Download Brain natriuretic peptide: is it a predictor of

Clinical Science (2001) 101, 621–628 (Printed in Great Britain)
Brain natriuretic peptide: is it a predictor of
cardiomyopathy in cirrhosis?
Florence WONG*, Samuel SIU†, Peter LIU† and Laurence M. BLENDIS*
*Division of Gastroenterology, The Toronto General Hospital, University of Toronto, 200 Elizabeth Street, Toronto M5G 2C4,
Ontario, Canada, and †Division of Cardiology, The Toronto General Hospital, University of Toronto, 200 Elizabeth Street,
Toronto M5G 2C4, Ontario, Canada
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Subtle cardiac abnormalities have been described in patients with cirrhosis. Natriuretic peptide
hormones have been reported to be sensitive markers of early cardiac disease. We postulate that
plasma levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide could be
used as markers of cardiac dysfunction in cirrhosis. The aim of the study was to evaluate the levels
of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide and their relationship
with cardiac structure and function in patients with cirrhosis. The study population comprised
36 patients with cirrhosis of mixed aetiologies, but with no cardiac symptoms ; 19 of the patients
had ascites and 17 did not. The subjects underwent (i) trans-thoracic two-dimensional
echocardiography, and (ii) radionuclide angiography for measurements of cardiac structural
parameters, diastolic and systolic function. Levels of N-terminal pro-atrial natriuretic peptide
and brain natriuretic peptide were also measured. The results were compared with those from
eight age- and sex-matched healthy volunteers. Compared with the controls, the baseline mean
ejection fraction was increased significantly in both patient groups (P l 0.02), together with
prolonged deceleration times (P l 0.03), left atrial enlargement (P l 0.03) and interventricular
septal thickening (P l 0.02), findings that are compatible with diastolic dysfunction. Levels of Nterminal pro-atrial natriuretic peptide and brain natriuretic peptide were significantly higher in
all patients with cirrhosis with ascites (P l 0.01 and P l 0.05 respectively), but in only some of
the pre-ascitic cirrhotic patients, compared with controls. All high levels of brain natriuretic
peptide were correlated significantly with septal thickness (P 0.01), left ventricular diameter
at the end of diastole (P l 0.02) and deceleration time (P 0.01). We conclude that elevated
levels of brain natriuretic peptide are related to interventricular septal thickness and the
impairment of diastolic function in asymptomatic patients with cirrhosis. Levels of brain
natriuretic peptide may prove to be useful as a marker for screening patients with cirrhosis for
the presence of cirrhotic cardiomyopathy, and thereby identifying such patients for further
investigations.
INTRODUCTION
Cardiovascular haemodynamic abnormalities have been
known for the past 50 years to be associated with cirrhosis
[1]. Cirrhotic patients have a hyperdynamic circulation,
which is manifested primarily as high cardiac output,
decreased systemic vascular resistance and widespread
arterial vasodilatation [1]. More recently, both cardiac
structural and functional abnormalities have also been
described in patients with cirrhosis [2,3]. These include
increased thickness of the left ventricle [2–4], associated
with diastolic dysfunction, and systolic incompetence
Key words : cardiomyopathy, cirrhosis, natriuretic peptides.
Abbreviations : ANP, atrial natriuretic peptide ; BNP, brain natriuretic peptide ; E\A ratio, ratio between early maximal ventricular
filling velocity (E velocity) and late diastolic or atrial velocity (A velocity) ; NT-ANP, N-terminal ANP.
Correspondence: Dr Florence Wong (e-mail florence.wong!utoronto.ca).
# 2001 The Biochemical Society and the Medical Research Society
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F. Wong and others
(the finding of a normal to increased baseline ejection
fraction that does not respond normally to physiological
challenges such as exercise), especially under conditions
of stress [5–7]. The constellation of abnormalities
has been termed cirrhotic cardiomyopathy. However,
cirrhotic cardiomyopathy is not a well-recognized condition. It is often confused with alcoholic cardiomyopathy. Furthermore, even when the changes
associated with cirrhotic cardiomyopathy are detected,
they are often dismissed because overt cardiac failure is
uncommon in cirrhosis. However, the occasional report
of unexpected deaths due to heart failure following liver
transplantation [8], transjugular intrahepatic portosystemic stent shunt insertion [9] and surgical portocaval
shunts [10] in cirrhotic patients would suggest that
cirrhotic cardiomyopathy may have clinical relevance in
the management of these patients. Furthermore cirrhotic
cardiomyopathy may be aggravated by sodium retention
in cirrhosis, with increases in total and central blood
volumes. Therefore early detection and intervention may
prove beneficial for these patients.
