Review

Cardiac biomarkers in heart failure

Michael E. Liquori
a,
, Robert H. Christenson
b
, Paul O. Collinson
c
, Christopher R. deFilippi
d
a
University of Maryland School of Medicine, Department of Internal Medicine, 22 S. Greene St, Baltimore, MD 21201, USA
b
University of Maryland School of Medicine, Department of Pathology, 22 S. Greene St, Baltimore, MD 21201, USA
c
St. George's Hospital, Clinical Blood Sciences, Blackshaw Rd, London SW17 0QT, UK
d
University of Maryland School of Medicine, Department of Medicine, 22 S. Greene St, Baltimore, MD 21201, USA
a b s t r a c t a r t i c l e i n f o
Article history:
Received 29 September 2013
Received in revised form 25 January 2014
Accepted 27 January 2014
Available online xxxx
Keywords:
Heart failure
Biomarkers
Cardiac
Troponin
Natriuretic peptide
Background: Heart failure is a syndrome characterized by the inability of the heart to meet the body's circu-
latory demands. Heart failure is a growing health issue worldwide and the prevalence of heart failure is expected
to rise as populations age. Therapies and interventions for a variety of cardiac conditions continue to advance and
biomarkers will play an increasing role in patient management.
Methods: This is a reviewof the clinical research inbloodbasedbiomarkers for diagnosis, prognosis and ther-
apeutic guidance of heart failure. The focus of this review is biomarkers that are currently available for clinical
measurement, and their current and potential for applications for managing heart failure patients.
Results: The various biologic pathways and physiologic processes of heart failure biomarkers represent a host
of different including inammation, remodeling, strain, neurohormonal activation, metabolism and cardiac
myocyte injury. The clinical characteristics and applications of each heart failure biomarker are discussed.
Conclusion: As populations age and effective treatments and interventions for coronary artery disease im-
prove, heart failure will increase in incidence and prevalence. Blood biomarkers will play an increasing role in
the early diagnosis, therapeutic monitoring and management of heart failure patients in the future.
2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rigths reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Markers of inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. C-reactive protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Myeloperoxidase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Tumor necrosis factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Markers of brosis and extracellular matrix remodeling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Procollagen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Galectin-3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. ST2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Matrix metalloproteinases and tissue inhibitors of metalloproteinases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Markers of biochemical strain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Natriuretic peptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Growth Differentiation Factor 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Markers of neurohormonal activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Copeptin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Adrenomedullin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Markers of cardiomyocyte injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
. Cardiac troponins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0
Clinical Biochemistry xxx (2014) xxxxxx
Corresponding author.
E-mail address: mliquori@umm.edu (M.E. Liquori).
CLB-08629; No. of pages: 11; 4C:
http://dx.doi.org/10.1016/j.clinbiochem.2014.01.032
0009-9120/ 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rigths reserved.
Contents lists available at ScienceDirect
Clinical Biochemistry
j our nal homepage: www. el sevi er . com/ l ocat e/ cl i nbi ochem
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
Introduction
Heart failure (HF) is a syndrome characterized by the inability of the
heart to meet the circulatory demands of the body leading to many
symptoms including dyspnea and fatigue. HF can arise from a host of
conditions involving the myocardium or heart valves. HF occurs in
about equal frequency with and without a reduced ventricular ejection
fraction(EF). Eachof these categories accounts for approximately 50%of
all cases [1]. Regardless of category, HF is staged according to the
American College of Cardiology/American Heart Association guidelines
(Table 1) [2]. Additionally, a patient's functional status can be classied
according to the NewYork Heart Association classication (Table 1) [2].
As can be seen from Table 1, there is overlap between HF stage and
NYHA classication of symptoms.
HF is a burgeoning health and healthcare problem. There are an es-
timated 20 million affected individuals worldwide [3], of which 5.7 mil-
lion are in the United States [4]. HF accounts for over one million
hospitalizations in the United States, over three million physician ofce
visits, and nearly 57,000 deaths annually [4]. In Canada hospitalizations
for heart failure were reported as more than 106,000 annually [5]. The
prevalence of HF is expected to continue to rise as early detection ther-
apies for myocardial infarction (MI), valvular diseases and arrhythmias
improve, thereby allowing patients to survive longer [3].
Despite its high prevalence, the diagnosis of HF remains difcult as
none of the signs and symptoms are specic or particularly sensitive.
Due to this, history and physical examination may not be sufcient to
reach the diagnosis. Traditional adjuncts to diagnosis include echocardi-
ography, stress testing, and various forms of radionuclide imaging. Each
of these has their short-comings and for this reason, diagnostic aids in
the form of blood-based biomarkers have been sought. Much research
for the past decade has examined numerous possible biomarkers and
in general these biomarkers can be broken down into six categories:
markers of inammation; extracellular matrix turnover and remodeling
markers; markers of biochemical strain; markers of neurhormonal acti-
vation; markers of nutrition and metabolism; and markers of cardio-
myocyte injury (Table 2). Given the large number of candidates, a
systematic manner of assessing biomarkers and identifying those most
likely to be relevant was needed. In 2007 Morrow and de Lemos [6]
put forth three criteria for the evaluation of new biomarkers: rst, the
marker must be able to be measured reliably, quickly, and at reasonable
cost; second, the marker must provide additional information that the
physician cannot obtain from a historical and physical examination;
and third, the marker must inuence clinical decision-making.
