Abstract
Background and aim N-terminal pro-B-type
natriuretic peptide (NT-proBNP) has diagnostic
and prognostic value in patients with heart fail-
ure. The present prospective study was designed
to assess whether changes in NT-proBNP levels
after surgical mitral valve repair reflect changes in
heart failure symptoms and changes in left atrial
size, left ventricular size and left ventricular
function. Methods The study population con-
sisted of 22 patients (mean age: 62.8 ± 14.2 years,
68% male) undergoing surgical mitral valve
repair. Serial NT-proBNP measurements, trans-
thoracic echocardiography and New York Heart
Association (NYHA) class assessment were per-
formed before and 6 months after surgery.
Results All patients underwent successful mitral
valve repair and no patients died during follow-
up. The decrease in NT-proBNP level was asso-
ciated with the reduction in left atrial dimension
(r = 0.72, P < 0.001), left ventricular end-systolic
dimension (r = 0.63, P = 0.002), left ventricular
end-diastolic dimension (r = 0.46, P = 0.031), and
the increase in fractional shortening (r = – 0.63,
P = 0.002). Finally, patients with decreasing NT-
proBNP levels revealed a significant improve-
ment in heart failure symptoms (NYHA class).
Conclusion Changes in NT-proBNP after sur-
gical mitral valve repair reflect changes in heart
failure symptoms and changes in left atrial and
ventricular dimensions and function.
Keywords Heart failure Æ Left ventricular
function Æ Mitral valve repair Æ
Natriuretic peptides
1 Introduction
The natriuretic peptides are endogenous cardiac
hormones that include atrial natriuretic peptide
(ANP), brain natriuretic peptide (BNP), and its
amino-terminal portion N-terminal pro-B-type
natriuretic peptide (NT-proBNP) [1, 2]. The BNP
peptides are synthesized in the ventricular myo-
cardium and released in response to ventricular
wall stress [3, 4]. In the clinical setting, both BNP
and NT-proBNP have been demonstrated to
provide important diagnostic and prognostic
information in patients with heart failure [5–8].
Recently, elevated plasma BNP levels have
been demonstrated in patients with chronic
H. H. H. Feringa (&) Æ P. Klein Æ J. Braun Æ
R. J. M. Klautz Æ A. van der Laarse Æ
E. E. van der Wall Æ R. A. E. Dion Æ J. J. Bax
Department of Cardiothoracic Surgery/Cardiology,
C-5, Leiden University Medical Center, Albinusdreef 2,
2333 ZA, Leiden, The Netherlands
e-mail: h.feringa@erasmusmc.nl
D. Poldermans Æ R. T. van Domburg
Cardiology, Erasmus Medical Center, Rotterdam,
The Netherlands
Int J Cardiovasc Imaging (2007) 23:159–165
DOI 10.1007/s10554-006-9138-z
123
ORIGINAL PAPER
Plasma natriuretic peptide levels reflect changes in heart
failure symptoms, left ventricular size and function
after surgical mitral valve repair
Harm H. H. Feringa Æ Don Poldermans Æ Patrick Klein Æ Jerry Braun Æ
Robert J. M. Klautz Æ Ron T. van Domburg Æ Arnoud van der Laarse Æ
Ernst E. van der Wall Æ Robert A. E. Dion Æ Jeroen J. Bax
Received: 7 June 2006 / Accepted: 15 July 2006 / Published online: 29 August 2006
Ó Springer Science+Business Media B.V. 2006
valvular disease [9–11]. In patients with chronic
mitral regurgitation, the severity of regurgitation
was directly related to the BNP levels [9–11]. The
effect of mitral valve repair on BNP levels how-
ever, has not been studied. Accordingly, the topic
of the current study was to evaluate the change in
BNP levels after surgical correction of severe
mitral regurgitation and to relate the findings to
left ventricular reverse remodeling and improve-
ment in clinical status after surgery.
2 Material and methods
2.1 Study population
Between July 2005 and September 2005, 22 con-
secutive patients undergoing mitral valve repair for
severe mitral regurgitation were prospectively
enrolled. All patients gave informed consent to
participate in the study and the study was conducted
in accordance with the Declaration of Helsinki.
Patients with mitral valve stenosis (mitral valve
area < 1.5 cm
2
)oraorticvalvedisease(severe
aortic stenosis or regurgitation) were not included.
Mitral regurgitation was related to cardiomy-
opathy in 11 patients, and to degenerative disease
in 11 patients.
