higher than in our study (6778 versus 4421 pg/mL on admission and 4137 versus 2779 pg/mL at discharge). However, their patients received lower doses of furosemide (90±22 mg/day, versus 304±186 mg/day in our study), were less likely to be treated with intravenous vasodilators or inotropes (28% versus 52% of our patients) and none received intra-aortic balloon counterpulsation. It is likely that the more aggressive treatment of our patients induced a decline in NT-proBNP levels, including those patients with more advanced HF, so that a short-term reduction in NT-proBNP was less predictive of outcome, compared with its absolute values at discharge. Our data are consistent with previous studies performed using pulmonary artery catheterisation [39] and Doppler-echocardiography [27] showing the prognostic importance of reaching low absolute values of LV filling pressure at discharge, independently from their values at admission.

4.4. Other prognostic variables
NYHA class was the only other variable selected by our multivariable model, in addition to NT-proBNP and cTnT. The role of the NYHA class was particularly important as it was the second variable selected after NT-proBNP in our CART analysis. When, as in our CART analysis, the cut-off value chosen for NT-proBNP is particularly high, clinical assessment allows further prognostic stratification of the patients with relatively low NT-proBNP levels.

Serum sodium has been consistently shown to have prognostic value in patients with advanced HF, even in the current era of treatment with ACE inhibitors and aldosterone antagonists [30,31]. Although significantly related to prognosis at univariable analysis (Table 1), it lost its predictive power at multivariable analysis. This seems to be related to the relatively small size of our study group as well as to the high predictive power of NT-proBNP. Renal function is an important determinant of prognosis amongst patients with acute HF. [2, 3] Renal function has recently been shown to have an additive prognostic value, compared to NT-proBNP plasma levels, in patients with acute HF. [40] Serum creatinine, BUN and GFR were also different between patients with and without poor prognosis in our study. The lack of independent value of renal function at multivariable analysis is likely caused by the relatively small size of our study group.

4.5. Study limitations
Our study is limited by the relatively small number of patients and by their relatively short follow-up. However, as our study group reflects the experience of a tertiary referral centre, our patients had a high event rate and this allowed significant conclusions regarding the role of serum biomarkers in the prognostic assessment of AHF to be drawn. Another major limitation of this study is the low percentage of female patients included. This reflects the practice of the investigators at the time of enrolment. This low percentage of female patients hinders any inference regarding the role of gender in the prognostic assessment of AHF patients and its interaction with NT-proBNP plasma levels. However, having all the patients treated and followed by the same group has the advantage of ensuring a greater homogeneity of data. Lastly, we did not measure serum C-reactive protein levels or other markers of inflammation. We cannot exclude that; similar to what was found in patients with acute coronary syndromes; serum markers of inflammation may also have an important additional role in patients with AHF.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Our study shows that, in patients with AHF, NT-proBNP plasma levels start to decline 24 h after the initiation of intravenous treatment, reach their nadir after 48 h and remain reduced at discharge. Plasma levels measured at discharge have the greatest prognostic power. A high percentage of patients (48%) have detectable cTnT plasma levels. NT-proBNP plasma levels at discharge, the detection of cTnT and NYHA class have independent prognostic value both for all-cause mortality and for all-cause mortality and cardiovascular hospitalisations.


   Acknowledgements
 
Measurements of NT-proBNP and cTnT plasma levels were performed by an independent laboratory, directed by Zdunek Dietmar, MD. All expenses for samples transportation and performance of the assays were covered by Roche Diagnostics, Ltd. We thank Ildiko Amann-Zalan, Bernhard Trauth and Zuzana Herrmann from Roche Diagnostics, Gmbh for their support during the study.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 

