Oxford Medicine Online: Biomarkers in Acute Heart Failure

Biomarkers in acute heart failure
Oxford Medicine Online
The ESC Textbook of Intensive and Acute

Cardiovascular Care (2 ed.)
Edited by Marco Tubaro, Pascal Vranckx, Susanna Price,
and Christiaan Vrints
Latest update
This online textbook has been comprehensively reviewed for the

February 2018 update, with revisions made to 28 chapters. Find
out more about the updates made.
Publisher: Oxford University Press Print Publication Date: Feb 2015

Print ISBN-13: 9780199687039 Published online: Feb 2018
DOI: 10.1093/med/ © European Society of Cardiology
9780199687039.001.0001
Chapter: Biomarkers in acute heart failure

Author(s): Rajiv Choudhary, Kevin Shah, and Alan Maisel
DOI: 10.1093/med/9780199687039.003.0037_update_003
Update:
Meta-analyses included confirming the utility of BNP, NT-proBNP, and

MR-proANP as negative predictors for acute heart failure and the
utility of NT-proBNP-guided outpatient HF management.
Page 1 of 33
Discussion added on a novel therapeutic agent for heart failure with

reduced ejection fraction: sacubitril-valsartan (LCZ696).
References added on biomarkers galectin-3, neutrophil gelatinase-

associated lipocalin, and procalcitonin.
A model utilizing a panel of biomarkers to assess response to

diuretics in acute HF is included as a potential additional role for
biomarkers in AHF.
The prognostic value of endothelin in acute HF for short and long-

term outcomes was included.
The recently published American Heart Association (AHA) Scientific

Statement on Biomarkers in HF was mentioned and cited.
3 new references
Updated on 22 Feb 2018. The previous version of this content can

be found here.
Summary
Acute heart failure continues to be a worldwide medical problem,

associated with frequent readmissions, high mortality, and a profound
economic impact on national health care systems. In the past decade,
biomarkers have shifted the way in which acute heart failure is
managed by the cardiologist. The search for the ideal biomarker to aid
in the diagnosis, prognosis, and treatment of acute heart failure is
ongoing. The natriuretic peptides have proved extremely useful in
determining whether acute dyspnoea has a cardiac aetiology. In
addition, recent trials have demonstrated the use of natriuretic
peptides in inpatient and outpatient prognosis, as well as in titrating
medications in outpatients with chronic heart failure to prevent acute
heart failure hospitalizations. Other emerging acute heart failure
biomarkers include mid-regional pro-adrenomedullin, mid-regional
proatrial natriuretic peptide, troponin, ST2, and neutrophil gelatinase-
associated lipocalin.
Contents
Page 2 of 33
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Summary [link]
Introduction [link]
The ideal biomarker [link]
Natriuretic peptides [link]
Natriuretic peptide biochemistry [link]
Natriuretic peptide pathophysiology and function [link]
Clinical utility of natriuretic peptide use in acute heart failure
[link]
Natriuretic peptide utility in the emergent setting [link]
Natriuretic peptide utility in the inpatient setting [link]
Natriuretic peptide utility in the outpatient setting [link]
Interpreting natriuretic peptide levels [link]
Concomitant conditions seen in the acute heart failure patient

[link]
Neutrophil gelatinase-associated lipocalin [link]
Procalcitonin [link]
High-sensitivity troponins [link]
Emerging biomarkers [link]

Galectin-3 [link]
Copeptin [link]
Mid-regional markers [link]
ST2 [link]
Conclusion [link]
Personal perspectives [link]
Further reading [link]
Introduction
Acute heart failure (AHF) remains one of the difficult conditions to

treat in the spectrum of cardiovascular diseases (CVDs). Biomarkers are
essential tools, which help the clinician to quantify the underlying
pathophysiological mechanisms and tailor AHF therapy accordingly. With
an explosion in biomarker research over the last decade, the role of
biomarkers in managing AHF patients is evident. As almost every AHF
patient presents through the emergency department (ED), an early
diagnosis and early initiation of treatment are key in achieving positive
outcomes. A rapid bedside diagnosis allows the clinician to grade the
severity of AHF and helps to ‘tailor’ the therapy effectively. Moreover, in
circumstances of equivocal radiographical and clinical symptoms,
biomarker testing can help clinicians by providing a more accurate
diagnostic view, thus preventing a misdiagnosis and aiding an early
initiation of treatment, especially in the acute setting.
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In this chapter we discuss in detail the use of natriuretic peptides, beyond

doubt, the most important biomarkers in AHF, but we also address the
diagnostic and prognostic utility of other emerging biomarkers that might
provide added value for the management of patients with AHF.
The ideal biomarker
A biomarker must contain several characteristics to be

considered an ideal AHF biomarker [1]. The ideal AHF biomarker,
depending on the nature of the condition being tested, must be highly
sensitive or specific. For instance, while screening for asymptomatic left
ventricle (LV) dysfunction, a high specificity allowing to ‘rule in’ the
disease is required [1, 2], whereas, in diagnosing symptomatic life-
threatening conditions such as an acute myocardial infarction (AMI), the
biomarker must be highly sensitive in allowing to ‘rule out’ the disease
effectively [1, 2]. The other characteristic refers to the biomarkers
measurability. In order to achieve this, a biomarker must carry a low
coefficient of variation (CV) (<10%), allowing the detection and reflection
of even minute changes in the disease state of the patient [2, 3].
Moreover, the technical measurement of the biomarker using assays must
be easy to perform and be able to be carried out by the bedside, allowing
a faster access to the clinical status of the patient. The ideal biomarker
must reflect ongoing pathophysiological changes in the AHF patient,
giving a sense of severity of the disease and helping clinicians chart the
disease progression. Moreover, biomarker levels must respond to ongoing
treatment, allowing the clinician to gauge the effectiveness of the therapy
and to titrate the treatment, as needed, to achieve positive outcomes.
Ideally, a biomarker or panel of biomarkers would affect clinical
management. For example, investigators have demonstrated the potential
of a panel of biomarkers to predict poor diuretic response [94].
Specifically, incorporation of biomarkers soluble ST2 (sST2) and
neutrophil gelatinase-associated lipocalin (NGAL) along with other
clinical indicators are associated with poor diuretic response in an acute
HF population. An additional role for an optimal biomarker would be to
provide information which affects clinical management. Finally, the ideal
biomarker must be cost-effective and applicable across all diverse
populations [2, 3].
Thus, an ideal AHF biomarker must be multifaceted, aiding clinicians

with not only the diagnosis and prognosis of the diseased state, but also
with predicting heart failure recurrence and helping clinicians tailor AHF
therapy by monitoring biomarker levels. Over the last decade, the
criteria, which the ideal AHF biomarker must fulfil, have certainly
evolved. Although natriuretic peptides, as AHF markers, get close, no
single biomarker meets all criteria, and researchers have therefore
suggested a multimarker approach to maximize AHF treatment and
management.
Page 4 of 33


