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Utility of B-natriuretic peptide as a rapid, point-ofcare test for screening patients undergoing
echocardiography to determine left ventricular
dysfunction
Alan S. Maisel, MD, FACC, Jen Koon, BSN, Padma Krishnaswamy, MD, Radmila Kazenegra, MD, Paul Clopton,
BSN, Nancy Gardetto, NC, Robin Morrisey, NC, Alex Garcia, BS, Albert Chiu, BS, and Anthony De Maria, MD,
FACC San Diego, Calif
Background Although echocardiography is an important tool for making the diagnosis of left ventricular (LV) dysfunction, the cost of this procedure limits its use as a routine screening tool for this purpose. Brain natriuretic peptide (BNP) accurately reflects ventricular pressure, and preliminary studies have found it to be highly sensitive and highly specific in diagnosing congestive heart failure in the emergency department. We hypothesized that BNP might therefore be useful as a
screening tool before echocardiography in patients with suspected LV dysfunction.
Methods Subjects included patients referred for echocardiography to evaluate the presence or absence of LV dysfunction. Patients with known LV dysfunction were excluded from analysis. BNP was measured by a point-of-care immunoassay
(Biosite Diagnostics, San Diego, Calif). The results of BNP levels were blinded from cardiologists making the assessment of
LV function. Patients were divided into those with normal ventricular function, abnormal systolic ventricular function, abnormal diastolic function, and evidence of both systolic and diastolic dysfunction.
Results Two hundred patients in whom LV function was unknown were studied. In the 105 patients (53%) whose ventricular function was subsequently determined to be normal by echocardiography, BNP levels averaged 37 ± 6 pg/mL.
This was significantly less than in those patients with either ultimate diastolic dysfunction (BNP 391 ± 89 pg/mL (P < .001)
or systolic dysfunction (BNP 572 ± 115 pg/mL (P < .001). A receiver-operator characteristic curve showing the sensitivity
and specificity of BNP against the echocardiography diagnosis revealed the area under the curve (accuracy) was 0.95.
At a BNP level of 75 pg/mL was 98% specific for detecting the presence or absence of LV dysfunction by echocardiography.
Conclusions A simple, rapid test for BNP, which can be performed at the bedside or in the clinic, can reliably predict
the presence or absence of LV dysfunction on echocardiogram. The data indicate that BNP may be an excellent screening
tool for LV dysfunction and may, in fact, preclude the need for echocardiography in many patients. (Am Heart J 2001;
141:367-74.)
Although patients with left ventricular (LV) dysfunction have improved survival on medications such as
angiotensin-converting enzyme inhibitors and β-blockers,1,2 this may be a difficult diagnosis to make by conventional criteria.3,4
No blood test can rapidly determine whether a patient
has LV dysfunction,5 and echocardiography may not
always be cost-effective as a screening device, especially
From the Division of Cardiology and the Department of Medicine, Veteran’s Affairs
Medical Center and University of California, San Diego.
Submitted August 16, 2000; accepted November 29, 2000.
Reprint requests: Alan Maisel, MD, VAMC Cardiology 111-A, 3350 La Jolla Village Dr, San Diego, CA 92161.
E-mail: [email protected]
4/1/113215
doi:10.1067/mhj.2001.113215
in those patients who have a low probability of cardiac
dysfunction.6,7
B-natriuretic peptide (BNP) is a cardiac neurohormone secreted from the cardiac ventricles as a response
to ventricular volume expansion and pressure
overload.8-10 BNP levels are elevated in patients with
symptomatic LV dysfunction and correlate with New
York Heart Association (NYHA) class as well as with
prognosis.10-19 However, the utility of plasma BNP as a
screening test has been limited by the same standard
assay issues common to other hormones or cytokines
also elevated in heart failure.20-22
By use of a rapid immunoassay for BNP, we sought to
determine whether BNP levels could serve as a screen
to patients referred for echocardiography at the San
Diego Veteran’s Health Care System.