A clinical diagnosis of cirrhotic cardiomyopathy is
often not made, since the signs of cardiac dysfunction are
subtle, and may be masked in cirrhotic patients by
sodium retention. Features of cirrhotic cardiomyopathy
can be detected by either two-dimensional Doppler
echocardiography or radionuclide ventriculography.
More recently, natriuretic peptide hormones such as
atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP) have been reported to be sensitive and
useful markers for early-stage heart disease [11–13],
and have provided an opportunity for early diagnosis of
cardiac dysfunction and intervention in other conditions
such as ischaemic heart disease and hypertension. ANP
levels have long been known to be elevated in cirrhosis
[14–16]. These have always been regarded as markers of
volume overload rather than markers of cardiac dysfunction in cirrhosis. However, N-terminal ANP (NTANP), a cleavage product of pro-ANP, has been
associated with left ventricular dysfunction [11,17]. Its
levels have not been reported in cirrhosis. BNP levels
have been found to be elevated in decompensated
cirrhosis [18], but levels in compensated cirrhosis are
more controversial, having been found to be either
normal or increased [18,19]. The significance of this
finding has never been determined. Therefore the aim of
the present study was to clarify further the status of the
natriuretic peptides as markers of cardiac dysfunction in
cirrhosis. In particular, this study aimed at answering the
following questions : (i) do plasma levels of natriuretic
peptides provide any information about abnormal cardiac
function in cirrhosis ? ; (ii) is there an association between
the plasma levels of natriuretic peptides and systolic and
diastolic dysfunction ? ; and (iii) can plasma natriuretic
peptides be used to identify early cirrhotic cardiomyopathy ?
# 2001 The Biochemical Society and the Medical Research Society
MATERIALS AND METHODS
Ethical approval for the study was granted by the Ethics
Committee of the Toronto General Hospital, University
Health Network. All control subjects and cirrhotic
patients gave informed consent for the study.
Patients
A study population of 36 patients (34 males, two females),
with biopsy-proven cirrhosis, were recruited from the
General Hepatology and Pre-Transplant Clinics of
the Toronto General Hospital. Of these, 17 patients had
no history of ascites or diuretic use. The absence of
ascites was confirmed by ultrasound before enrolment.
These patients were therefore termed pre-ascitic cirrhotic
patients. The remaining 19 patients had obvious ascites
clinically, and this was confirmed on ultrasound. Nine
pre-ascitic and 12 ascitic patients had alcoholic cirrhosis,
but had been abstinent from alcohol for at least 6 months
before enrolment. This was documented by questionnaires completed by the patient and his family during
repeated clinic visits and by near-normal serum
γ-glutamyltransferase levels. Cirrhosis was related to
hepatitis C infection in nine patients and to hepatitis B
infection in another two. Two patients had cryptogenic
cirrhosis, while the remaining two patients had autoimmune hepatitis and drug-induced cirrhosis as a result
of flutamide use respectively. All were ambulatory
patients who had been stable and free of gastrointestinal
bleeding in the previous 3 months. A negative history
with regard to hypertension and cardiac and pulmonary
disease, a normal clinical examination by a cardiologist,
and normal ECG, chest X-ray, spirometry and oximetry
were mandatory for inclusion in the study. In addition,
all cirrhotic patients had to have normal blood pressure
readings on at least two separate occasions before
enrolment. A group of eight age- and sex-matched
healthy individuals with no history of cardiac or pulmonary disease together with a normal ECG and blood
pressure served as controls. The demographics of all
study subjects, and baseline parameters including the
Pugh score in all cirrhotic patients, are given in Table 1.