Natriuretic peptides
Natriuretic peptides are circulatory peptide hormones, which

are synthesized and released from the myocardial cells, in direct response
to ventricular changes in volume and pressure [4]. Natriuretic peptides
have gained widespread recognition and are considered benchmark
biomarkers in the diagnosis and prognostication of AHF. Natriuretic
peptide testing in the ED allows the clinician to accurately diagnose acute
decompensated heart failure (ADHF), especially when conventional tests,
such as physical examinations and radiographic imaging, have been
inconclusive.
Natriuretic peptide biochemistry
Natriuretic peptides belong to a family of structurally similar peptides,

consisting of atrial natriuretic peptide (ANP), brain natriuretic peptide
(BNP), and C-type and D-type natriuretic peptide [5]. Of these, BNP has
widespread clinical applications, due to its in vitro stability, compared to
other peptides. The BNP gene is activated as a direct result of several
stimuli such as cardiomyocyte stretch, cardiomyocyte injury, and/or death
and hypoxia [5, 6]. This gene encodes the 134-amino acid preproBNP
precursor molecule. Glycosylation of the preproBNP molecule yields a 26-
amino acid signal sequence and the 108-amino acid proBNP molecule [6].
The protein-cleaving enzymes corin and furin cleave this proBNP peptide
to produce the biologically active 32-amino acid BNP peptide and the
inactive 76-amino acid amino terminal (NT)-proBNP fragment [6, 7] (see
Figure 37.1). Once in the circulation, BNP exerts its physiological
effects by binding guanylyl cyclase receptors, referred to as natriuretic
peptide receptors A and B, and initiating a signalling cascade mediated
via cyclic guanosine monophosphate (cGMP). Plasma BNP has a half-life
of about 20 min, whereas plasma NT-proBNP has about 70 min [5–7]. BNP
is cleared from the circulation by binding natriuretic peptide receptor C
and, to some extent, via degradation by neutral endopeptidases. BNP is
renally excreted, and, in patients with renal function impairment, BNP
levels might be elevated, due to decreased excretion. NT-proBNP, on the
other hand, is mainly excreted via the kidneys (55–65%), and the rest via
the liver, musculoskeletal tissue, and head and neck [8].
Page 5 of 33


Figure 37.1
Illustrative representation of AHF pathophysiology, along with biomarker-
specific sites of involvement. LVD, left ventricular dysfunction; LVEDP, left
ventricular end-diastolic pressure; LVEDV, left ventricular end-diastolic
volume; PCWP, pulmonary capillary wedge pressure; RAAS, renin–
angiotensin–aldosterone system; AVP, arginine vasopressin (antidiuretic
hormone); ADHF, acute decompensated heart failure; SVR, systemic
vascular resistance; HR, heart rate; NGAL, neutrophil gelatinase-
associated lipocalin; HS-Troponins, high-sensitivity troponins.
Reproduced from McGrath MF and de Bold AJ. Determinants of
natriuretic peptide gene expression. Peptide. 2005; 26(6): 933–943 with
permission from Elsevier.
Natriuretic peptide pathophysiology and function
Natriuretic peptides are hormones synthesized in the heart which

regulate the water–electrolyte balance in the body. ANP and BNP are
released in response to atrial and ventricular wall stretch. Therefore,
elevated levels of natriuretic peptides are a result of the body’s response
to a volume-overloaded state. The compensatory mechanisms, which are
activated in response to a decreased plasma volume, include the RAAS,
the sympathetic system, the inflammatory pathway, and the
neurohormonal system [9, 10] (see Figure 37.2). Collectively, they
work to maintain the plasma volume by affecting Na+ and water
homeostasis. In healthy individuals, BNP is synthesized in the atria and
ventricles, but, in specific conditions, such as HF, associated with volume
expansion and pressure overload, BNP gene synthesis occurs mainly in
the ventricle [11]. Studies have shown that this synthesis occurs in
‘bursts’, due to the presence of a destabilized nucleic acid sequence in
the BNP gene identified as ‘TATTTAT’ [11, 12]. The physiological
functions of BNP act to counter the effects caused due a decreasing
cardiac output. Once in the circulation, BNP induces vasodilation and
promotes natriuresis and kaliuresis; furthermore, it inhibits the actions of
Page 6 of 33


the sympathetic nervous system, and, more importantly, it inhibits RAAS.

Interestingly, BNP has anti-fibrotic and anti-inflammatory effects on the
heart, thus exerting an overall cardioprotective effect [11, 12].
Figure 37.2
Schematic representation of the natriuretic peptide gene structure and
biosynthesis in humans. ANF, atrial natriuretic factor/atrial natriuretic
peptide; BNP, B-type natriuretic peptide; CNP, C-type natriuretic peptide.
Reproduced with permission from McGrath MF and de Bold AJ.
Determinants of natriuretic peptide gene expression. Peptide. 2005;
26(6): 933–43.
Clinical utility of natriuretic peptide use in acute heart failure
As a quantitative marker of heart failure, natriuretic peptide levels are

best interpreted as a continuous variable. The higher the value, the
greater the likelihood that the dyspnoea is due to heart failure. The
clinical implications of natriuretic peptide use in AHF revolve around
their ability to differentiate cardiac dyspnoea from non-cardiac dyspnoea.
BNP levels have been shown to correlate with New York Heart
Association (NYHA) functional classes and are inversely related to the
calculated EF of the LV [13]. Moreover, BNP levels directly correlate with
the measured pulmonary capillary wedge pressures, thus providing an
almost accurate estimation of LV systolic dysfunction [14]. Similarly, NT-
proBNP levels are fast gaining a stronghold in the management and
diagnosis of heart failure patients. With a longer half-life when compared
to BNP, NT-proBNP survives longer in the plasma and provides similar
information regarding heart failure severity and disease progression [11].
Although natriuretic peptide levels are unable to distinguish systolic from
diastolic heart failure, elevated BNP and NT-proBNP reflect a wide array
of cardiac pathophysiology such as diastolic function, right ventricular
size and function, valvular heart disease, filling pressures, heart rhythm,
and coronary ischaemia [15]. Thus, their use has gained widespread
acceptance as standard of care for the management of heart failure
patients.
Page 7 of 33


