Interact CardioVasc Thorac Surg 2008;7:419-424. doi:10.1510/icvts.2007.168039
© 2008 European Association of Cardio-Thoracic Surgery
Institutional report - Valves |
Preoperative, postoperative and 1-year follow-up N-terminal pro-B-type natriuretic peptide levels in severe chronic aortic regurgitation: correlations with echocardiographic findings
Alessandro Della Cortea,*,1,
Gemma Salernoa,
Emilio Chiosib,
Diana Iarussia,
Giuseppe Santarpinoa,
Maurizio Miragliaa,
Silvio Navigliob and
Marisa De Feoa
a Department of Cardiothoracic and Respiratory Sciences, Second University of Naples, V Monaldi Hospital, Naples, Italy
b Department of Biochemistry and Biophysics, Second University of Naples, Italy
Received 14 September 2007;
received in revised form 4 March 2008;
accepted 5 March 2008
1 PhD program ‘Medical and Surgical Physiopathology of the Cardio-Respiratory System and Associated Biotechnologies’, Second University of Naples 
 Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
*Corresponding author. Via P. Neruda 6, 81031, Aversa-CE, Italy. Tel.: +39 081 8111987; fax: +39 081 5464594.
E-mail address: aledellacorte{at}libero.it (A. Della Corte).
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Abstract
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B-type natriuretic peptide is synthesized in response to increased ventricular wall stress (WS) and hypertrophy. To serially evaluate amino-terminal-pro-BNP (NT-pBNP) serum levels in patients undergoing aortic valve replacement (AVR) for severe chronic aortic regurgitation (AR), blood samples were drawn preoperatively, 15 days postoperatively, at 6- and 12-month follow-up in 25 consecutive patients. Two-dimensional echocardiography was performed concomitantly, assessing left ventricular (LV) dimensional and functional parameters, including WS. Correlations between NT-pBNP, clinical and echocardiographic data were assessed by non-parametric statistics. Median preoperative NT-pro-BNP was 276 pg/ml (IQR=85–1056), being normal or mildly increased in 20 patients, overly increased in five. The most significant correlations of preoperative NT-pBNP were with diastolic (r=0.80, P<0.001) and systolic (r=0.75, P<0.001) meridional WS and inversely with time from symptom onset (r=–0.67, P=0.001). NT-pBNP increased 15 days postoperatively (568 pg/ml, P=0.006 vs. preoperative), then decreased at 6 months (144 pg/ml, P<0.001) to remain stable at 1 year (108 pg/ml, P=0.16). Long-term follow-up NT-pBNP showed direct correlation with diastolic WS (r=0.56, P=0.02). Higher preoperative levels of NT-pBNP predicted greater magnitude of total LV mass regression at follow-up (r=–0.65, P=0.002) independent of preoperative LV mass index, showing that NT-pBNP may have a potential prognostic usefulness in adjunct to echocardiography.
Key Words: Aortic valve replacement; Chronic aortic regurgitation; B-type natriuretic peptide; Amino-terminal B-type natriuretic peptide; Left ventricular remodeling; Postoperative left ventricular mass regression
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1. Introduction
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Increasingly, plasma B-type natriuretic peptide (BNP) and amino-terminal-pro-BNP (NT-pBNP) levels are being incorporated into clinical practice, especially for assessment, prognostic stratification and management of heart failure [1]. As far as aortic valve disease is concerned, the role of BNP has been extensively addressed only in the setting of aortic stenosis [2]. Conversely, very few studies [3, 4] have addressed BNP in aortic regurgitation (AR). Both preoperative ventricular physiopathology and postoperative remodeling processes after aortic valve replacement (AVR) importantly vary according to the type of disease (stenosis or regurgitation) [5], therefore the proved meaningfulness of BNP assessment in aortic stenosis cannot be applied to AR, and selected AR patient series are required.
The aim of the present prospective observational study was to assess possible correlations between pre- and post-operative NT-pBNP plasma levels and echocardiographic parameters of LV morphology and function in patients undergoing aortic valve replacement for severe chronic aortic regurgitation.
