626355

research-article2016
ACC0010.1177/2048872615626355European Heart Journal: Acute Cardiovascular CareMair et al.

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SOCIETY OF
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European Heart Journal: Acute Cardiovascular Care

Will sacubitril-valsartan diminish the 2017, Vol. 6(4) 321­–328

© The European Society of Cardiology 2016
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https://doi.org/10.1177/2048872615626355
DOI: 10.1177/2048872615626355
peptide testing in acute cardiac care? journals.sagepub.com/home/acc

Johannes Mair1, Bertil Lindahl2, Evangelos Giannitsis3,

Kurt Huber4, Kristian Thygesen5, Mario Plebani6, Martin Möckel7,
Christian Müller8 and Allan S Jaffe9; the Biomarker Study Group of the
European Society of Cardiology Acute Cardiovascular Care Association

Abstract
Since the approval of sacubitril-valsartan for the treatment of chronic heart failure with reduced ejection fraction,
a commonly raised suspicion is that a wider clinical use of this new drug may diminish the clinical utility of B-type
natriuretic peptide testing as sacubitril may interfere with B-type natriuretic peptide clearance. In this education paper
we critically assess this hypothesis based on the pathophysiology of the natriuretic peptide system and the limited
published data on the effects of neprilysin inhibition on natriuretic peptide plasma concentrations in humans. As the
main clinical application of B-type natriuretic peptide testing in acute cardiac care is and will be the rapid rule-out of
suspected acute heart failure there is no significant impairment to be expected for B-type natriuretic peptide testing
in the acute setting. However, monitoring of chronic heart failure patients on sacubitril-valsartan treatment with
B-type natriuretic peptide testing may be impaired. In contrast to N-terminal-proBNP, the current concept that the
lower the B-type natriuretic peptide result in chronic heart failure patients, the better the prognosis during treatment
monitoring, may no longer be true.

Keywords
Sacubitril-valsartan, natriuretic peptides, B-type natriuretic peptide, diagnosis, heart failure, acute cardiac care

Date received: 31 October 2015; accepted: 18 December 2015

Introduction
A novel compound, sacubitril-valsartan, an angiotensin
receptor neutral endopeptidase (neprilysin; EC 3.4.24.11)
inhibitor, was recently documented to improve outcomes in
patients with systolic heart failure (HF).1 It is a salt com-
plex of valsartan and sacubitril, the neprilysin inhibitor
prodrug that is processed in the liver into its active moiety,2
which then interacts with a variety of vasoactive peptides
including enhancing natriuretic peptide (NP) activity.2
Since its recent approval for the treatment of symptomatic
chronic HF with reduced ejection fraction in the USA and
the European Community a commonly raised suspicion is
1Department of Internal Medicine III – Cardiology and Angiology,
Medical University Innsbruck, Austria
2Department of Medical Sciences, Uppsala University and Uppsala
Clinical Research Center, Sweden
3Medizinische Klinik III, University of Heidelberg, Germany
4Department of Medicine, Cardiology and Intensive Care Medicine,
Wilhelminen Hospital, Austria
5Department of Cardiology, Aarhus University Hospital, Denmark
6Department of Laboratory Medicine, University Hospital Padova, Italy
7Division of Emergency Medicine and Department of Cardiology,
Charité- Universitätsmedizin Berlin, Germany
8Department of Cardiology and Cardiovascular Research Institute Basel,
University Hospital Basel, Switzerland
9Mayo Clinic and Medical School, USA

that the clinical use of this agent will diminish the clinical
utility of B-type natriuretic peptide (BNP) testing because
sacubitril may inhibit BNP degradation. In this paper we
will critically assess this hypothesis based on the known
Corresponding author:
Johannes Mair, Department of Internal Medicine III – Cardiology and
Angiology, Anichstrasse 35, A-6020 Innsbruck, Austria.
Email: Johannes.Mair@i-med.ac.at
322 European Heart Journal: Acute Cardiovascular Care 6(4)

Figure 1.  Clearance of natriuretic peptides with interference of sacubitril-valsartan.