Natriuretic peptide levels are part of the ESC and American College of
Cardiology Foundation (ACCF)/AHA heart failure management guideline
algorithm, for diagnosing and excluding heart failure [16]. Natriuretic
peptide levels aid in the diagnosis, prognosis, and risk stratification of
AHF patients. Measuring natriuretic peptide levels also aids the clinician
to judge the response to therapy and allows titrating AHF therapy to
better improve treatment outcome [17, 18]. A meta-analysis of 37 unique
study cohorts described the rule-out thresholds recommended in the 2012
European Society of Cardiology guidelines for heart failure; plasma B
type natriuretic peptide, NTproBNP, and MRproANP have excellent ability
to exclude acute heart failure [19].
Natriuretic peptide utility in the emergent setting
The Breathing Not Properly study [20] was one of the largest multicentre
trials demonstrating the clinical value of using BNP levels in heart failure
patients with acute dyspnoea presenting to the ED. In >1500 patients
presenting to the ED with acute dyspnoea, adding BNP levels to clinical
judgement improved the diagnostic accuracy to 81%. A BNP level of <100
pg/mL was able to rule out heart failure, yielding a 90% sensitivity, 76%
specificity, and 90% NPV, whereas a BNP value of >500 pg/mL was able
to rule in heart failure, yielding a PPV of 87%. Adding BNP levels to
clinical decision making reduced the physician’s indecision rate from 43%
to 11%. Finally, a BNP level of 100 pg/mL was found to be the strongest
independent predictor of heart failure (83%), proving to be more accurate
than the NHANES (67%) and Framingham criteria (73%).
Studies have demonstrated a comparative efficacy of BNP and NT-proBNP

levels in discerning heart failure in the acute setting. The PRIDE study
[21] established age-stratified NT-proBNP levels in ruling out heart
failure. NT-proBNP levels of <300 pg/mL achieved a 99% NPV.
Furthermore, NT-proBNP levels were the strongest independent predictor
for diagnosing AHF. Table 37.1 provides an overview of NT-proBNP
cut-points for diagnosing and ruling out heart failure.
Table 37.1a Factors increasing natriuretic peptide levels
Age
Right heart failure
Renal failure
Valvular disorders
Liver disease
Page 8 of 33


Sepsis
subarachnoidal haemorrhage (SAH)
Stroke
Trauma
Anaemia
Table 37.1b Factors decreasing natriuretic peptide levels
Obesity
Flash pulmonary oedema
Pericardial tamponade
BNP serves as an excellent surrogate for LV function, particularly the

end-diastolic wall stress. In 160 patients with heart failure, there was a
significant correlation between BNP levels and LV end-diastolic stress and
LV end-diastolic pressure (r = 0.88; r = 0.29, respectively) [22]. In an
attempt to assess the diagnostic utility of BNP levels and left ventricle
ejection fraction (LVEF), as determined by 2D echocardiography, BNP
levels achieved an area under the curve (AUC) of 0.89 vs 0.78 for EF in
diagnosing heart failure. Most importantly, a combined knowledge of BNP
levels, along with EF, the clinical history, and radiographic imaging
correctly classified 97.3% of the patients with heart failure [23].
Despite the reported superiority of natriuretic peptides in diagnosing

heart failure, natriuretic peptides do not distinguish systolic heart failure
from preserved-EF heart failure, thus natriuretic peptide testing remains
an adjunct to conventional testing and must not be used as a stand-alone
measure or replace current tools, such as echocardiography or
radiographic imaging, in diagnosing heart failure.
Page 9 of 33


Natriuretic peptide utility in the inpatient setting
A review of heart failure databases and registries estimates the in-

hospital mortality of AHF to be around 4–7%. The most common causes of
acute decompensation, leading to admission, include ACS, arrhythmias
such as atrial fibrillation, valvular disorders, impaired renal function, and
non-compliance to diet and/or medications [24].
In a subanalysis of the large-scale prospective Euro-Heart Failure Survey

II, the characterization of AHF patients and identification of clinical risk
predictors revealed that patients with a lower mortality at 1 year were
more likely to have new-onset or de novo heart failure, compared to
ADHF. Moreover, the use of ACE-Is or ARBs, β-blockers, and lipid-
lowering agents was more common among the survivors. Several factors
were associated with a worse prognosis, such as a history of previous MI,
elevated blood urea nitrogen (BUN) and creatinine, anaemia, and low
serum Na+ concentrations. LV systolic dysfunction was found to be a
strong independent predictor of short-term and long-term mortality [25].
Inpatient monitoring of BNP levels not only allows the clinician to judge
response to therapy, but also provides prognostic information. A >46%
reduction in BNP levels from admission, together with an absolute BNP
level of <300 pg/mL at discharge, was associated with a significantly
lower rate of rehospitalizations and deaths [26]. Results from the I-
PRESERVE trial [27] demonstrated that, in patients with preserved-EF
heart failure, NT-proBNP levels of >339 pg/mL were associated with an
increased rate of AEs. Monitoring BNP levels in AHF can allow a clinician
to judge treatment response and appropriately titrate therapy to achieve
better outcomes. Moreover, elevated BNP levels may reflect failure to
ongoing treatment, warranting the need for more aggressive therapy. The
IMPROVE-CHF trial [28] revealed that NT-proBNP testing in acutely
dyspnoeic patients presenting to the ED improved diagnostic accuracy
when added to clinical judgement. Moreover, it positively impacted direct
medical costs of ED visits, rehospitalization over 60 days, and the
duration of ED visits. Rapid BNP testing has been shown to reduce the
length of stay and thus lower costs of treatment. In a clinical study of
participants randomly assigned to standard care vs care utilizing BNP
levels, it was found that, in the BNP arm, the total cost of treatment was
$5410, compared to $7264 in the standard care arm [29]. That said, serial
natriuretic peptide testing is usually discouraged, since only marked
deviations from the baseline natriuretic peptide levels (>60% for BNP,
and >50% for NT-proBNP) have been shown to be associated with clinical
improvement in AHF patients.
In a retrospective analysis of 908 patients hospitalized with ADHF,

investigators evaluating the effect of renal function on the prognostic
accuracy of NT-proBNP found no interaction between eGFR and NT-
proBNP levels in predicting mortality risk at 1 year. They also reported
that a single cut-off value of NT-proBNP at 5180 ng/mL was an
independent predictor of 1-year mortality, irrespective of the residual
Page 10 of 33