American Heart Journal
March 2001
368 Maisel et al
Methods
Study population
The study was approved by the University of California
Institutional Review Board and conducted at the San Diego
Veteran’s Health care System between June and October
1999. Two hundred consecutive patients referred for echocardiography to evaluate LV function and consented to be studied were included from a total of 262 patients referred for LV
function during this time period. The 62 patients with known
LV dysfunction were excluded from analysis. Patients referred
for echocardiography to assess valve disease, the presence of
a vegetation, or to rule out a cardiac cause of stroke were not
included in this database. Both outpatients and inpatients
were included in this study, and approximately 24% of the
sampling population consisted of inpatients.
Echocardiography
Two-dimensional, M-Mode, spectral, and color flow Doppler
echocardiograms were obtained with commercially available
instruments operating at 2.0 to 3.5 mHz. Two-dimensional
imaging examinations were performed in the standard fashion
in parasternal long- and short-axis views and apical 4- and 2chamber views.23 Pulsed Doppler spectral recordings were
obtained from a 4 × 4–mm sample volume placed at the tips
of the mitral leaflets and in the pulmonary vein and that was
adjusted to yield the maximal amplitude velocity signals. All
data were copied to 0.5-inch VHS videotape for subsequent
playback, analysis, and measurement.
Two-dimensional echocardiograms were subjected to careful visual analysis to detect regional contractile abnormalities.
LV systolic and diastolic volumes and ejection fractions were
derived from biplane apical (2- and 4-chamber) views with use
of a modified Simpson’s rule algorithm.24 The transmitral
pulsed Doppler velocity recordings from three consecutive
cardiac cycles were used to derive measurements as follows: E
and A velocities as the peak values reached in early diastole
and after atrial contraction, respectively, and deceleration
time as the interval from the E wave to the decline of the
velocity to baseline. In addition, pulmonary venous systolic
and diastolic flow velocities were obtained as the maximal values reached during the respective phase of the cardiac cycle,
and the pulmonary venous “A” reversal as the maximal velocity of retrograde flow into the vein after the P wave of the
electrocardiogram (ECG). Finally, the LV isovolumetric relaxation time (IVRT) was obtained from the apical 5-chamber
view with a continuous wave cursor or, if possible, a pulsed
Doppler sample volume positioned to straddle the LV outflow
tract and mitral orifice to obtain signals from aortic valve closure or the termination of ejection and mitral valve opening or
the onset of transmitral flow. IVRT was taken as the time in
milliseconds from the end of ejection to the onset of LV filling. All echocardiograms were interpreted by experienced
cardiologists who were blinded to the BNP levels.
Echocardiographic classifications
Normal ventricular function. Normal ventricular function
was defined by normal LV end-diastolic (3.5-5.7) and endsystolic dimensions (2.5-3.6), no major wall motion abnormalities, an ejection fraction of >50%, and no evidence of
impaired or restrictive relaxation abnormalities.
Systolic dysfunction. Systolic dysfunction was defined by
an ejection fraction less than 50% or either global hypokinesis
or discrete wall motion abnormalities.
Diastolic dysfunction. Diastolic dysfunction was defined as
impaired relaxation, restrictive pattern, and pseudonormal
pattern on the basis of the definitions below.
1. Impaired relaxation: E/A ratio <1 and deceleration time
>240 ms in patients <55 years old and E/A ratio <0.8 plus
deceleration time >240 ms in patients ≥55 years old.
IVRT measurements, which were available in approximately one half of the patients, was >90 ms in 90% or
more of patients were abnormal E/A ratio changes or
deceleration time >240 ms.
2. Restrictive: E/A ratio >1.5 and deceleration time <150 ms.
Confirming evidence included pulmonary vein diastolic >
pulmonary vein systolic, pulmonary “A” reversal > forward mitral A wave duration, pulmonary vein diastolic
flow reversal, IVRT < 70 ms. Confirming evidence by one
or more of the above was seen in >50% of patients.
3. Pseudonormal E/A ratio >1 and deceleration time >240
ms. Confirmation by Valsalva maneuver when possible.