Few biomarkers have successfully fullled each of these criteria.
However, there are several promising targets. In this review, we will
focus on markers that are either available for utilization by clinicians
or have at least been evaluated rigorously in multiple research studies.
Markers of inammation
Inammation is now widely accepted as a component of the patho-
genesis and progression of HF. This, however, has not always been the
case. Initially, attempts were made to explain HF froma purely hemody-
namic perspective. This hemodynamic hypothesis was unable to ade-
quately explain the progression of HF so alternative explanations were
sought. In 1996, Seta et al. put forth the cytokine hypothesis.[7] In
this, they suggested that the progression of HF is, at least in part,
explained by the activation of cytokine cascades following an initial car-
diac insult. At rst, many of these cytokines may serve adaptive and
compensatory purposes. However, with continued and excessive pro-
duction of these cytokines, they become maladaptive and contribute
to the progression of HF. In this section, we will discuss three of the
most studied circulating markers of inammation.
C-reactive protein
C-reactive protein (CRP) is a 23-kDa pentraxin protein which is
known to be involved in the immune response. With the introduction
of high sensitivity assays in the 1990s it became possible to measure
subtle manifestations of systemic inammation resulting in multiple
insights into the role of inammation in a variety of cardiovascular
pathophysiologies. CRP has been demonstrated to be both a mediator
of inammation as well as a marker for the presence of an inammatory
process [8]. There has been great interest in CRP in many disease
processes over the years. In the cardiac arena, CRP has been studied
for its relation to atherosclerosis, coronary artery disease (CAD), acute
coronary syndromes (ACS), and HF. Ultimately these evaluations led
to mixed results.
Elevated levels of CRP have been shown to predict future vascular
events, even out to 20 years [8]. CRP has been found to be prognostic
of poor outcomes in multiple settings. In a large group of patients with
stable CAD and preserved ejection fraction, CRP was a strong predictor
of new HF, MI, stroke, cardiovascular death and new diabetes [9]. In a
groupof patients withACS fromthe OPUS-TIMI 16 trial, CRPwas strong-
ly associated with deathor newHF in both the short termand long term
[10]. In patients with HF, CRP levels corresponded to New York Heart
Association (NYHA) class and poor outcomes [11,12]. An elderly cohort
from the Heart & Soul Study who had known CAD were shown to have
higher rates of hospitalization for HF, regardless of a prior history of HF,
if they had elevated CRP levels [13]. CRP has alternately been associated
with diastolic dysfunction alone [13,14] or systolic function alone
[15,16]. Michowitz et al. showed that CRP levels were predictive of HF
hospitalizations in patients with systolic but not diastolic dysfunction
[12]. Numerous studies have demonstrated that the addition of CRP to
B-type natriuretic peptide (BNP) provides greater prognostic informa-
tion than either marker alone [14,1618].
However, a large population based study showed that whereas
CRP levels were elevated in patients with higher levels of subclinical
atherosclerosis, this relationship was not independent of other markers
of atherosclerosis [19]. Furthermore, CRP has not been shown to be
prognostic in all studies [20,21]. Even when CRP has been shown to be
a predictor of CAD, its prognostic ability was moderate at best [22]. Ad-
ditionally, CRP levels are not reduced by treatment with ACE inhibitors
[9] or spironolactone [23] but they are reduced with statins [24]. The re-
duction of CRP levels has been conrmed in multiple studies; unfortu-
nately the reduction in CRP levels in HF patients with the use of
statins has not resulted in improved outcomes [25,26].
Despite the fact that measurement of CRP is readily available for clin-
ical use and generally the assays are in harmony across different labora-
tory platforms, it is not currently part of the guidelines for screening,
diagnosing or prognosticating in HF [27].
Table 1
Stages of heart failure and NYHA classication of heart failure as per the American College of Cardiology/American Heart Association. From reference [2].
Stages of heart failure Classes of heart failure
A At risk for HF but no structural heart disease or HF symptoms I No limitation of physical activity. No HF symptoms with ordinary physical activity
B Structural heart disease but no symptoms of HF II Mild limitation of physical activity. HF symptoms with ordinary physical activity.
C Structural heart disease with symptoms of HF III Marked limitation of physical activity. HF symptoms with less than ordinary physical activity.
D Advanced HF requiring specialized interventions IV Symptoms of HF at rest.
2 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
Myeloperoxidase
Oxidative stress arises when there is an imbalance between produc-
tion of reactive oxygen species (ROS) and anti-oxidant defense mecha-
nisms. Oxidative stress negatively effects endothelial function and the
cardiovascular system. As it is difcult to directly measure ROS, surro-
gate markers have been identied [28]. One of the most studied is
myeloperoxidase (MPO). It is noteworthy that the correct sample type
for MPO measurement is heparinized blood; measurement in serum
can lead to uncertain results.
