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European Journal of Heart Failure 2006 8(3):257-262; doi:10.1016/j.ejheart.2005.08.004
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© 2005 European Society of Cardiology

The effect of aortic valve replacement on plasma B-type natriuretic peptide in patients with severe aortic stenosis — one year follow-up

Nils O. Neverdala, Cathrine Wold Knudsenb, Trygve Husebyeb, Øystein A. Vengena, John Pepperc, Mons Liea and Theis Tønnessena,*

a Department of Cardiothoracic Surgery, Ullevâl University Hospital Oslo, Norway
b Department of Cardiology, Ullevâl University Hospital Oslo, Norway
c Department of Cardiac Surgery, The Royal Brompton Hospital London, UK

* Corresponding author. Tel.: +47 23015268. E-mail address: thto{at}uus.no


   Abstract
Top
 Abstract
1. Introduction
 2. Methods and patients
 3. Results
 4. Discussion
 References
 
Background: B-type natriuretic peptide (BNP) is synthesized in cardiac tissue in response to increased wall stress and myocardial hypertrophy.

Aims: In patients with severe aortic stenosis (AS) we examined the effect of aortic valve replacement (AVR) on plasma BNP and association between BNP and left ventricular mass index (LVMI) preoperatively and in the reverse-remodeling phase twelve months postoperatively. We also examined the correlation between BNP and NYHA-class and between BNP and age.

Methods and Results: Plasma BNP analyses and echocardiographic measurements were performed preoperatively, before discharge after AVR, and at twelve months in twenty-two patients. BNP was additionally measured at six months. Preoperatively, BNP was 283±45 pg/ml (mean±SEM). Following an immediate postoperative increase (441±38 pg/ml), BNP values decreased towards normal values at six and twelve months (139±25 and 130±18 pg/ml, respectively). LVMI was 206.5±15.8 g/m2 preoperatively and decreased to 119.7±7.2 g/m2 at twelve months with a correlation between LVMI and BNP preoperatively only (r=0.45, p<0.05). There was no correlation between BNP and NYHA-class, whereas BNP correlated to age both pre- and post-operatively.

Conclusion: We report an increase in plasma BNP in patients with AS. Following a further transient increase postoperatively, BNP levels decreased at six and twelve months after AVR. BNP correlated with LVMI preoperatively, and with age both preoperatively and at twelve months.

Key Words: BNP • Aortic valve replacement • Left ventricular hypertrophy • Regression • Aortic stenosis • Remodeling

Received March 16, 2005; Revised June 28, 2005; Accepted August 22, 2005


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods and patients
 3. Results
 4. Discussion
 References
 
B-type natriuretic peptide (BNP) is mainly synthesized in cardiac ventricular tissues [1], and increased left ventricular wall stress is an important stimulator of BNP synthesis [2]. BNP has been shown to increase in plasma in patients with various cardiovascular diseases such as cardiac hypertrophy [3], heart failure [4] and coronary syndromes [5]. BNP exerts various effects within the cardiovascular system. In addition to diuretic and vasodilatory effects it is considered a protective peptide in that it counteracts hypertrophy of cardiomyocytes and myocardial fibrosis [6].

Circulating BNP is known to increase in patients with myocardial hypertrophy associated with hypertension [3]. It is well recognized that patients with aortic stenosis develop concentric myocardial hypertrophy due to pressure overload. However, little is known about BNP levels in patients with aortic stenosis and how operative treatment with aortic valve replacement and subsequent reduction in afterload with regression of hypertrophy, affects plasma levels of BNP.

Thus, the aim of the present study was to examine the effect of aortic valve replacement on plasma BNP levels up to twelve months after operation for severe aortic stenosis. Moreover, we aimed to examine whether there is any correlation between left ventricular mass index (LVMI) and plasma levels of BNP preoperatively and twelve months postoperatively. In addition, we also wanted to examine whether there was any correlation between plasma BNP and functional status of the patients (determined as NYHA-class and six minutes walking test) and between BNP and age.

Twenty-two patients were included in the study and plasma BNP and echocardiographic measurements were performed preoperatively, immediately postoperatively and at twelve months. BNP was also measured at six months. Additionally, estimation of NYHA-class and 6 min walking test were performed preoperatively and at twelve months.