Systolic plus diastolic-restrictive. Systolic plus diastolicrestrictive was defined as ejection fraction less than 50% with
global hypokinesis or discrete wall motion abnormalities and
deceleration time <150 ms.
Measurement of BNP plasma levels
During initial evaluations, a small sample (5 mL) was collected into tubes containing potassium EDTA (1 mg/mL
blood). BNP was measured with the Triage B-Type Natriuretic
Peptide test (Biosite Diagnostics, San Diego, Calif). The Triage
BNP Test is a fluorescence immunoassay for the quantitative
determination of BNP in whole blood and plasma specimens.
The concentration of BNP in the specimen is proportional to
the fluorescence bound in the detection lane of the device
and was quantified by the portable Triage meter. When possible, BNP levels were measured in whole blood and processed
within 4 hours. Otherwise, samples were spun down and the
plasma frozen until the sample was analyzed (1-2 days). Figure
1 shows a high correlation between the assay used in this
study (Biosite Diagnostics) and the Shiono radioimmunoassay
(RIA) (Shionogi, Osaka, Japan). The range of detectable levels
are 1 to 1300 pg/mL. The average 95% confidence limit of the
analytical sensitivity of the test is less than 5 pg/mL (95% confidence interval 0.2-4.8 pg/mL). The average total imprecision
is 10.1% at mean values of 28 pg/mL and 16.2% at mean levels
of 1080.4 pg/mL. There is no significant cross-reactivity with
endothelin-1, α-atrial natriuretic peptide, or aldosterone.
Statistical analysis
Group comparisons of BNP values were made with t tests for
independent samples and analyses of variance. In all cases these
were computed with raw BNP values and repeated with logtransformed BNP values because the BNP distribution was positively skewed. Both versions yielded the same conclusions.
Sensitivity, specificity, and accuracy were computed for
BNP with a selection of possible cut points. The diagnostic
utility of BNP alone was compared with the echocardiographic probability of LV dysfunction with receiver-operator
characteristic (ROC) curves.
American Heart Journal
Volume 141, Number 3
Maisel et al 369
Figure 1
Figure 2
Correlation between two assays for BNP: Triage Cardiac assay
(Biosite Diagnostics, and Shiono RIA, Shionogi), n = 42
patients. Measurements done in parallel, same day.
Mean and SEM for normal and abnormal LV dysfunction.
Table I. Patient characteristics
No.
Age (y)
Sex (male/female)
All normal
All abnormal
History of hypertension
History of diabetes
History of coronary artery disease
History of shortness of breath
History of edema
200
65.32 ± 0.9
189/11
53%
48%
65%
34%
46%
52%
28%
Figure 3
Characteristics of all 200 patients recruited into the study. History included presence
or absence of diabetes, hypertension, or coronary artery disease and symptoms
included presence or absence of shortness of breath or edema when referred for
echocardiogram.
Results
The characteristics of the 200 patients are shown in
Table I. Fifty-two percent of patients had unsubstantiated complaints of dyspnea, whereas the remaining
were essentially asymptomatic. Nearly all patients had
risk factors for heart disease, including 46% with a history of coronary artery disease.
Figure 2 presents BNP values (mean and SE) for
patients classified as either “normal LV function” or
“abnormal LV function” groups. Patients diagnosed
with abnormal LV function (n = 95) had a mean BNP
concentration of 489 ± 75 pg/mL, whereas the normal
LV function group (n = 105) had a mean BNP concentration of 29.5 ± 62.4 pg/mL. The group difference
was significant in raw (P < .001) and log (P < .001)
form.
