Established and Novel Biomarke

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Established and novel
Review
Future Cardiology
biomarkers in ST-elevation
myocardial infarction
Jonathan W Waks1 & Benjamin M Scirica†1
1
TIMI Study Group, Cardiovascular Medicine, Department of Medicine, Brigham & Women’s Hospital,
Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
†
Author for correspondence: Tel.: +1 617 278 0145 n Fax: +1 617 734 7329 n [email protected]
Cardiac biomarkers assist in the diagnosis of and risk stratification in acute

coronar y syndromes. In ST-elevation myocardial infarction (STEMI), rapid
diagnosis and initiation of reperfusion via primary percutaneous coronary
intervention or fibrinolysis is often based on the clinical history and presenting
ECG, but measurement of biomarkers in the early and/or late phases of STEMI
may allow the selection of patients who are at increased or decreased risk of
subsequent complications. Although the measurement of only three biomarkers
(troponin, natriuretic peptides and C-reactive protein) are currently included in
practice guidelines, more than 20 other novel cardiac biomarkers have been
proposed to provide improved risk stratification after a STEMI.
Despite considerable advances in the manage- cTn

ment and treatment of coronary artery dis- Cardiac troponins are cytoskeletal proteins
ease, myocardial infarction (MI) remains a involved in contraction and relaxation of car-
significant cause of morbidity and mortality diac myocytes that are also markers of myocar-
worldwide [1,2] . Over the last few years there dial injury and necrosis. Troponin-T (cTnT) is a
has been explosive growth in the discovery and 37 kDa protein that rises 3–4 h after the onset
clinical application of novel cardiac biomarkers of necrosis and remains elevated for 10–14 days,
both for the diagnosis of and risk stratifica- while troponin-I (cTnI) is a 23.5 kDa protein
tion in acute coronary syndromes (ACS) [3] , that can be detected by conventional cTnI
although few have become firmly established assays within 4–6 h after onset of necrosis and
in clinical practice. Ideal novel cardiac bio- remains elevated for 4–7 days [7] . Unlike cre-
markers are highly sensitive for and specific atine kinase (CK) or CK-MB, cTnI and cTnT are
to cardiac disease, and provide information highly specific to myocardial tissue and therefore
above and beyond traditional biomarkers and reduce the incidence of false-positive results [7] .
established methods of risk assessment includ- Although cTnI is found only in cardiac myo-
ing the GR ACE [4] , GUSTO [5] , and TIMI cytes, low levels of cTnT can be found in various
risk scores [6] . For a biomarker to have clini- diseases of skeletal muscle [8] . The delay between
cal use, it must be readily measurable, provide onset of necrosis and the detection of cTn using
information that is both useful and reproduc- conventional assays prevents the use of troponins
ible across multiple populations, and allow the within the first few hours of ACS, and in patients
clinician to alter therapy in a meaningful way who present very soon after symptom onset with
[3] . Current guidelines recommend measure- symptoms and ECG findings consistent with
ment of cardiac troponin (cTn) in all patients STEMI, a negative cTn should not delay rapid
with MI, and consideration of measuring triage and reperfusion [7] . High-sensitivity cTn Keywords
C-reactive protein (CRP) and/or natriuretic assays that can detect much lower concentrations
n acute coronary syndromes
peptides (B-type natriuretic peptide [BNP] of cTn are currently being evaluated and their
n biomarkers n copeptin
and N-terminal proBNP), although the clini- impact on earlier diagnosis and risk stratification n C-reactive protein
cal utility in measuring the later three is less following STEMI remains to be evaluated [9] . n growth‑differentiation
well established [7] . After successful reperfusion with percutaneous factor-15 n heart-type fatty
acid binding protein
This article will review the clinical applica- coronary intervention (PCI) or fibrinolytics, tro- n natriuretic peptides
tion of the established biomarkers troponin, ponin levels rapidly peak and then begin to fall n outcomes n ST-elevation
natriuretic peptides, and CRP in ST-elevation due to the ‘washout’ phenomenon [10] . myocardial infarction
n troponin
myocardial infarction (STEMI), and discuss Both cTnI and cTnT have been evaluated
novel biomarkers that have recently emerged in STEMI to estimate infarct size, and in this part of
as potential markers of risk and/or targets respect, troponin has been shown to perform
of therapy. as well as CK-MB [11] . Admission cTn levels
10.2217/FCA.11.31 © 2011 Future Medicine Ltd Future Cardiol. (2011) 7(4), 523–546 ISSN 1479-6678 523
Review Waks & Scirica
correlate poorly with infarct size, likely due to but no significant difference in mortality when