   2. Methods and patients
Top
 Abstract
 1. Introduction
 2. Methods and patients
3. Results
 4. Discussion
 References
 
2.1. Patients and protocol
Twenty-two patients with severe aortic stenosis (defined as mean aortic valve gradient >50 mm Hg or aortic valve area <0.7 cm2 or symptomatic aortic stenosis) who were eligible to transthoracic echocardiography were prospectively included in this study from Ullevål University Hospital, Oslo, Norway. To minimize the potentially confounding factors of implanting valves made of different materials from different manufacturers, we included only patients receiving a porcine bioprosthesis. Patients receiving a bioprosthesis are not routinely treated with warfarin postoperatively in our department, thus, a potential effect of warfarin on plasma BNP was avoided. The patients received either a stented valve (Mosaic, Medtronic, Inc., Minneapolis, Minnesota, USA) or a stentless valve (Freestyle, Medtronic, Inc.). Both valves are composed of the same material and preserved with the same anti-calcification protocol. No patients underwent additional valve surgery, however, eight patients received additional coronary artery bypass grafting (CABG) (see Tables 1 and 2 for patient characteristics). Blood samples and echocardiographic measurements were performed preoperatively, before discharge (normally at the second postoperative day) and at twelve months, whereas additional blood samples were collected at six months. NYHA-class determination and 6 min walking test were performed by a trained cardiologist preoperatively and at twelve months. Informed written consent was obtained from each patient. The study protocol was approved by the local ethical committee and conforms with the Declaration of Helsinki. No patients were lost to follow-up.


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  		Table 1 Patient characteristics and preoperative data

 


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  		Table 2 Hemodynamic and functional data

 
2.2. BNP analysis
Blood was drawn from an antecubital vein into chilled, standard EDTA tubes (1 mg/ml blood) and kept on ice. Within 30 min the blood was centrifuged and the plasma fraction was immediately frozen and kept at –70 °C until analyzed. BNP was analyzed using a commercially available kit (Triage BNP test, Biosite Diagnostics, Inc., San Diego, California, USA). The kits were generous gifts from Biosite Diagnostics Inc. Intra-assay variation are 9.5%, 12.0% and 13.9% for BNP levels of 28.8, 594.0 and 1180.0 pg/ml, respectively [7]. The measurable range of this assay is 5.0 to 1300.0 pg/ml.

2.3. Echocardiography
Echocardiographic examination was performed by a trained cardiologist and recorded on videotapes. All recordings were examined by an experienced echocardiographer blinded to patient details. Left ventricular mass (LVM) was calculated from the M-mode registration of the LV in parasternal long axis. All measurements were performed in accordance with the recommendations of the American Society of Echocardiography [8]. LVM, ejection fraction, peak gradients, and effective orifice area (EOA) were obtained using standard formulae. LVM was estimated using the Penn Convention formula. Ejection fraction was calculated as (LV diastolic volume–LV systolic volume) divided by LV diastolic volume. Aortic valve flow velocities were assessed by continuous-wave Doppler and peak aortic velocity was used to determine peak aortic valve gradients. EOA was calculated using the continuity equation as follows: (left ventricular outflow tract diameter/2)2x3.14x(time velocity integral of left ventricular outflow tract (cm)) divided by (time velocity integral across the aortic prosthesis (cm)). All indexed values were obtained by dividing by body surface area according to the formula of Mosteler.

2.4. Statistical analyses
Data are presented as means±standard error of the mean (SEM). They were analyzed using SigmaStat, version 3.0, Jandel Scientific GmbH, Erkrath, Germany. One way ANOVA or one way repeated measures ANOVA were used where appropriate. For data that were not normally distributed, one way ANOVA on ranks was used. Multiple comparisons were corrected for by Dunnetts Test. The BNP data were logarithmically transformed to fit a normal distribution examining the relation between two continuous variables by linear regression. P<0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods and patients
 3. Results
4. Discussion
 References
 
3.1. Patient characteristics
Patient characteristics are presented in Tables 1 and 2. As expected, both peak aortic valve gradient, EOA index (EOAI), LVMI, NYHA-class and walking distance improved significantly twelve months postoperatively (Table 2). CRP was transiently increased 2 days postoperatively (203.1±13.1 mg/l) but remained normal at six and twelve months. Mean creatinine values were unchanged throughout the follow-up period. Patient medication is presented in Table 3.


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  		Table 3 Patient medications, (n=number of patients)

 
3.2. BNP measurements
Preoperatively, mean plasma BNP was 283±45 pg/ml (Fig. 1). There was a dramatic increase immediately postoperatively to 441±38 pg/ml whereas at six and twelve months plasma values decreased to 139±25 and 130±18 pg/ml, respectively.


