Download Natriuretic Peptide Testing in Heart Failure

Natriuretic Peptide Testing in Heart Failure
Han-Na Kim and James L. Januzzi, Jr
Circulation 2011;123;2015-2019
DOI: 10.1161/CIRCULATIONAHA.110.979500
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CLINICIAN UPDATE
Natriuretic Peptide Testing in Heart Failure
Han-Na Kim, MD, MPH; James L. Januzzi, Jr, MD
C
ase presentation 1: A 78-year-old
woman with a history of morbid
obesity, coronary artery disease,
chronic obstructive pulmonary disease,
and chronic kidney disease (serum creatinine 2.0 mg/dL) presented to the
emergency department with worsening
dyspnea. Her ECG shows no acute
ischemic changes; her chest radiograph reveals chronic emphysematous
changes with mild bilateral infiltrates.
Her lung examination is notable for
diffuse wheezing, and she has chronic
lower extremity edema. Her aminoterminal pro-B-type natriuretic peptide
(NT-proBNP) level is 5500 pg/mL
(upper limit of normal is ⬍1800 pg/mL
for age ⬎75 years). Does this patient
have acutely decompensated heart failure (ADHF)?
Overview: Natriuretic
Peptides in Acute Dyspnea
Many patients presenting with acute
dyspnea (including those with ADHF)
have multiple coexisting medical disorders that may complicate their diagnosis
and management. Diagnostic uncertainty in the setting of acute dyspnea is
associated with longer hospital length of
stay, more diffuse diagnostic and therapeutic efforts, increased healthcare costs,
and higher likelihood for repeat heart
failure (HF) hospitalization or death.1
The addition of testing for brain natriuretic peptide (BNP) or NT-proBNP to
standard clinical assessment has been
shown to be valuable for an accurate
and efficient diagnosis and prognostication of HF, and the use of BNP or
NT-proBNP may be associated with
improved clinical outcomes.2– 4
Pathophysiology of
Natriuretic Peptides in
Heart Failure
Circulating levels of BNP/NT-proBNP
are normally very low in healthy individuals. In response to increased myocardial wall stress due to volume- or
pressure-overload states (such as in
HF), the BNP gene is activated in
cardiomyocytes. This results in the
production of an intracellular precursor propeptide (proBNP108); further
processing of this propeptide results in
release of the biologically inert aminoterminal fragment (NT-proBNP) and
the biologically active BNP (Figure 1).
In addition, a significant portion of
BNP or NT-proBNP detected by current
assays includes uncleaved proBNP108,
whereas BNP concentrations also include the detection of various subfragments that arise from the degradation
of the intact BNP hormone. The bio-
logical activity of BNP includes stimulation of natriuresis and vasorelaxation; inhibition of renin, aldosterone,
and sympathetic nervous activity; inhibition of fibrosis; and improvement in
myocardial relaxation.
Although released in a 1:1 ratio, the
measured NT-proBNP level is higher
than that of BNP, in part because
NT-proBNP is passively cleared from
the circulation more slowly (half-life
of 120 versus 20 minutes). Unlike BNP,
NT-proBNP is not cleared by natriuretic
peptide (NP) receptors or neutral endopeptidases. Rather, NT-proBNP is
cleared by various organs, including
the skeletal tissue, liver, and kidneys.5 A common misconception is
that NT-proBNP is more dependent
on renal function for clearance than
is BNP; both are equally cleared by
the kidneys.6
Diagnostic Applications of
Brain Natriuretic Peptide or
Amino-Terminal Pro-B-Type
Natriuretic Peptide in
Acutely Decompensated
Heart Failure
Brain natriuretic peptide and NT-proBNP
levels are increased in HF, and correlate
well with ventricular wall stress and
severity of HF.2,7 The Breathing Not
From the Cardiology Division, Massachusetts General Hospital, Boston MA.
Correspondence to James L. Januzzi, Jr, MD, FACC, Cardiology Division, Massachusetts General Hospital, Yawkey 5984, 55 Fruit St, Boston, MA
02114. E-mail [email protected]
(Circulation. 2011;123:2015-2019.)
© 2011 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.110.979500
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by on May 30, 2011
2015
2016
Circulation
May 10, 2011
Figure 1. Biology of the natriuretic peptide system. BNP indicates brain natriuretic peptide; NT-proBNP, amino-terminal pro-B-type natriuretic peptide; and DPP-IV, dipeptidyl peptidase-4.