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2. Materials and methods
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2.1. Patient selection
Patients were prospectively enrolled in the study when fulfilling the following criteria: pure chronic aortic regurgitation requiring surgery; absence of congestive heart failure; absence of chronic renal or pulmonary disease; no associated cardiomyopathy; no associated valve (except trace mitral regurgitation) or coronary disease. Criteria for initial exclusion or subsequent removal from the study were: endocarditis; obesity (body mass index >29 kg/m2); arrhythmias; thyroid disease; re-operation for bleeding; valve sparing procedures. Concurrent patients complying with the inclusion criteria and receiving biological valve substitutes were not enrolled to obtain homogeneity of patient age (that influences NT-pBNP levels [6]) and of postoperative valvular hemodynamic performance. Thus, of the 44 patients undergoing isolated aortic valve replacement for chronic aortic regurgitation between September 2005 and July 2006, 25 could be included, after approval of the study protocol by our institutional Ethics Committee and obtainment of patient informed consent. All the study patients had severe aortic regurgitation according to the most recent guidelines for echocardiographic grading of valve regurgitation [7]. Between the 6th and 12th month of follow-up four patients were withdrawn from the study due to new-onset atrial fibrillation (2 patients), significant increase in serum creatinine level (1 patient) or need for pacemaker implantation (1 patient).
2.2. NT-pBNP measurements
Blood samples were drawn from an antecubital vein one day before surgery (preoperative time-point) and at 15 days (early postoperative time-point), 6 months and 12 months (follow-up time-points) after aortic valve replacement, and collected in gel filled tubes. Serum was separated by centrifugation and stored at –80 °C until analysis. NT-pBNP level was measured by an electrochemiluminescence immunoassay (Elecsys proBNP) using an Elecsys 2010 analyzer (Roche Diagnostics, Mannheim, Germany). The low detection limit of the NT-proBNP assay was 5 pg/ml, while the functional sensitivity was <50 pg/ml and working range (imprecision profile  10% coefficient of variation) extended up to about 35,000 pg/ml [1]. The assays were carried out in accordance with the producer's manual. Laboratory operators were blinded to patient identity and characteristics.
2.3. Echocardiography assessments
All study patients underwent physical examination and echocardiographic assessment by two experienced cardiologists blinded to laboratory results, at each time point. Functional status according to the New York Heart Association (NYHA) and the time elapsed from first symptom onset (symptom-to-surgery time) were recorded for all patients except two, who had always been asymptomatic despite progressive LV dimension increase. Standard M-mode measurements and bi-dimensional tracings were carried out according to the American Society of Echocardiography recommendations [8]; LV mass was computed by the bi-dimensional method of area-length [8] and the ratio of mass to end-diastolic volume (mass/volume ratio) was used as an index of concentricity of ventricular geometry. All measurements were indexed to body surface area. In addition, an estimate of LV end-systolic and end-diastolic meridional (MWS) and circumferential stresses (CWS) was obtained by bi-dimensional methods [9] introducing cuff sphigmomanometry measured blood pressure values in the stress formulas, according to a validated extrapolation [10]. Systolic stress estimates were also used to achieve an index of sphericity, i.e. the CWS/MWS ratio [9].
2.4. Statistical analysis
Echocardiographic parameters and clinical data are presented as mean±S.D. NT-pBNP values (expressed in picograms per milliliter) showed a non-Gaussian, positively skewed distribution, therefore peptide levels are summarized as median values and interquartile range (IQR) and non-parametric tests were used for correlations between peptide levels and echocardiographic parameters (Spearman's correlation) and for comparisons between different time-points (Wilcoxon rank-sum test). For the same reason, the natural log transformation was used when NT-pBNP values were introduced in linear regression multivariable models and for graphics. The  2-test with Fisher's exact correction was used for comparisons of categorical variables. Normally distributed data were compared by means of the paired and unpaired t-tests. All statistical tests were two-tailed and significance was set at P<0.05.
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3. Results
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3.1. Preoperative NT-pBNP
Preoperative data are reported in Table 1. Preoperative NT-pBNP level (median 276 pg/ml, IQR=85–1056) showed an important heterogeneity: it was frankly normal in seven patients and increased in the other 18, five of whom presented preoperative NT-pBNP levels more than 10-fold higher (median 1759 pg/ml, IQR=1653–2536) than the rest of the study population (median 155 pg/ml, IQR=85–329; P<0.001). Significant correlations between preoperative NT-pBNP and clinical and echocardiographic parameters are reported in Fig. 1 and Table 2. Among the most significant findings there was the negative correlation with the CWS/MWS ratio (r=–0.73, P<0.001), indicating that neuroendocrine activation correlated with ventricular functional sphericity. Importantly, this latter relation remained significant in linear regression when including age, NYHA class and symptom-to-operation time as covariates (β=–2.0, S.E.=0.31; P<0.001).
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Table 1 Preoperative clinical data, echocardiographic parameters and NT-pBNP levels. Data are summarized as means±S.D.