Figure 3 shows the breakdown of patients with
abnormal LV function into purely systolic (n = 53),
purely diastolic (n = 42), and the combination of systolic plus diastolic (n = 14) on the basis of echocardiog-
BNP values for the different subclasses of LV dysfunction,
namely, all systolic, all diastolic, and all systolic plus diastolic
dysfunction. The group systolic plus diastolic dysfunction is a
subgroup of all systolic dysfunction. Data are expressed as
mean ± SEM.
raphy. Values for all abnormal LV function groups are
significantly higher than for the normal LV function
group (P < .001). Patients with systolic plus diastolicrestrictive dysfunction had significantly higher BNP values (1077 ± 272 pg/mL) than pure systolic (567 ± 113
pg/mL) or pure diastolic function alone (391 ± 89
pg/mL) (P < .0001). The ejection fraction of the systolic plus diastolic-restrictive group was 34% versus
45% for the pure systolic patients.
American Heart Journal
March 2001
370 Maisel et al
Table II. BNP levels: normal versus abnormal
BNP levels
(pg/mL)
38.5
46
55
65
75
Sensitivity (%)
95 (88-98)
93 (85-97)
92 (84-96)
88 (80-94)
86 (78-92)
Specificity (%)
66 (56-74)
80 (71-97)
86 (76-91)
91 (84-96)
98 (93-100)
Positive
predictive
value (%)
Negative
predictive
value (%)
71 (63-79)
81 (72-87)
85 (77-91)
90 (82-95)
98 (92-100)
93 (85-97)
81 (72-87)
92 (84-96)
90 (82-94)
89 (82-94)
Accuracy (%)
80
86
89
90
93
Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of various BNP levels. The various cut points were obtained from ROC curve analysis.
Figure 4
Table III. Normal LV function versus abnormal LV function
Normal
Abnormal
LV function LV function
(n = 105)
(n = 95)
Age >55 y
Clinical presentation
History of hypertension
History of diabetes
History of coronary artery disease
History of shortness of breath
History of edema
BNP levels (pg/mL)
>80
>100
>120
ROC curve comparing the sensitivity and specificity of BNP and
echocardiography diagnosis of LV dysfunction. Selected BNP
values are indicated in picograms per milliliter.
An ROC curve showing the sensitivity and specificity
of BNP against the echocardiography diagnosis for LV
function in all 200 patients is shown in Figure 4. The
area under the curve (accuracy) was 0.959 (0.9320.987).
Table II represents the sensitivity, specificity, positive and negative predictive values, and accuracy of
various BNP levels in determining LV function with use
of echocardiography as the gold standard. The different cut points were picked from the ROC curve. As
can be seen, a BNP level cutoff value at 38.5 pg/mL
was 95% sensitive for the detection of LV dysfunction
and 66% specific. Levels at or below 38.5 pg/mL had a
negative predictive value of 93%. A BNP cut point of
75 pg/mL exhibited the best specificity (98%), best
positive predictive value (98%), and the highest accuracy (93%).
Table III shows characteristics of patients belonging
to the two groups (normal and abnormal LV function).
As can be seen, histories of hypertension, diabetes, and
71%
90%
56%
28%
33%
42%
24%
75%
40%
60%
63%
32%
1%
1%
1%
85%
83%
80%
Clinical presentation and BNP levels among the two groups of patients—normal and
abnormal LV function, by echocardiography. Abnormal group included either systolic dysfunction, diastolic dysfunction, or both systolic and diastolic dysfunction.
coronary disease are frequently seen in both groups of
patients. Yet BNP levels >100 pg/mL were seen in only
1% of patients with normal ventricular function compared with 80% of patients with abnormal ventricular
function (P < .001).
Figure 5 shows a depiction of all cardiac referrals for
assessment of LV function. Twenty-four percent of
patients in the referral group had known LV dysfunction. The mean BNP in this group was 798 ± 106
pg/mL. Sixty percent of patients referred had unknown
LV function. Breakdowns of BNP levels in these groups
are discussed above.
Discussion
Early detection of LV dysfunction enables administration of treatment that can improve survival and increase
well-being.2,6 But ventricular dysfunction may be difficult to diagnose because patients may be asymptomatic,
and abnormal findings on physical examination are
often absent.3,4 Echocardiography, the most commonly
used method to diagnose LV dysfunction, is one of the
fastest growing procedures in cardiology.25 However,
American Heart Journal
Volume 141, Number 3
Maisel et al 371
Figure 5
A pie chart representing all referrals for echocardiography to evaluate LV function at San Diego Veterans Administration Medical Center between June and October 1999. This group includes both outpatients and inpatients.
both the limited availability of echocardiography in
community settings and its expense may not make it
the best screening test for patients with low probability
of LV dysfunction.