  1. McMurray J., McDonagh T., Morrison C.E., Dargie H.J. Trends in hospitalisation for heart failure in Scotland 1980-1990. Eur Heart J (1993) 14:1158–1162.[Abstract/Free Full Text]
  2. Nieminen M.S., Bohm M., Cowie M.R., et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J (2005) 26:384–416.[Free Full Text]
  3. Cleland J.G., Swedberg K., Follath F., et al. The EuroHeart Failure survey programme a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J (2003) 24:442–463.[Abstract/Free Full Text]
  4. Stewart S., MacIntyre K., Hole D.J., Capewell S., McMurray J.J. More ‘malignant’ than cancer? Five-year survival following a first admission for heart failure. Eur J Heart Fail (2001) 3:315–322.[Abstract/Free Full Text]
  5. Richards M., Troughton R.W. NT-proBNP in heart failure: therapy decisions and monitoring. Eur J Heart Fail (2004) 6:351–354.[Abstract/Free Full Text]
  6. Cheng V., Kazanegra R., Garcia A., et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol (2001) 37:386–391.[Abstract/Free Full Text]
  7. Gardner R.S., Ozalp F., Murday A.J., Robb S.D., McDonagh T.A. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J (2003) 24:1735–1743.[Abstract/Free Full Text]
  8. O'Brien R.J., Squire I.B., Demme B., Davies J.E., Ng L.L. Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LV. Eur J Heart Fail (2003) 5:499–506.[Abstract/Free Full Text]
  9. Gackowski A., Isnard R., Golmard J.L., et al. Comparison of echocardiography and plasma B-type natriuretic peptide for monitoring the response to treatment in acute heart failure. Eur Heart J (2004) 25:1788–1796.[Abstract/Free Full Text]
  10. Logeart D., Thabut G., Jourdain P., et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure. J Am Coll Cardiol (2004) 43:635–641.[Abstract/Free Full Text]
  11. Bettencourt P., Azevedo A., Pimenta J., Frioes F., Ferreira S., Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation (2004) 110:2168–2174.[Abstract/Free Full Text]
  12. Doust J.A., Pietrzak E., Dobson A., Glasziou P. How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review. BMJ (2005) 330:625–634.[Abstract/Free Full Text]
  13. Januzzi J.L., van Kimmenade R., Lainchbury J., et al. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients The International Collaborative of NT-proBNP Study. Eur Heart J (2006) 27:330–337.[Abstract/Free Full Text]
  14. Bayes-Genis A., Lopez L., Zapico E., et al. NT-ProBNP reduction percentage during admission for acutely decompensated heart failure predicts long-term cardiovascular mortality. J Card Fail (2005) 11(5 Suppl):S3–S8.[CrossRef][Web of Science][Medline]
  15. Missov E., Calzolari C., Pau B. Circulating cardiac troponin I in severe congestive heart failure. Circulation (1997) 96:2953–2958.[Abstract/Free Full Text]
  16. Horwich T.B., Patel J., MacLellan W.R., Fonarow G.C. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation (2003) 108:833–838.[Abstract/Free Full Text]
  17. Ishii J., Cui W., Kitagawa F., et al. Prognostic value of combination of cardiac troponin T and B-type natriuretic peptide after initiation of treatment in patients with chronic heart failure. Clin Chem (2003) 49:2020–2026.[Abstract/Free Full Text]
  18. Perna E.R., Macin S.M., Canella J.P., et al. Ongoing myocardial injury in stable severe heart failure: value of cardiac troponin T monitoring for high-risk patient identification. Circulation (2004) 110:2376–2382.[Abstract/Free Full Text]
  19. Gheorghiade M., Gattis Stough W., Adams K.F. Jr., et al. The Pilot Randomized Study of Nesiritide Versus Dobutamine in Heart Failure (PRESERVD-HF). Am J Cardiol (2005) 96(6A):18G–25G.[CrossRef][Web of Science][Medline]
  20. Bertinchant J.P., Combes N., Polge A., et al. Prognostic value of cardiac troponin T in patients with both acute and chronic stable congestive heart failure: comparison with atrial natriuretic peptide, brain natriuretic peptide and plasma norepinephrine. Clin Chim Acta (2005) 352:143–153.[CrossRef][Web of Science][Medline]
  21. Kazanegra R., Cheng V., Garcia A., et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail (2001) 7:21–29.[CrossRef][Web of Science][Medline]