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Fig. 1. Preoperative NT-pBNP level showed an inverse relation with the symptom-to-surgery time (r=–0.67, P=0.001), although there were few patients with a recent onset and yet low NT-pBNP level. Dashed line represents fit line (quadratic relation), bold lines represent 95% confidence intervals.
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Table 2 Correlations of preoperative NT-pBNP level with clinical and echocardiographic variables. Note the absence of significant correlation with preoperative LV mass index and the strong correlations with stress estimates.
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3.2. Postoperative changes in NT-pBNP levels
Operative data are reported in Table 3. The trends of NT-pBNP level changes are shown in Fig. 2. The median early postoperative value was significantly increased in the overall study sample compared to median preoperative level (P=0.006). However, in all patients a subsequent significant reduction at six months was observed (144 pg/ml; P<0.001), then a further non-significant reduction led to a normal median 1-year level (108 pg/ml, IQR 74–151).
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Table 3 Perioperative data. Continuous variables are summarized as mean±S.D., categorical variables as number (%)
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Fig. 2. NT-pBNP levels at the four time-points of the study. Note that, although the median value increased at 15 days, in the 5 patients who had the highest preoperative levels, NT-pBNP decreased significantly at 15 days (954 pg/ml, IQR=443–1384 vs. 1759 pg/ml, IQR=1653–2536; P=0.03), while in the other 20 it increased from 155 (IQR=85–329) pg/ml to 557 (IQR=470–816) pg/ml (P<0.001). Error bars represent 95% confidence intervals.
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3.3. Postoperative correlates of NT-pBNP levels
NT-pBNP serum level at 15 days postoperatively correlated with age (r=0.64, P<0.001), but proved independent of any LV morphological parameter. Notably, there was no relation to postoperative peak troponin I level (r=0.24), cross-clamping (r=0.21) and cardio-pulmonary bypass times (r=0.11). In the later follow-up, NT-pBNP levels were strongly correlated to previous time-point NT-pBNP levels (relation between 6-month and 1-year values: r=0.79, P<0.001). As to follow-up echocardiographic parameters, the only significant correlation was observed with 6-month LV diastolic dimension (r=0.52, P=0.03) and diastolic MWS (r=0.56, P=0.02).
3.4. Postoperative LV remodeling
In the early postoperative period, both LV internal dimensions and LV mass significantly decreased (P<0.001) (Fig. 3), but an increase of the mass/volume ratio was observed, i.e. ventricular geometry showed greater concentricity than preoperatively (Fig. 3). Consistently, while systolic CWS and systolic MWS decreased (P=0.025 and P=0.021 vs. respective preoperative values) within the first 15 post-operative days, diastolic stresses remained stable (P=0.9 and P=0.33) (Fig. 4).
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Fig. 3. (a) LV mass index changes following AVR; (b) LV end-systolic volume changes following AVR; (c) trend of the mass-to-volume ratio following AVR. *=P<0.05 vs. preoperative.
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Fig. 4. (a) Systolic meridional WS trend following AVR; (b) Diastolic meridional WS trend following AVR. *=P<0.05 vs. preoperative.
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Preoperative NT-pBNP levels predicted the extent of overall postoperative (1-year vs. preoperative) change in LV mass (r=–0.65, P=0.002) (Fig. 5). Noteworthy, this correlation with the magnitude of LV mass regression was confirmed after adjustment for preoperative LV mass index (β=–0.56, R2=0.75, P<0.001). In fact, the total rate of LV mass regression did not correlate with preoperative LV mass index (r=0.05, P=0.8).
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Fig. 5. Correlation between preoperative NT-pBNP level and overall magnitude of LV mass index (LVMI) change in the follow-up.
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4. Discussion
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This was the first study to assess serial NT-pBNP levels pre- and postoperatively in patients undergoing AVR for AR: currently, the role of cardiac natriuretic peptides in AR has been investigated only in the non-surgical setting [3, 4].
A remarkable heterogeneity in preoperative NT-pBNP levels was found, even in such a selected small series excluding patients with cardiac failure, coronary disease, arrhythmias and other conditions associated with natriuretic peptide overproduction. This heterogeneity may be partially explained by the different length of time elapsed from decompensation but it was more significantly related to different degrees of ventricular sphericity (ratio between circumferential and meridional stress). A direct correlation of BNP levels with LV mass index was found by Eimer and coworkers [3] in the asymptomatic stage of chronic AR, while in the present series of mostly symptomatic patients this correlation did not emerge: as a possible explanation, while in the asymptomatic patient (compensatory hypertrophy phase) BNP levels are proportional to the amount of cardiomyocytes producing it, when ventricular adaptation is not compensatory anymore and symptoms are more likely to occur, then wall stress increases causing disproportioned production of neuropeptide.