MPO has been studied in the context of chest pain and ACS. In the
CAPTURE trial, patients who presented with recurrent chest pain or
ACS had their MPO levels analyzed and were followed for 30 days
[29]. It was found that with increasing levels of MPO there were higher
rates of cardiac events. In a similar study of 604 patients presenting to
the emergency department (ED) with chest pain, MPO levels were
foundto be higher compared to a cohort of healthy controls; the highest
values were in those who had an MI. In this study MPOlevels correlated
with increased rates of adverse cardiac events out to 6 months [30].
These results were subsequently corroborated in another group of
acute MI patients [31].
Studies in animal models revealed that MPO is involved in ventricu-
lar remodeling in the post-MI setting [32]. Subsequently, this correla-
tion was also sought in humans. A prospective study of stable
outpatients revealed that patients with HF had higher numbers of acti-
vated polymorphonucleosites (the major source of MPO) and higher
levels of MPO compared to controls. This MPO elevation was indepen-
dent of other variables regardless of HF etiology [33]. Additionally, it
was found that patients with chronic systolic HF had higher levels of
MPOcomparedto healthy controls, andthese levels increased according
to NYHA class and were correlated with BNP levels [34]. The ADEPT
study largely corroborated these data, nding that MPO level directly
correlated with advancing stages of HF and that higher levels of MPO
predicted poor outcomes [35].
However, MPOhas been shown to be of little diagnostic utility in the
setting of acute dyspnea. For example, MPO measurements performed
as part of the BASEL Vstudy were not able to diagnose HF indyspnea pa-
tients, but levels greater than 99pmol/L were associated with increased
mortality [36]. In a multicenter, prospective, observational study, Shah
et al. conrmed that MPO was not able to diagnose HF in the dyspnea
setting [37]. Additionally, in contrast with the BASEL study, they
found that MPO levels did not correlate with mortality and added no
Table 2
Classication of biomarkers in heart failure. From reference [151].
Marker source Biomarker Utility
Inammation C reactive protein (CRP, Section 2.1) 2
Pentraxin 3
Myeloperoxidase (Section 2.2) 2
Uric acid/xanthine oxidase
Tumor Necrosis Factor (TNF, Section 2.3) 2
Interleukin 6 (IL-6)
Osteoprotegrin
Monocyte chemoattractant factor
FasR
CD40
P selectin
E selectin
L selectin
Intercellular adhesion molecule 1 (ICAM-1)
Vascular cell adhesion molecule 1 (VCAM-1)
Vascular endothelial growth factor (VEGF)
Placenta growth factor (PlGF)
Hepatic growth factor (HGF)
Endothelial growth factor (EGF)
Extracellular matrix turnover and remodeling Matrix metalloproteinases & tissue inhibitors of matrix metalloproteinases (Section 3.4) 2
Procollagen type III aminopropeptide (PIIINP, Section 3.1) 2, 3
Procollagen type I carboxy-terminal peptide (PIP, Section 3.1) 2
Procollagen type I amino-terminal peptide (PINP)
Type I collagen telopeptide (ICTP, Section 3.1) 2
Basement membrane laminin (BML)
Tenascin C
Osteopontin
Interleukin 33/ST2 (Section 3.3) 2, 3?
Galectin-3 (gal-3, Section 3.2) 2
Biochemical strain Natriuretic peptides (Section 4.1) 1,2 3
Growth differentiation factor (GDF-15, Section 4.2) 2
Neurohormonal activation Aldosterone
ADH/copeptin (Section 5.1) 2
Adrenomedullin (Section 5.2) 2
Apelin
Endothelin
Relaxin
Urotensin
Nutrition and metabolism Albumin
Ghrelin
Leptin
Adiponectin
Resistin
Cardiomyocyte injury Cardiac troponins (Section 6.1) 1, 2
Heart fatty acid binding protein (HFBP)
Myosin light chains (MLC)
1. Diagnostic of heart failure; 2. Prognostic inheart failure; 3. Guides therapy inheart failure Biomarkers that are inbold and italics are discussedinthe section number following the name.
3 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
prognostic information to that of BNP. In the setting of acute HF, MPO
appears to have limited clinical utility.
Tumor necrosis factor
It has been known since at least 1990 that tumor necrosis factor-
(TNF) levels may be elevated in the setting of HF,[38] but the role of
TNF in HF is complicated. Initially, TNF appears to have a mild inotropic
effect; however, in the long term, TNF becomes a cardio-depressant
[39]. While there have been ndings to the contrary [40,41], most stud-
ies have conrmed that TNF and/or its soluble receptors sTNF-RI and
sTNF-RII are elevated in chronic HF [4245]. Many studies have also
demonstrated that TNF levels predict poor outcomes [4346] and TNF
may add prognostic information to that provided by BNP [43].
