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European Journal of Heart Failure 2006 8(5):509-514; doi:10.1016/j.ejheart.2005.10.013
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© 2005 European Society of Cardiology

Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy

Maria Vittoria Pitzalisa,*, Massimo Iacoviellob, Francesca Di Serioc, Roberta Romitod, Pietro Guidab, Elisabetta De Tommasib, Giovanni Luzzib, Matteo Anacleriob, Lucia Varrasoc, Cinzia Forleob and Nicola Pansinic

a Department of Internal Medicine, Division of Cardiology, The Brody School of Medicine, East Carolina University 600 Moye Boulevard, 27834 Greenville, NC, USA
b Institute of Cardiology, University of Bari Italy
c UO Patologia Clinica I-Policlinico Bari, Italy
d Institute of Cardiology, "Salvatore Maugeri" Foundation IRCCS Cassano, Italy

* Corresponding author. Tel.: +1 252 744 1429; fax: +1 252 744 5884. E-mail address: pitzalism{at}ecu.edu


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objective: To evaluate the role of brain natriuretic peptide (BNP) in predicting the progression of heart failure (HF) after cardiac resynchronization therapy (CRT).

Background: It has been shown that BNP predicts the prognosis and can guide the treatment of HF.

Methods: We studied 50 consecutive patients (61±10 years, 23 male) with HF (8 with ischaemic cardiomyopathy), NYHA class III, left bundle branch block, left ventricular ejection fraction (LVEF) ≤35% (mean 24±6%) who underwent CRT. All patients were taking conventional HF therapy and were clinically stable. Plasma BNP levels were evaluated by two-site dual-monoclonal immunochemiluminescent assay before, and 1 month after CRT. The predictive value of BNP was assessed using univariate and multivariate regression analyses.

Results: During follow-up (mean 19±12 months), HF progression was observed in 14 patients (11 were hospitalised and 3 died after worsening of HF). Multivariate analysis showed that BNP levels before (HR: 2.07; CI: 1.19–3.62; p=0.01) and 1 month after CRT (HR: 2.23; CI: 1.26–3.94; p=0.006) were significantly related to events. At 1 month, a BNP level >91.5 pg/ml had 89% sensitivity, 59% specificity, and negative and positive predictive values of 96% and 33%, respectively, for HF progression after 12 months.

Conclusions: HF patients with high BNP values after 1 month of CRT have worse prognosis during follow-up. Therefore, in these patients other therapeutic options should be considered.

Key Words: Heart failure • Cardiac resynchronization therapy • Echocardiography • Ventricular remodelling • Brain natriuretic peptide

Received May 13, 2005; Revised September 13, 2005; Accepted October 19, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
The prognosis of patients with advanced heart failure remains poor despite advances in medical management [1,2]. Cardiac resynchronization therapy (CRT) is a valuable treatment option for patients with severe heart failure (HF) and left ventricular conduction disturbances [3-6], but up to 30-40% of patients receiving CRT do not benefit from it [7-9]. In heart failure, the mechanism underlying the improvement induced by CRT is mainly related to the reversal of mechanical asynchrony, which is why identifying the presence of mechanical ventricular asynchrony helps to identify CRT responders [8-11]. In responders, left lateral wall pacing optimises ventricular loading conditions, increases systolic function and reduces mitral regurgitation, thus allowing reversal of the remodelling process. In this scenario, neurohormonal activity could be reduced as a consequence of reverse remodelling and lead to further anatomo-functional improvement. On the basis of these considerations, it is possible to hypothesize that neurohormonal status may play a role in identifying and/or managing those who are most likely to benefit from CRT. In this setting, plasma brain natriuretic peptide (BNP) levels reflect both haemodynamic status and neurohormonal activation [12], and measurement of BNP levels can be very useful in diagnosing and prognostically stratifying HF patients [13,14]. Furthermore, high plasma BNP levels after treatment optimisation are associated with a higher probability of events, suggesting that BNP measurements can help to guide HF treatment [15].

The aim of this study was to evaluate the prognostic value of plasma BNP levels in patients with advanced HF, who were receiving CRT.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
All consecutive patients with NYHA class III chronic HF of any aetiology, who had been taking conventional medical HF therapy for at least 3 months and who were scheduled for CRT in our institution, in the period between December 2000 and December 2003, were eligible to participate in this study. All patients had left bundle branch block (LBBB) with a QRS duration of >130 ms, and a left ventricular ejection fraction (LVEF) <35%. All patients were required to be clinically stable, without any spontaneous or provoked angina, or the need for revascularisation procedures. Other exclusion criteria were; acute cardiac failure, coronary artery bypass graft or myocardial infarction within the previous 3 months; valvular stenosis; previous valve replacement or reconstruction; or a history of chronic atrial fibrillation.