Figure 1
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  		Fig. 1 Plasma BNP in patients preoperatively (preop.), two days postoperatively (postop.) and at six and twelve months (mo.) postoperatively. Data are presented as means±SEM. *p<0.05 vs preoperative value.

 
Mean LVMI was 206.5±15.8 g/m2 preoperatively and decreased significantly to 119.7±7.2 g/m2 at twelve months. There was a significant association between LVMI and log 10 BNP preoperatively as determined by linear regression (Fig. 2A, r=0.45, p<0.05), whereas we were not able to detect any association between the two at twelve months postoperatively (Fig. 2B, r=0.10, p=0.60).


Figure 2
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  		Fig. 2 Correlation between left ventricular mass index (LVMI) and plasma log 10 BNP preoperatively (A) and twelve months postoperatively (B). Dashed lines show 95% confidence and prediction intervals.

 
Preoperatively, there was no correlation between log 10 BNP and peak aortic gradient (r=0.14, p=0.54) or EAOI (r=0.18, p=0.45). There was also no correlation between LVMI and peak aortic gradient (r=0.00, p=1.00). Moreover, we detected no correlation between BNP and maximal CK-MB immediately postoperatively, neither was there a correlation with CRP levels. Furthermore, we measured no differences in BNP or CK-MB plasma levels between the patients receiving stented (Mosaic) compared to stentless valves (Freestyle).

Although there were significant improvements in NYHA-class and walking distance at twelve months compared to the values preoperatively, there was no correlation between the NYHA-class and BNP levels either preoperatively or at twelve months postoperatively.

Preoperative BNP levels were not significantly different between men and women. However, there was a significant positive correlation between age and BNP levels both preoperatively (Fig. 3A) and twelve months postoperatively (Fig. 3B).


Figure 3
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  		Fig. 3 Correlation between age and plasma log 10 BNP preoperatively (A) and twelve months postoperatively (B). Dashed lines show 95% confidence and prediction intervals.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods and patients
 3. Results
 4. Discussion
References
 
In the present study we have shown that plasma BNP is significantly increased in patients with severe aortic stenosis and myocardial hypertrophy. Following operation with implantation of an aortic bioprosthesis there was a transient increase in BNP immediately postoperatively. Both at six and twelve months there was a significant decrease in BNP levels compared to the preoperative levels although normal values were not reached within twelve months. There was a reduction in LVMI postoperatively as a sign of reverse-remodeling, however, plasma BNP was only correlated with LVMI before the operative treatment and not at twelve months postoperatively. We found a significant correlation between BNP levels and age both preoperatively and at twelve months, the latter showing the strongest correlation.

It has been shown that left ventricular wall stress [2,9] and hypertrophy of cardiomyocytes [10] are associated with increased plasma BNP. Aortic stenosis is a disease characterized by increased afterload, increased left ventricular wall stress and myocardial hypertrophy. Preoperatively, we found a significant correlation between LVMI and BNP. This is in accordance with earlier observations [11]. The preoperative high levels of BNP and the correlation to LVMI might be useful information in timing aortic valve surgery although the present study was not designed to answer this question.

We measured no correlation between plasma BNP and NYHA-class or walking distance in the present study. In contrast to this finding, previous studies have reported a positive correlation between NYHA-class and natriuretic peptides [4,12]. However, an increase in NYHA-class might be the result of various pathophysiological processes which might not necessarily be correlated to an increase in plasma BNP. Our patient population with a predominant increase in afterload and preserved left ventricular function is different from patients in for example ischemic heart failure in many aspects and this might in part explain the difference found in the present study and that by Maisel et al. [4]. Moreover, more than half of our patients were in NYHA-class I or II preoperatively, and thus there was little room for NYHA-class improvement in these patients even though plasma BNP decreased significantly. A lack of correlation might also be caused by the limited number of patients in the present study combined with difficulties assessing the NYHA-class correctly in older patients with a mean age of 76 years. Based on the absence of correlation between both BNP and NYHA-class and between BNP and peak aortic gradient, it seems likely that the increased BNP in the present study is related more to left ventricular mass as such than to functional status of the patient or the gradient across the aortic valve.