  22. Johnson W., Omland T., Hall C., et al. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol (2002) 39:1623–1629.[Abstract/Free Full Text]
  23. Fitzgerald R.L., Cremo R., Gardetto N., et al. Effect of nesiritide in combination with standard therapy on serum concentrations of natriuretic peptides in patients admitted for decompensated congestive heart failure. Am Heart J (2005) 150:471–477.[CrossRef][Web of Science][Medline]
  24. O'Neill J.O., Bott-Silverman C.E., McRae A.T. III, et al. B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure. Am Heart J (2005) 149:363–369.[CrossRef][Web of Science][Medline]
  25. Miller W.L., Hartman K.A., Burritt M.F., Borgeson D.D., Burnett J.C. Jr., Jaffe A.S. Biomarker responses during and after treatment with nesiritide infusion in patients with decompensated chronic heart failure. Clin Chem (2005) 51:569–577.[Abstract/Free Full Text]
  26. O'meara E., Chong K.S., Gardner R.S., Jardine A.G., Neilly J.B., McDonagh T.A. The Modification of Diet in Renal Disease (MDRD) equations provide valid estimations of glomerular filtration rates in patients with advanced heart failure. Eur J Heart Fail (2006) 8:63–67.[Abstract/Free Full Text]
  27. Pozzoli M., Traversi E., Cioffi G., Stenner R., Sanarico M., Tavazzi L. Loading manipulations improve the prognostic value of Doppler evaluation of mitral flow in patients with chronic heart failure. Circulation (1997) 95:1222–1230.[Abstract/Free Full Text]
  28. Swedberg K., Cleland J., Dargie H., et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J (2005) 26:1115–1140.[Free Full Text]
  29. Fonarow G.C., Adams K.F. Jr., Abraham W.T., Yancy C.W., Boscardin W.J. ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA (2005) 293:572–580.[Abstract/Free Full Text]
  30. Lee D.S., Austin P.C., Rouleau J.L., Liu P.P., Naimark D., Tu J.V. Predicting mortality among patients hospitalised for heart failure: derivation and validation of a clinical model. JAMA (2003) 290:2581–2587.[Abstract/Free Full Text]
  31. Klein L., O'Connor C.M., Leimberger J.D., et al. Lower serum sodium is associated with increased short-term mortality in hospitalised patients with worsening heart failure: results from the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) study. Circulation (2005) 111:2454–2460.[Abstract/Free Full Text]
  32. Felker G.M., Leimberger J.D., Califf R.M., et al. Risk stratification after hospitalisation for decompensated heart failure. J Card Fail (2004) 10:460–466.[CrossRef][Web of Science][Medline]
  33. Harrell F.E. Jr., Lee K.L., Califf R.M., et al. Regression modelling strategies for improved prognostic prediction. Stat Med (1984) 3:143–152.[Web of Science][Medline]
  34. Akike H. A new look at statistical model identification. IEEE Trans Automat Contr (1974) AC19:716–723.[CrossRef]
  35. Mockel M., Muller R., Vollert J.O., et al. Role of N-terminal pro-B-type natriuretic peptide in risk stratification in patients presenting in the emergency room. Clin Chem (2005) 51:1624–1631.[Abstract/Free Full Text]
  36. R Development Core Team. R: A language and environment for statistical computing. (2006) Vienna, Austria: R Foundation for Statistical Computing. Available at: http://www.R-project.org.
  37. Gheorghiade M., De Luca L., Fonarow G.C., Filippatos G., Metra M., Francis G.S. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol (2005) 96:11G–17G.[Web of Science][Medline]
  38. Maytin M., Colucci W.S. Cardioprotection: a new paradigm in the management of acute heart failure syndromes. Am J Cardiol (2005) 96:26G–31G.[Web of Science][Medline]
  39. Stevenson L.W., Dracup K.A., Tillisch J.H. Efficacy of medical therapy tailored for severe congestive heart failure in patients transferred for urgent cardiac transplantation. Am J Cardiol (1989) 63:461–464.[CrossRef][Web of Science][Medline]
  40. van Kimmenade R.R., Januzzi J.L. Jr., Baggish A.L., et al. Amino-terminal pro-brain natriuretic peptide, renal function, and outcomes in acute heart failure: redefining the cardiorenal interaction? J Am Coll Cardiol (2006) 48:1621–1627.[Abstract/Free Full Text]

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