The natriuretic peptides (NPs) are cleared by two different mechanisms, that is, enzymatic degradation and by binding to natriuretic peptide recep-
tor (NPR) C. All NPs bind to NPR C but A-type natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) have higher affinities than B-type
natriuretic peptide (BNP). The major known biological effects of NPs are mediated by binding to NPR A and NPR B receptors. Both have guanylyl
cyclase activity, and the second messenger of NP is cyclic guanosine monophosphate (cGMP). ANP is the most important ligand of NPR A receptor,
and BNP binds with markedly lower affinity. The main ligand of NPR B is CNP. The major biological effects of NPR C receptor binding is receptor-
mediated endocytosis with subsequent NP degradation; however, adenylate cyclase (AC) inhibition with reduction of intracellular cyclic adenosine
monophosphate (cAMP) concentrations has also been found. Neutral endopeptidase (neprilysin, NEP) is a major contributor to human ANP and
CNP degradation. It cleaves the ring of both peptides, which is essential for receptor binding. Intact human BNP is only a poor NEP substrate, and
high BNP concentrations may even inhibit NEP. Thus, the NEP inhibitor sacubitril mainly augments ANP and CNP activity and has smaller effects on
human BNP degradation. The combination with valsartan additionally inhibits the renin–angiotensin–aldosterone system by blocking the angiotensin
1 receptor. This combination is important because NEP also degrades angiotensin II. AT: angiotensin; s: soluble.

pathophysiology of the cardiac NP system and the limited
published data on the effects of neprilysin inhibition on NP
plasma concentrations in humans.
Pathophysiology of the cardiac NP
system and circulating NP forms
It is outside the scope of this paper to provide a detailed
review on the pathophysiology and metabolism of the car-
diac NPs, which has been done recently;3–7 instead only the
essentials are briefly summarised in the text and figures.
The family of NPs comprises atrial or A-type natriuretic
peptide (ANP), B-type or brain natriuretic peptide (BNP),
C-type natriuretic peptide (CNP) and urodilatin, which is a
renal isoform of ANP isolated from human urine. ANP and
BNP are key regulators of the body’s regulation of volume
and blood pressure homeostasis. They do this by activating
transmembrane guanylyl cyclase and elevating intracellular
cyclic guanosine monophosphate (cGMP), which induces
subsequent increases in renal sodium and water excretion
and stimulation of vasodilation (see Figure 1). NPs also
have an anti-hypertrophic function in the heart and prevent
adverse vascular remodelling. ANP and BNP are primarily
secreted from the heart in response to increased myocardial
stretch mediated by volume or pressure overload, and thus
NP increases can be regarded as markers of ‘cardiac stress’.
In contrast to ANP, only limited amounts of BNP are stored
in atrial granules, so most BNP secretion requires gene
transcription and subsequent peptide synthesis mostly in
the ventricles (see Figures 2 and 3). In settings where acute
changes in atrial stretch occur the changes in ANP concen-
trations are more rapid and pronounced than BNP changes.
However, with chronic myocardial stretch there is upregu-
lation of ventricular NP production and particularly BNP.
ANP is synthesised as a precursor (preproANP, 151
amino acids). After removal of the signal peptide in the
endoplasmatic reticulum, proANP (126 amino acids) is
stored in secretory granules of atrial cardiomyocytes (see
Figure 2). Upon secretion proANP is thought to be pro-
cessed by the serin protease corin, which is anchored on the
cell surface, at the site arginine-98–serine-99 generating a
98-amino acid N-terminal peptide (NT-proANP) and a
28-amino-acid C-terminal hormonally active peptide (ANP,
see Figure 4). These peptides circulate without binding to
Mair et al. 323

Figure 2.  Synthesis, processing and circulating forms of pro A-type natriuretic peptide derived peptides.
The exact nature and distribution of circulating pro A-type natriuretic peptide (ANP) derived molecules in healthy individuals and patients with vari-
ous cardiac diseases is still uncertain. Apart from ANP and N-terminal proANP (NT-proANP) and their degradation products, intact proANP has
been described, which is hormonally acive itself. It may also be processed in the circulation to ANP. aa: amino acids.