the initial delay between necrosis and cTn eleva- patients with ≥50% STRes were stratified by
tion [12,13] . Troponin-T measured between 24 and cTnI [24] .
96 h after primary PCI, however, is correlated In the CLARITY-TIMI 28 trial, cTnT mea-
with infarct size as measured by cardiac MRI sured on admission and prior to fibrinolysis was
4 days after onset of symptoms [13,14] and cTnI associated with 30-day cardiovascular death;
measured 3 to 72 h after primary PCI or fibri- compared with patients with negative initial cTnT,
nolysis is correlated with infarct size as assessed patients with cTnT above and below the median
by 4–7 day cardiac MRI [15,16] or 3-day assess- of 0.12 ng/ml had an adjusted odds ratio (OR)
ment of a-hydroxybutyrate deshydrogenase [12] . of 5.8 (p < 0.001) and 4.6 (p = 0.002), respec-
cTnI measured at 24 or 48 h is also useful in tively. Patients with cTnT above 0.12 ng/ml were
identifying patients with STEMI who will have also more likely to have initial TIMI flow 0 or 1
reduced left ventricular ejection fraction (LVEF) or die prior to angiography and had higher rates
at the time of angiography [17] , predischarge [18] of no STRes at 90 min. Troponin on admission
or 4 months later [19] . further risk stratified patients who had already
Troponin has also been evaluated as a non- been stratified by STRes, and patients with com-
invasive marker of successful reperfusion. plete STRes and negative initial troponin had a
Microvascular obstruction (MVO) has been <1% risk of 30-day cardiovascular death, while
correlated with poor outcomes following a those with no STRes and a troponin >0.12 ng/ml
MI [20] , and STEMI patients who have residual had a 15% risk of 30-day cardiovascular death
MVO detected on MRI, despite restoration of (Figure 1) [25] .
TIMI 3 flow, experience a higher peak value A selection of studies evaluating the associa-
and slower release of cTnT and cTnI than those tion between cTn and adverse cardiovascular
without MVO [21,22] . Patients with elevated cTnI outcomes in the short and long term are sum-
on admission experience less ST-segment reso- marized in Table 1. As can be seen, there are some
lution (STRes) [23–25] , lower rates of post PCI conflicting results regarding the optimal time
TIMI 3 flow [18,26] and more malignant reperfu- to measure cTn and the magnitude of utility in
sion arrhythmias [27] . using troponin for risk stratification.
A sub-study of the GUSTO-IIa trial found Persistently and/or minimally elevated cTnT
that admission cTnT was strongly correlated with levels have also been associated with poor out-
mortality in STEMI patients treated with fibri- comes. In a prospective study of 1807 patients
nolysis, with cTnT >0.1 ng/ml associated with approximately 4 weeks after a STEMI using a
higher 30-day mortality (13.0 vs 4.7%) [28] . In a cTnT assay with a lower limit of detection of
second analysis including a mix of ACS patients 0.01 ng/ml and a value of 0.1 ng/ml as the upper
(58% STEMI), the time at which cTnT turned limit of normal, 39% of patients had detect-
positive was also associated with 30-day mortal- able cTnT, and a cTnT level of only 0.04 ng/ml
ity; patients with admission cTnT >0.1 ng/ml was associated with a hazard ratio (HR) of 1.8
had higher 30-day mortality than those who (p = 0.02) for all-cause mortality and a HR of
were initially cTnT negative but turned positive 1.5 (p = 0.03) for nonfatal MI during a follow-up
by 16 h, or those who remained cTnT negative period of 1042 days [30] .
throughout (10 vs 5 vs 0%, respectively) [29] .
In the ASSENT-2 and ASSENT-PLUS tri- Natriuretic peptides
als, patients with an admission cTnI >0.1 µg/l B-type natriuretic peptide is secreted in response
were less likely to experience STRes ≥50% at 60 to increased hemodynamic stress on ventricular
(32.8 vs 44.3%; p = 0.03) and 180 min (65.5 vs myocardial tissue [31,32] , although it can also be
85.5%; p < 0.001), and had increased 30-day upregulated and released in response to various
(9.5 vs 2.0%; p < 0.001) and 1-year (13 vs 4%; nonhemodynamic factors [7,33,34] . BNP produc-
p < 0.001) mortality compared with those who tion proceeds via a 134 amino acid molecule pre-
were cTnI negative on admission, although, proBNP that is cleaved into proBNP and subse-
after multivariate adjustment, the effect of quently into equimolar ratios of 32 amino acid
cTnI was just beyond statistical significance BNP and 76 amino acid N-terminal proBNP
(p = 0.08–0.12). When STRes at 60 min was (NT-proBNP) [35] . BNP and atrial natriuretic
combined with admission cTnI, however, there peptide (ANP) have similar functions (increases
was a large difference in 1-year mortality among in glomerular filtration rate [GFR], natriuresis,
patients with <50% STRes who were stratified diuresis and systemic vasodilation [33,36]), but
by cTnI above or below 0.1 µg/l (18.2 vs 5.0%), BNP secretion is more tightly regulated by rapid
524 Future Cardiol. (2011) 7(4) future science group