Giventhe strong evidence for the role of TNF inHF, studies were con-
ducted with the aim of identifying TNF as a therapeutic target. At least
four trials were started including RECOVER, RENAISSANCE, RENEWAL,
and ATTACH. The rst three of these examined the effect of etanercept
(a decoy receptor for TNF) but were each stopped early as it was
found that there was no benet to treatment [47]. The ATTACH study,
which examined iniximab, was also stopped early as there was a
higher rate of HF and death in the treatment arm[48]. Despite the initial
potential of TNF, anti-TNF agents have not demonstrated benet in the
management of HF [49].
Markers of brosis and extracellular matrix remodeling
Procollagen
Collagen scar formation has been found to play an important role in
the remodeling of cardiac tissue following MI and in the development of
HF. For this reason markers of collagen synthesis and turnover have
been studied as a non-invasive methodology to determine the extent
of cardiac brosis.
Procollagen type III amino-terminal propeptide (PIIINP), a marker of
collagen synthesis, is one of the most studied brosis markers. In the
setting of acute MI, PIIINP has been shown to be elevated in patients
with MI compared to those without [50]. In this same MI patient popu-
lation, higher levels of PIIINP also predicted left ventricular dilatation
and the development of HF at 1 year [50]. In patients with chronic HF
PIIINP level is also an independent predictor of mortality [51]. Further-
more, in anolder adult community based population study PIIINP levels,
in addition to carboxyl-terminal telopeptide of collagen type I (CITP), a
collagen I degradation marker differentiated those with and without HF
[52]. Interestingly, unlike NT-proBNP there was no difference found in
PIIINP or CITP levels between those withpreserved versus reduced ejec-
tion fraction HF [52]. The interpretation of systemic brosis markers can
be complex, for in contrast to PIINP and CITP, C-terminal propeptide of
procollagen type I (PIP), a marker of type I collagen synthesis in the
same study didn't differentiate between those with and without HF
[52]. Data from the Framingham Heart Study also identies the limita-
tions of systemic markers of brosis for detection of structural heart
disease. In this cross sectional analysis, PIIINP didn't correlate with nd-
ings of either systolic or diastolic dysfunction in subject without symp-
tomatic HF [53]. However, absence of correlation with cardiac imaging
evidence of brosis may reect the increased sensitivity of these
markers compared to current imaging techniques. For example, elevat-
ed PIP levels were found in asymptomatic carriers of sarcomere muta-
tions predisposing for hypertrophic cardiomyopathy (versus controls)
who as of yet had no increase in LV mass or evidence of myocardial
brosis by cardiac magnetic resonance imaging [54].
Fibrosis markers may have a role in selecting patients for future
therapy. In a sub-study of RALES, which included patients hospitalized
with NYHA class III and IV symptoms with reduced LVEF, high levels
of PIIINP were associated with poor outcomes and these levels were re-
duced by treatment with the aldosterone antagonist spironolactone
[55]. For only those patients with levels above the median of PIIINP,
this reduction resulted in improved outcomes (Fig. 1). These data sug-
gest that the benet of aldosterone antagonism in HF may, at least in
part, be related to limiting extracellular matrix turnover.
Galectin-3
Galectin-3 (gal-3) is a -galactosidase binding lectin that is
expressed and secreted by macrophages [56]. In a rat HF model, Sharma
et al. found that gal-3 was over expressed [57] and that this expression
occurred even before the development of frank HF. In the same study,
Sharma et al. also showed that an infusion of gal-3 into the pericardium
of healthy rats led to cardiac broblast proliferation, collagen deposition
and left ventricular dysfunction. Finally, Sharma et al. showed that gal-3
levels were elevated in patients with aortic stenosis and depressed EF
compared to those without depressed EF.
Multiple studies have been performed evaluating the diagnostic and
prognostic potential of gal-3inHF patients. The rst, andone of the larg-
est studies, occurred in a subgroup of the PRIDE (Pro-BNP Investigation
of Dyspnea in the Emergency Department) study [58]. In this popula-
tion, van Kimmenade et al. demonstrated that gal-3 was signicantly el-
evated in HF patients compared to those without HF. However, gal-3
was inferior to N-terminal proBNP (NT-proBNP) for the diagnosis of
acute HF. Importantly, gal-3 was a superior predictor of death or HF hos-
pitalization compared to NT-proBNP. The combination of gal-3 and NT-
proBNP provided additive prognostic ability to that of NT-proBNP alone.
In a separate subgroup from PRIDE, gal-3 levels correlated with right
ventricular failure and were found to be independently predictive of
4-year mortality [59]. In a subgroup from the Deventer-Alkmaar Heart
Failure study (DEAL-HF), 240 patients were followed for 12 months
and gal-3 was found to predict mortality independent of NT-proBNP.
It was again demonstrated that the combination of gal-3 and NT-
proBNP made for improved prognostication compared to NT-proBNP
alone [60]. Subgroup analysis from the Coordinating Study Evaluating
Outcomes of Advising and Counseling inHeart failure (COACH) trial cor-
roborated the prognostic value of gal-3 in HF patients [61]. This study
was the rst to suggest that its prognostic ability was greater in heart
failure with preserved EF than in heart failure with reduced EF. Milting
et al. found that in terminal HF patients going for ventricular assist de-
vice (VAD) placement, gal-3 levels were signicantly elevated com-
pared to controls [62]. Of those patients who received a VAD, higher
gal-3 levels were associated with death from multi-organ failure. Serial
Fig. 1. 30-month mortality according to treatment group and Procollagen type III amino-
terminal propeptide (PIIINP) baseline levels (below/above median [med]) in patients
with a left ventricular ejection fraction b35% and New York Heart Association class III or
IV heart failure symptoms randomized to spironolactone (spirono) versus placebo.