Figure 3.  Synthesis, processing and circulating forms of pro B-type natriuretic peptide derived peptides.
The exact nature and distribution of circulating pro B-type natriuretic peptide (BNP) derived molecules in healthy individuals and patients with vari-
ous cardiac diseases is still uncertain. Glycosylation of proBNP in the amino acid (aa) sequence of N-terminal-pro B-type natriuretic peptide (NT-
proBNP) is a post-translational modification occurring within the cardiomyocytes. The extent of glycosylation at threonine 71 influences proBNP
processing by furin and thereby the production of the hormonally active BNP 1-32. Furin and corin are involved in the intramyocardial degradation
of proBNP into BNP 1-32 and NT-proBNP 1-76 within cardiomyocytes or during secretion. Processing of secreted proBNP in blood appears to
occur by furin. Immunoreactive BNP and NT-proBNP forms of high and low molecular mass (MM) have been described in patients, which still need
to be better characterised using state-of-the art analytical techniques of proteomics. BNP 1-32 is the major physiologically active hormone, but in
patients with heart failure it is found in low plasma concentrations. ProBNP and NT-proBNP as well as their split products have low or no hormonal
activity. ER: endoplasmatic reticulum; ir: immunoreactive.
324 European Heart Journal: Acute Cardiovascular Care 6(4)
Figure 4.  Structure of A-type and B-type natriuretic peptides.
Both are small peptides (A-type natriuretic peptide (ANP) 28 amino acids, B-type natriuretic peptide (BNP) 32 amino acids) with a highly homolo-
gous ring structure, which is formed by a disulfide bond between two cysteine residues. Identical amino acids are marked in black. The intact ring
structure is essential for receptor binding.
plasma proteins. In addition, several split products of ANP
and NT-proANP, but also intact proANP, have been detected
in HF patients.6 At the mid-region of proANP little proteo-
lytic degradation occurs.8 Recent data suggest that it is the
unproceesed proANP that is the more important stimulator
of biological activity.9
Figure 3 summarises our current understanding of BNP
synthesis and processing. The initial gene product is pre-
proBNP 1-134, which undergoes removal of a 26-amino
acid signal peptide in the sarcoplasmatic reticulum during
translation, leading to the formation of proBNP 1-108.
ProBNP may be glycosylated post-translation at several
sites in its N-terminus to a variable degree,10,11 and glyco-
sylation at amino acid 71 threonine appears to be involved
in the regulation of proBNP processing by furin.12
Subsequently, proBNP is cleaved by prohormone con-
vertases, such as furin and corin, to release the 76-amino
acid N-terminal portion NT-proBNP 1-76, and the biologi-
cally active C-terminal 32-amino acid molecule BNP 1-32
(see Figure 4). The cleavage site is located between amino
acids 76 and 77. Furin is a membrane-associated endopepti-
dase, and in contrast to corin it is ubiquitously found in vari-
ous tissues. An increase in furin activity in the blood of
acutely decompensated HF patients as well as a decrease in
proBNP glycosylatioin have been reported.13 Thus, some
processing of proBNP can occur in the blood as well. It has
been recognised that both BNP and NT-proBNP are modi-
fied into a mixture of various fragments in the blood (see
Figure 3). At the mid-region of NT-proBNP little proteolytic
degradation occurs.8 Intact circulating proBNP, glycosylated
NT-proBNP and glycosylated proBNP have been observed
in HF patients.11,14 Only a small portion of BNP circulates as
the full-length BNP 1-32, and plasma from HF patients con-
tains diverse degraded forms truncated from the N and
C-terminal end (e.g. BNP 3-32, 5-31, 8-31, 1-25, 1-26).15
Due to short in-vitro half life, ANP itself turned out to be
not suitable for routine diagnostics, but NT-proANP or
mid-regional proANP, BNP and NT-proBNP are all suitable
routine laboratory biomarkers for HF.16–20 The N-terminal
fragments from the prohormones can serve as a surrogate
marker for the actual natriuretic hormone.
NP clearance and possible
interferences of sacubitril
NP clearance has recently been reviewed by Potter.5 In
brief, ANP clearance is rapid (half-life approximately 2
minures) compared with BNP (half-life approximately 20
Mair et al. 325
minures) in men. Clearance of NPs occurs by two major
mechanisms, that is, enzymatic extracellular degradation
by neprilysin and intracellular degradation by insulin-
degrading enzymes, as well as by binding to the NP recep-
tor C. The primary role of this receptor, which is expressed
in many tissues, is to clear NPs by internalisation and deg-
radation (see Figure 1). It binds all three NP family mem-
bers. Insulin degrading enzyme is a cytosolic enzyme,