2.2 Assessment of symptoms and follow-up
Clinical evaluation and assessment of symptoms
using New York Heart Association (NYHA)
class was conducted by the patient’s referring
cardiologist and was confirmed by an independent
cardiothoracic surgeon at the time of hospital
admission. A clinical follow-up was performed at
6 months after mitral valve repair to evaluate the
change in NYHA class. During the 6-month fol-
low-up period, adverse events including non-fatal
myocardial infarction, repeat mitral valve sur-
gery, cerebrovascular events, renal dysfunction
and hospitalization for heart failure were noted.
2.3 Echocardiography
Prior to surgery, transthoracic echocardiography
was performed in all patients. The patients were
imaged in the left lateral decubitus position by
using a commercially available system (Vingmed
Vivid Seven, General Electric—Vingmed,
Milwaukee, WI, USA). Using a 3.5 MHz trans-
ducer, images were obtained at a depth of 16 cm
in the parasternal (long- and short-axis images)
and apical views (2- and 4-chamber images).
From parasternal M-mode acquisitions, the left
atrial diameter and left ventricular dimensions
(end-systolic and end-diastolic diameter) were
determined and the fractional shortening was
calculated. The severity of mitral regurgitation
was graded semi-quantitatively from color-flow
Doppler in the conventional parasternal long-axis
and apical 4-chamber images. Mitral regurgitation
was characterized as mild = 1+ (jet area/left atrial
area < 10%), moderate = 2+ (jet area/left atrial
area 10–20%), moderately severe = 3+ (jet area/
left atrial area 20–45%), and severe = 4+ (jet
area/left atrial area > 45%) [12]. Immediately
after surgery, transesophageal echocardiography
was performed to assess residual mitral valve
regurgitation. A transthoracic echocardiogram
was repeated at 6 months follow-up to assess left
atrial and ventricular dimensions, fractional
shortening, the presence of residual mitral valve
regurgitation, the transmitral diastolic gradient,
the length of leaflet coaptation and the mitral
valve area. Two experienced cardiologists who
were blinded to the BNP levels and clinical data
analyzed the echocardiographic data.
2.4 NT-proBNP measurement
Venous blood samples were collected on the day
before and 6 months after surgery with the
patient at rest and in semi-supine position. The
samples were collected in chilled ethylene-dia-
mine-tetra-acetic acid vacutainers and were
immediately placed on ice. After centrifugation,
the plasma samples were stored at – 80°C until
assay. Plasma NT-proBNP concentrations was
measured with an electrochemiluminescence
immunoassay kit (Elecsys 2010, Roche GmbH,
Mannheim, Germany). The method is a ‘sand-
wich’-type quantitative immunoassay based on
polyclonal antibodies against epitopes in the
N-terminal part of pro-BNP [13]. Assays were
performed by a laboratory technician blinded to
the patient’s clinical data.
160 Int J Cardiovasc Imaging (2007) 23:159–165
123
2.5 Statistical analysis
The change in NT-proBNP levels from baseline
to 6 months follow-up was calculated and
expressed as percentage values. Changes in left
atrial dimension, left ventricular end-systolic and
end-diastolic dimensions and fractional shorten-
ing were also calculated and expressed as per-
centage values. Continuous data were expressed
as mean (±SD) or median (interquartile range)
when the distributions were skewed and compared
using the Student t-test or the Mann–Whitney U-
test when appropriate. Categorical data were
compared using the Fisher’s exact test. Group
comparisons were performed with analysis of
variance (ANOVA) techniques. The Pearson
correlation coefficient was used to assess the
association between changes in NT-proBNP levels
and changes in echocardiographic variables. For
all tests, a P value < 0.05 was considered signifi-
cant. All analysis was performed using SPSS-11.0
statistical software (SPSS Inc., Chicago, Illinois).
3 Results
3.1 Baseline characteristics
The baseline characteristics of the 22 patients
(mean age 62.8 ± 14.2 years, 68% male) are
summarized in Table 1. Eight patients (36%)
were in NYHA class II, 5 (23%) in class III and 9
(41%) in class IV (mean NYHA class 3.1 ± 0.9).
Prior to surgery, all patients presented with se-
vere mitral valve regurgitation (grade 3–4+), with
a mean regurgitation grade of 3.6 ± 0.5. Mean left
atrial dimension was 4.9 ± 0.7 cm, mean left
ventricular end-systolic dimension 4.5 ± 0.8 cm,
mean left ventricular end-diastolic dimension
6.1 ± 0.8 cm and mean fractional shortening
26.8 ± 7.3%. Median NT-proBNP level at base-
line was 418 ng/l (interquartile range: 204–
1258 ng/l).