Study design
The study was performed with the control subjects and
pre-ascitic cirrhotic patients consuming a metabolic diet
containing 200 mmol of sodium and 1.5 litres of fluid per
day for 7 days. This sodium intake was chosen because
the associated volume expansion has been shown to
increase the subtle cardiac dysfunction in some preascitic cirrhotic patients [2]. Furthermore, both control
subjects and pre-ascitic cirrhotic patients have been
shown to achieve a steady state after consuming this diet
for 7 days [20] ; this would ensure that a change in volume
status was not introduced as a confounding factor in
these two groups. In contrast, ascitic cirrhotic patients
Brain natriuretic peptide in cirrhosis
Table 1 Baseline demographics of the control subjects and
patients with cirrhosis
Significance of differences : *P 0.05, **P 0.01 compared with controls ;
†P 0.05 compared with pre-ascitic cirrhotic patients.
Cirrhotic patients
Parameter
Controls
Pre-ascitics
Ascitics
n
Age (years)
Sex (male/female)
Haemoglobin (g/l)
International normalized ratio
Albumin (g/l)
Bilirubin (µmol/l)
Pugh score
8
48p3
6/2
133p3
1.04p0.02
46p1
12p3
–
17
50p2
17/0
136p3
1.37p0.05*
39p1
28p3
5.9p0.3
19
52p2
17/2
121p4
1.68p0.10**
32p2*
40p7**
10.0p0.4†
Aetiology of cirrhosis
Alcohol
Hepatitis C virus
Hepatitis B virus
Cryptogenic
Drug-induced
Autoimmune hepatitis
9
7
–
1
–
–
12
2
2
1
1
1
stop). An increase in the isovolumic ventricular relaxation
time and the deceleration time, and a decreased E\A
ratio, suggest abnormal left ventricular diastolic filling
[3,4], or abnormal left ventricular relaxation.
On day 9 of the study, 3 h after their usual breakfast, all
subjects underwent a supine radionuclide angiography
study for measurements of cardiac chamber volumes and
ejection fraction, a measure of systolic function. The best
septal view was used to determine the end-systolic and
end-diastolic volumes using the modified Links method
[22].
After completion of cardiac measurements on day 9, all
study subjects, while remaining supine, had blood
samples drawn into pre-chilled tubes containing EDTA
and aprotinin for measurements of NT-ANP and BNP.
Blood samples were centrifuged immediately at 4 mC at
3000 rev.\min for 10 min before the plasma was frozen
at k70 mC until analysis. Blood samples were also drawn
for complete blood count, prothrombin time and liver
function tests for calculation of the Child–Pugh score
[23].
Procedures
Echocardiography
retain sodium avidly even on a low sodium intake ;
therefore these patients were placed on a diet containing
20 mmol of sodium and 1.0 litre of fluid per day for 7
days. Day 1 of the study was the first day of the diet. All
medications that could potentially affect cardiac function
or volume status, such as β-blockers and diuretics, were
withheld from day 1. None of the ascitic patients received
a paracentesis for 2 weeks prior to the study.
All study subjects underwent (i) trans-thoracic echocardiography to assess cardiac structure and diastolic
function ; (ii) a radionuclide angiography to assess cardiac
chamber volumes and ejection fraction, and (iii) blood
sampling for measurements of NT-ANP and BNP after
having been in a supine posture for at least 2 h.
Protocol
On day 8 of each study group’s respective diet, all
subjects underwent a trans-thoracic echocardiographic
examination to assess left ventricular systolic and diastolic chamber dimensions, interventricular septal thickness and left ventricular relative wall thickness [21].
Diastolic function was assessed by measuring the E\A
ratio (where the E velocity is the early maximal ventricular filling velocity, and the A velocity is the late
diastolic or atrial velocity), an assessment of the degree of
impairment of diastolic relaxation, as well as the isovolumic relaxation time (the period of time from the
closure of the aortic valve to the opening of the mitral
valve) and the deceleration time (the time period during
which the ventricle inflow decelerates to a complete
A comprehensive trans-thoracic echocardiographic
examination was performed using commercially available
cardiac ultrasound machines (Hewlett Packard, Andover,
MA, U.S.A.). Patients were placed in the left lateral
decubitus position, and standard parasternal, apical and
substernal views were obtained. Pulsed and colour flow
Doppler techniques were used to interrogate the isovolumic relaxation and deceleration times. All images
were then recorded on VHS tapes for off-line analysis.