Averagely, NT-pBNP increased early in the postoperative period although in a minority of patients, who had remarkably higher preoperative levels (>1500 pg/ml), it decreased after surgery: similar coexistence of inverse patterns, even in clinically homogeneous series, has been already reported in aortic stenosis patients [2]. BNP gene expression is promoted not only by mechanical stretch, but also by pro-inflammatory, oxidative and trophic stimuli [11, 12]. Thus, the early postoperative increase in NT-pBNP could be also influenced by unspecific stimuli including cardiopulmonary bypass and anesthesia [13]. Indeed a three-fold increase vs. baseline has been reported by Georges and coworkers [13] after operation, irrespective of the type of surgical procedure. We found no correlation with postoperative creatin-kinase and troponin levels, suggesting that the ischemic mechanism in the setting of cardioplegic protection was not the major stimulus. Considering the long time-span between operation and first assessment compared to the half-life of NT-pBNP, it is likely that 15-day serum levels in this study were influenced also by other postoperative rather than intra-operative factors, possibly including the lack of diastolic wall stress decrease (Fig. 3): while in aortic stenosis AVR immediately improves diastolic function, in the setting of AR it is followed by an early worsening of LV compliance and filling parameters [5], related to the slower recovery from LV hypertrophy, compared to the acute volume decrease. In fact we found a significant relation of postoperative NT-pBNP with diastolic stress.
Another relevant finding of the present study was that higher NT-pBNP levels before operation were predictive of more adequate long-term remodeling, as suggested by the greater rate of LV mass regression: this association was highly significant and, importantly, independent of baseline LV mass index. Such evidences emphasize the biological role of BNP in the remodeling process of the stressed LV: the peptide is over-expressed in response to diastolic fiber length increase via angiotensin II production [11], constitutively participating in the mechanisms of stress-dependent angiotensin-mediated myocardial hypertrophy and interstitial fibrosis [14]. Notably, in the present study, NT-pBNP levels were more strongly correlated to diastolic than systolic stress, consistently with the abovementioned experimental studies [11] and with other clinical series [13]. As local anti-fibrotic effects of BNP have been recognized, it may be produced in the active phases of hypertrophy to limit concurrent collagen apposition, thus counterbalancing the local renin-angiotensin system [15]. In the light of these insights, we may suppose that relatively lower preoperative BNP levels identified those AR patients in which a greater degree of fibrosis had developed compared to those with higher BNP production, accounting for a more limited postoperative LV mass decrease. The direct relation with the amount of postoperative LV mass regression, without correlation with preoperative LV mass index, suggests a potential role for NT-pBNP assay in adjunct to preoperative echocardiography, for prognostic stratification of patients scheduled for AVR for chronic AR.
It should be acknowledged that the use of cuff sphygmomanometry pressures to determine wall stress has been validated only for end-systolic stress [10]; however, this limitation should not have affected the correlations found with NT-pBNP levels, but only the reliability of diastolic stress values in absolute terms. Besides the aforementioned lack of invasive stress determination, and the small number of patients enrolled so far, other limitations included the lack of LV filling and relaxation parameter assessment and of precise information about preoperative time duration of the disease: we could only base on the time elapsed between first symptoms and surgery.
In conclusion, in chronic AR, NT-pBNP may possibly assume a relevant clinical usefulness: a higher preoperative level was significantly related to higher diastolic and systolic wall stress, but probably most importantly it was also associated with greater potential for LV mass regression in the follow-up, independent of preoperative echocardiographic LV mass index. The hypothesis that such findings may reflect an active role of BNP in the inhibition of pro-fibrotic pathways during hypertrophy development needs further verification in larger studies.
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Conference discussion
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Dr. J. Pepper (London, UK): Can I just ask if you examined the gradients across the new valve postoperatively and whether there was any correlation between higher gradients across the valve and failure of the BNP to fall and failure of LV mass regression to progress normally?
Dr. Della Corte: These were all patients with pure aortic regurgitation.
Dr. Pepper: Yes, but once you put the valve in you might have given them a bit of stenosis.
Dr. Della Corte: We initially included in the analysis also the projected effective orifice area, not the gradient actually but the effective orifice area, and it did not correlate with BNP in the postoperative period.
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Abstract
1. Introduction