From reference [55].
4 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
measures of gal-3 did not add any further prognostic value as the level
remained relatively stable over a 6 month period [61]. Other studies
have also conrmed the independent prognostic ability of gal-3
[6365].
It has been suggested that gal-3 levels may be able to assist in guid-
ing therapy. Gal-3 was found to identify patients with ischemic reduced
ejection fraction HF who benet from statin therapy [66]. However this
nding has not been conrmed in prospective studies. It has been
suggested that gal-3 might be used to predict 30-day readmission
after hospitalization for HF treatment [67]. The notion is that patients
with higher gal-3 values at discharge are at greater risk and may benet
fromcloser or more intensive monitoring post discharge. Studies testing
this utilization of gal-3 are incomplete at this writing.
ST2
ST2 is a member of the Toll-Like/IL-1 receptor superfamily [68]. ST2
has both a transmembrane (ST2L) and a soluble (sST2) form with the
functional ligand for each being IL-33 [69]. Interaction of IL-33 with
ST2L appears to activate the NF-B and MAPK signaling pathways [68].
This interaction has been shown to prevent apoptosis by inducing ex-
pression of anti-apoptotic factors and to improve cardiac function and
survival post-MI in a rat model [70]. Sanada et al. demonstrated that
IL-33 also acts through ST2L to antagonize neurohormonally induced
(reninangiotensin and/or sympathetic) cardiomyocyte hypertrophy
[71]. Sanada et al. also found that sST2 blocked these cardioprotective
effects of IL-33 [71], leading to the hypothesis that sST2 acts as a
decoy receptor [68].
ST2 expression is known to be upregulated in cardiac myocytes
undergoing mechanical strain and in the setting of acute MI sST2 levels
are increased [72]. Shimpo et al. built on this and showed that in AMI
patients, elevated levels of sST2 were predictive of subsequent new HF
or death [73]. Sabatine et al. conrmed this nding in a group of ST ele-
vation MI (STEMI) patients and demonstrated that the addition of sST2
to NT-proBNP improved risk stratication [74]. Weir et al. were able to
demonstrate that, in the setting of AMI, baseline sST2 levels correlated
inversely with both baseline LVEF and 24-week LVEF in patients who
already had an LVEF b40% [75]. Change in sST2 levels from baseline to
24 weeks was shown to correlate with LV end diastolic volume [75].
Additionally, they found a direct relationship between sST2 levels,
infarct magnitude, and the amount of infarct remodeling.
sST2 has also been widely studied in dyspneic patients suspected of
having acute decompensated HF as well as those with established HF. In
a substudy analysis from PRIDE, Januzzi et al. evaluated sST2 and NT-
proBNP levels in patients with acute dyspnea [76], and found that
sST2 levels were higher amongst those patients with acute HF com-
pared to those without; however sST2 was not as diagnostically useful
as NT-proBNP. On the other hand, sST2 levels were strongly predictive
of both 1- and 4-year mortality in this cohort, irrespective of the dys-
pnea etiology.[76,77] Boisot et al. studied serial sST2 levels in the setting
of acute HF for 90 days andfoundthat those patients whohad a minimal
decrease in sST2 levels over time had a signicantly higher incidence of
death compared to those who had a decrease of N15% [78]. In chronic
HF, sST2 was found to be prognostic of sudden cardiac death [79]. This
has led to the suggestion that sST2 could potentially be included in a
multimarker scoring systemthat alsoincludes NT-proBNP andhighsen-
sitivity cardiac troponin T (hs-cTnT) to stratify patients into low, medi-
um, andhigh risk groups for suddendeathand improve the allocation of
implantable cardiac debrillators [80]. ST2, either based ona single level
or following trends with serial testing might also be used to predict hos-
pitalization for HF including short-term readmission [81].
Matrix metalloproteinases and tissue inhibitors of metalloproteinases
Matrix metalloproteinases (MMPs) are a group of zinc-dependent
endopeptidases involved in the degradation of extracellular matrix
proteins and the breakdown of biologically active molecules that are
involved in chemoactivation. The MMPs are inhibited by a class of mol-
ecules known as tissue inhibitors of metalloproteinases (TIMPs). It has
been suggested that an imbalance between MMPs and TIMPs resulting
in excess MMP activity plays a role in ventricular remodeling [28].
MMPs and TIMPs have been studied extensively in cardiac disease,
specically in the setting of MI and HF. In MI, elevated levels of MMP-
3 [82] and TIMP-1 [83] have been found to predict left ventricular EF.