Radionuclide angiography
A detailed description of the technique of cardiac
chamber volume measurements using radionuclide angiography can be found in [24]. Briefly, red blood cells were
labelled using [**mTc]pertechnetate. The cardiac volumes
were measured based on regional activity corrected for
attenuation. The ejection fraction and cardiac volumes
were analysed using semi-automated software. Quality
assurance studies in our Nuclear Cardiology Laboratory
have established the standard error of the estimate of left
ventricular ejection fraction calculation to be less than
2 % using the semi-automated technique. The standard
error of the estimate of ventricular volume calculation is
less than 5 ml [25].
Laboratory analysis
A complete blood count, assessment of prothrombin
time and liver function tests were performed using
standard laboratory automated techniques. Plasma
concentrations of NT-ANP and BNP were measured by
# 2001 The Biochemical Society and the Medical Research Society
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F. Wong and others
Table 2 Baseline haemodynamics and cardiac structure and function for control subjects
and patients with cirrhosis
Significance of differences : *P
0.05 compared with controls ; †P
0.05 compared with pre-ascitic cirrhotic patients.
Cirrhotic patients
Parameter
Controls
Pre-ascitics
Ascitics
n
Heart rate (beats/min)
Mean arterial pressure (mmHg)
Ejection fraction ( %)
End-diastolic volume (ml)
End-systolic volume (ml)
Left atrial size (mm)
Left ventricular diameter at end-diastole (mm)
E/A ratio
Isovolumic relaxation time (ms)
Deceleration time (ms)
Interventricular septal thickness (mm)
Posterior wall thickness (mm)
Left ventricular mass (g)
8
66p5
91p5
58.9p1.6
106p14
43p6
39.5p2.6
48.8p1.7
1.40p0.20
78.9p4.8
196p13
9.1p0.5
8.9p0.6
146p12
17
71p2
90p2
64.7p2.6*
112p11
46p5
43.3p1.6*
50.4p1.2
1.19p0.10
89.8p2.7*
227p11
10.6p0.3*
9.8p0.3
175p10
19
71p4
88p2
64.1p1.6*
108p8
38p4
42.0p1.3*
44.6p1.28*†
1.18p0.07
92.7p3.8*
250p11*
10.9p0.3*
9.4p0.3
195p13
RIA. Dried plasma extracts were reconstituted with RIA
buffer (Phoenix Pharmaceuticals, Mountain View, CA,
U.S.A.). RIA standard curves with 10–1280 pg of NTANP\tube or 1–128 pg of BNP\tube were generated in
parallel with sample extracts. Samples were incubated
with a primary rabbit anti-NT-ANP or anti-BNP serum
for 16 h at 4 mC. Tracer, i.e. "#&I-NT-ANP or "#&I-NTBNP, was added and incubated for 24 h at 4 mC to achieve
competitive binding with antiserum. A secondary antibody to the primary antibody was used to separate
bound from free tracer and NT-ANP or BNP, which was
achieved with a goat anti-(rabbit IgG) serum bound to
solid-phase beads. After incubation for 90 min at roo
temperature, the tubes were spun at 1700 g for 20 min at
4 mC. The supernatant was aspirated off and radioactivity
in the remaining pellet was counted in a γ-radiation
counter (Model 1470 Wizard, Wallac ; Fisher Scientific,
Unionville, ON, Canada) for 1 min. Bound relative to
maximum binding percentages (%B\Bmax) against those
of NT-ANP or BNP standard concentrations were
calculated, from which amounts of NT-ANP or BNP for
unknown samples were determined. The lower limit of
detection for ANP is 5 pg\ml, and that for BNP is
7 pg\ml. The coefficient of variation for ANP is 8.6 %,
while that for BNP is 10.8 %.
Statistical analysis
All results were expressed as meanpS.E.M. For each
parameter, the differences between the three study groups
were assessed by ANOVA. Correlation analysis was
used to determine the relationships between the cardiac
parameters and natriuretic peptide levels. A P value of
0.05 was considered to be statistically significant.