Established & novel biomarkers in ST-elevation myocardial infarction Review
changes in gene expression and has a different

pattern of tissue distribution, found predomi-
nantly in ventricular myocytes [33] . BNP has a
half-life of 18 min, while NT-proBNP has a half-
life of 1–2 h [35] . Stimuli that increase BNP cause
a proportionally larger increase in NT-proBNP, 16
making the latter a more sensitive and easier 14
30-day CV death (%)

to assay biomarker [32] . After acute MI, BNP
rises rapidly and in proportion to the size of the 12
infarct, peaking at 24–36 h, with changes also 10
seen during some cases of post-MI ventricular 8
remodeling and infarct expansion [7,37,38] .
6
Admission levels of NT-proBNP are higher in None
4
n
non-STEMI (NSTEMI) than in STEMI, poten-
io
ut
tially due to increases in delay from symptom Partial
l
2
so
re
onset to treatment in NSTEMI patients [37,39– Complete
ST
0
41] . Even after correcting for time from symptom
in
>median
≤median
Undetectable
-m
onset to presentation, however, NT-proBNP levels
90
remain significantly higher in NSTEMI [37] , sug-
gesting an alternate and diagnosis specific release
mechanism such as recurrent ischemia prior to
Baseline troponin T
true infarction or cytokine activation [37,39] . BNP
levels are correlated with increasing age, lower Figure 1. Rates of 30-day cardiovascular death stratified by baseline
GFR, female gender, and lower ejection fraction, troponin and 90-min ST-segment resolution.
but have been shown to be independent of these CV: Cardiovascular.
factors across multiple studies of MI [7] . Reproduced from [25] with permission from Elsevier.
Like troponin, natriuretic peptides can be
used to estimate infarct size after a STEMI. NT-proBNP cut off value also likely varies
In 174 patients treated with primary PCI who depending on when the blood sample is taken
had infarct size and myocardial salvageability relative to the onset of ACS, and what infor-
assessed by SPECT imaging, patients with highly mation is desired (prognosis, infarct size or
elevated admission NT-proBNP (≥1864 ng/l) success of reperfusion) as there are significant
had significantly larger areas of infarction com- changes in BNP levels early in the course of a
pared with those with NT-proBNP < 1864 ng/l STEMI, and levels obtained later in the course
(35 vs 19%; p < 0.001), but reperfusion therapy of a STEMI may provide different and/or addi-
was equally effective regardless of NT-proBNP tional information than levels obtained only at
level. After multivariate adjustment, includ- admission [40] . In an early study of serial mea-
ing adjustment for infarct size, NT-proBNP surement of NT-proBNP and wall motion index
level >1864 ng/l was associated with a HR of score, although NT-proBNP measured at all
2.3 for 1-year mortality (p = 0.03) [42] . Other time points between 14 and 192 h after a STEMI
recent studies have shown a similar relationship was associated with wall motion abnormalities
between elevated levels of NT-proBNP and and LV dysfunction, measurements at 73–120 h
larger infarct size [43–45] . demonstrated the strongest association [38] .
Elevations in pre-PCI BNP and NT-proBNP In one small observational study of 96 patients
levels have been associated with lower TIMI treated with primary PCI, BNP increased sig-
myocardial perfusion grade [46] , lower rates of nificantly from 62.9 pg/ml to 223 pg/ml in
normal TIMI flow, and higher rates of no-reflow the first 24 h and BNP measured at 24 h was
or MVO after PCI [45,47–49] , as well as incom- superior to admission BNP in terms of the rela-
plete ST-segment resolution [50–52] , more severe tionship with in-hospital mortality, reinfarction,
coronary artery disease as measured by Coronary arrhythmia, advanced congestive heart failure
Artery Surgery Study (CASS) scoring at the time (CHF) or stroke [54] . BNP measured 7 weeks
of angiography [50] and left ventricle (LV) dilation after a STEMI selects patients with persistently
at 6 months [53] . elevated levels (>80 pg/ml) to be at significantly
Based on BNP kinetics, the optimal time to higher risk of cardiovascular events compared
measure BNP or NT-proBNP after a STEMI with those with BNP levels that fall (relative
has been investigated. The optimal BNP or risk [RR]: 4.0), or those that have an initially
future science group www.futuremedicine.com 525

Table 1. Selective studies of troponin with data on patient outcomes.
526
Author (year) Patients (n) Study type Reperfusion Outcome Ref.
strategy
Review
Byrne et al. 1237 Observational Primary PCI No difference in 1-year mortality based on peak cTnT in Cox proportional hazards model [169]
(2010)
Sherwood et al. 1250 Substudy of Fibrinolysis Stratified by admission cTnT (ng/ml): negative, 0.01–0.12, 0.12–11.08: [25]
(2010) CLARITY-TIMI 28 30-day CV death: 1.5, 4.5, 9.5% (p < 0.001)
RCT 30-day CHF: 1.9, 3.0, 5.8% (p = 0.005)
30-day MI: 8.6, 5.5, 3.7% (p < 0.001)
Waks & Scirica
OR: 4.6 (1.7–12.1) and 5.8 (2.3–14.7) for 30-day CV death for low and high cTnT elevation, respectively,
vs negative cTnT
Hasan et al. 168 Observational Primary PCI HR: 1.1 (1.0–1.1) and HR: 1.1 (1.1–1.2) for MACE and CHF based on peak cTnT levels during 210-day [170]
(2009) follow-up
Kurz et al. 82 Observational Primary PCI No difference in CV events during 205-day follow-up based on admission, day 1, day 2 or day 3 cTnT [171]
(2009) OR: 6.2 (1.2–33.2) for day 4 cTnT ≥2.69 µg/l
Jeong et al. 207 Observational Primary PCI No difference in 1-year death, reinfarction, CHF or MACE based on admission cTnI [82]
(2008)
Foussas et al. 786 Observational Fibrinolysis RR: 1.5 (1.2–2.2) for 30-day cardiac death for highest admission cTnI tertile (1.3–54.9 ng/ml) vs lowest [23]
(2007) cTnI tertile (0–0.3 ng/ml)
Ohlmann et al. 87 Observational Primary PCI Admission cTnI >0.06 ng/ml not associated with adverse 42-month outcomes [74]
(2006) cTnI >30 ng/ml at 72 h associated with an OR of 9.4 (2.1–43.5) for subsequent mortality
Björklund et al. 516 Substudy of Fibrinolysis 30-day mortality 9.5 vs 2.0% (p < 0.001) and 1-year mortality 13.0 vs 4.0% (p < 0.001) for admission [24]
(2004) ASSENT-2 and cTnT ≥0.1 µg/l
ASSENT-PLUS OR for 30-day and 1-year mortality not significant after multivariate adjustment
RCTs
Kurowski et al. 226 Observational Primary PCI Unadjusted OR 4.6 (1.5–14.5) and 4.6 (1.6–12.8) for 30-day and 1-year cardiac mortality for admission [17]
(2002) cTnT ≥0.1 µg/l. After adjusting for time from symptom onset, admission cTnT was no longer significant
Future Cardiol. (2011) 7(4)