3.2 Surgical results and follow-up
Mean length of hospital stay was 9.8 ± 4.3 days.
Transesophageal echocardiography immediately
after surgery demonstrated competent valves with
minimal residual mitral valve regurgitation in all
patients (mitral regurgitation grade 0 in 13
patients, 59% and grade 1 in 9 patients, 41%). All
patients survived the 6-month follow-up period
and no patients were lost to follow-up. During
hospital stay and follow-up, none of the patients
required repeat mitral valve surgery. Adverse
events, including nonfatal myocardial infarction,
cerebrovascular events, hospitalization for heart
failure or endocarditis were not observed. Two
patients (9%) developed renal dysfunction in the
postoperative period which was successfully
treated with a short period of renal dialysis. None
of the patients presented with renal dysfunction at
6 months follow-up. Median NT-proBNP level at
6 months follow-up was 426 ng/l (interquartile
range 196–1172 ng/l). In 10 patients (45%), NT-
proBNP levels decreased >10% and in 12
patients (55%) NT-proBNP level remained
unchanged or increased >10% as compared to
baseline values.
The patient population was subsequently
divided into patients with a decrease in plasma
NT-proBNP level versus patients with unchanged/
increased NT-proBNP plasma levels (Table 1).
Baseline characteristics were comparable between
the 2 groups, including baseline NT-proBNP lev-
els. Only left atrial dimension was somewhat lar-
ger in patients with decreasing NT-proBNP levels
after surgery as compared to those with increasing
NT-proBNP levels (P = 0.04).
3.3 Changes in NT-proBNP levels
and symptoms
NYHA class deteriorated in 3 patients (14%),
remained unchanged in 5 (23%) and improved in
14 (64%). The 10 patients with decreased NT-
proBNP levels exhibited a mean improvement in
NYHA class of 2.0 ± 1.1, whereas the 12 patients
with unchanged/increased NT-proBNP levels
revealed a small but significant worsening in
NYHA class (0.3 ± 0.9, P < 0.001 versus baseline).
3.4 Changes in NT-proBNP levels
and echocardiographic variables
The transthoracic echocardiogram at 6 months
follow-up revealed a mean mitral regurgitation
Int J Cardiovasc Imaging (2007) 23:159–165 161
123
grade of 0.5 ± 0.7, mean length of leaflet coapta-
tion of 0.9 ± 0.2 cm, mean mitral valve area of
2.6 ± 0.9 cm
2
, and mean transmitral diastolic
gradient of 3.3 ± 1.2 mmHg. At follow-up, mean
left atrial dimension was 4.4 ± 0.5 cm, mean left
ventricular end-systolic dimension 4.2 ± 0.9 cm,
mean left ventricular end-diastolic dimension
5.8 ± 0.6 cm, and mean fractional shortening
28.0 ± 10.7%. The 10 patients with decreased NT-
proBNP levels demonstrated significant reverse
left ventricular remodeling, with a reduction in
left ventricular end-systolic dimension from
4.7 ± 1.0 cm to 3.8 ± 0.9 cm (P = 0.042), a
reduction in left ventricular end-diastolic dimen-
sion from 6.5 ± 0.8 cm to 5.7 ± 0.6 cm
(P = 0.036) and a reduction in left atrial dimen-
sion from 5.3 ± 0.6 cm to 4.3 ± 0.5 cm
(P = 0.001). Conversely, reverse left ventricular
remodeling was not observed in the 12 patients
with unchanged/increased NT-proBNP levels.
