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European Journal of Heart Failure 2006 8(8):832-840; doi:10.1016/j.ejheart.2006.02.006
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© 2006 European Society of Cardiology

Decrease in plasma B-type natriuretic peptide early after initiation of cardiac resynchronization therapy predicts clinical improvement at 12 months

Milos Kubáneka,*, Ivan Máleka, Jan Bytesníka, Petr Frídla, Lucie Riedlbauchováa, Ludmila Karasováb, Véra Lánskác and Josef Kautznera

a Department of Cardiology, Institute for Clinical and Experimental Medicine Vídenská 1958/9, Prague 140 21, Czech Republic
b Department of Clinical Chemistry, Institute for Clinical and Experimental Medicine Prague, Czech Republic
c Department of Medical Statistics, Institute for Clinical and Experimental Medicine Prague, Czech Republic

* Corresponding author. Fax: +420 4024728225. E-mail address: mikb{at}medicon.cz


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
 References
 
Background: Decrease in neurohormonal activation during pharmacotherapy for chronic heart failure (CHF) is associated with haemodynamic and clinical improvement. We tested the hypothesis that changes in neurohormonal activation after initiation of cardiac resynchronization therapy (CRT) predict its long-term clinical effect.

Methods: The study group included 43 patients with CHF (37 males, mean age 62±9 years, NYHA class 3.2±0.4, QRS duration 195±24 ms) who underwent successful implantation of a CRT system. Pharmacotherapy remained stable during the first 3 months of follow-up. Plasma levels of B-type natriuretic peptide (BNP) and big endothelin-1 (big ET-1) were evaluated before and 3 months after implantation. Clinical, echocardiographic and exercise parameters were monitored for a mean period of 25.8±6.7 months.

Results: At 12 months of follow-up 13 non-responders were identified (no improvement in NYHA class (n=10), urgent heart transplantation (n=2) and death due to progressive heart failure (n=1)). CRT resulted in a significant reduction in neurohormone levels (BNP 345.4±346 vs. 267.7±320.8 pg/ml, p<0.01, big ET-1 3.11±1.50 vs. 2.50±1.56 fmol/ml p<0.05), especially in responders. Percentage change in BNP level was a stronger predictor of long-term clinical improvement than clinical, echocardiographic and exercise parameters at 3 months of follow-up.

Conclusions: Percentage change in plasma BNP levels from baseline to 3 months was the strongest predictor of long-term response to CRT and may have potential to predict outcome.

Key Words: B-type natriuretic peptide • Big endothelin-1 • Chronic heart failure • Cardiac resynchronization therapy

Received June 2, 2005; Revised November 4, 2005; Accepted February 8, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
 References
 
Cardiac resynchronization therapy (CRT) has become an accepted treatment modality for patients with advanced chronic heart failure (CHF) and intraventricular conduction delay. Early studies have documented an acute haemodynamic benefit, specifically a significant decrease in pulmonary artery and wedge pressures, and improvement in cardiac output, pulse pressure and left ventricular dp/dt [1-5]. Subsequent clinical trials have confirmed the potential of CRT to improve functional class, exercise tolerance and quality of life. Some studies have also shown a reduction in the number of re-hospitalisations for CHF, related to CRT. More importantly, mounting evidence suggests that CRT can reverse progression of heart failure (reverse remodelling) [6-18]. All the above changes induced by CRT appear to result in a significant reduction in total mortality [19].

Surprisingly, data on the impact of CRT on neurohormonal activation are relatively scarce, despite the fact that both B-type natriuretic peptide (BNP) and big endothelin-1 (big ET-1) correlate with functional class and/or haemodynamics, and are independent predictors of prognosis in patients with CHF [20-28]. Decrease in BNP and big ET-1 associated with drug treatment in patients with CHF correlates with improvement in haemodynamic parameters [29-31], clinical status and prognosis, including number of hospitalisations for deterioration of CHF [32-39].

The aim of this study was to evaluate the effect of CRT on plasma levels of BNP and big ET-1. Specifically, we studied whether basal levels and/or change in neurohumoral activation during treatment are related to clinical efficacy of CRT.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
 References
 
2.1. Study population
The study population included 43 consecutive patients (37 males, age 62±9 years) who underwent successful implantation of a CRT system between August 2001 and October 2002. Baseline characteristics of the study population are listed in Table 1.