Matetzky et al. 110 Observational Primary PCI Admission cTnI ≥0.4 ng/ml associated with a RR of 5.2 (1.0–26.3) for the composite of death, MI or CHF [18]
(2000) at 30 days, and a increase in long-term cardiac mortality (11 vs 0%, p = 0.012) during 426 days of
follow-up
Ohman et al. 12,666 Substudy of Fibrinolysis +cTnT on admission associated with increased 24 h (6.7 vs 2.2%) and 30-day (15.7 vs 6.2%) mortality [172]
(1999) GUSTO-III RCT (p = 0.001)
HR: 2.1 (1.7–2.5) for 30-day mortality with a +cTnT
Newby et al. 734 Substudy of Fibrinolysis 30-day mortality 10.4 vs 3.2% and 1-year mortality 14.1 vs 4.5% (p < 0.001) for admission cTnT [29]
(1998) (58% STEMI) GUSTO-IIa RCT >0.1 ng/ml
Patients who were initially cTnT negative who then turned positive had intermediate risk between those
who were initially cTnT positive or those who remained cTnT negative
cTnT at 16 h was more strongly associated with 1-year mortality than was admission or 8 h cTnT
HR: 1.5 (p = 0.011) and 1.4 (p = 0.008) for 30-day and 1-year mortality with +cTnT on admission
CHF: Congestive heart failure; CTnl: Cardiac troponin I; CTnT: Cardiac troponin T; CV: Cardiovascular; HR: Hazard ratio; MACE: Major adverse cardiovascular event; MI: Myocardial infarction; OR: Odds ratio;
PCI: Percutaneous coronary intervention; RCT: Randomized controlled trial; RR: Relative risk; STEMI: ST-elevation myocardial infarction.
future science group

low level of BNP that rises to >80 pg/ml during
Death or congestive heart failure (%)

follow-up (RR: 2.3) independent of LVEF and 22
B-type natriuretic p < 0.001
repeated measurement of BNP provides infor- peptide levels 20
mation on dynamic short term cardiovascular Baseline–month 4 18
risk [55] . High–high 16
Low–high p < 0.001
In the Z phase of the A to Z trial, serial BNP 14
High–low
12
measurements were made at hospital discharge Low–low
10
and 4 months. Although the trial included a mix
8
of ACS patients (~40% STEMI), the results p = 0.05
6
were similar when restricted to patients with 4
STEMI. Compared to patients with persistently 2
low (<80 pg/ml) levels of BNP, patients with 0
BNP levels that remained >80 pg/ml had the 120 240 360 480 600
highest risk of death or new CHF during 2-year Days after month 4 visit
follow-up, followed by those who had an initial No. at risk
BNP ≤80 pg/ml that was elevated >80 pg/ml at High–high 137 128 121 91 59 35
4 months, and then those with an initial BNP Low–high 77 77 70 65 43 17
>80 pg/ml that was ≤80 pg/ml at 4 months High–low 330 322 292 225 161 97
(Figure 2) [56] .
Low–low 2929 2877 2777 2539 2232 1649
Short term changes in BNP also appear to be
significant. In a secondary analysis of the WEST Figure 2. Cumulative incidence of death or new or worsening congestive
heart failure based on the change in B-type natriuretic peptide over
trial, NT-proBNP measured 72–96 h or 30 days 4 months after myocardial infarction. ‘High’ refers to B-type natriuretic peptide
after reperfusion, and the change in NT-proBNP >80 pg/ml and ‘low’ refers to B-type natriuretic peptide ≤80 pg/ml. p-values are
from baseline to 72–96 h, were more strongly for comparison with the low–low group.
correlated with the 30-day composite of death, Reproduced with permission from [56] © 2005 American Medical Association.
reinfarction, refractory ischemia, CHF, car- All rights reserved.
diogenic shock and major arrhythmia, and
infarct size than was baseline NT-proBNP [57] . levels that were normal, above normal but below
In a smaller observational study of 25 STEMI the median [742 ng/l], and above the median,
patients and serial NT-proBNP measurements, respectively). Of note, over 50% of the patients
significant short term changes in NT-proBNP in the study had normal NT-proBNP levels,
were observed, and patients with successful likely related to early measurement in the course
reperfusion had a NT-proBNP peak at approx- of MI [50] .
imately 24 h, while those without successful Despite the multitude of studies demonstrat-
reperfusion had persistently elevated levels [40] . ing that elevated levels of NT-proBNP or BNP
Both long and short term adverse out- are associated with adverse cardiovascular out-
comes have been associated with elevations of comes after STEMI, data supporting therapies
BNP/NT-proBNP. In the ENTIRE-TIMI 23 that would reduce levels of natriuretic peptides
study, BNP >80 pg/ml measured 2–4 days after are sparse. The clinical utility of inhibiting the
presentation was associated with an increase in renin-angiotensin-aldosterone system (RAAS)
2, 7, and 30 day (17.4 vs 1.8%; p < 0.001) mor- after ACS to reduce both hemodynamic stress
tality and BNP was superior to cTnI and CRP and levels of natriuretic peptides was assessed in
as a marker of increased risk. Elevated levels of the AVANT GARDE-TIMI 43 trial. A total of
BNP were also associated with failed reperfu- 1101 ACS patients (58.5% STEMI) with elevated
sion and incomplete STRes [52] . Increases in both levels of NT-proBNP (>400 pg/ml) or BNP
1 and 10-month mortality were observed with (>80 pg/ml) 3–10 days after admission and with-
BNP measured at 2–3 days after the onset of out clinical evidence of CHF or a LVEF ≤40%,
symptoms in a subset of the OPUS-TIMI 16 were randomized to the direct renin inhibitor
trial. Notably, patients in the lowest quartile of aliskiren, the angiotensin receptor blocker val-
BNP (<43.6 pg/ml) had a 10-month mortality sartan, the combination of aliskiren and valsar-
well below 1% [58] . tan, or placebo, and had serial NT-proBNP and/
In a substudy of 782 patients treated with or BNP sampling over 8 weeks. Treatment with
fibrinolytics in the ASSENT-2 and ASSENT- aliskiren and/or valsartan reduced blood pressure
PLUS trials, higher age adjusted admission compared with the placebo, but there was no dif-
NT-proBNP was associated with greater 1-year ference between any treatment arm and placebo
mortality (3.4, 6.5 and 23.5% for NT-proBNP in the reduction of NT-proBNP or BNP over