MMP-3, [82] MMP-9 [83] and TIMP-1[83] have all been associated
with poor outcomes. However, in the setting of HF, the data have been
inconsistent. Some studies have shown that MMP-2 and MMP-9 are
elevated [84,85], but this is not a consistent nding [86]. TIMP-1 has
consistently been found to be elevated in HF[8587] but has only occa-
sionally been shown to provide prognostic information [86]. Likewise,
the data for MMP-9 has been found to be conicting, with levels being
non-prognostic in several studies [85,86], while being identied as
independently prognostic of poor outcomes in other studies [88]. It is
unclear at this time whether or not this class of molecules will have
clinical application.
Markers of biochemical strain
Natriuretic peptides
The natriuretic peptides are a group of neurohormones which affect
body uid homeostasis via natriuresis and diuresis [69]. The natriuretic
peptides also decrease vasoconstrictionby decreasing angiotensinII and
norepinephrine synthesis [69]. There are two main types of natriuretic
peptides: BNP and A-type natriuretic peptide (ANP). The most exten-
sively studied of these peptides is BNP.
BNP is synthesized as a pre-prohormone and is released in response
to volume overload and wall stress [89] which made BNP an attractive
target for aiding in the diagnosis of HF. In a prospective study of 1586
dyspnea patients presenting to the ED, the Breathing Not Properly
study found that BNP levels were more accurate than any history or
physical exam nding in identifying those patients whose dyspnea
was secondary to HF [90]. Similarly, the PRIDE study looked at 600
patients presenting to the ED with complaints of dyspnea. In PRIDE
NT-proBNP levels were found to be the strongest predictor of a diagno-
sis of HF.[91] Studies directly comparing NT-proBNP and BNP measure-
ments have generally found them equivalent for the diagnosis of acute
HF[9294] and both are also strongly prognostic of outcomes in acute
HF patients [9599].
BNP's diagnostic and prognostic abilities are rmly established and
the current area of study is whether BNP can serve as a therapeutic
guide for the management of HF. In an early study from 2000,
Troughton et al. examined this question in a group of 69 patients with
NYHAclass II-IVHF [100]. This study showed that having physicians tar-
get a goal for NT-proBNP of b200 pmol/L versus not knowing the results
of the test led to increased use of angiotensin converting enzyme (ACE)
inhibitors and spironolactone. The patients in the NT-proBNP guided
group also had fewer cardiovascular events. Since that time, multiple
moderately sized studies have been conducted using NT-proBNP and
BNP levels to guide outpatient HF therapy. The reduction in all-cause
mortality is summarized in a meta-analysis shown inFig. 2 [101]. Signif-
icant reductions in HF hospitalizations are also seen with a natriuretic
peptide guided approach to therapy [101]. Additionally, natriuretic pep-
tide guidedcare has beenassociated with favorable LVstructural chang-
es compared to usual care with greater increases in LVEF and greater
decreases in both LV end systolic and end diastolic volumes [102]. A de-
nitive multi-center NIH funded study (GUIDE-IT, www.clinicaltrials.
gov) is nowunderway to determine if recently hospitalized HF patients
with reduced LVEF would have reduced hospitalizations and mortality if
following an outpatient management strategy guided by NT-proBNP
levels versus usual care.
5 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
Most of the work to date has only examined the role of BNP or NT-
proBNP in HF. Traditionally this was due to the fact that ANP was very
difcult to measure owing to its analytical instability [103]. However,
an assay for the stable mid regional-proANP (MR-proANP) has been de-
veloped. This new assay was used as part of the BACH study [104]. In
BACH, MR-proANP was non-inferior to BNP for the diagnosis of acute
HF. When used with BNP, MR-proANP added to the diagnostic accuracy.
The authors suggested that MR-proANP may be most clinically useful in
those patients in whom BNP levels are less reliable (i.e. obesity or
renal failure).
Growth Differentiation Factor 15
GrowthDifferentiation Factor 15 (GDF-15) is a member of the TGF-
superfamily. In healthy subjects, GDF-15 is only expressed in the central
nervous system and the placenta [105]. However, GDF-15 may be
expressed by many tissues, including the heart, in response to injury,
hypoxia or exposure to cytokines. In the heart, GDF-15 has been found
to have anti-hypertrophic effects [106,107]. Animal models have
shown that GDF-15 expression is up regulated following MI [106]. In
vitro studies have revealed that GDF-15 is highly expressed after expo-
sure to oxidized low density lipoprotein and expression of GDF-15 has
been found to co-localize to human arteriosclerotic blood vessels
[108], whichsuggests that GDF-15 is highly expressedin atherosclerosis
and likely in CAD.
In chronic HF patients, Kempf et al. showed that GDF-15 levels are
signicantly elevated when compared to controls [109]. More recently,
this nding has been challenged by Daniels, et al. who showed that
GDF-15 levels in community dwelling older adults with no antecedent
cardiovascular disease were predictive of all cause, cardiovascular and
non-cardiovascular death [110]. In a second study by Kempf et al.,
they found that GDF-15 levels correlated with NYHA class as well as
NT-proBNP [111]. GDF-15 has also been demonstrated to be a predictor
of poor outcome in HF patients [111,112]. GDF-15 may play a role in risk
stratication in HF and more studies are needed to elucidate this
potential.