which is also found in membrane preparations. It initially
cleaves ANP and BNP outside the ring. ANP and CNP are
much better insulin degrading enzyme substrates than
BNP.21 Neprilysin is a zinc-containing, membrane-bound,
ectoenzyme that cleaves various peptide substrates includ-
ing insulin β-chain, β-amyloid and various peptide hor-
mones of relevance in HF, such as angiotensin II,
endothelin-1, bradykinins, substance P, adrenomedullin,
calcitonin gene-related peptide and NPs.5 Neprilysin is
widely expressed, for example, in kidneys, lungs and vas-
cular endothelial cells, and can be released from the cell
surface yielding soluble neprilysin with catalytic activity.22
Neprilysin cleaves ANP and CNP at the cysteine–phenyla-
lanine bond and breaks the ring structure, which eliminates
receptor binding. Human BNP is a poorer substrate for
neprilysin and is not cleaved at the conserved cysteine–
phenylalanine bond.23 Neprilysin inhibitors failed to block
BNP degradation by human kidney membranes.24 Human
BNP is also a poor substrate for insulin degrading enzyme,
suggesting that another yet unidentified leupeptin-sensitive
protease may be mainly responsible for its catabolism.25
Clinical results in men: reported
effects of sacubitril-valsartan
treatment on NP concentrations
Oral neprilysin inhibitors elevate NP system activity as
assessed by increases in plasma and urine cGMP concentra-
tions in humans.26,27 As discussed above this effect may
rely more on ANP than BNP because neprilysin plays a
more significant role in ANP degradation, whereas human
BNP is relatively resistant to neprilysin degradation.5,23,24
The known effects of oral sacubitril-valsartan treatment on
neuroendocrine hormones are an increase in plasma ANP in
dogs,26 and a dose-dependent increase (maximum approxi-
mately 4 hours after oral administration) in plasma cGMP
(up to an average of approximately 40% in a dose escalat-
ing study). These data provide evidence for the biological
activity of the agent in healthy human volunteers,26 with
increases in NP system activity,28 renin concentrations and
activity and angiotensin II.
In the PARADIGM-HF study,1,27 plasma BNP and uri-
nary cGMP concentrations were significantly higher in the
sacubitril-valsartan group at 4 weeks and at 8 months in
association with markedly better outcomes than in the
enalapril group. This was suggested to reflect apparent NP
system augmentation. However, the observed relative
average BNP increase was small compared with the cGMP
increase (on average only about 10% versus 90%, respec-
tively). In contrast, NT-proBNP and cardiac troponin T
were significantly lower (average decline of about 30%
and 20%, respectively) in the sacubitril-valsartan group
reflecting a sustained reduction in cardiac wall stress and
associated myocardial injury. The population in the study
was composed of chronic systolic HF patients with mild to
moderate symptoms (70% New York Heart Association
class II, left ventricular ejection fraction <40%, mean
30%). It was those with class II HF who seemed predomi-
nantly to benefit.
In the earlier PARAMOUNT trial,29 in which sacubitril-
valsartan was studied in patients with chronic HF and pre-
served ejection fraction, there was a significant and greater
decline in NT-proBNP (on average about 25%) 12 weeks
after treatment compared to valsartan alone, which was
associated with left atrial reverse remodelling and improve-
ment in symptoms at 36 weeks. In that trial patients were
required to have a NT-proBNP greater than 400 ng/l at
screening. There was a rapid (at 4 weeks) and sustained
decline in NT-proBNP at 36 weeks, but at 36 weeks the dif-
ference between both treatment groups was no longer sta-
tistically significant.29
It should be noted that in both large clinical trials, BNP
and NT-proBNP were measured with assays from only one
manufacturer each, which has limitations (see below). To
date, ANP and NT-proANP results have not been reported
in humans taking sacubitril-valsartan. In addition, it appears
that marked BNP elevations inhibit endogenous circulating
neprilysin activity.22 This supports the important role of the
hormonal feedback system to protect against severe cardiac
stress by reducing degradation of NPs and other vasoactive
peptides of importance in HF. This may be a partial explan-
tation for why neprilysin inhibition may be more effective
in milder HF as in the PARADIGM trial.1 In summary, all
these reported study findings are consistent with an aug-
mentation of NP family activity by sacubitril-valsartan
treatment. However, reported average BNP and NT-proBNP
changes, although statistically significant, were within the
known relatively large week-to-week biological variation
of these biomarkers.30,31
Reported results of NP testing
in clinical studies of sacubitril:
limitations and analytical pitfalls