the study period. When results were restricted correlate well with infarct size assessed by cardiac
to only those patients with STEMI, all patients MRI, although levels of CRP on admission and
experienced a 57.5% reduction in NT-proBNP at 2 months (prior to and after infarction induced
over 8 weeks regardless of their randomization inflammation) do not [70] . CRP measured at 48 or
to active treatment or placebo. The study was 72 h, but not on admission, has also been shown
not powered to detect differences in clinical out- to correlate with enzymatically measured infarct
comes and there was no observed difference in size [74,75] . One study which showed that even
the composite outcome of cardiovascular (CV) admission CRP was independently associated
death, MI, or CHF between treatment arms, with larger infarct size 1–2 weeks after primary
although adverse events were more common in PCI enrolled patients within 24 h of symptom
patients randomized to aliskiren and/or valsartan onset, and this relatively late presentation may
compared with placebo [59] . explain their disparate results [76] .
In a multitude of studies, admission BNP and C-reactive protein and highly sensitive CRP
NT-proBNP have been demonstrated to either (hsCRP; a CRP assay with increased sensitiv-
add prognostic value, or be superior to established ity) measured prior to thrombolytic therapy
risk scores such as Killip Class, GRACE score, correlate with success of reperfusion. Elevated
GUSTO score and TIMI risk score [60–64] . Table 2 levels are associated with less TIMI 3 flow at 90
summarizes studies involving clinical outcomes min [77] or 4–5 days [78] , and elevated hsCRP
and BNP/NT-proBNP. tertiles prior to fibrinolysis are associated with a
1–3 fold increase in failed reperfusion as assessed
CRP & highly sensitive CRP by 90–120 min STRes [23,78] . As with tropo-
Inflammation is a key mediator in the devel- nin, patients with persistent MVO have higher
opment of atherosclerosis and the subsequent peak CRP levels at 48 h [70] , and patients with
onset of ACS [65,66] . CRP, a member of the pen- elevated preprocedural CRP levels have reduced
traxin family of plasma proteins, is a approxi- perfusion as assessed by post-PCI myocardial
mately 1000 amino acid hepatically produced blush grade [79] and TIMI myocardial perfusion
acute-phase reactant that is induced by IL-6, grade [80] , and a modest increase in rates of no-
is potentially both a mediator and nonspecific reflow (OR: 1.02 [1.01–1.04] per 1 mg/l increase
marker of systemic inflammation [67] , and has in baseline CRP) [76] .
been extensively studied in stable coronary artery The association between levels of CRP and
disease (in terms of its relationship to atheroscle- both short and long-term adverse outcomes have
rosis) where it has been shown to significantly been extensively evaluated in STEMI, although
improve risk stratification and identify patients the optimal time to measure CRP is not entirely
who may benefit from intensive statin therapy clear and different time points may provide dif-
[68] . The utility of inflammatory markers in ACS ferent prognostic information. Although there
is more problematic as myocardial necrosis itself was no association between admission hsCRP
causes inflammation and thus elevated levels of and 30-day death, MI, CHF, or reperfusion
CRP may simply reflect greater infarct size. Early success in a substudy of the ENTIRE-TIMI
measurements of CRP within the first 6 h after 23 trial [52] , and smaller studies have similarly
symptom onset, however, may be more likely to found a lack of association between admission
reflect pre-existing inflammation as opposed to CRP and 1-year adverse outcomes [81,82] and 48 h
inflammation induced by necrosis [69] . CRP has CRP and 42-month adverse outcomes [74] , many
a half-life of approximately 19 h, and its levels other studies of CRP/hsCRP have supported
decrease rapidly when the inflammatory source an association between early measurement of
driving its production ceases [67] . After MI, CRP CRP/hsCRP and unfavorable prognosis.
levels peak at approximately 2–4 days [67,70– In a study of 234 STEMI patients treated
72] and begin to decrease within 1 week [70] . with primary PCI, CRP ≥0.3 mg/dl measured
Interestingly, CRP appears to contribute to post- at presentation and within 6 h of symptom onset
MI inflammation and remodeling by activating was associated with a OR of 7.1 (2.2–26.3;
complement within areas of infarction [67] and p = 0.002) for in-hospital adverse events includ-
thus direct anti-CRP therapy has been proposed ing coronary artery re-occlusion, reinfarction,
as a potential mechanism to improve reperfusion need for repeat revascularization and death [69] .
injury and remodeling [73] . Similarly, in 319 patients treated with fibrino-
Infarcted myocardium causes a self-limited lysis, increasing admission CRP tertiles were
inflammatory response, and levels 2 days and associated with increases in both in-hospital
1 week after STEMI treated with primary PCI and approximately 2-year cardiac mortality [78] .