Although studies using logistic regression models
with features of the history, physical examination,
chest x-ray film, and ECG have been used to predict the
probability of an abnormal echocardiogram,7,26 a simple, rapid blood test that is both sensitive and specific
for LV dysfunction would be of significant clinical benefit. The test should reliably rule out LV dysfunction
with an adequate positive predictive value.
The fact that increased levels of neurohumoral factors
such as norepinephrine, renin, and endothelin-1 have
been found to be significant prognostic predictors in
congestive heart failure (CHF) suggests an important
role of these vasoconstrictors in the pathogenesis of
CHF.27-34 However, the use of these neurohumoral factors to diagnose LV dysfunction is impractical, in large
part because of difficult assay characteristics, general
instability of the compounds, and wide-ranging, often
overlapping values.35,36
BNP is a 32 amino acid polypeptide containing a 17
amino acid ring structure common to all natriuretic
peptides.37 The source of plasma BNP is cardiac ventricles, which suggests that it may be a more specific indicator of ventricular disorders than other natriuretic
peptides.5,8,32 The nucleic acid sequence of the BNP
gene contains the destabilizing sequence “tatttat,”
which suggests that turnover of BNP messenger RNA is
high and that BNP is synthesized in bursts.8 This release
appears to be directly proportional to ventricular volume expansion and pressure overload.8-11,32 BNP is an
independent predictor of high LV pressure10 and correlates to NYHA classification.11
BNP as a screen for LV dysfunction
BNP appears to be a useful addition in the evaluation
of possible CHF.13-15,18 In a community-based study
where 1653 subjects underwent cardiac screening, the
negative predictive value of BNP of 18 pg/mL was 97%
for LV systolic dysfunction.14 In a study of 122 consecutive patients with suspected new heart failure referred
by general practitioners to a rapid-access heart failure
clinic for diagnostic confirmation, a BNP level of 76
pg/mL, chosen for its negative predictive value of 98%
for heart failure and similar to the cutoff value in the
current study, had a sensitivity of 97%, a specificity of
84%, and a positive predictive value of 70%.13 Finally,
Davis et al15 measured the natriuretic hormones atrial
natriuretic peptide and BNP in 52 patients with acute
dyspnea and found that admission plasma BNP concentrations more accurately reflected the final diagnosis
than did ejection fraction or concentration of plasma
atrial natriuretic peptide.
Point-of-care testing of BNP
This is the first study that examines the utility of a
rapid, point-of-care test for BNP to predict LV dysfunction as determined by echocardiography. This immuno-
American Heart Journal
March 2001
372 Maisel et al
assay is automatic, uses 5 mL of whole blood, and is
small enough to use at the bedside or the echocardiography clinic. Our findings suggest that BNP may be a
useful screen for patients with LV dysfunction and
yields an ROC curve of 0.959 compared to echocardiography. This accuracy is similar to that of the prostatespecific antigen for prostate cancer detection, which
had an area under the curve (AUC) of 0.94 and is superior to those of Papanicolaou smears and mammography (AUC 0.70 and 0.85, respectively).38-40 We found
that BNP levels were elevated in both systolic and diastolic dysfunction, with the highest values being
reported in patients with systolic dysfunction plus a
decreased mitral valve deceleration time. Interestingly,
this group of patients has also been shown to have the
worst prognosis of all echocardiogram classifications of
LV dysfunction.12,17
The European Society of Cardiology recently published its recommendations regarding the diagnosis of
isolated diastolic heart failure, which included the presence of symptoms, presence of normal or mildly
reduced systolic function, and evidence of abnormal LV
relaxation and filling, diastolic distensibility, and diastolic stiffness.41 Our results are similar to those of Redfield et al,42 who studied 657 subjects with normal systolic function and found that BNP levels were higher in
those with isolated diastolic dysfunction. Although BNP
levels cannot differentiate between systolic and diastolic dysfunction, elevated BNP levels likely represent
true diastolic dysfunction when systolic function is normal by echocardiography.