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  		Table 1 Baseline characteristics for the study group overall, and for the responders (R) and non-responders (NR)

 
Three subjects had a history of valvular heart disease — two underwent aortic valve replacement for aortic regurgitation and one underwent mitral valve replacement for mitral regurgitation. All subjects had advanced CHF (NYHA class III-IV) despite optimized drug therapy. Other criteria for CRT implant included the presence of intraventricular conduction delay (QRS duration≥140 ms), LV dilation (LV end-diastolic diameter or LVEDD>60 mm) and dysfunction (LV ejection fraction≤35%). Drug treatment remained stable for the first trimester of CRT.

2.2. CRT system implantation
Out of 34 patients in sinus rhythm, 32 underwent implantation of a biventricular pacemaker (Insync III, Medtronic Inc, Minneapolis, MN, USA) and two patients received a biventricular implantable cardioverter-defibrillator (Insync ICD, Medtronic Inc, Minneapolis, MN, USA) for secondary prophylaxis of sudden cardiac death. The remaining 9 patients presented with atrial fibrillation, of these, seven received a dual-chamber pacemaker connected as biventricular with minimum AV delay (Kairos DR coated or Axios DR coated, Biotronik GmbH, Berlin, Germany) and two underwent implantation of a biventricular implantable cardioverter-defibrillator (Insync ICD, Medtronic Inc, Minneapolis, MN, USA). In the nine patients with atrial fibrillation, four patients underwent an upgrade of previously implanted single-chamber ventricular pacemaker to biventricular system while the other patients had de novo implant with subsequent catheter ablation of AV junction.

Commercially available leads were used for right atrial, right and left ventricular pacing or for pacing and defibrillation, respectively. The left ventricular pacing leads were inserted transvenously via the subclavian route, and positioned in the posterolateral or lateral cardiac veins. The other leads were placed in the high right atrium and in the midseptal or apical region of the right ventricle. The mean duration of the procedure was 177±33 min (range 46-195) with fluoroscopic time of 9±6 min (range 1-25). Complications occurred in four subjects: one patient had an asymptomatic dissection of coronary sinus during implant of the LV lead, two patients required repositioning of the LV lead for phrenic nerve stimulation and dislodgement, one subject had a new system implanted following local infection in the pocket one month after primary implant.

All patients with sinus rhythm had the CRT system programmed in DDD mode and lower basic rate in order to achieve atrial tracking at rest. Atrioventricular delay was optimized to maximize aortic velocity time integral by Doppler echocardiography [40]. Patients with atrial fibrillation had the device programmed to biventricular VVIR mode (backup pacing rate 80bpm).

2.3. Biochemical assays
Blood samples were drawn from an antecubital vein in the morning before and 3 months after the implant, following 30 min of bed rest in the supine position. Blood for measurement of plasma BNP was transferred to a chilled tube containing ethylenediaminetetraacetic acid (EDTA) (1 mg/ml) and aprotinin (500 kallikrein inactivator U/mL). Blood for measurement of big ET-1 was withdrawn into a chilled tube with EDTA (1 mg/ml). Test tubes were immediately placed on ice and centrifuged at 4 °C. Plasma samples were stored at –70 °C until assay.

Plasma BNP concentrations were measured using a specific immunoradiometric assay (nonextracted) for human BNP (Shionogi Co. Ltd., Osaka, Japan) as reported previously [20,48]. Plasma big ET-1 levels were measured using a direct enzyme immunoassay for the quantitative determination of human big endothelin-1 (Biomedica, Vienna, Austria) as described in detail elsewhere [22,48].

2.4. Study protocol
Peripheral blood samples for analysis of neurohormones and serum creatinine were drawn at baseline and 3 months after initiation of CRT. At baseline, history, clinical status, drug therapy, echocardiographic parameters and cardiopulmonary exercise testing were evaluated. At 3, 6, 12, 18 and 24 months after implantation of the CRT system, clinical status, drug therapy and echocardiographic data were assessed. In addition, cardiopulmonary exercise testing was performed at 3, 12 and 24 months. At one year of follow-up, patients who were in the same or a worse NYHA class, those who had undergone urgent heart transplantation and/or those who died from cardiac causes, were classified as non-responders to CRT.