The study was approved by the local Ethics Committee, and all of the patients gave their written informed consent.

2.2. Protocol
Between 10 and 5 days before CRT implantation, all patients underwent clinical examination, 12-lead ECG, mono- and two-dimensional echocardiographic and Doppler evaluations, a cardiopulmonary stress test, and BNP determination. The same evaluations were repeated 1 month after implantation, when the patients were paced using the optimal mode and settings. The electro- and echo-cardiographic analyses have been previously described [8,9].

2.2.1. Echocardiographic examination
Echocardiographic recordings were made using a phased-array echo-Doppler system (Philips, NL, Sonos 5500) equipped with a 3 Mhz transducer. After resting for 10 min, the patients were examined in the left lateral recumbent position using standard parasternal, short and long axis, and apical views. Intra-ventricular asynchrony was evaluated by calculating the delay between the motion of the septum and left posterior wall (septal-to-posterior wall motion delay, SPWMD, ms) [8,9]. Calculations were also made of left ventricular end-diastolic diameter (LVEDD), left ventricular ejection fraction (LVEF) and mitral regurgitation (MR, quantified using arbitrary units).

2.2.2. Cardiopulmonary test
The patients underwent symptom-limited cycloergometer exercise testing (10 W/min), assessment of oxygen consumption (VO2) was performed by mass spectrometry (Sensormedics System 2900, Anaheim, CA). VO2 at peak exercise (VO2 peak) was defined as the highest oxygen consumption measured during the last 30 s of the symptom-limited exercise test, and expressed as millilitres per kilogram per minute.

2.2.3. BNP assays
Blood samples were taken after the patient had been resting in a supine position for at least 30 min. Samples were collected into tubes containing aprotonin (500 kU/ml blood) and EDTA (1.5 mg/ml blood), and centrifuged at 4 °C (2000xg, 5 min) within 30 min. The plasma was aspirated, dispensed into plastic tubes and stored at –70 °C, prior to assay. The plasma BNP concentrations were determined using the Bayer ADVIA Centaur® BNP method (two-site dual-monoclonal immunochemiluminescent assay) by physicians who were blinded to patient clinical outcome. The total imprecision (CV) of the assay, assessed in compliance with the NCCLS EP5-A protocol, was 3.7%, 3.2%, 3.2%, and 4.1% at BNP concentrations of 41.3, 397, 1517, and 1010 pg/ml, respectively. The detection limit (analytical sensitivity) was 1.13 pg/ml and the lowest BNP concentrations with a CV ≤20% (functional sensitivity) was 4.36 pg/ml. The ADVIA Centaur® BNP method was linear for BNP concentrations from 4.52 to 4550 pg/ml (NCCLS EP6-P protocol).

2.2.4. Pacemaker implantation
Twenty-seven patients received a biventricular pacemaker (Contak TR CHFD, Guidant, MN, USA or InSync III, Medtronic, MN, USA), and 23 patients received a biventricular cardioverter-defibrillator (Contak CD CHFD or Contak Renewal, Guidant, MN, USA or InSync ICD or InSync Marquis, Medtronic, MN, USA or Epic HF V-339, St. Jude Medical, MN, USA). Left ventricular pacing was obtained transvenously using a unipolar lead with an over-the-wire system (Easytrak, Guidant, MN, USA; Attain OTW, Medtronic, MN, USA; Aescula, St. Jude Medical, MN, USA) positioned, in all cases, in the lateral or posterolateral cardiac vein as previously described [8]. The pacing mode was programmed in DDD, with the lower rate set at 50 bpm. The atrioventricular interval was optimised using Doppler echocardiography. Re-evaluations of coronary-sinus lead position, pacing mode, and programming of timing intervals were performed 1, 3, 6 and 12 months after pacemaker implantation.

2.2.5. Follow-up
The subjects were followed-up as outpatients in our heart failure clinic for at least 12 months, by physicians who were blinded to BNP plasma levels. The evaluated clinical endpoint was the progression of heart failure, defined as death, urgent heart transplantation or hospitalisation due to increased heart failure, or symptoms of progression in the presence of a change in heart failure medication as indicated by any of the following: a 50% increase in the dose of oral medication, the addition of a new class of medication, the addition of intravenous medication, or the introduction of heart failure medication not administered at the time of enrolment [16,17].