Table 2. Selective studies of B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide with data on patient outcomes.
Author (year) Patients (n) Study type Reperfusion Outcome Ref.
strategy
Ezekowitz et al. 64 Substudy of Primary PCI 24 h but not baseline NT-proBNP was independently associated with lower LVEF at 3 months [45]
(2010) APEX-AMI RCT

Jarai et al. 1016 Substudy of Primary or Increasing concentrations of NT-proBNP at randomization were associated with increasing rates of [64]
(2010) ASSENT-4 RCT facilitated PCI cardiogenic shock (1.9, 5.9 and 14.9% for NT-proBNP <67 pg/ml, 68–1482 pg/ml and
>1482 pg/ml, respectively)
NT-proBNP >1482 pg/ml associated with an adjusted HR of 3.43 (1.23–29.57) for in-hospital
cardiogenic shock
Kwon et al. 1052 Observational Primary PCI Admission NT-proBNP >991 pg/ml associated with OR of 3.7 (1.1–12.0) for in-hospital mortality (7.4 [173]
(2009) analysis of vs 1.3%; p < 0.001)
KAMIR registry
Jeong et al. 207 Observational Primary PCI BNP on admission was not associated with 1-year mortality, heart failure or reinfarction [82]
(2008)
Sabatine et al. 1239 Substudy of Fibrinolysis Increasing quartiles of NT-proBNP on presentation associated with increasing CV death (1.4, 1.0, [46]
(2008) CLARITY-TIMI 28 5.1 and 10.5%; p < 0.0001), CHF (1.7, 2.7, 2.0 and 6.8%; p = 0.018), MI and stroke
RCT NT-proBNP at angiography (mean 96 h) was more strongly associated with CV death and CHF than
NT-proBNP at baseline (OR: 14.9 [3.5–63.8] vs 1.3 [0.6–2.7])
Kuklinska et al. 86 Observational Primary PCI Admission BNP >99.2 pg/ml associated with an OR of 732.2 (29.1–18402.9; p = 0.0001) for CV [63]
(2007) events (death, stroke and recurrent ischemia) during 1-year follow-up
Ezekowitz et al. 331 Substudy of Primary PCI NT-proBNP at baseline, 24 or 72 h was independently associated with 90-day composite end point [174]
(2006) COMMA RCT of death, CHF, shock or stroke
Björklund et al. 782 Substudy of Fibrinolysis 1-year mortality 3.4, 6.5 and 23.5% for admission NT-proBNP normal, higher than normal but less [50]
www.futuremedicine.com
(2006) ASSENT-2 and than the median (742 ng/l) and greater than the median, respectively
ASSENT-PLUS RCTs
Morrow et al. 4266 Substudy of the Primary PCI or BNP >80 pg/ml prior to hospital discharge, 4 months and 8 months associated with HRs of 2.5 [56,175]
(2005) (40% STEMI) Z phase in the fibrinolysis (2.0–3.3), 3.9 (2.6–6.0) and 4.7 (2.5–8.9), respectively, and independent of CHF symptoms
A to Z RCT (if presented No association between admission BNP and recurrent MI
within 12 h) Normalization of BNP below 80 pg/ml at 4 months associated with improved outcomes
Grabowski 126 Observational Primary PCI Admission BNP >100 pg/ml was more common in patients with longer time from symptom onset to [47]
et al. (2004) presentation, but was independently associated with OR of 16.3 (1.4–186.7) for risk of
42-day mortality
Galvani et al. 1756 Substudy of Primary PCI or In STEMI: admission NT-proBNP associated with increasing 30-day mortality based on increasing [41]
(2004) (35% STEMI) EMAI trial fibrinolysis quartiles of NT-proBNP (≤107, 108–353, 354–1357 and ≥1358). Patients in the highest quartile had
an OR of 7.0 (1.9–25.6) for 30-day mortality
de Lemos et al. 2525 Substudy of N/A BNP measured a mean of 40 h after onset of chest pain associated with increasing 10-month and [58]
(2001) (33% STEMI) OPUS-TIMI 16 RCT 30-day mortality, MI and CHF
BNP: B-type natriuretic peptide; CHF: Congestive heart failure; CV: Cardiovascular; HR: Hazard ratio; LVEF: Left ventricular ejection fraction; MI: Myocardial infarction; NT-proBNP: N-terminal pro B-type natriuretic
Established & novel biomarkers in ST-elevation myocardial infarction
peptide; OR: Odds ratio; PCI: Percutaneous coronary intervention; RCT: Randomized controlled trial; STEMI: ST-elevation myocardial infarction.
Review
529
In an observational study of 861 STEMI discharge, 30 days and 4 months compared