2.5. Follow-up evaluation
2.5.1. Clinical assessment
NYHA class [41], blood pressure, heart rate and CHF compensation status were assessed during each clinical follow-up visit. The dose of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and betablockers was expressed as the percentage of the maximal daily dose according to the latest ESC guidelines [42].

2.5.2. Echocardiography
Two-dimensional Doppler-flow echocardiography was performed to assess left ventricular ejection fraction, diastolic dimensions and the degree of mitral regurgitation (Vivid 7, Vingmed-General Electrics, Horten, Norway). Left ventricular ejection fraction was calculated using the single plane method. Mitral regurgitation was diagnosed by colour Doppler and quantified using a semiquantitative scale of 1 to 4 [43].

2.5.3. Cardiopulmonary exercise testing
Cardiopulmonary exercise testing was performed using symptom-limited bicycle ergometry with 25 W increases in workload every 3 min. Minute ventilation (VE), oxygen consumption (VO2) and carbon dioxide output (VCO2) were measured by heated pneumotachograph and mass spectrometry (Sensormedics system, Viasys Healthcare Inc., Conshohocken, Pennsylvania, USA). The VE/VCO2 slope was calculated as the slope of the regression line relating VE to VCO2 during exercise. The VE/VCO2 slope and the value of VE/VCO2 at peak exercise (VE/VCO2 peak) were markers of ventilatory response.

2.6. Statistical analysis
Continuous variables were expressed as the mean±SD. Comparison of data was performed using the Student t test for paired and unpaired data and/or by means of nonparametric Wilcoxon and Mann-Whitney test, when appropriate. For all tests a probability value of p<0.05 was considered significant.

To evaluate the predictive value of changes in BNP and big ET-1 plasma levels, receiver operating characteristic (ROC) analysis was performed, the area under the curve (AUC) calculated and possible cut-off points were selected. Stepwise discriminatory analysis was employed for multivariate analysis. Statistical analysis was performed using SYSTAT 10 software (SPSS Inc. 2000, Chicago, Illinois, USA).

2.7. Ethics
The investigation conforms to the principles outlined in the Declaration of Helsinki, and was approved by the regional ethics committee. All subjects provided their written informed consent to participate.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
 References
 
The mean follow-up was 25.8±6.7 months (range 6.6 to 36.5 months). All patients were followed for longer than 24 months, except for the patients who died or who underwent heart transplantation. A total of 13 patients were identified as non-responders at 12 months of follow-up: 10 patients showed no improvement in NYHA functional class, two underwent urgent heart transplantation and one died due to CHF progression. All the criteria for non-responders were evaluated at 12 months of follow-up.

3.1. Neurohormones
A statistically significant decrease in plasma levels of BNP and big ET-1 was observed at 3 months of follow-up (Table 2). This favourable change in plasma levels of BNP and big ET-1 only occurred in patients who were subsequently identified as clinical responders to CRT. In contrast, plasma levels of both neurohormones increased in the non-responders despite baseline values which were similar to the responders. Renal function and drug regimen and dosage did not change significantly during the first 3 months of follow-up (Table 2).


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  		Table 2 Changes in neurohormonal characteristics and renal function after CRT

 
In order to assess the predictive value of change in BNP and/or big ET-1 in differentiation between responders and non-responders, ROC and AUC parameters were analyzed. Percent change in BNP ({Delta}BNP%) was associated with the largest AUC (0.872±0.067, 95% confidence interval 0.734-0.954), followed by absolute change in BNP ({Delta}BNP pg/ml) (AUC=0.833±0.075, 95% confidence interval 0.688-0.929). Other parameters included absolute changes in big ET-1 ({Delta}big ET-1 fmol/ml) (AUC=0.795±0.081, 95% CI 0.644-0.902 and percent changes in big ET-1 ({Delta}big ET-1 %) (AUC=0.792±0.082, 95% CI 0.641-0.901). Thus, {Delta}BNP% was found to be the optimal discriminator. Fig. 1 shows individual patient values and optimal cut-off point. A drop in {Delta}BNP% of more than –6.7% differentiated responders from non-responders with 90% sensitivity and 77% specificity. Positive predictive value reached 90% and negative predictive value 77%. However, this limit for {Delta}BNP% is a type of post hoc limit, which could overestimate the predictive importance.


Figure 1
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  		Fig. 1 Individual values of percent change in BNP level ({Delta}BNP%) in responders (Rs) and non-responders (NRs). The figure illustrates selection of cut-off point.