of interpretations due to non-
specific nature of the current
commercial BNP and NT-proBNP
immunoassays
These issues are complex32 and may not be of great rele-
vance for the use of NPs as laboratory markers of HF. They
are, however, important from a pathophysiological and
326 European Heart Journal: Acute Cardiovascular Care 6(4)
pharmacological point of view. Immunoassays rely on anti-
bodies that measure an epitope within the target molecule
and not necessarily the actual full peptide. Thus, antibodies
to NT-proANP and ANP immunoassays often have cross-
reactivities with proANP and its fragments. For example,
the commercially available so-called mid-regional proANP
assay detects this peptide as a fragment, in intact
NT-proANP, and proANP as well.33 BNP immunoassays
are also heterogenous and measure both proBNP and BNP
as well as BNP breakdown products with varying assay
dependent cross-reactivities.34 BNP peptides do not sub-
stantially cross-react with NT-proBNP assays, and
NT-proBNP peptides do not substantially cross-react with
BNP assays. However, there is substantial assay-specific
cross-reactivity of proBNP with commercial BNP and
NT-proBNP assays.34 The cross-reactivity of the commer-
cial NT-proBNP assay with NT-proBNP and proBNP is
dependent on the degree of glycosylation of both mole-
cules, because glycosylation inhibits the assay’s antibody
binding.10,14 Thus a significant amount of circulating
NT-proBNP and proBNP may be missed in individual
patients.14 Therefore, to obtain a better understanding of the
effects of sacubitril-valsartan on BNP the marker should be
measured with additional assays that detect different
epitopes on BNP, and NT-proBNP should be evaluated in
deglycoslytated samples. Research immunoassays for
measuring total NT-proBNP, total BNP and the total sum of
proANP derived peptides have been developed.6,13–15,35 It is
therefore important to consider the assay cross-reactivities
when interpreting the data from these clinical studies.27,29
Because of the cross-reactivity of proBNP with BNP immu-
noassays and the effects of NT-proBNP glycosylation on
recovery of circulating forms, drug-induced changes in
proBNP glycosylation and furin and corin-mediated cleav-
age may not be reflected by changes in BNP and NT-proBNP
immunoassay test results.
Thus, future clinical trials should consider these analyti-
cal limitations and should measure BNP with at least two
commercial assays using different BNP antibodies, or ide-
ally also test for ‘total BNP’ and/or ‘total NT-proBNP’
using research assays.32 ANP and NT-proANP/proANP
changes induced by sacubitril-valsartan in men still need to
be investigated in more detail in clinical trials, which is also
true for CNP changes.
Implications of sacubitril-valsartan
for NP testing in clinical practice
Measurement of NPs plays a significant role in the assess-
ment of HF patients.16,17 Their main clinical routine appli-
cation in acute cardiac care is for the the rapid rule-out of
acute HF in patients evaluated for acute dyspnoea. Using
decision limits of 100 ng/l (BNP), 300 ng/l (NT-proBNP)
and 120 pmol/l (mid-regional proANP) they have high neg-
ative predictive values (90–98% in a meta-analysis).16,17,34
However, the positive predictive values for all three NPs
for HF are less robust (56–67%).16–20,36 Therefore, a second
markedly higher rule-in cut-off is frequently recommended
to increase clinical specificity for HF,16,36 leaving an oblig-
tory grey area in which diagnostic accuracy is limited. In
addition, NP increases are also found in a variety of other
diseases including renal failure.16
In addition, in acute HF NP value decreases from admis-
sion to predischarge are useful for risk stratification.
Decreases of more than 30% of baseline values are a marker
of good prognosis.37,38 In addition, the absolute predis-
charge value also has prognostic significance.38,39
Despite the above discussed possible analytical limita-
tions, based on the recent data on the effects of sacubitril-
valsartan on BNP and NT-proBNP, the interpretation of
NT-proBNP testing in HF appears to be unaffected by
neprilysin inhibition. It is also unlikely that the diagnostic
utility of BNP testing will be significantly impaired by this
new drug as usually patients suspected of having HF with-
out established HF will not be treated before proof of diag-
nosis. Chronic HF patients or hypertensive patients on
sacubitril-valsartan treatment developing HF symptoms
may be challenging without knowing their previous BNP
baseline values. However, the relative increases in BNP
plasma concentrations reported in the PARADIGM HF
trial27 were modest (median baseline BNP value approxi-
mately 200 ng/l to a median of about 225 ng/l in the sacubi-
tril-valsartan arm). BNP concentrations greater than 500