# 2001 The Biochemical Society and the Medical Research Society
RESULTS
Cardiac structural parameters
Both the pre-ascitic and ascitic cirrhotic patients had
significantly increased interventricular septal thickness
compared with the control subjects (P l 0.017). Left
ventricular posterior wall thickness, as well as left ventricular mass, were increased in both groups of cirrhotic
patients compared with the controls ; however, the differences were not statistically significant (P 0.05)
(Table 2). Left atrial size in both the cirrhotic groups
was significantly increased compared with that in the
controls (P l 0.03).
Systolic and diastolic function
No wall motion or valvular abnormalities were noted
during the echocardiological examination for both the
controls and the cirrhotic patients. The radionuclide
angiography ejection fraction was significantly higher in
both groups of cirrhotic patients compared with the
controls (Table 2). Neither the end-diastolic nor the endsystolic volume was significantly different in the cirrhotic
patients compared with the controls (P 0.05). The
ascitic, but not the pre-ascitic, cirrhotic patients had
a significantly smaller left ventricular diameter at the
end of diastole compared with the controls (P l 0.03)
(Table 2).
The E\A ratio, a measure of the degree of impairment
of diastolic relaxation, was reduced in the cirrhotic
patients compared with the control subjects, but the difference was not statistically significant. However, the
isovolumic relaxation time was significantly prolonged in
both the pre-ascitic (P l 0.05) and the ascitic (P l 0.04)
Brain natriuretic peptide levels (ng/L)
Brain natriuretic peptide in cirrhosis
Figure 1 NT-ANP and BNP levels in control subjects and in
pre-ascitic and ascitic cirrhotic patients
Pre-ascitic (L), pre-ascitic patients with low natriuretic peptide levels ; pre-ascitic
(H), pre-ascitic patients with high natriuretic peptide levels. Significance of
differences : *P 0.05 compared with controls, FP 0.05 compared with
pre-ascitic (L).
patients (Table 2). Likewise, the deceleration time was
increased in both cirrhotic groups, and significantly so in
the ascitic cirrhotic patients (P l 0.03) (Table 2).
Natriuretic peptide levels
NT-ANP levels were similar in the controls and the preascitic cirrhotic patients (Figure 1). In contrast, the ascitic
cirrhotic patients had significantly higher NT-ANP
levels (P l 0.01). Likewise, BNP levels were similar in
the controls and the pre-ascitic cirrhotic patients, but the
ascitic cirrhotic patients had significantly higher levels
compared with the controls (P l 0.05) (Figure 1).
When the individual results for NT-ANP and BNP
levels were analysed in the pre-ascitic group, a subgroup
of 10 of the 17 patients were found to have higher
natriuretic peptide levels than the mean of the control
group ; only six of these 10 patients with higher natriuretic
peptide levels had alcohol as the aetiology of their
cirrhosis. When the pre-ascitic cirrhotic group was
separated into subgroups with high and low levels of
natriuretic peptides, the levels in the former group were
significantly increased compared with those in the
Figure 2 Correlations between BNP levels and interventricular thickness (top), deceleration time (middle) and
left ventricular mass (bottom)
Data are from the subgroup of pre-ascitic patients with high BNP levels and the
ascitic patients.
control group (P l 0.02 for NT-ANP ; P 0.01 for
BNP) (Figure 1). However, there was no statistically
significant difference in any of the cardiac parameters
between the subgroups with high and low hormone
levels.
When the natriuretic peptide hormone levels of the
high pre-ascitic cirrhotic subgroup and the ascitic cirrhotic patients were combined and correlated with
parameters of cardiac structure and function, BNP
showed a significant correlation with septal thickness
(P 0.01), left ventricular diameter at end-diastole (P l
# 2001 The Biochemical Society and the Medical Research Society
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F. Wong and others
0.02) and deceleration time (P 0.01) (Figure 2). There
was no correlation between NT-ANP levels and any of
the cardiac parameters.