 
3.2. Clinical parameters
CRT produced a significant improvement in NYHA functional class that remained stable over 24 months of follow-up (Table 3). Baseline systolic blood pressure was significantly higher in responders than in non-responders (Table 1). A significant reduction in systemic blood pressure was observed in non-responders at six months (Table 3), which might indicate worsening of dyssynchrony or progression of disease.


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  		Table 3 Changes in clinical, echocardiographic and exercise parameters during CRT-responders (R) and non-responders (NR)

 
3.3. Echocardiography
Reasonable quantification of mitral regurgitation was possible in 83% of patients at baseline and in 84%, 72%, 74%, 83% and 69% at 3, 6, 12, 18 and 24 months of follow-up, respectively. A statistically significant decrease in LVEDD and in the degree of mitral regurgitation was observed, together with an improvement in LVEF (Table 3). This favourable change occurred predominantly in the responders.

3.4. Cardiopulmonary exercise testing
Cardiopulmonary exercise testing could not be performed in all subjects, as follows. Extra-cardiac limitation precluded testing at baseline in 19% of subjects. Low compliance prevented testing in some patients during follow-up. Testing was performed in 86% of patients at 3 months, in 83% at 12 months, and in 56% at 24 months. A significant improvement in exercise duration, peak exercise systolic blood pressure (peak SBP), peak VO2 and a drop in VE/VCO2 slope and VE/VCO2 peak were observed at 3 months (Table 3). Increase in peak SBP was largely determined by higher increase in SBP during exercise ({Delta}SBP). Again, these favourable results were predominantly observed among responders and remained stable during follow-up.

3.5. Progression of disease
Clinical responders to CRT were less frequently hospitalised for CHF decompensation as compared to non-responders: 6 episodes in 3 of 30 patients vs. 11 episodes in 6 of 13 patients, p<0.05. The groups also differed in the progression of the disease. Among the 30 responders, one patient died suddenly (15.8 months after implant) and one patient died due to progression of CHF (32.6 months after implant). Of 13 non-responders, two subjects died due to progression of CHF (8.8 and 17.5 months after implant), three underwent urgent heart transplant (6.6, 11.6 and 15.7 months after implant, respectively) and two others were transplanted electively (20.3 and 24 months after implant). Cardiac death and/or heart transplantation were thus more frequent among non-responders (2/30 vs. 7/13, p<0.01). The duration of follow-up was significantly longer in the responders as compared to the non-responders: 840±137 days (483-1094) vs. 619±237 days (203-954), p<0.001.

3.6. Medical treatment
No significant change in medical treatment was observed after three months of follow-up (Table 4 - See Appendix A. Supplementary data). Responders tolerated higher doses of betablockers at baseline and the dosage increased during follow-up. Doses of angiotensin receptor blockers, hydrochlorothiazide and digoxin did not change significantly.

3.7. Prediction of response to CRT
Prediction of long-term outcome of CRT was assessed both from parameters at implant and three months later. Stepwise discriminatory analysis of implant data revealed QRS width following implant as the most predictive of therapeutic response to CRT. However, this parameter would correctly identify only 70% of responders and 61% of non-responders (67% of all subjects).

Univariate analysis revealed that after three months of follow-up, responders showed more pronounced improvement in NYHA class ({Delta}NYHA):–1.1±0.5 vs. –0.7±0.5, p=0.07. They also presented with a decrease in LVEDD, and an increase in LVEF, peak SBP and peak VO2 (Table 3). This favourable change was associated with a significant decrease in BNP and big ET-1 (Table 2) and responders tolerated higher dose of betablockers (Table 4). Stepwise discriminatory analysis included baseline parameters and {Delta}NYHA, {Delta}LVEF, {Delta}BNP%, {Delta}big ET-1 % and the dose of betablockers at three months of follow-up. {Delta}BNP% and {Delta}LVEF at three months of follow-up were identified and would correctly identify 87% of responders and 77% of non-responders (84% of all subjects). Importantly, the result of stepwise discriminatory analysis did not change when the exercise data (peak VO2 and peak SBP at 3 months) were added to the previous model.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Appendix A. Supplementary data
 References
 
1) The results of the study can be summarized as follows: A significant decrease in plasma levels of BNP and big ET-1 was observed after three months of CRT, and this change predicted improvement in clinical status at 12 and 24 months of follow-up. 2) Responders to CRT presented with favourable changes in echocardiographic parameters (LVEF, LVEDD, degree of mitral regurgitation), improvement in cardiopulmonary exercise testing parameters (peak VO2, peak SBP, ventilatory response), with fewer hospitalisations for CHF and a lower occurrence of the combined end-point (cardiac mortality and heart transplantation) during follow-up. 3) Percent change in BNP from baseline to three months of follow-up was identified as the most powerful predictor of long-term clinical outcome.