Markers of neurohormonal activation
Copeptin
Arginine vasopressin (vasopressin; antidiuretic hormone; AVP;
ADH) is a peptide hormone synthesized inthe hypothalamus andstored
in the posterior pituitary gland. ADHis known to have both antidiuretic
and vasoconstrictive properties. Levels of ADH have been shown to be
elevated in patients with HF [113,114]. The excess ADH can lead to
hyponatremia, uid accumulation, and systemic vasoconstriction. Un-
fortunately, it is difcult to measure ADH levels as a large proportion
of the hormone is protein bound and the half-life of ADH is only 24
min. However, a portion of the ADH precursor protein is very stable,
can easily be measured, and correlates with ADH levels (r = 0.78, p
b 0.0001) [115]. This precursor protein is the C-terminal aspect of pro-
ADH, coined copeptin [116]. Copeptin has been studied in the setting
of MI and HF.
In the MI setting, as part of the LAMP (Leicester Acute Myocardial in-
farction Peptide) study, Khanet al. found that copeptin levels are elevat-
ed in the immediate post-MI period [117]. Khan et al. went on to show
that copeptin was higher in patients with ST elevation MI than those
with non-ST elevation MI. Additionally, these copeptin levels were
found to correlate with higher risk of death or new HF. Lastly, Khan
et al. demonstrated that copeptin was additive to the prognostic ability
of NT-proBNP. In survivors of MI, copeptin has been shown to inversely
Fig. 2. All-cause mortality meta-analysis of individual trials using BNP or NT-proBNP with clinical judgment versus clinical judgment alone for guiding chronic heart failure therapy.
From reference [101].
6 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
correlate with LVEF, correlate directly with left ventricular volume and
is associated with increased left ventricular remodeling and progression
to HF [118].
In the BACH study high levels of copeptin were associated with in-
creased 90-day mortality, HF-related ED visits, and HF hospitalizations
[119]. The prognostic ability of copeptin in acute HF was subsequently
conrmed and it is also prognostic in chronic HF [120124]. Stoiser
et al. found that copeptin was more strongly predictive of death than
BNP, but BNP was a better predictor of HF hospitalization[123]. Neuhold
et al. have demonstrated that copeptin correlates with NYHA class and
conrmed that copeptin is superior to BNP and NT-proBNP for predic-
tion of mortality [122].
Based on the above data and the availability of ADH receptor
blockers, copeptin levels were being considered to guide HF therapy.
The large multi-center EVEREST trial looked at tolvaptan (a vasopressin
V
2
-receptor antagonist) in patients hospitalized for HF without measur-
ing copeptin [125]. The authors found that tolvaptan did not have an
effect on long-term morbidity and mortality compared to placebo.
Studies are now being designed to specically target patients with
high copeptin levels with an ADH receptor blocker.
Adrenomedullin
Adrenomedullin (ADM) is a member of the calcitonin gene-related
peptide family. ADM was initially discovered in the human adrenal
medulla and has since been found in numerous other tissues including:
the vasculature, lungs, heart, and adipose tissue. ADMhas been found to
have cardioprotective effects whichinclude: positive inotropy, vasodila-
tion, diuresis, natriuresis, anti-hypertrophic, anti-apoptotic, and anti-
brotic effects [126]. These effects were conrmed in the setting of HF
when Nagaya et al. infused ADM intravenously in HF patients [127].
The inotropic effect of ADM has been shown to be much stronger in
the atria than in the ventricles [128]. As it is difcult to measure ADM
levels directly given its short half-life, the contemporary method is to
measure its precursor, mid-regional pro-ADM (MR-proADM) [103]. As
MR-proADM is a newer assay, the observations presented herein is a
mixture of ADM and MR-proADM.
In asymptomatic, high-risk patients without incident ACS or HF,
Nishida et al. found that elevated levels of MR-proADM correlated
with increased risk of future CV events [129]. In the post-MI setting,
data from the LAMP study showed that elevated levels of MR-proADM
were predictive of death or subsequent HF hospitalization [130]. In
that study, Khan et al. found MR-proADM was comparable to NT-
proBNP and the combination of the two provided increased prognostic
information. In addition, MR-proADM was a predictor of mortality in
patients who developed HF following an MI, presented with acute HF
or had chronic HF [104,131133].
MR-proADMhas also been evaluated as a potential diagnostic tool in
dyspneic patients with or without HF. Potocki et al. found that levels
were higher in patients who were found to have acute HF compared
to those with acute exacerbation of chronic obstructive pulmonary dis-
ease [134]. As MR-proADM is not cardiac specic it cannot be reliably
used as a diagnostic aid in the setting of acute HF. However, in keeping
with its role as a prognostic marker, in the BACHstudy MT-proADMwas
found to be a stronger prognosticator than BNP at 90 days [104].