renal function. Moreover, in patients with acute worsening of renal

function, defined as an increase in serum creatinine of >0.3 mg/dL, only
patients with persistently elevated NT-proBNP levels, in addition to
worsening renal function, were at increased risk of mortality. The study
suggests that, in patients hospitalized with ADHF and declining renal
function, rising NT-proBNP levels occur not only due to decreased renal
clearance, but also due to progressing disease severity [30].
Discharging the AHF patient is often difficult, due to the complex nature
of heart failure aetiology and a poor correlation between clinical
symptoms and signs and ongoing pathophysiological processes.
Moreover, over-aggressive treatment may harm the kidneys and
exacerbate renal dysfunction, directly increasing the risk of morbidity
and mortality [31]. Diuresis is one of the hallmarks of ADHF treatment
but should be carefully undertaken, since aggressive over-diuresis can
impair renal function and increase the risk of morbidity and mortality of
the patient. The haemodynamic profile of AHF patients can be
categorized on the basis of tissue perfusion, providing an estimate of the
cardiac output, and congestion referring to the level of fluid overload. On
the basis of this categorization, heart failure patients can be classified as
‘warm’ or ‘cold’, depending on the level of perfusion, and as ‘dry’ or ‘wet’,
depending on their level of fluid congestion. In inpatient management of
heart failure patients, heart failure therapy must be aimed at achieving a
dry or euvolaemic state with adequate perfusion [32]. This is achieved by
determining the patient’s ‘dry BNP’ level, which refers to the true BNP
level in the absence of fluid overload, also known as the euvolaemic BNP.
The BNP level in the presence of fluid congestion or fluid overload is
referred to as ‘wet BNP’. Thus, an adequate diuresis is crucial in the
acute decompensated state with fluid overload [32, 33].
Page 11 of 33


Natriuretic peptide utility in the outpatient setting
Natriuretic peptide use to guide outpatient heart failure therapy remains

a controversial topic with equivocal results. Almost more than a decade
ago, Troughton et al. [34] demonstrated a positive benefit by titrating
heart failure therapy to achieve NT-proBNP levels of <1700 pg/mL in
patients with newly decompensated heart failure, established after a 9-
month follow-up period. Since then, several large multicentre trials have
attempted to assess the effects of natriuretic peptide-guided heart failure
therapy on future AE rate and cardiovascular mortality. The STARS-BNP
trial [35] randomized participants to receive either standard treatment or
treatment titrated to achieve a BNP level of <100 pg/mL. Results
reported a 50% reduction in deaths due to heart failure in the BNP-
guided arm. The multicentre TIME-CHF trial [36] randomized 499
participants, with a mean age of 76 years, to NT-proBNP-guided therapy
in order to achieve NT-proBNP levels <400 pg/mL in participants 75
years or younger, and NT-proBNP levels <800 pg/mL in participants 75
years or older, and to symptom-guided therapy. The results reported an
improvement in heart failure admissions and the overall mortality in the
NT-proBNP arm, only in the 75 years or younger age group and in those
with one (or fewer) comorbidity. Similarly, the results from the
BATTLESCARRED multicentre trial [37] revealed a reduction in 3-year
mortality in participants aged 75 years or less. A meta-analysis of 12
trials published in 2014 demonstrated the use of NT-proBNP-guided
therapy reduced all-cause mortality and HF-related hospitalization but
not all-cause hospitalization, whereas BNP-guided therapy did not
significantly reduce both mortality and morbidity [38].
In conclusion, the use of cardiac NPs to guide pharmacologic therapy

significantly reduces mortality and HF-related hospitalization in patients
with chronic HF.
The AHF treatment and management paradigm has significantly evolved

over the past decade. Figure 37.3 demonstrates a conceptual framework
to manage care in HF patients.
Page 12 of 33


Figure 37.3
Conceptual approach for natriuretic peptide-guided heart failure care.
Reproduced from Troughton R, Felker GM & Januzzi JL jr. Natriuretic
peptide-guided heart failure management. European Heart Journal. 2014;
35: 16–24 with permission from Oxford University Press.
While studies suggest the use of serial NP testing as a tool to provide

incremental clinical information on risk stratification and prognosis, the
use of NP to monitor disease progression and guide HF treatment has
shown to be superior to standard care. In a meta-analysis by Troughton et
al., NP-guided therapy reduced all-cause mortality in patients aged <75
years with chronic HF and impaired LV systolic function [39].
Although the underlying mechanisms by which natriuretic peptide-guided

therapy exerts its beneficial effect remain unclear, authors have alluded
to optimization of dosing as a possible role in improving outcomes, rather
than just aggressive therapy.
Page 13 of 33


Interpreting natriuretic peptide levels
Certain factors must be considered while interpreting natriuretic peptide

levels in the acute setting. First, a thorough clinical examination and a
rapid BNP testing to establish the diagnosis and initiate therapy must be
considered. Second, a delay in initiating treatment is associated with poor
outcomes; thus, treatment should be begun as soon as a diagnosis is
made. Finally, markedly elevated BNP levels have been shown to
significantly increase the risk of mortality; thus, such patients might
benefit from intensive care monitoring, especially in the presence of other
organ dysfunction.
Another important caveat to monitoring and interpreting BNP and NT-

proBNP levels is recognizing biological variability. In patients admitted
with AHF, fluctuation in NP levels are often seen, and studies have shown
that a change in BNP levels of >40% and a change in NT-proBNP levels of
>25% indicate changing physiological state [40].
Although the natriuretic peptide cut-off values used to diagnose and

exclude heart failure have been established, natriuretic peptide values
referred to as grey zone values (see Table 37.2) often arise in heart
failure patients [41]. Several underlying conditions, such as obesity, renal
dysfunction, pulmonary disease, ACS, diastolic dysfunction, sepsis, and
valvular disorders, can alter natriuretic peptide levels [41, 42]. Thus, care
should be taken while interpreting natriuretic peptide levels in the heart
failure patient in the presence of concomitant conditions. Novel therapies
such as LCZ-696 (sacubitril-valsartan) have a neprilysin inhibitor
component, which decreases degradation of endogenous natriuretic
peptides. Preliminary studies have demonstrated that this drug increases
circulating levels of BNP, while NT-proBNP levels should not be affected
[43]. This drug has recently made international guidelines to be
considered in the management of chronic HF. Thus, awareness of its
effects on the natriuretic peptide system will be paramount in the
management of HF. Table 37.3 provides an overview of conditions
associated with increasing or decreasing natriuretic peptide levels.
Table 37.2 Natriuretic peptide grey zone values
BNP NT-proBNP
100–400 pg/mL <50 years: 300–450 pg/mL
50–75 years: 300–900 pg/mL
>75 years: 900–1800 pg/mL
Page 14 of 33