patients, admission CRP was associated with with placebo, but regardless of randomization,
a HR of 2.2 (1.9–2.6; p < 0.001) for 30-day patients who had larger decreases in CRP by
mortality by Cox regression analysis and CRP 30 days had a significantly lower risk of adverse
provided information beyond that provided by cardiac outcomes [88] .
TIMI risk score [83] . In a substudy of the OPUS- Statin therapy reduces CRP independent of
TIMI 16 trial (33% STEMI), increasing quar- lipid effects [88] , the IL-6/CRP/complement
tiles of hsCRP measured at enrollment (median inflammatory axis represents a potential thera-
40 h after onset of symptoms) were associated peutic target, and complement depletion has
with increased rates of mortality and CHF at been shown to reduce infarct size in experimen-
30 days and 1 year, but the strength of asso- tal models of MI [89] . In the COMMA trial, a
ciation between outcomes and CRP decreased placebo controlled trial of a bolus or bolus plus
with increasing time from onset of symptoms. 20 h infusion of the C5 complement inhibitor
Overall, patients with a STEMI and hsCRP pexelizumab, treatment was associated with a
>15 mg/l had a 3–4 fold increase in the rates of reduction in CRP during the infusion period [71] ,
30-day and 1-year mortality [84] . In an obser- and although there was no difference in the pri-
vational study of 146 STEMI patients treated mary endpoint of biochemically assessed infarct
with primary PCI, hsCRP above the median of size at 72 h, there was a significant reduction in
2.37 mg/l prior to PCI was associated with an the secondary endpoints of 90-day (5.9 vs 1.8%;
OR of 20.7 (3.2–132.8; p = 0.001) for 30-day RR: 0.30; p = 0.014) and 6-month (7.4 vs 3.2%;
major adverse cardiovascular events (MACE) OR: 0.43; p = 0.035) mortality [90] .
and reduced LVEF (55 vs 61%; p = 0.008) [85] .
C-reactive protein on admission may also Copeptin
provide information on long-term cardiovas- Arginine vasopressin (also known as antidi-
cular risk. In a sub-analysis of 379 patients in uretic hormone) is a 9 amino acid hormone
the On-TIME trial, CRP measured at admis- synthesized in the hypothalamus and secreted
sion was associated with significantly higher by the posterior pituitary in response to hemo-
rates of all-cause mortality and reinfarction at dynamic and osmotic stimuli. Through inter-
1 year [75] . In a retrospective analysis of 758 actions with a variety of tissue specific recep-
STEMI patients, hsCRP on admission was asso- tors, vasopressin contributes to osmoregulatory
ciated with a HR of 1.03 (1.01–1.06; p = 0.008) and cardiovascular homeostasis [91,92] . Accurate
for mortality and reinfarction over a period of measurement of vasopressin levels is challeng-
approximately 2 years [86] , and in the BIAS ing because over 90% of vasopressin is platelet
study, which enrolled STEMI patients who pre- bound, it is rapidly cleared from the circulation
sented a mean of 4.3 h after chest pain onset, with a half-life of approximately 20 min, it is
admission hsCRP was associated with a HR of unstable in stored blood samples and its small
2.1 (1.6–2.7; p < 0.001) for 5-year cardiovascular size creates technical difficulties for measure-
death [87] . ment [93] . Copeptin (also known as C-terminal
Like troponin and BNP, the change in CRP pro-vasopressin) is a 39 amino acid peptide that
over time is another important marker of risk. is released in equimolar amounts to vasopressin
In a substudy of 3813 patients in the A to Z when the vasopressin precursor protein pro-vaso-
trial (39% STEMI), patients had hsCRP mea- pressin is enzymatically cleaved into vasopressin,
sured at 30 days and 4 months after random- neurophysin II, and copeptin, and circulating
ization into phase Z, with the goal of measur- copeptin levels directly reflect circulating vaso-
ing inflammation after resolution of the acute pressin levels [93] . Compared to vasopressin,
inflammatory response related to myocardial copeptin is remarkably stable both in the cir-
necrosis. At 30 days there was no difference culation and in stored blood samples and new
in hsCRP between patients with STEMI or assays are highly sensitive for its detection [94] .
NSTEMI, but a hsCRP >3 mg/l was associ- Following a MI, elevated levels of vasopressin
ated with a HR of 3.9 (1.8–8.6; p < 0.001) for may cause adverse effects via increases in periph-
cardiovascular death and a HR of 3.4 (1.4–7.9; eral vasoconstriction and afterload, increases
p < 0.001) for CHF during 2 years of follow-up in renal free water retention and preload, and
compared with patients with hsCRP <1 mg/l. alterations in cardiac myocyte protein synthesis
Patients with hsCRP between 1 and 3 mg/l leading to hypertrophy and fibrosis [95] . In the
had intermediate risk. Statin therapy resulted LAMP study, copeptin was measured 3–5 days
in a larger decrease in hsCRP between hospital after admission in 980 patients with acute MI