Properly Multinational Study2 and the
Pro-BNP Investigation of Dyspnea in
the Emergency Department7 showed
that NP levels were more accurate for
diagnosis or exclusion of ADHF than
clinical judgment, particularly in the
context of diagnostic uncertainty.8 When
added to comprehensive clinical assessment, BNP and NT-proBNP are both
incrementally useful for diagnosis of
ADHF, and both are endorsed in current
practice guidelines for HF evaluation
(particularly when diagnostic indecision
is present).9
Interpretation and
Differential Diagnosis of
Elevated Natriuretic
Peptide Levels
Elevated concentrations of BNP or
NT-proBNP are powerfully associated
with the presence of HF; however,
there is no value for either that is 100%
diagnostic for HF. Both BNP and
NT-proBNP may be elevated in a
number of other disease states, and
patient factors may influence results.
Among HF syndromes, systolic dysfunction and HF with preserved ejection fraction may cause elevated BNP
or NT-proBNP, although HF with preserved ejection fraction may be associated with lower values of both
peptides than HF due to systolic
dysfunction.10 In addition, other relevant cardiac diagnoses, including right
ventricular failure (due to primary cardiac pathology or secondary to pulmonary embolism or pulmonary hypertension),11 valvular heart disease,12 and
arrhythmias such as atrial fibrillation13
may cause elevation of BNP or
NT-proBNP. In addition to cardiovascular variables that influence NP concentrations, advancing age and renal
dysfunction may lead to higher values
without overt HF, whereas obesity
may result in unexpectedly lower BNP
or NT-proBNP concentrations, even in
those with HF.14,15
Overall, the recommended approaches for use of BNP or NT-proBNP
for the exclusion and identification of
ADHF work well. To troubleshoot complex situations such as renal disease,16,17
adjustment in cutoff points may help
(Table).
Another important situation is the
patient with a gray zone BNP or
NT-proBNP value. Approximately
20% of patients with acute dyspnea
have BNP or NT-proBNP levels that
are above the cutoff point to exclude
HF but too low to definitively identify
it. Knowledge of the differential diagnosis of non-HF elevation of NP, as
well as interpretation of the BNP or
NT-proBNP value in the context of a
clinical assessment, is essential20; gray
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Kim and Januzzi
Table.
HF Natriuretic Peptide Testing
2017
Suggested Cut Points for BNP and NT-proBNP Use in Several Situations
Cutoff Value,
pg/mL
Sensitivity, %
Specificity, %
PPV, %
NPV, %
Reference
To exclude ADHF
BNP
NT-proBNP
⬍30–50
97
62
71
96
2
⬍300
99
68
62
99
7
To identify ADHF
Single cutoff point strategy
BNP
⬍100
90
76
79
89
2
NT-proBNP
⬍900
90
85
76
94
7
18
Multiple cutpoint strategy
⬍100 to exclude;
90
73
75
90
100–400: gray zone
*
*
*
*
⬎400 to rule in
63
91
86
74
⬍450 for age ⬍50 y
90
84
88
66
19
⬍200
88
63
83
72
17
(1) ⬍1200, all ages
89
72
74
94
16
170 for BMI ⬍25 kg/m2
90
77
78
90
15
110 for BMI 25–35 kg/m2
90
77
77
90
54 for BMI ⱖ35 kg/m2
91
70
70
91
⬍900, no adjustment for BMI
87
76
79
90
Age-stratified cut points, no adjustment for BMI
86
90
85
95
BNP, gray zone approach
NT-proBNP, age-stratified
approach
⬍900 for age 50–75 y
⬍1800 for age ⬎75 y
Special situations
Renal dysfunction (GFR ⬍60
mL 䡠 min 䡠 1.73 m⫺2)
BNP
NT-proBNP
or
(2) age-stratified approach, above
Obesity
BNP
NT-proBNP
14
PPV indicates positive predictive value; NPV, negative predictive value; ADHF, acutely decompensated heart failure; BNP, brain natriuretic peptide; NT-proBNP,
amino-terminal pro-B-type natriuretic peptide; GFR, glomerular filtration rate; and BMI, body mass index.
* indicates not applicable.
zone values are not without prognostic
meaning, however, and should be approached with caution.20
In our patient, if the initial BNP concentration had been 90 pg/mL (upper
limit of normal is ⬍200 pg/mL for renal
dysfunction), or if her NT-proBNP had
been 450 pg/mL, in an elderly female
with renal dysfunction, ADHF would
be less likely as the primary cause of
her symptoms. However, we should
keep in mind that HF with preserved
ejection fraction might be present, or
values might have been low because of
her morbid obesity. On the other hand,
her NT-proBNP of 5500 pg/mL is
most consistent with ADHF, irrespective of age or renal function. As be-
fore, interpretation of the NP result in
the clinical context is very important.