DISCUSSION
The present study confirms previous findings of subtle
changes in cardiac structure and function in patients with
cirrhosis [2,3]. Baseline systolic function, as measured by
ejection fraction, appeared normal. In contrast, diastolic
filling parameters were abnormal, as demonstrated by
slow ventricular relaxation and impaired ventricular
filling. There was associated thickening of the heart, as
demonstrated by an increased interventricular septal
thickness. Although the pre-ascitic cirrhotic patients had
changes that were significantly different from the
controls, the abnormalities were more obvious in
the ascitic cirrhotic patients.
Cardiac dysfunction has not been recognized as a
feature of cirrhosis in itself. Many cirrhotic patients do
not undergo routine cardiological examination. Even
when cardiac investigations are performed, the ECG and
chest X-ray are often normal. Routine two-dimensional
echocardiography often shows a normal ejection fraction,
as well as normal valvular function. Therefore it is not
surprising that cardiac abnormalities often are not identified in cirrhosis, especially if diastolic function is not
routinely assessed. In contrast, in ischaemic heart disease
and hypertension, structural and functional changes in
the heart are prominent, easily diagnosed and used
routinely as independent risk factors for the development
of cardiac failure [26,27]. Although overt cardiac failure is
uncommon in cirrhosis, unexpected cardiac deaths have
occurred following surgery in patients with cirrhosis
[8–10], suggesting that better assessment of cardiac
function is needed in these patients.
Natriuretic peptide hormones have been used in the
screening and diagnosis of cardiac disease for many years
[28]. Markedly elevated levels of circulating ANP have
been found in patients with heart disease of various
aetiologies [29]. Because ANP is synthesized mainly in
the atria, elevated levels primarily reflect increased atrial
pressure associated with heart failure. NT-ANP, a
cleavage product of pro-ANP and a major circulating
form of the hormone, has been reported to be a better
marker of left ventricular dysfunction than ANP [30]. Its
concentrations are considerably higher than those of
ANP, due to slower clearance. However, the sensitivity
of NT-ANP appears to be not as high as that of BNP as
a marker of left ventricular dysfunction [12,31,32],
especially in asymptomatic patients. BNP is synthesized
mainly by myocytes of the left ventricle in response to
volume overload or an increase in left ventricular enddiastolic pressure [33]. Thus BNP stimulation can be the
result of impaired systolic function and\or diastolic
# 2001 The Biochemical Society and the Medical Research Society
relaxation [33]. The fact that elevated levels of BNP can
identify asymptomatic patients with diastolic dysfunction in the absence of systolic abnormalities has made it a
useful screening tool for the detection of cardiac dysfunction.
Our cirrhotic patients with ascites indeed had elevated
levels of both NT-ANP and BNP, suggesting the
presence of cardiac dysfunction. This was despite a
normal clinical cardiological examination, ECG and chest
X-ray. It is interesting to note that the pre-ascitic cirrhotic
patients as a group did not show any evidence of elevated
natriuretic peptide hormone levels, despite the fact that
the echocardiographic and radionuclide findings suggested the presence of structural and functional abnormalities. However, careful analysis of the individual patients
revealed that some, but not all, pre-ascitic patients had
elevated natriuretic peptide hormone levels. This may
explain the controversy in the literature with regard to
BNP levels in pre-ascitic cirrhotic patients [18,19], as
only some, but not all, pre-ascitic cirrhotic patients
have cirrhotic cardiomyopathy. This is analogous with
a previous finding that, while many pre-ascitic cirrhotic
patients showed an increase in systolic pressure with
an increase in cardiac volume following sodium loading,
some such patients actually showed an inverse pressure\
volume relationship, i.e. increased volume resulted in
a decrease rather than an increase in systolic pressure
[2]. These combined results suggest that only some,
but not all, pre-ascitic cirrhotic patients have evidence
of cardiac dysfunction. Alcohol does not appear to be a
contributory factor to the development of cirrhotic
cardiomyopathy, as only some of the patients with
cardiac dysfunction had alcohol as the aetiology of
their cirrhosis. Furthermore, the ventricles are dilated
with systolic dysfunction in alcoholic cardiomyopathy,
in contrast with the ventricular hypertrophy with diastolic dysfunction observed in cirrhosis.