Table 37.3 Factors affecting natriuretic peptide levels in patients with

heart failure
Factors decreasing natriuretic peptide levels
Obesity
Flash pulmonary oedema
Pericardial tamponade
Factors increasing natriuretic peptide levels
Age
Right heart failure
Renal failure
Valvular disorders
Liver disease
Sepsis
SAH
Trauma
Stroke
Anaemia
Concomitant conditions seen in the acute heart

failure patient
Neutrophil gelatinase-associated lipocalin
AKI in AHF patients is multifactorial, resulting from the administration of

nephrotoxic agents to the instillation of IV dye and aggressive diuresis,
etc. (see Figure 37.4). In the acute setting, creatinine has been shown
to lag behind an insult, thus proving to be an inferior indicator of acute
kidney injury (AKI). neutrophil gelatinase-associated lipocalin (NGAL),
Page 15 of 33


secreted by the renal epithelial cells of the proximal tubules. has shown
robust evidence in detecting early AKI.
Figure 37.4
Illustration of factors affecting the interrelationship between the heart
and kidney function, and an overview of the nephrotoxic agents most
commonly associated with AKI in the AHF patient.
NGAL is a 25 kDa lipoprotein, containing a 178-amino acid structure, and

is encoded by the LCN2 gene [44–46]. In humans, NGAL is expressed in
neutrophils and, to some extent, in the respiratory and gastrointestinal
(GI) tracts, besides being expressed in the kidneys. NGAL functions as
part of the innate immunity by binding bacterial siderophores and
limiting bacterial growth. In AHF burdened by AKI, NGAL is secreted
within 2 hours and is easily detectable in the urine and serum [44–46].
The GALLANT trial [47] assessed the diagnostic and prognostic utility of
NGAL, along with BNP, in 188 patients with ADHF presenting to the ED.
Results revealed elevated NGAL levels in patients with increased AEs
within a 30-day follow-up period. Moreover, NGAL was an independent
predictor of adverse events (AEs). Finally, adding BNP testing to NGAL
achieved an overall net reclassification improvement of 29.8% patients,
with elevated NGAL and BNP levels carrying the highest risk (HR 16.85).
The Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure
Study (AKINESIS) sought to determine whether NGAL was superior to
creatinine for prediction of worsening renal failure in hospitalized
patients with acute HF treated with intravenous diuretic agents [48]. This
trial demonstrated plasma NGAL was not superior to creatinine for the
prediction of worsening renal failure or adverse in-hospital outcomes.
NGAL is an emerging marker of AKI, and a rapid detection of NGAL by

the bedside may allow clinicians to avoid kidney injury by avoiding over-
diuresis and holding angiotensin-converting enzyme inhibitors (ACE-Is)/
angiotensin receptor blockers (ARBs), especially in the presence of
normal creatinine levels. Moreover, NGAL may be more than just a
marker of tubular dysfunction and may reflect worsening cardiac function
Page 16 of 33


and increasing disease severity, portending to an increase in short-term

mortality.
Procalcitonin
Patients with AHF often have an underlying bacterial pulmonary

infection, which can be missed due to absent radiographical signs and
normal blood counts. Since almost all patients with AHF present to the
ED with a chief complaint of dyspnoea, it remains crucial to identify and
treat the non-cardiac causes of dyspnoea, if any. Since heart failure is a
disease affecting individuals >75 years of age, the burden of mortality is
high in this age group in the presence of concomitant infection [49, 50].
Misdiagnosis and inappropriate treatment can further exacerbate the
problem and worsen the underlying heart failure. Several mechanisms
have been posited to explain a worsening heart failure in the presence of
bacterial infection, some of which include an impaired cardiac
contractility, due to an increased bacterial uptake by cardiomyocytes, and
the activation of the inflammatory cascade, leading to worsening of
haemodynamic pressures [51, 52].
The role of procalcitonin (PCT) use in patients with AHF lies in its ability
to discern an underlying bacterial pulmonary infection, especially in the
absence of radiographic signs and negative blood testing [53]. PCT is a
12.8 kDa peptide with a 116-amino acid structure and is encoded by the
CALC 1 gene located on the short arm of chromosome 11 [54, 55]. In the
presence of a bacterial infection, PCT messenger RNA (mRNA)
upregulation is induced by the bacterial endotoxin, resulting in its release
from the neuroendocrine cells of the lungs, intestines, and peripheral
mononuclear cells. Moreover, certain pro-inflammatory cytokines, such as
tumor necrosis factor α (TNF-α), interleukin (IL)-1β, and IL-6, mediate
PCT release. In non-infective states, PCT is further metabolized to the
biologically active calcitonin in the neuroendocrine C cells of the thyroid
[55–57].
Maisel et al. [58] demonstrated that using PCT levels can improve the
diagnostic accuracy in detecting bacterial pneumonia in AHF patients.
Moreover, PCT levels improved the AUC from 0.79 to 0.86 when added to
radiographic imaging. In patients with pneumonia, PCT levels ranged
from 0.07 to 0.58 ng/mL, compared to 0.05–0.12 ng/mL in patients
without pneumonia. PCT was found to be superior to white cell counts in
predicting pneumonia. Finally, a survival curve analysis revealed that
patients in the lowest quintile (PCT <0.05 ng/mL) had a 92% 90-day
survival rate, compared to patients in the fifth quintile (PCT >0.21 ng/
mL), achieving an 80.5% 90-day survival rate. The study alluded to the
possibility of using PCT levels to guide antibiotic use in AHF patients with
bacterial pneumonia.
In a recently published retrospective multicentre analysis of 4 698

patients with varying severity of heart failure, PCT levels were found to
be significantly higher in patients with bacterial infection complicated by
Page 17 of 33


heart failure, compared to those with simple bacterial infections. The

study suggested that heart failure may interfere with PCT expression.
Results revealed that, in non-infected patients, PCT levels were
significantly elevated in patients with increasing severity of heart failure.
The study alluded to the consideration and implementation of higher PCT
cut-off values in NYHA class II-IV heart failure patients [59]. Other
studies have shown that patients with decompensated HF, without clear
signs of infection, who have elevated PCT have poorer in-hospital and
post-discharge outcomes [60].
Although further trials assessing the utility of PCT levels in infected heart
failure patients are needed, natriuretic peptide use, in conjunction with
PCT, has been shown to improve the diagnostic accuracy of an underlying
bacterial pulmonary infection. Moreover, the study also demonstrated
that a BNP level of >400 ng/mL, along with PCT of >0.21 ng/mL, was
able to accurately identify all patients with AHF and an underlying
bacterial pneumonia.
The role of PCT in the infected heart failure patient is manifold and
certainly of high clinical value. PCT testing can not only allow the
detection of an underlying bacterial pneumonia, but it can also guide
antibiotic therapy in such patients. Randomized clinical trials are needed
to further test this hypothesis.
High-sensitivity troponins
High-sensitivity troponins refer to troponins that are measured in the