Mean left ventricular end-systolic dimension was
4.3 ± 0.6 cm at baseline versus 4.5 ± 0.7 cm
(P = 0.43) at follow-up, and mean left ventricular
end-diastolic dimension was 5.9 ± 0.9 cm at
baseline versus 5.8 ± 0.6 cm at follow-up
(P = 0.66). Mean left atrial dimension did also
not change (4.7 ± 0.7 cm versus 4.5 ± 0.6 cm,
P = 0.67). Scatter plots demonstrating the corre-
lation between changes in NT-proBNP level and
changes in echocardiographic variables during the
6-month follow-up period after mitral valve sur-
gery are presented in Fig. 1. Decreases in NT-
proBNP levels at follow-up were significantly
correlated with reductions in left atrial dimension
(r = 0.72, P < 0.001), left ventricular end-systolic
dimension (r = 0.63, P = 0.002), and left ventric-
ular end-diastolic dimension (r = 0.46, P = 0.031),
indicating reverse remodeling; conversely,
increases in NT-proBNP levels were related to
increases in the different dimensions, indicating
Table 1 Baseline clinical characteristics of the study population divided into patients with increasing and decreasing
N-terminal pro-B-type natriuretic peptide levels
Overall (n = 22) Decreasing
NT-proBNP levels
(n = 10)
Increasing
NT-proBNP levels
(n = 12)
P value
Clinical variables
Age (years) 62.8 ± 14.2 63.3 ± 13.5 62.4 ± 15.3 0.89
Male gender 15 (68.2) 7 (70.0) 8 (66.7) 1.00
Hypertension 4 (18.2) 3 (30.0) 1 (8.3) 0.29
Diabetes mellitus 3 (13.6) 2 (20.0) 1 (8.3) 0.57
Chronic obstructive pulmonary disease 4 (18.2) 1 (10.0) 3 (25.0) 0.59
Peripheral arterial disease 3 (13.6) 3 (30.0) 0 (0) 0.078
History of stroke 0 (0) 0 (0) 0 (0) –
New York Heart Association class 2.9 ± 1.0 3.3 ± 0.9 2.8 ± 0.8 0.23
Medication
Angiotensin-converting enzyme inhibitors 10 (45.5) 6 (60.0) 4 (33.3) 0.39
Beta-blockers 8 (36.4) 5 (50.0) 3 (25.0) 0.38
Diuretics 9 (40.9) 4 (40.0) 5 (41.7) 1.00
Reason of mitral regurgitation
Degenerative disease 11 (50.0) 5 (50.0) 6 (50.0) 1.00
Cardiomyopathy 11 (50.0) 5 (50.0) 6 (50.0) 0.17
Echocardiographic measurements
Mitral regurgitation, grade 3.6 ± 0.5 3.7 ± 0.5 3.6 ± 0.5 0.54
Left atrial dimension (cm) 4.9 ± 0.7 5.2 ± 0.6 4.7 ± 0.7 0.040
Left ventricular end-systolic dimension (cm) 4.5 ± 0.8 4.7 ± 1.0 4.3 ± 0.6 0.21
Left ventricular end-diastolic dimension (cm) 6.1 ± 0.8 6.3 ± 0.7 5.9 ± 0.9 0.27
Fractional shortening (%) 26.8 ± 7.3 25.4 ± 8.3 28.0 ± 6.6 0.42
Baseline LN NT-proBNP level (ng/l) 6.2 ± 1.5 6.6 ± 1.4 5.8 ± 1.5 0.18
Values are expressed in mean ± standard deviation or in number (%). NT-proBNP denotes N-terminal pro-B-type
natriuretic peptide
162 Int J Cardiovasc Imaging (2007) 23:159–165
123
ongoing dilatation. Moreover, decreases in
NT-proBNP levels at follow-up were significantly
correlated with improved fractional shorting
(r = – 0.63, P = 0.002), indicating improved sys-
tolic function.
4 Comments
BNP has been used extensively in the diagnosis
and prognosis of patients with heart failure [5–8].
More recently, Sutton and colleagues demon-
strated in 49 patients with mitral regurgitation
and preserved left ventricular ejection fraction
that plasma levels of BNP and NT-proBNP levels
were directly related to the severity of mitral
valve regurgitation [11]. In addition, Detaint et al.
evaluated 124 patients with chronic mitral regur-
gitation and demonstrated that BNP levels were
correlated with long-term outcome [14]. In par-
ticular, higher BNP levels independently pre-
dicted mortality and the combined endpoint of
mortality and heart failure. Moreover, the authors
demonstrated that BNP levels in chronic mitral
Fig. 1 Scatter plots demonstrating the correlation
between changes in plasma N-terminal pro-B-type natri-
uretic peptide level (NT-proBNP) and changes in
echocardiographic variables (A. left atrial dimension; B.
left ventricular end-systolic dimension; C. left ventricular
end-diastolic dimension; D. fractional shortening) during
the 6-month follow-up period after mitral valve surgery.
Of note, negative changes in left atrial dimension, left
ventricular end-systolic dimension and left ventricular
end-diastolic dimension indicate reductions in dimensions
(reverse remodeling), whereas positive changes indicate
ongoing dilatation. A positive change in fractional
shortening indicates an increase in systolic function,
whereas a negative change in fractional shortening
indicates a decrease in systolic function. Negative changes
in NT-proBNP indicate a reduction in plasma levels after
surgery, whereas positive changes indicate an increase in
plasma levels after surgery
Int J Cardiovasc Imaging (2007) 23:159–165 163
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