Volume overload leading to activation of neurohormones, including noradrenaline [34], angiotensin and
aldosterone [35,36], has been implicated in cardiac
hypertrophy and fibrosis, resulting in structural
remodelling with increased collagen accumulation in the
interstitium, which greatly increases myocardial stiffness.
The increased left ventricular wall tension in turn
activates the release of BNP, and to a lesser extent ANP.
Both ANP and BNP have potent natriuretic, diuretic and
vasodilatory properties. Their presence may be regarded
as counter-regulatory to the actions of the sympathetic
and renin–angiotensin–aldosterone systems. Therefore
both ANP and BNP represent an in-built mechanism to
counteract the development of heart failure, while at the
same time providing a marker for the early detection of
cardiac dysfunction.
The fact that there was a significant correlation
between the elevated BNP levels, but not NT-ANP levels
(when including pre-ascitic and ascitic patients), and
Brain natriuretic peptide in cirrhosis
interventricular septal thickness and deceleration time
suggests that BNP is a better marker than NT-ANP of
diastolic function in cirrhosis. Elevated BNP levels have
been shown to accurately reflect isolated diastolic dysfunction in the absence of systolic failure [37] with a
sensitivity of 85 % and a specificity of 74 % [32]. The fact
that elevated BNP levels were also correlated with the left
ventricular diameter at end-diastole suggests that
increased intraventricular volume also contributed to
BNP secretion. The combined effects of a thicker left
ventricle together with increased intraventricular volume
would result in a higher left ventricular end-diastolic
pressure, leading to increased ventricular wall stress,
thereby stimulating BNP secretion. The presence of a
large left atrium compared with the controls suggests that
the diastolic dysfunction was associated with increased
atrial pressure, thereby accounting to some extent for the
raised NT-ANP levels.
Although Doppler indices of diastolic filling have been
validated by catheterization assessment, other factors,
such as preload, afterload, left ventricular function,
arrhythmias and the presence of mitral valve disease, may
confound these Doppler indices [38]. In the present study
we have minimized the influence of these confounding
physiological factors, as our patients were in normal
sinus rhythm, had preserved left ventricular systolic
function and did not have valvular abnormalities. In
addition, preload was kept constant, as patients were not
taking diuretics and their salt and water intake was kept
constant during the study period. The effect of age was
minimized, as the mean ages of the three study groups
were similar. As the Doppler parameters were obtained at
rest, we are not able to comment on the effect of exercise
on diastolic filling.
Thus we have shown that abnormal plasma levels of
BNP do provide information about abnormal cardiac
function in patients with cirrhosis, and that elevated
levels of BNP correlate best with diastolic dysfunction in
these patients. Because cardiac dysfunction is largely
asymptomatic in cirrhosis, clinical assessment is not
always reliable, and since investigations such as echocardiography and radionuclide angiography are timeconsuming and costly as screening procedures, BNP
levels may be used as a simple, feasible and reliable
indicator of cardiac abnormalities in these patients. A
high level of BNP in the absence of any medications,
especially diuretics, should suggest the need for further
cardiac investigations, while a normal or low BNP level
has excellent negative predictive value. Thus BNP may be
used to identify patients who may benefit from therapeutic interventions such as the use of β-blockers or
angiotensin receptor antagonists.
In conclusion, the present study demonstrates that, in
patients with cirrhosis, natriuretic peptide levels were
increased in those patients with cardiac dysfunction, and
that BNP levels were related to interventricular septal
thickness and impairment of diastolic function. BNP
shows promise as a screening test for the need for further
cardiac investigations [34], and may eventually prove to
be a marker of successful therapeutic intervention in
cirrhosis.
ACKNOWLEDGMENTS
We thank Dr Gordon Moe of St Michael’s Hospital,
Toronto, for performing the NT-ANP and BNP assays,
Jim Graba for performing the echocardiological
examinations, Yasmin Alidina for performing the radionuclide angiography studies, and Shona Mackenzie for
her nursing support. P. L. is The Heart and Stroke Polo
Chair Professor in Cardiovascular Research, University
of Toronto, Canada.
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Received 7 June 2001; accepted 1 August 2001
# 2001 The Biochemical Society and the Medical Research Society