Download A feeling in the waters: diagnosis of heart failure

Clinical Science (2004) 106, 111–112 (Printed in Great Britain)
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A feeling in the waters: diagnosis of heart
failure using urinary natriuretic peptides
Henry KRUM and Danny LIEW
NHMRC Centre of Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine,
Monash University Central and Eastern Clinical School, Alfred Hospital, Melbourne, Victoria 3004, Australia
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Plasma levels of brain natriuretic peptide (BNP) and N-terminal pro-BNP (N-BNP) are highly
sensitive markers of ventricular dysfunction and/or hypertrophy and, in established disease, offer
prognostic value and may be useful for guidance of therapy. Ng and co-workers report in this
issue of Clinical Science that urinary levels of N-BNP may be as useful as plasma levels for the
discrimination of patients with and without heart failure. This raises the potential for a relatively
simple urine test that could be used for the diagnosis of heart failure. Roles in prognostication
and the guidance of therapy may also be possible but, perhaps of most significance, measurement
of urinary N-BNP may be applied to screening of patients at high risk of heart failure. The main
limitations of the study were that the sample of heart failure patients comprised only 34 individuals
with New York Heart Association functional Class IV and that the observed correlation between
levels of urinary N-BNP and plasma creatinine seemed counter-intuitive. The latter issue needs
clarification, as renal impairment is a frequent co-morbidity among patients with heart failure and
will potentially confound any observed association between ventricular dysfunction and urinary
N-BNP levels. Another caveat is that it is unclear if testing for urinary N-BNP can be cheaply
and conveniently administered on a large scale. Nevertheless, this first demonstration of elevated
N-BNP in the urine of patients with heart failure raises a number of exciting possibilities with regard
to the management of patients with established or possible heart failure. Further investigation is
required and eagerly awaited.
Among the complex neurohormonal alterations that
occur in heart failure is activation of the natriuretic peptides, which exert counter-regulatory actions to the raft of
co-activated vasoconstrictors and anti-natriuretic factors.
The three known natriuretic peptides, atrial natriuretic
peptide (ANP), brain natriuretic peptide (BNP) and
C-type natriuretic peptide (CNP), induce natriuresis
and diuresis, promote vascular relaxation, inhibit the synthesis and action of vasoconstrictor peptides and inhibit sympathetic nervous activity [1–4]. ANP and BNP
are synthesized by cardiac myoctyes and released primarily in response to atrial stretch. CNP seems to occur
widely in the body, including in endothelial cells [5].
Somewhat paradoxically, because their actions are generally overwhelmed by those of vasoconstrictors and
anti-natriuretic factors in established heart failure, levels
of natriuretic peptides are reliable markers of ventricular
dysfunction and correlate with disease severity. BNP has
been the most widely studied, and consistent populationbased data have now accumulated to show that plasma
levels of BNP, and its precursor N-terminal pro-BNP
(N-BNP), are highly sensitive to the presence of ventricular dysfunction and/or hypertrophy, even among asymptomatic individuals [6,7]. This high sensitivity makes
the assays useful for discriminating between cardiac
and non-cardiac causes of dyspnoea, particularly in the
emergency setting [8]. Plasma BNP and N-BNP levels
also offer prognostic value in existing heart failure [9,10]
and predict for future heart failure following myocardial
infarction [11]. In addition, plasma N-BNP has been
shown to be useful for guidance of heart failure therapy
[12].
Against this background, the report by Ng et al. [13]
in this issue of Clinical Science is of particular interest
Key words: diagnosis, heart failure, urinary natriuretic peptide, validity.
Abbreviations: ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, C-type natriuretic peptide; N-BNP,
N-terminal pro-BNP.
Correspondence: Professor Henry Krum (e-mail [email protected]).
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Comment
and potential importance. The study compared urinary
levels of N-ANP, N-BNP and CNP and plasma levels
of N-BNP between patients hospitalized for heart failure
and age- and sex-matched patients with echocardiographically determined normal systolic function. A significant
elevation was observed in all four measurements of
natriuretic peptides among heart failure patients and, in
the case of the urinary parameters, this finding was noted
even after adjustment for urinary creatinine. The receiver
operated characteristic (ROC) for urinary N-BNP for
the diagnosis of heart failure was very similar to that of
plasma N-BNP.
These data raise the potential for a relatively simple
urine test that could be used for the diagnosis of heart
failure. Roles in prognostication and the guidance of
heart failure therapy may also be possible (in line with
the uses of plasma BNP and N-BNP) but, perhaps of
most significance, measurement of urinary N-BNP may
be applied to screening of patients at high risk of heart
failure to select those for subsequent, more definitive
tests. Indeed, a home N-BNP diagnostic kit, in a manner
similar to that of testing for other biological substances
in urine, may be a future reality, especially if designed to
be fully or semi-quantitative.
However, a number of caveats need to be considered.
First, the sample of heart failure patients comprised only
34 individuals and, although they were consecutively
recruited, similar observations in a much larger cohort
would be required before the findings can be considered
sufficiently robust.
Secondly, the range of values observed for urinary
N-BNP was much smaller than that for plasma N-BNP,
suggesting that urinary N-BNP may be less sensitive a
discriminator between less severe forms of heart failure
and normal subjects. Indeed, the subjects of the study were
all of New York Heart Association functional Class IV
on admission to hospital. Clinically, it is not difficult to
make a diagnosis in a patient with Class IV symptoms
and there would be greater utility in urinary N-BNP
being able to discriminate between less severe disease
(where the diagnosis may be in doubt) and patients with
symptoms for reasons other than cardiac disease. Even
better would be a demonstration of a correlation between
levels of urinary N-BNP and objective measurements
of ventricular dysfunction across a wide range of both
scales.
Thirdly, the association between levels of urinary
N-BNP and renal impairment remains unclear. Ng et al.
[13] found that urinary N-BNP correlated with plasma
creatinine, which is counter-intuitive given that excretion
of N-BNP is dependent on glomerular filtration [14].
This issue needs clarification as renal impairment is a frequent co-morbidity among patients with heart failure and
will potentially confound any observed association between ventricular dysfunction and urinary N-BNP levels.
Finally, for any test to have clinical utility, it also
needs to be reproducible and, importantly, relatively
inexpensive and convenient to administer. Ng et al. [13]
have developed assays for urinary natriuretic peptides
that seem to have reasonable reproducibility, at least in
the limited setting of their study, but there is no indication
that these can be cheaply and widely applied.
Nevertheless, despite these caveats, this first demonstration of elevated N-BNP in the urine of patients with
heart failure raises a number of exciting possibilities
with regard to the management of this progressive, lethal
condition. Further investigation is required and eagerly
awaited.
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Received 8 October 2003; accepted 9 October 2003
Published as Immediate Publication 9 October 2003, DOI 10.1042/CS20030330
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2004 The Biochemical Society