Natriuretic Peptides and
Prognosis in Heart Failure
Across all stages of HF, elevated BNP
or NT-proBNP concentrations are at
least comparable prognostic predictors
of mortality and cardiovascular events
relative to traditional predictors of outcome in this setting,21 with increasing
NP concentrations predicting worse
prognosis in a linear fashion. This prognostic value may be used to stratify
patients at the highest risk of adverse
outcomes (Figure 2).22
In ADHF, an initial value of BNP or
NT-proBNP is prognostically useful;
however, a follow-up measurement after therapy provides incremental prognostic value. Observational studies
suggest that when BNP/NT-proBNP
concentrations decrease by 30% or
more in this setting, a better prognosis
is expected than when values fail to
decrease or actually increase.23 However, prospective randomized studies
definitively supporting in-hospital monitoring are not yet available.
Future Directions:
Natriuretic Peptides for
Guided Management of
Chronic Heart Failure
Case Presentation 2: The 78-year-old
woman discussed in case 1 is found to
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2018
Circulation
May 10, 2011
Figure 2. Age-adjusted Kaplan-Meier survival curve of mortality at 1 year associated
with an elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration at emergency department presentation with dyspnea in those with acutely decompensated heart failure. Reproduced from Januzzi et al22 with permission of the publisher. Copyright © 2006, American Medical Association.
have an ejection fraction of 35% and is
treated with a loop diuretic, as well as
with maximum-dose angiotensinconverting enzyme inhibition and carvedilol. She is discharged home and seen
in her cardiologist’s office for follow-up,
where she feels physically as she did at
her baseline examination, with only mild
dyspnea on maximal exertion. Her
NT-proBNP level is 2150 pg/mL; on
recheck 3 months later, it is 4800
pg/mL, but she remains unchanged
clinically. What is the meaning of this
finding, and how might the clinician
respond?
Elevated BNP (above approximately
125 pg/mL) or NT-proBNP (above approximately 1000 pg/mL) values are
prognostically meaningful in chronic
HF, and a rising pattern is predictive of
impending adverse outcome, irrespective of other subjective and objective
prognostic metrics. Furthermore, therapies that are favorable for chronic HF
(such as ␤-blockers, vasodilators, or
aldosterone blockers) tend to lower
concentrations of BNP or NT-proBNP.
Thus, there is increasing interest in
guiding HF therapy with BNP or
NT-proBNP, with the goal of lowering
concentrations of these markers (and
maintaining their suppression) as part
of the therapeutic approach in HF.
Although evidence is increasing that
NP-guided outpatient management of
HF may improve clinical outcomes,4
more information is needed before
adoption of such an approach, which is
currently being tested in clinical trials.24 Nonetheless, an HF patient on an
ostensibly stable medication program
with a rising NP concentration is at
high risk for adverse outcome and
should be scrutinized closely for opportunities to optimize management.
Follow-Up of Cases 1 and 2
The optimal treatment strategy for our
78-year-old patient in case 1 would be
to ascertain the cause of ADHF, while
simultaneously administering decongestive therapy with intravenous loop
diuresis. In the meantime, optimization
of her HF medical regimen, including
uptitration of the angiotensin-converting
enzyme inhibitor dose and a review of
and potential increase in the dose of
her ␤-blocker (when safely able to do
so) would be indicated; the addition of
an aldosterone blocker is recommended if persistent New York Heart
Association functional class III or IV
symptoms are present. Follow-up NP
measurement at the time of discharge
would be useful to ensure adequacy
of therapy, while serving to facilitate
a smooth transition to outpatient
management.
In case 2, an increasing NP concentration in a seemingly unchanged outpatient with chronic HF should prompt
assessment and reaction. Among the
causes of a rising BNP or NT-proBNP
in a seemingly stable outpatient are
noncompliance with medication, an inadequate medication program, dietary
indiscretions, coronary ischemia, atrial
arrhythmia, and progressive decline in
cardiovascular function. In this context, whether or not the patient appears
to be on a maximal treatment program,
reassessment of the patient is indicated. This includes possible investigation for causes of a rising NP value, as
well as simultaneous uptitration of
medications when possible; consideration for eligibility for therapies such
as cardiac resynchronization therapy
or implantable-cardioverter defibrillator implantation is also reasonable.
Acknowledgments
The authors would like to thank Drs Paul
Clopton, Lori Daniels, and Alan Maisel for
their assistance.
Disclosures
Dr Januzzi has received significant grant
support from Roche Diagnostics, Siemens,
and Critical Diagnostics. Dr Kim reports
no conflicts.
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KEY WORDS: heart failure 䡲 natriuretic peptides
䡲 case management 䡲 biomarkers 䡲 prognosis
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