4.1. Comparison with previous studies
Several other studies have reported a decrease in natriuretic peptide levels among responders to CRT [11,44-46]. The most recent study also reported a significant drop in big ET-1 in response to CRT [46]. However, in all of these studies, neurohormone levels were studied 6 to 9 months after initiation of CRT. Thus, the main importance of this paper appears to be that the long-term outcome of CRT could be predicted by changes in neurohormone levels earlier after implant of the CRT system (i.e. after three months). This may identify a subgroup of patients who should be followed more closely as they have potential for further progression of the disease.

The most extensive neurohormonal evaluation during CRT was performed in the CARE-HF study [19]. As compared with patients in the medical-therapy group, patients in the CRT group had similar plasma levels of N-terminal pro-BNP at 3 months of follow-up. However, at 18 months, plasma levels of N-terminal pro-BNP were lower among patients in the CRT group. These results cannot be interpreted without detailed knowledge of pharmacotherapy and changes in renal function in both groups. A substudy in patients on stable pharmacotherapy during the first trimester of follow-up would be useful.

4.2. Prediction of therapeutic response to CRT
Recent data indicate that intraventricular and interventricular dyssynchrony assessed by tissue Doppler imaging might be significant predictors of LV functional recovery and reversed remodelling after CRT [10,11]. Although we did not compare the predictive value of dyssynchrony markers with plasma BNP, our results suggest that significant decrease in plasma BNP at three months of CRT could be an important predictor of clinical response. Furthermore, analysis of ROC suggested that the decrease in BNP should be expressed as percentage change. Percentage change in BNP was a more powerful predictor of long-term benefit of CRT than NYHA class, conventional echocardiographic parameters and cardiopulmonary exercise testing at 3 months of the follow-up. Importantly, our results suggest that baseline neurohumoral activation does not predict the effect of CRT. This has also been observed in other studies [10,45].

4.3. Practical implications
Our results may have important implications for definition of clinical responders to CRT. Different definitions are used in the literature and there appears to be a shift from functional parameters such as NYHA class, 6-min walk test and/or quality of life towards morphological parameters that document reverse LV remodelling and/or towards harder clinical data such as cardiopulmonary exercise testing, morbidity and mortality [47]. Assessment of plasma levels of BNP at three months of follow-up could be used as another parameter to define clinical response to CRT, especially in patients who do not tolerate cardiopulmonary testing or who cannot undergo reliable echocardiographic evaluation.

4.4. Study limitations
The study was an epidemiological follow-up pilot study, without clear hypotheses in advance. Multiple hypotheses can generate significances by chance.

The power of the study was low and the confidence intervals wide because there were only 13 non-responders. Although percent change in BNP appeared to be the strongest predictor, the wide confidence intervals around the prediction overlap those of many other predictors and combined with the small study size, limits our confidence that percent change in BNP is the best predictor.

The other limitation is that we did not assess intraventricular and interventricular dyssynchrony by tissue Doppler. Therefore, we could not compare predictive values of these parameters with the parameters evaluated in this study.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Appendix A. Supplementary data
 References
 
Our data confirm that CRT is associated with a significant decrease in plasma levels of BNP and big ET-1 at three months of follow-up. These changes from the baseline values predicted subsequent clinical improvement at 12 months of follow-up that persisted over the next 12 months. Among all parameters studied, percentage change in BNP plasma level at three months versus baseline was identified as the strongest predictor of long-term clinical status. Therefore, assessment of plasma levels of BNP might have potential to predict outcome in CRT patients.


   Appendix A. Supplementary data
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
References
 
Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.ejheart.2006.02.006.


   Acknowledgement
 
This study was funded by the grant of the Ministry of Health of the Czech Republic No:VZ IKEM: CEZ L 17/98: 00023001.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Appendix A. Supplementary data
 References
 

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