2.2.6. Statistical analysis
The data are presented as mean values±standard deviation. A natural logarithm transformation of BNP values was used to normalize the distribution. Continuous variables were compared using Student's t test for dependent (intra-group) and independent (inter-group) comparisons, and frequencies by means of Fisher's test. Survival was analysed using Cox's proportional hazards model, and expressed as hazard ratios (HR) and 95% confidence intervals (CI). The variables found to be significantly associated with the events at univariate analysis were included in a multivariate Cox regression model. The event-free curves were based on Kaplan-Meier analyses. In patients with multiple events, analysis was restricted to the first event. Subjects were censored if they died of causes unrelated to HF. A p value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Clinical and therapeutic characteristics of the 50 patients enrolled are shown in Table 1. During follow-up (mean 19±12 months, median 16 months), HF progression was observed in 14 patients. Three patients died following hospitalisation for acute HF refractory to therapy, two patients were hospitalised for pulmonary oedema (one patient was subsequently transplanted), and 9 patients showed signs of exacerbation of HF (severe peripheral congestion and/or worsening of dysponoea) which was not controlled by increased oral medication and requiring hospitalisation. One patient died due to non-cardiac causes. In 9 patients HF progression occurred during the first year of follow-up. Twenty-two of the 30 patients aged <65 years met the criteria to be listed for heart transplantation. On the basis of functional improvement after CRT, 11 patients were removed from the active heart transplantation list. During follow up, no ICD shocks occurred. The only intervention detected was overdrive pacing on ventricular tachycardia in two patients, but this was not associated with haemodynamic worsening.


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  		Table 1 Baseline clinical characteristics

 
3.1. Baseline evaluation
Of the parameters evaluated at baseline, only SPWMD and plasma BNP levels were significantly associated with HF progression at univariate and multivariate analysis (Table 2).


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  		Table 2 Cox univariate and multivariate regression analysis

 
3.2. BNP changes after 1 month
In the patient group overall, plasma BNP levels did not change significantly after 1 month (145±134 at baseline vs. 148±171 pg/ml). No correlations were found between changes in BNP values ({Delta}BNP) and changes in the haemodynamic and functional parameters. Patients with ischaemic cardiomyopathy were characterised by an increase in BNP values when compared to patients with non-ischaemic disease (257±296 vs. –3±231, p<0.05). Patients with HF progression showed an increase in BNP values compared with patients who did not (160±413 pg/ml vs. –9±146 pg/ml, p<0.05). In a multivariate model, both baseline natural logarithm of BNP levels and of {Delta}BNP after 1 month were significantly associated with HF progression (HR: 3.70; 95% CI: 2.05-6.66; and HR: 2.93; 95% CI: 1.62-5.30, respectively).

3.3. One-month evaluation
After 1 month of CRT, the patients with HF progression showed a longer QRS, higher LVEDD, and higher NYHA class and plasma BNP levels (Table 2); multivariate analysis showed that only NYHA class and BNP values were significantly related to events (Table 2). In a multivariate model including changes in mechanical asynchrony (SPWMD) and in BNP levels after 1 month, both variables remained significantly associated with HF worsening (p=0.031 and p=0.042, respectively). Kaplan-Meier curves using the median 1-month BNP value (91.5 pg/ml) are shown in Fig. 1: a BNP above the median value had 89% sensitivity, 59% specificity, and negative and positive predictive values of 96% and 33% in identifying HF progression occurring during the first year of follow up.


Figure 1
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  		Fig. 1 Kaplan-Meier curves of patients with BNP levels of >91.5 pg/ml and <91.5 pg/ml after 1 month. BNP=brain natriuretic peptide.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The main result of this study is that BNP levels play a predictive role in identifying HF progression among patients undergoing CRT. The baseline evaluation offers additional information to that of mechanical asynchrony, thus leading to a better definition of HF outcome. However, the strongest information concerning clinical outcome comes from BNP levels measured after 1 month of CRT: low BNP levels at this time identify patients with a better prognosis.