ng/l, the frequently used rule-in decision limit for HF,16,36
were rare (75% percentile of BNP concentrations in the
sacubitril-valsartan arm approximately 450 ng/l). Thus, the
high negative predictive value for the exclusion of acute
HF for BNP testing will be maintained in patients with
sacubitril-valsartan treatment. The positive predictive value
of the rule-in cut-off of 500 ng/l may, however, be reduced
to some extent and the proportion of patients with grey
zone BNP values is likely to increase.
In contrast, for treatment monitoring of chronic HF
patients on sacubitril-valsartan the current concept of the
lower the BNP test result the better the prognosis may no
longer be true. New BNP assay specific cut-offs for risk
stratification may need to be derived for BNP testing in
ongoing clinical HF trials with sacubitril-valsartan. One
could even suggest using an increase in BNP to define who
might respond to sacubitril-valsartan or to assess patient
compliance. However, after an initial rise, which is mark-
edly smaller than in the case of cardiac decompensation,
BNP may reach a new steady state during sacubitril-valsar-
tan treatment and then begin to drop long term, if marked
clinical improvement occurs. Undoubtedly, more clinical
data are needed. From the perspective of following patients
with serial values, it appears that NT-proBNP testing may
be superior for monitoring patients taking sacubitril-valsar-
tan as the current concept of the lower the better appears to
be still valid. The potential of the BNP/NT-proBNP ratio
Mair et al. 327
(BNP possibly reflecting the action of the drug and
NT-proBNP reflecting the effects of the drug on the heart)
for chronic HF monitoring with sacubitril-valsartan also
remains to be further investigated.
It is tempting to speculate that NT-proANP/mid-regional
proANP behaves in a similar way to NT-proBNP without
impairment of its diagnostic and prognostic utilities in HF
patients, but no data have been published so far, and this
still remains to be demonstrated.
Conclusion: critical clinical
concepts
•• The clinical utility of BNP testing to rule out HF rap-
idly will not be negatively impaired by sacubitril-
valsartan treatment.
•• The clinical interpretation of NT-proBNP test results
in patients with HF is unaffected by neprilysin inhi-
bition based on the currently published data.
•• Available data suggest that the concept of the lower
the BNP test result the better the prognosis in treat-
ment monitoring of chronic HF may no longer be
true for patients on sacubitril-valsartan. This concept
appears to be maintained for NT-proBNP testing in
chronic HF.
•• Analytical pitfalls of commercial BNP and
NT-proBNP assays have to be considered in the
design of future clinical trials, particularly when
testing the hypothesis that the action of sacubitril-
valsartan is reflected by BNP concentrations and the
effects on the heart are reflected by NT-proBNP
concentrations.
Conflict of interest culating N-terminal fragments of A- and B-type natriuretic
During recent years JM received consulting fees from Philips
Health Care Incubator and lecture fees from Roche Diagnostics.
BL received research support from bioMerieux and Fiomi, as well
as speaker/consulting honoraria from bioMerieux, Roche,
Radiometer, Philips, ThermoFisher and Fiomi.
EG received honoraria for lectures from Roche Diagnostics,
BRAHMS ThermoFisher and Mitsubishi Chemical Europe. He
has received an institutional research grant from Roche
Diagnostics and serves as a consultant for Roche Diagnostics and
BRAHMS ThermoFisher.
KH received lecture fees From Novartis.
MP received consulting fees from Roche Diagnostics, Abbott
Diagnostics and Siemens Health Care Diagnostics.
MM received lecture and consulting fees from Novartis, Roche
Diagnostics and BRAHMS ThermoFisher, and research grants
from Roche Diagnostics and BRAHMS ThermoFisher.
CM received research grants from the Swiss National Science
Foundation and the Swiss Heart Foundation, the European Union,
the Cardiovascular Research Foundation Basel, 8sense, Abbott,
Astra Zeneca, ALERE, BRAHMS ThermoFisher, Critical
Diagnostics, Nanosphere, Roche, Siemens, Singulex, Sphingotec
and the University Hospital Basel, as well as travel support or
speaker/consulting honoraria from Abbott, ALERE, Astra Zeneca,
BG medicine, Biomerieux, BRAHMS, Cardiorentis, Daiichi
Sankyo, Lilly, MSD, Novartis, Pfizer, Roche, Siemens and Singulex.
ASJ has or presently consults for Abbott, Alere, Roche,
Radiometer, Siemens, Beckman, Trinity, ET Healthcare, Dart
Neurosciences, Lpath, Diadexus, Novartis and theheart.org.
KT has no conflicts of interest to declare.
Funding
This research received no specific grant from any funding agency
in the public, commercial, or not-for-profit sectors.
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