bloodstream, using highly sensitive assays [61]. These assays are able to
detect even minute elevations in troponin levels, while maintaining a low
coefficient of variation (CV) (<10%) and a diagnostic cut-off at the 99th
percentile of the general population [61]. Since several different assays
have been utilized, the analytical variability must be considered while
interpreting high-sensitivity troponin levels [62]. Myocyte injury, leading
to cellular death, can vary from 20 min to 4 hours, depending on several
factors such as the infarct size, the condition of the vascular endothelium,
etc. Several conditions can cause troponin leaks into the circulation; only
a markedly elevated rise (>10%) from the baseline is indicative of MI and
warrants intensive cardiac care [62, 63]. High-sensitivity troponin is
elevated in the majority of AHF patients and is associated with many
markers of disease severity (i.e. prevalence of ischaemic heart disease
and worse renal function). Additionally, baseline and peak changes from
baseline levels in AHF are associated with poor clinical outcomes,
including 6-month mortality [64].
Emerging biomarkers
Galectin-3
Page 18 of 33


Galectin-3 is a protein secreted by activated macrophages, resulting in

the proliferation of cardiac fibroblasts and collagen deposition, which
ultimately causes cardiac fibrosis [65, 66]. In patients with heart failure,
galectin-3 levels have been found to be elevated, denoting its link to
cardiac remodelling. Its utility in AHF patients is that of predicting short-
term and long-term prognosis [65, 66].
In rodent models, an infusion of galectin-3 led to an increased collagen

deposition, and ultimately an impaired cardiac function. Moreover, in
rodent models with decompensated heart failure, galectin-3 levels were
grossly elevated [67]. In 599 patients presenting to the ED with acute
dyspnoea, measured plasma levels of galectin-3, along with NT-proBNP
and apelin, revealed that galectin-3 levels were markedly elevated in
participants with heart failure, compared to those without. Galectin-3 was
the strongest independent predictor of 60-day mortality, yielding an AUC
of 0.74 on receiver operator curve (ROC) analysis and an odds ratio (OR)
of 10.3; P <0.01. Furthermore, in combination with NT-proBNP, elevated
galectin-3 levels were a better predictor of mortality [68].
In another interesting analysis of 592 patients hospitalized with heart

failure, galectin-3 levels did not provide additive prognostic information
at 6 months. However, in patients with preserved-ejection fraction (EF)
heart failure, elevated galectin-3 levels were associated with worse
prognosis, when compared to those with reduced-EF heart failure [69]. In
the cardiac transplant population, serum galectin-3 levels remained
significantly elevated the majority of patients after transplantation [70].
Interestingly, elevated levels appear associated with renal dysfunction
and this may be not only a model of cardiac remodeling but also systemic
dysfunction.
Galectin-3 is a strong prognostic marker and, in the AHF patient, is

indicative of ongoing cardiac remodelling. Furthermore, recent trials
have further explored the role of galectin-3 in predicting mortality in AHF
patients. Data suggest that, although galectin-3 is a robust prognostic
marker, elevated levels might be indicative of renal dysfunction, which
might be attributed to fibroblast activation, resulting in renal fibrosis.
Thus, in AHF patients, elevated galectin-3 levels might not only indicate
higher risk, but may also be indicative of an impending renal failure.
Copeptin
The role of arginine vasopressin (AVP), also known as the antidiuretic

hormone (ADH), in heart failure patients is well established. A decrease
in the plasma volume and an increased serum osmolality trigger the
release of ADH from the posterior pituitary gland, causing fluid retention
[71, 72]. In the most severe cases of heart failure, hyponatraemia is often
observed as a direct result of this mechanism. The AVP precursor
molecule is synthesized in the hypothalamus and stored in the posterior
pituitary gland [57, 58]. Due to its in vitro instability and rapid clearance,
AVP is difficult to measure. Copeptin is the more stable and measurable
Page 19 of 33


portion of the AVP molecule. Copeptin is the C-terminal portion of the

AVP precursor molecule and is released in equimolar amounts, along with
AVP. Copeptin has a 39-amino acid structure and functions similarly to
AVP [73].
The role of copeptin in AHF is prognostic in nature. In a subanalysis of

the multicentre BACH trial, patients with elevated copeptin levels were
found to have the highest risk of mortality and readmissions at 90 days.
Patients at the highest quartile of copeptin levels were at an increased
risk of 90-day mortality (HR 3.85). On multivariate analysis, copeptin,
along with NT-proBNP and Na+ levels, achieved a net reclassification
improvement of 32.7% for the 90-day mortality endpoint. Cox regression
analysis revealed that patients with elevated copeptin levels and
hyponatraemia were at highest risk for heart failure-related readmissions,
heart failure-related ED visits, and death. As mentioned before, in
patients with severe heart failure, excess AVP levels result in
hyponatraemia. Moreover, excessive diuretic use can also contribute to
worsening hyponatraemia. The study alluded to the role of using AVP
antagonists to treat hypervolaemic hyponatraemia in such patients with
heart failure [74].
RCTs testing the role of using AVP antagonists are needed to better judge
their effectiveness in AHF patients. Nevertheless, copeptin serves as an
excellent prognostic marker for predicting short-term mortality in AHF
patients.
Mid-regional markers
Peptides are often immeasurable, due to several factors such as in vitro

instability and short half-life due to rapid plasma clearance. Mid-regional
markers refer to the stable and easily measurable mid-regional fragments
of these peptides. The development of newer immunoassays makes it
easier to measure these mid-regional epitopes of circulating hormonal
peptides [62]. ANP, as mentioned before, performs an array of
physiological functions when released into the bloodstream, in direct
response to atrial and ventricular volume and pressure [75, 76]. But their
instability, coupled with a high plasma clearance, made it difficult to
measure ANP. MR-proANP, which refers to the more stable mid-regional
fragment of ANP, can now be measured using novel immunoassays
directed to the mid segment [62, 63].
A subanalysis of the BACH trial revealed that a cut-point of 130 pmol/L

for MR-proANP was non-inferior to BNP at a 100 pg/mL cut-point in
diagnosing AHF; furthermore, MR-proANP significantly added to the
diagnostic performance of BNP and NT-proBNP. Importantly, MR-proANP
was shown to provide additive diagnostic information where natriuretic
peptides were inconclusive. In another study, MR-proANP levels assessed
in 187 patients with NYHA functional classes III–IV heart failure found
that patients with increased MR-proANP levels were at increased risk of
cardiovascular mortality (HR 7.6). Clinical trials have thus far
Page 20 of 33


demonstrated both the diagnostic and prognostic utilities of MR-proANP

[77]. Recent studies have confirmed similar diagnostic power between
MR-proANP, BNP, and NT-proBNP for AHF [78].
The other mid-regional marker in discussion is MR-proADM.