The results of this study can be extended to other
venues where rapid screening for left ventricular dysfunction is important.12,17,18 We recently evaluated
point-of-care testing of 250 patients seen in the emergency department for acute dyspnea. At the cut point
for BNP of 80 pg/mL, the negative predictive value
was 98%. BNP levels added significantly to variables
found in the history, physical examination, and the
laboratory. Patients whose dyspnea was subsequently
found to be the result of pulmonary disease had BNP
levels 10-fold less than those of patients with CHF.
Twenty-nine of 30 cases of acute dyspnea misdiagnosed by emergency department physicians would
have been correctly identified had BNP levels been
available.43
Role of BNP in asymptomatic or minimally symptomatic LV dysfunction
It is estimated that 3% of the population above the
age of 45 years may have ventricular dysfunction and
that 50% of them may be asymptomatic.44 The National
Institutes of Health sponsored Studies of Left Ventricular Dysfunction (SOLVD) in patients with asymptomatic
LV dysfunction, demonstrated humoral activation characterized by increases in the natriuretic peptides with-
out activation of the circulating renin-angiotensin system.45 In the current study we found that nearly half
the patients were asymptomatic, yet BNP levels were
elevated in the majority of patients.
Our data amplify the suggestion of Mair et al,46 who
concluded that there is sufficient evidence to encourage physicians to gain experience with BNP as a supplement in the diagnosis of patients suspected of having heart failure. The current study demonstrates the
usefulness of BNP for selecting patients for further cardiac evaluation. It is clear that BNP should not replace
imaging techniques in the diagnosis of CHF because
these methods provide complementary information. An
increase in BNP is serious enough to warrant follow-up
echocardiography. Because BNP also provides information on neurohormonal activation in CHF, which is
independent and of additive prognostic value to hemodynamic variables, BNP might also be helpful for the
cardiologist to monitor therapy and disease course in
patients with CHF and for estimating prognosis in these
patients.47,48
Limitations
This was an observational study done at a single Veteran’s hospital, so one must be careful about generalizing the results to the entire population. Both the AUC
from an ROC, as well as the negative predictive values
are dependent on the patient population studied. Our
population represents generally older, predominantly
male, veterans.
Echocardiographic recordings form the basis of the
diagnosis of systolic and diastolic dysfunction in the
current study. Numerous previous reports have validated the ability of cardiac ultrasonography to detect
abnormalities of contractile function and to quantitate
LV volumes and ejection fraction.23,24 All patients in
this study so designated had clear-cut evidence of LV
systolic dysfunction. Although diastolic dysfunction
implies an abnormal relationship between LV volume
and pressure, echocardiography is capable of assessing
only parameters related to volume. Therefore transmural and pulmonary venous flow velocities provide
only indirect measurements of diastolic performance.
Nevertheless, these parameters have been shown to
provide reliable markers of impaired diastolic function
and are applied for this purpose in clinical practice.
Finally, in this study BNP is being used to identify
“any” impairment of ventricular function rather than
“significant” impairment. Thus symptoms in such
patients are not necessarily of cardiac origin and could
challenge the value of labeling those patients as “abnormal” with BNP.
Conclusion
An easy, rapid test for BNP, which can be performed
at the bedside or clinic, with a whole blood sample,
American Heart Journal
Volume 141, Number 3
can reliably predict the presence or absence of LV dysfunction on echocardiography. We believe that BNP may
be an excellent screening tool for LV dysfunction, especially in the community where the greatest burden of disease exists and where there is limited access to echocardiography. In this setting it is likely that BNP analysis
would greatly assist in appropriateness of patient referral
and in the optimization of drug therapy.
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