Markers of cardiomyocyte injury
Cardiac troponins
There are several markers of cardiomyocyte injury including the
cardiac troponins, heart fatty acid binding protein, creatinine kinase
MB and myosin light chain 1. As the troponins are currently the most
clinically relevant they will be the focus of this section. The cardiac tro-
ponins are cardiac isoforms of proteins from the troponin-tropomyosin
complex foundincardiomyocytes andthere are two maintypes: cardiac
troponin T (cTnT) and cardiac troponin I (cTnI). These proteins are
known to be elevated in the plasma following myocardial injury and
the troponins have become the essential component for the denition
of MI [135]. Not only are the troponins elevated in ACS, they have also
been demonstrated to be elevated in the setting of HF [80,136141].
In a small study by La Vecchia et al., it was shown that patients with
severe HF can have elevations of cTnI even without ischemia [136].
Additionally, the study showed that cTnI was a very strong predictor
of 3-month mortality. In a study of HF patients being evaluated for
transplant, Horwich et al. found that cTnI was detectable in 49% of the
patients using a conventional cTnI assay [137]. The presence of cTnI
was shown to inversely correlate with LVEF over time and the presence
of cTnI carried a relative risk of 2.05 for mortality compared to those
without measurable cTnI. The elevation of troponins in the setting of
Fig. 3. Detectable cardiac troponin level and stage of HF (HF staging as shown in Table 1).
7 M.E. Liquori et al. / Clinical Biochemistry xxx (2014) xxxxxx
Please cite this article as: Liquori ME, et al, Cardiac biomarkers in heart failure, Clin Biochem (2014), http://dx.doi.org/10.1016/
j.clinbiochem.2014.01.032
acute HF and their prognostic ability has subsequently been demon-
strated in several other studies [138141]. Over time, newer assays for
the troponins have become available with higher sensitivity (hs)
allowing for detection of very low levels of troponins in the blood. In a
study by Pascual-Figal et al., elevated levels of hs cTnT were strongly
predictive of death in the setting of acute HF [80].
The troponins have also been extensively studied in the context of
stable chronic HF. With the advent of the hs assay studies were conduct-
ed to the compare the new assays to earlier generation assays. In 2007,
Latini et al. compared hs cTnT to the conventional assay to evaluate cir-
culating levels of cTnT in patients with stable chronic HF [142]. In this
study of over 4,000 patients, cTnT measured by the conventional assay
was detectable in only 10% of patients compared to 92% of patients
when measured by the new hs cTnT assay. The hs cTnT assay was
superior for risk stratication of patients compared to the conventional
assay. Similar ndings were reported by Tsutamoto et al. in 2010 [143].
Tentzeris et al. have also shown that hs cTnT levels increase with in-
creasing NYHAclass andare strongly associated withall-cause mortality
and HF hospitalizations [124]. Masson et al., utilizing serial measures of
hs cTnT reported comparable outcomes from two large studies, GISSI-
HF as well as the original VAL-HEFT study [144].
hs troponin assays have also been studied in the general population.
Troponin elevation, as measured using a conventional assay, in the gen-
eral population is rare (approximately 0.74%), but is more common in
patients with an increasing number of cardiac co-morbidities [145,146].
In contrast, with the hs cTnT assay, troponin is detectable in 2567% of
the general population [147149]. A summary of the prevalence of
detectable cardiac troponin levels based on assay and stage of HF (see
introduction section) is shown in Fig. 3. Minor elevation of cTnT as
measured by the hs assay was associated with more left ventricular
hypertrophy, depressed LVEF and greater coronary calcium score
[149]. There is a corresponding increase in risk of new-onset HF, cardio-
vascular mortality and ischemic cardiovascular events with HF being
the predominant event (Fig. 4) [148]. It is notable that the risk in this
large community based cohort is greatest for new-onset HF and not
events related to acute coronary syndromes. This suggests that the pri-
mary mechanism of cTnT release in this setting is not due to small
asymptomatic myocardial infarctions, but perhaps other mechanisms
for myocyte cell death. Cardiac troponin levels were also found to be dy-
namic over time (measurement interval 23 years) in a large minority
of older asymptomatic adults. The risk of bothnew-onset HF and cardio-
vascular death was associated with the direction of the trajectory of
levels of cTnT [147]. This suggests that even at an advanced age there
may be modiable factors that that can change the trajectory of cardiac
injury and modify the risk of development of symptomatic HF or cardio-
vascular death.
Conclusion
During the last decade extensive research has been conducted in
biomarkers and HF. While BNP and the cardiac troponins are ubiquitous
in clinical practice, there are a host of other promising biomarkers
which have the potential to be diagnostic, prognostic, and therapeutic
aids extending from an asymptomatic general population to those hos-
pitalized with acute HF. It is unlikely that any single one of the markers
will prove to be the sole necessary aid in all HF settings. As data con-
tinues to accumulate, rigorous application of rigorous statistical tech-
niques will be critical to sort out biomarkers that are contenders and
not pretenders for adding value to clinical care.[150] That being said,
biomarkers will likely nd critical roles in guiding outpatient HF thera-
py, predicting near and long-term readmission and identifying those
asymptomatic subjects who are at the highest risk for progression to
symptomatic HF.
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