Adrenomedullin, first isolated from the phaeochromocytoma extract, is a
vasodilatory peptide with a 52-amino acid structure [79]. Adrenomedullin
is synthesized in cardiomyocytes and fibroblasts and released into the
circulation, in direct response to an increased wall stretch. Other factors
stimulating adrenomedullin release are thought to be neurohormonal
activation, along with angiotensin II and endothelin-1 [79–81]. But a rapid
plasma clearance and a short-half life (22 min) make it unfavourable for
clinical use, whereas the mid-regional fragment MR-proADM is a more
stable peptide [80, 82]. Recently, endothelin-1 (ET-1) was studied for its
prognostic value in the acute HF population from the Acute Study of
Clinical Effectiveness of Nesiritide in Decompensated Heart Failure
(ASCEND-HF) trial [95]. ET-1, a potent vasoconstrictor, was found to be
associated with worsened inpatient and long-term mortality, independent
of natriuretic peptides.
In the aforementioned study, MR-proADM proved superior to BNP and

NT-proBNP in predicting 90-day mortality in patients with AHF. MR-
proADM outperformed troponin in a multivariate analysis. Additionally,
MR-proADM has been shown to improve the diagnosis of AHF in elderly
patients (>70 years old) when combined with natriuretic peptides [83].
Moreover, MR-proADM, together with copeptin, in predicting 14-day
mortality yielded the best AUC of 0.81. Similar results were obtained in a
study by Potocki et al. [82], which demonstrated the superior
performance of MR-proADM to natriuretic peptides in predicting 30-day
mortality.
The diagnostic and prognostic value of mid-regional markers is apparent.

With more clinical trials exploring the role of these markers in AHF, their
utility in diagnosis and risk stratification of AHF patients seems highly
promising.
ST2
ST2 is a marker of myocardial remodelling and, at a molecular level, plays

a distinct role in promoting myocardial fibrosis [84]. Identified as a
member of the IL-1 receptor family, ST2 has two isoforms. The soluble
isoform, denoted as sST2, and the membrane-bound receptor form,
denoted as ST2L, both of which are expressed in cardiac myocytes. ST2L
bind its functional ligand IL-33, and this ST2L/IL-33 interaction exerts a
protective effect by preventing ventricular remodelling which occurs in
response to mechanical stress [85, 86]. sST2 competes with IL-33,
resulting in the loss of this protective effect and promoting myocardial
fibrosis. Moreover, sST2 functions as a decoy receptor, limiting the
cellular levels of IL-33 [86, 87].
Page 21 of 33


Studies have alluded to the prognostic nature of sST2. Unlike natriuretic

peptides, sST2 is not affected by renal function, age, obesity, or atrial
fibrillation [88]. In 593 patients with dyspnoea presenting to the ED, sST2
levels were significantly higher in those with AHF. In patients with
systolic heart failure, sST2 levels were higher, compared to patients with
non-systolic heart failure (0.67 ng/mL vs 0.42 ng/mL, respectively) [89].
As most patients with systolic heart failure have myocardial remodelling,
sST2 levels indicate a poor prognosis. In such patients, therapy may be
aimed at suppressing cardiac remodelling and a closer monitoring of such
patients. Moreover, when used in conjunction with natriuretic peptides,
sST2 adds to the prognostic information. In assessing the association
between sST2 levels and the cardiac structure determined by
echocardiography, participants with elevated levels of both sST2 and BNP
were at five times the risk of 1-year mortality, when compared to neither
sST2 nor BNP being elevated [90]. In those hospitalized for AHF, a
decrease of this novel biomarker by 15.5% or greater reduces the short-
term risk of mortality [91]. Beta-blockers, mineralocorticoid antagonists,
and angiotensin receptor antagonists have all shown some evidence in
their ability to reduce levels of sST2 [92, 93].
Conclusion
The role of biomarkers in the management and understanding of

acute HF continues to evolve. The American Heart Association published
a Scientific Statement in 2017 specifically addressing the role of
biomarkers in HF [96]. This statement addresses the use of biomarkers in
screening, diagnosis, management and prognostic assessment of patients
with HF. With respect to acute HF, the use of biomarkers including
natriuretic peptides, troponin, copeptin, MRproADM, and sST2 are all
mentioned to help better understand the pathophysiology and improve
management of this condition.
BNP and NT-proBNP are benchmark biomarkers of cardiac stress and are
part of the AHF management guideline algorithm. But certain co-existing
conditions, such as pulmonary/systemic infection, valvular dysfunction,
renal failure, obesity, etc., can affect biomarker levels. In the presence of
‘grey zone’ biomarker levels, clinicians must look for these comorbid
conditions before making a definitive diagnosis of heart failure. AHF
treatment should be aimed at lowering the ‘wet BNP’ level, in order to
achieve the patient’s ‘dry BNP’ level before discharge. In patients with
AHF and superimposed bacterial pneumonia, the use of PCT allows the
clinician to identify an underlying bacterial pneumonia when other testing
has proved inconclusive. NGAL may help in the detection of early kidney
injury, and, in the setting of AHF, elevated NGAL levels may indicate
kidney injury due to aggressive diuresis or the use of nephrotoxic agents
(ACE-I/ARB, spironolactone, IV dye). Thus, monitoring NGAL levels may
allow the clinician to successfully diurese the patient without harming the
Page 22 of 33


kidneys. Prognostic markers, such as mid-regional peptides, offer additive

information on short-term and long-term mortality of the AHF patient.
Troponins are established markers of myocyte death/injury. Although

there are several conditions which result in non-specific elevated levels of
troponin, high-sensitivity assays, detecting even minute changes in
troponins, allow a clinician to gauge the ongoing cellular damage. Newer
markers, such as galectin-3, belong to a class of myocyte remodelling
markers, and elevated levels suggest ongoing fibrotic change, which
requires treatment aimed at preventing further worsening of myocardial
remodelling. Copeptin levels are indicative of salt/water homeostatic
change, necessitating the use of AVP antagonists to block the effects of
ADH and treat hyponatraemia, the electrolyte imbalance most frequently
encountered in severe AHF patients. Newer markers, such as mid-
regional peptides, are neurohormonal markers. Although current data
demonstrate promising diagnostic and prognostic capabilities of these
markers in AHF, further research is needed to better define their role in
the AHF patient. Finally, ST2 is a marker for myocyte stress, and elevated
levels have been shown to favour a poor prognosis. Table 37.4 provides
an overview of the strength of evidence for biomarkers discussed in this
section.
Table 37.4 Strength of evidence for individual markers in diagnosis,

prognosis, and guided treatment
Diagnostic Prognostic Biomarker-

capability capability guided
treatment
Natriuretic +++ +++ +++

peptides
NGAL + ++ +
Procalcitonin +++ ++ ++
High- ++ +++ ++
sensitivity
troponins
Galectin-3 – ++ +
Copeptin – +++ +
MR-proADM – +++ +
Page 23 of 33