Immediately postoperatively there was a dramatic increase in plasma BNP. Since BNP is produced by ventricular cardiomyocytes as a response to stress, one might speculate that the increase in BNP postoperatively is due to direct myocardial damage associated with ischemia or cardioplegia during aortic cross clamping. However, we did not find support for this hypothesis since there was no correlation between BNP and the specific marker of myocardial damage, creatine kinase isoenzyme MB (CK-MB). Another possible explanation for the increase in plasma BNP immediately postoperatively could be that BNP is a marker of an acute phase reaction since CRP is also increased. However, we found no correlation between CRP and BNP, making this hypothesis less likely. The mechanisms for the abrupt increase in BNP postoperatively are presently unknown. In a recent publication, Georges et al. [13] reported that a postoperative increase in BNP was not related to any specific type of cardiac surgery, and postulated that the increase was associated with other factors related to surgery such as anesthesia, sternotomy, hemodynamic alterations etc.

Although it has previously not been clear how plasma BNP changes in patients up to one year after operation for aortic stenosis, Qi et al. [14] have measured N-terminal proBNP (Nt-proBNP) in plasma following aortic valve replacement. They found, however, no significant alterations in Nt-proBNP in patients during a one year postoperative follow-up. Since proBNP is cleaved into the biologically active BNP and Nt-proBNP, it would be expected that these peptides follow the same pattern in plasma following operation for aortic stenosis. However, studies have shown that in vivo half-life of Nt-proBNP is longer than for BNP [15] suggesting that BNP might be more suitable for measuring short-term variations (e.g. in the perioperative phase). Because of its longer half-life, Nt-proBNP might be equally good or better when monitoring long-term variations in plasma levels (such as twelve months postoperative follow-up). Therefore, the differences of the present study and the study by Qi et al. [14] are most likely not based on biological differences of the two peptides, but rather based on differences in study populations. Qi et al. detected no regression of LMVI after aortic valve replacement, and preoperative LVMI was lower than in the present study. This might indicate that the patients in that study had less severe strain to the left ventricle than those in the present.

It is known that reverse-remodeling takes place in the heart following operation for aortic stenosis [16,17]. First, there is a reduction in the size of cardiomyocytes. Secondly, there is a reduction in cardiac fibrosis. The first phase takes place from the first months up to a year after surgery, whereas the second phase takes place from one year and might continue for several years [16]. Even though BNP is a marker of myocardial hypertrophy, it also inhibits myocyte growth and fibrosis [18]. Although BNP was significantly decreased at six and twelve months postoperatively it was still elevated compared to the normal population [19,20]. The fact that BNP levels were still elevated at six and twelve months in the present study might indicate that BNP is a marker of insufficient reverse-remodeling with an ongoing stimulus for BNP synthesis. On the other hand, since BNP inhibits myocyte growth and fibrosis, the high levels of BNP immediately postoperatively combined with the moderately increased levels at six and twelve months might indicate a more direct role for BNP in the reverse-remodeling process. By reducing fibrosis, BNP might reduce diastolic myocardial stiffness and improve diastolic dysfunction. Such a role for BNP has been suggested in an experimental study in which it was reported that pressure overload induced a higher degree of ventricular fibrosis in mice genetically lacking BNP as compared to wild-type mice [21]. Moreover, it has demonstrated beneficial effects of BNP administration to patients with symptomatic diastolic heart failure [22].

We measured a positive correlation between age and BNP both preoperatively and at twelve months. However, the robust design of the present study in that each patient was his own control, avoiding the inter-individual variation (such as differences in age), secured that the variations in plasma BNP throughout the study protocol were not masked by the age-related variations. It should also be noted that in a study examining the correlation between plasma BNP and age in 60 persons up to the age of 83 with normal left ventricular function, none had plasma BNP above 75 pg/ml [19]. This indicates that the elevated plasma BNP in our patients is not a result of increased age, a statement also supported by other studies [20,23].

In conclusion, we report an increase in plasma BNP in patients with severe aortic stenosis with a further increase immediately after aortic valve replacement. BNP levels decreased over the next six and twelve months, normal values were, however, not fully reached. BNP correlated with LVMI only preoperatively. We could not demonstrate any correlation between BNP and functional state neither preoperatively nor twelve months postoperatively. Further studies are needed to investigate the biological consequences of the changes in plasma BNP demonstrated in the present study.


   Acknowledgements
 
The authors are grateful to the staff at Dept. of Cardiothoracic Surgery, Dept. of Cardiology, Institute for Experimental Medical Research at Ullevål University Hospital, Oslo, Norway and Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, UK.

The study was supported by research grants from Medtronic, Inc., and The Ingegerd and Viking Olov Bjørk Scholarship received by Dr Theis Tønnessen.


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

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