These findings improve our knowledge of how to optimise the therapeutic options offered to HF patients, particularly CRT. Over the last few years, there has been increasing evidence of the usefulness of CRT in the treatment of severe HF patients with left ventricular conduction disturbances. Beneficial effects of CRT are reported by a number of studies showing a reversal of remodelling, improved LVEF, decreased mitral regurgitation, and clinical improvements in exercise tolerance and the quality of life [3,4,18]. A reduction in the risk of death or hospitalisation for any cause, for CRT when compared with optimal pharmacological therapy alone has also been demonstrated [5]. However, up to 30-40% of the patients receiving CRT do not benefit from it [7-9]. On the basis of these considerations, researchers have sought to evaluate parameters other than LBBB as a means of prospectively identifying patients suitable for CRT, in particular, echocardiographic parameters reflecting left ventricular asynchrony [8-11]. The presence of ventricular asynchrony is becoming increasingly popular in the clinical arena to better define candidates for CRT; however, it only explores one dimension of heart failure. BNP, by reflecting functional status and neurohormonal activation could be useful in further tailoring biventricular pacing in patients with HF.

BNP is widely considered a useful marker for the diagnosis and prognosis of HF, and as a means of guiding drug treatment [13-15,19,20]. The presence of high plasma BNP levels is associated with an increased risk of death or hospitalisation due to HF progression [13,14]. The titration of HF treatment based on the reduction in plasma N-BNP concentrations has been found to be superior to treatment with empirical trial-based therapy dictated by clinical acumen [15]. In CRT patients, it has been suggested that BNP reflects different degrees of reverse remodelling, thus giving a measure of the effectiveness of the haemodynamic response [21].

We found that plasma BNP levels >91.5 pg/ml 1 month after CRT, identifies a group of patients at high risk of HF progression. Up to now, the decision to implant a CRT device has been based on the clinical severity of heart failure and QRS duration. Even when echocardiographic measures of mechanical asynchrony are taken into consideration [6], there are a number of patients who do not benefit from CRT and their prognosis is poor. Also, the identification of these non-responders is not easy at a clinical level, since the benefits can appear, up to 6 months after implantation. Thus, the possibility of having a measurement which can predict heart failure progression, independently from clinical and echocardiographic parameters, is of great interest. This is supported by the fact that patients at the highest risk could receive more aggressive clinical management; such as re-evaluation of coronary-sinus lead position, pacing mode, programming of timing intervals and basic heart rate, shorter between visit intervals, extra clinical examination, more aggressive therapeutic strategies, cardiac transplantation or other surgical options.

It is interesting to note that baseline plasma BNP levels also offer some information about HF progression after CRT (although weaker than that offered by the 1-month samples); i.e., the higher the BNP values, the worse the prognosis. The prognostic value of BNP cannot be explained by differences in baseline clinical and/or therapeutic stability because all of our patients were in a stable clinical condition and had been taking optimal medical treatment for at least 3 months. High baseline BNP values may reflect a different anatomical and/or functional substrate of HF, thus offering information other than that provided by intraventricular asynchrony as both parameters were independent predictors of outcome. Furthermore, baseline BNP evaluations offer additional information to that provided by mechanical dyssynchrony in selecting candidates for CRT, who mainly benefit from the clinical point of view. Patients with ventricular asynchrony and high BNP values could experience exacerbations of HF during follow-up despite improved systolic function after CRT. The ability of BNP to predict the event is related to the fact that the peptide reflects the complex functional and anatomical status of the cardiovascular system as a whole, and may therefore be a more sensitive parameter of clinical status. However, these suggestions should be substantiated in a controlled study, to clarify whether in patients with high BNP values, CRT should be avoided because it does not improve prognosis or whether in patients with low BNP, CRT should be avoided because these patients already have a good prognosis.

BNP levels after 1 month have a stronger predictive value than those at baseline as shown in Fig. 2. This is explained by the fact that high BNP levels at 1 month identify patients with stable high values and those whose BNP levels increase after CRT. The characterization of patients with high BNP values at baseline was not the aim of the present study but it would be interesting to establish whether these patients would benefit from a different and/or more aggressive therapeutic strategy or whether CRT implantation should be postponed.


Figure 2
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  		Fig. 2 Plot of BNP values at baseline and at 1 month. The values are shown on a natural logarithmic scale. Patients with heart failure progression during follow-up are represented by closed circles, those without heart failure progression by open circles. Dotted lines refer to the median value of BNP at baseline and that at 1 month. BNP=brain natriuretic peptide.

 
In conclusion, plasma BNP levels in HF patients offer useful information about the clinical outcome following implantation of a biventricular pacemaker. High BNP levels 1 month after CRT implantation, identify patients who are likely to experience a higher incidence of hospitalisations and death due to HF progression. Therefore, evaluating BNP levels at this time could greatly influence the management of patients with a CRT device.


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

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