ST2 + ++ +
The future for AHF biomarkers revolves around a ‘multimarker’ strategy.

Moreover, their role in guiding AHF therapy remains controversial but
has shown promise. Further randomized clinical trials are needed to
better explore this possibility.
Personal perspectives
Biomarkers have definitely entered the mainstream in treating
and managing patients with heart failure presenting through the
emergency department. Their applications in triaging heart failure
patients, facilitating early diagnosis, and titrating treatment have
been successfully demonstrated. Although there exist certain caveats
to their use in the emergent and inpatient setting, the future will
certainly see a more integrated approach, utilizing a ‘multimarker
strategy’, to better evaluate the heart failure patient. Moreover,
emerging biomarkers have provided a more comprehensive
understanding of the complex underlying pathophysiology. Finally, the
treatment paradigm might see a shift towards a more biomarker-
guided therapy.
Further reading
1. De Luca L, Fonarow GC, Adams KF, et al. Acute heart failure
syndromes: clinical scenarios and pathophysiologic targets for therapy.
Heart Fail Rev 2007;12:97–104.
2. Fonarow GC, Heywood JT, Heidenreich PA, Lopatin M, Yancy CW.

Temporal trends in clinical characteristics, treatments, and outcomes for
heart failure hospitalizations, 2002 to 2004: findings from acute
decompensated national registry (ADHERE). Am Heart J 2007;153:1021–
8.
3. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal pro-BNP

investigation of dyspnea in the emergency department (PRIDE) study. Am
J Cardiol 2005;95:948–54.
4. Maisel AS, Krishnaswamy P, Nowak RM, et al. Breathing not properly

multinational study investigators. Rapid measurement of B-type
natriuretic peptide in the emergency diagnosis of heart failure. N Engl J
Med 2002;347:161–7.
Page 24 of 33


5. Maisel AS, Mueller C, Fitzgerald R, et al. Prognostic utility of plasma

neutrophil gelatinase-associated lipocalin in patients with acute heart
failure: The NGAL EvaLuation Along with B-type NaTriuretic Peptide in
acutely decompensated heart failure (GALLANT) trial. Eur J Heart Fail
2011;13:846–51.
6. Maisel A, Mueller C, Nowak R, et al. Mid-region pro-hormone markers

for diagnosis and prognosis in acute dyspnea: results from the BACH
(Biomarkers in Acute Heart Failure) trial. J Am Coll Cardiol 2010;55:
2062–76.
7. Maisel AS, Nakao K, Ponikowski P, et al. Japanese-Western Consensus

Meeting on Biomarkers. Int Heart J 2011;52:253–65.
8. Maisel A, Neath SX, Landsberg J, et al. Use of procalcitonin for the

diagnosis of pneumonia in patients presenting with a chief complaint of
dyspnea: results from the BACH (Biomarkers in Acute Heart Failure) trial.
Eur J Heart Fail 2012;14:278–86.
9. McMurray JJV, Adamopoulos S, Anker SD, et al. ESC Guidelines for the
diagnosis and treatment of acute and chronic heart failure 2012. Eur
Heart J 2012;33:1787-847.
10. Thygesen K, Mair J, Mueller C, et al. Recommendations for the use of

natriuretic peptides in acute cardiac care. Eur Heart J 2012;33:2001–6.
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Biomarkers in acute heart failure

Oxford Medicine Online

The ESC Textbook of Intensive and Acute

This online textbook has been comprehensively reviewed for the

Publisher: Oxford University Press Print Publication Date: Feb 2015

Biomarkers in acute heart failure

Chapter: Biomarkers in acute heart failure

Meta-analyses included confirming the utility of BNP, NT-proBNP, and

Discussion added on a novel therapeutic agent for heart failure with

References added on biomarkers galectin-3, neutrophil gelatinase-

A model utilizing a panel of biomarkers to assess response to

The prognostic value of endothelin in acute HF for short and long-

The recently published American Heart Association (AHA) Scientific

Updated on 22 Feb 2018. The previous version of this content can

Acute heart failure continues to be a worldwide medical problem,

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Concomitant conditions seen in the acute heart failure patient

Emerging biomarkers [link]

Acute heart failure (AHF) remains one of the difficult conditions to

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In this chapter we discuss in detail the use of natriuretic peptides, beyond

The ideal biomarker

A biomarker must contain several characteristics to be

Thus, an ideal AHF biomarker must be multifaceted, aiding clinicians

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Natriuretic peptides are circulatory peptide hormones, which

Natriuretic peptide biochemistry

Natriuretic peptides belong to a family of structurally similar peptides,

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Natriuretic peptide pathophysiology and function

Natriuretic peptides are hormones synthesized in the heart which

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the sympathetic nervous system, and, more importantly, it inhibits RAAS.

Clinical utility of natriuretic peptide use in acute heart failure

As a quantitative marker of heart failure, natriuretic peptide levels are

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Natriuretic peptide utility in the emergent setting

Studies have demonstrated a comparative efficacy of BNP and NT-proBNP

Table 37.1a Factors increasing natriuretic peptide levels

Right heart failure

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subarachnoidal haemorrhage (SAH)

Table 37.1b Factors decreasing natriuretic peptide levels

Flash pulmonary oedema

BNP serves as an excellent surrogate for LV function, particularly the

Despite the reported superiority of natriuretic peptides in diagnosing

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Natriuretic peptide utility in the inpatient setting

A review of heart failure databases and registries estimates the in-

In a subanalysis of the large-scale prospective Euro-Heart Failure Survey

In a retrospective analysis of 908 patients hospitalized with ADHF,

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renal function. Moreover, in patients with acute worsening of renal

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