(80% STEMI and 68% treated with fibrinoly- such as troponin and is therefore a potential early
sis). Copeptin levels peaked early and plateaued marker of myocardial ischemia and/or necro-
by day 3–5, were higher in patients with STEMI sis [100,101] . The release kinetics of H-FABP are
compared with NSTEMI and in patients with similar to those of myoglobin, but because of
LV dysfunction (10.1 pmol/l vs 5.9 pmol/l; its greater cardiac specificity, H-FABP is a more
p < 0.005), but were not associated with recur- sensitive marker of myocardial injury. In ACS,
rent MI. After logistic regression analysis, higher H-FABP levels peak approximately 4 h after
copeptin levels were independently associated symptom onset, returning to baseline within
with an increased risk of death or heart fail- 24 h [100] .
ure at 60 days (OR: 4.1; p < 0.005). Copeptin In a study of 328 patients with mixed ACS
levels above or below the median of 7.0 pmol/l (47% STEMI), patients with STEMI had
provided additional prognostic information in higher levels of H-FABP on presentation than
patients who had already been risk stratified by patients with non-ST-elevation ACS. STEMI
NT-proBNP levels, with particular utility in patients with a H-FABP level greater than the
patients with NT-proBNP above the median of median of 9.8 µg/l had significantly higher rates
914 pmol/l [95] . of cardiac death or nonfatal MI at 6 months
In another small study of 274 patients with (13.2 vs 2.1%; p = 0.04), and a nonsignificant
acute MI (84% with STEMI and 65% treated trend towards higher rates of cardiac death or
with fibrinolysis), elevations in copeptin nonfatal MI at 30 days, but there was no rela-
3–5 days after MI were associated with greater tionship between admission cTnT and 30-day
LV dysfunction, greater LV remodeling, or 6-month outcomes. In multivariate analysis
and increasing rates of clinical heart failure confined to STEMI patients, an admission
(HR: 3.0; p = 0.032). Copeptin had a stronger H-FABP level above 9.8 µg/l was associated with
association with LVEF at 5.5-month follow-up a RR of 11.3 (1.41–90.6; p = 0.02) for cardiac
than LVEF at discharge, suggesting a progressive death or nonfatal MI at 6 months, but troponin
and deleterious effect of vasopressin on cardiac was not independently associated with cardiac
remodeling [96] . outcomes. H-FABP may offer advantages over
Prior to widespread clinical application, the traditional use of troponin at the time of pre-
copeptin requires further study. As copeptin is sentation due to earlier detection within the first
not cardiac specific, different underlying disease hours of MI [102] , although this difference will
states may require the use of alternate cut-off be minimized with upcoming high-sensitivity
points [93] and the factors that can affect circu- troponin assays.
lating levels, such as corticosteroids [97] , remain The prognostic value of H-FABP was also
to be clarified. Vasopressin remains a potential evaluated in the OPUS-TIMI 16 trial (33%
pharmacologic target for mediating risk follow- STEMI). Among STEMI patients with H-FABP
ing a MI and copeptin is a potential marker for >8 ng/ml, there was a HR of 3.1 (1.9–5.2) for
patients who would benefit from such therapy. the risk of death, MI or CHF during 10-month
Vasopressin antagonists have been approved for follow-up, and H-FABP provided additional
treatment of hyponatremia [98] , but studies have information about patient risk beyond that
been disappointing in patients with heart fail- established by troponin and BNP [103] .
ure [99] . No studies have yet been undertaken to In a sub-analysis of the prospective obser-
evaluate the effects of vasopressin antagonism vational study EMMACE-2 (~25% STEMI),
following MI. H-FABP was measured 12–24 h after the onset
of chest pain. When stratified by quartiles,
Heart-type fatty acid binding protein higher levels of H-FABP were associated with
Heart-type fatty acid binding protein (H-FABP) increased 1-year all-cause mortality indepen-
is a 15-kDa cytoplasmic fatty acid binding pro- dent of cTn status, with a HR of 4.8–6.6 for
tein with primary importance in transporting the highest quartile compared with the lowest
long chain fatty acids, mediating gene expression quartile [104] .
and protecting against high concentrations of H-FABP has also been investigated as a marker
long chain fatty acids during periods of ischemia of successful reperfusion in STEMI patients
in cardiac myocytes. Although not entirely car- treated with fibrinolysis. 54 patients in the TIMI
diac specific, levels in the myocardium are sig- 14 trial had H-FABP measured at baseline, and
nificantly higher than in other tissues [100] . Due then at 60, 90 and 180 min after fibrinolysis.
to its small size, H-FABP is able to diffuse out H-FABP levels rose faster and to higher levels
of myocytes more rapidly than larger molecules in patients with patent infarct related arteries

(IRA) than those with occluded IRAs, although lower HR than NT-proBNP (1.77 vs 2.06).
H-FABP could not differentiate TIMI-3 flow The c-statistics of GDF-15 and NT-proBNP for
from TIMI-2 flow [105] . A small sub-study of death or heart failure at 1 year were not statisti-
the GUSTO trial revealed similar results [106] . cally different (0.73 vs 0.76) but the combination
of GDF-15 and NT-proBNP yielded a superior
Growth-differentiation factor-15 c-statistic of 0.81. Patients with GDF-15 above the
Growth-differentiation factor-15 (GDF-15) median of 1470 ng/l had a significantly higher rate
(also known as macrophage inhibitory cyto- of death or heart failure during follow-up than
kine-1, placental bone morphogenic protein, and those below the median and this relationship per-
nonsteroidal anti-inflammatory drug-activated sisted even when patients were also stratified by
gene 1), is an approximately 30 kDa member of NT-proBNP levels. When patients were stratified
the TGF-b superfamily that is synthesized via by diagnosis of NSTEMI vs STEMI, however,
nitric oxide related pathways [107,108] . While not GDF-15 was only associated with death or heart
cardiac specific or normally present in healthy failure in those patients with NSTEMI [111] . The
cardiac myocytes [107] , it is rapidly and highly difference in utility of GDF-15 in STEMI patients
expressed in the setting of oxidative stress, pres- within these two studies could be explained by dif-
sure/volume overload [107] and cardiac ischemia, ferences in when GDF-15 was measured (90 min
where it likely has a cardioprotective role [108,109] . vs 3–5 days), as the ASSENT trials demonstrated
In a substudy of 741 patients in the ASSENT-2 that the prognostic utility of GDF-15 was lower
and ASSENT-Plus trials, 72.7% of patients had in day 5 blood samples compared with admission
levels of GDF-15 above 1200 ng/l (the pre- blood samples [110,111] .
determined upper limit of normal in healthy
individuals) on presentation, and increasing Midregional pro-atrial natriuretic peptide
levels of GDF-15 correlated with multiple estab- Atrial natriuretic peptide (ANP) is a 28 amino
lished baseline risk factors. Unlike troponin, acid peptide which, like BNP, promotes natri-
higher GDF-15 levels were not associated with uresis, diuresis and vasodilation [36] , but it has a
an increase in time from symptom onset to pre- short half-life and is therefore difficult to mea-
sentation. As the GDF-15 level increased, so did sure accurately and reliably. ANP is produced by
the risk of 30-day and 1-year mortality (1.0 and cleavage of a precursor molecule proANP, into its
2.1% for GDF-15 <1200 ng/l, 3.6 and 5.0% for 98 amino acid N-terminal region (NT-proANP)
GDF-15 1200–1800 ng/l, and 9.8 and 14.0% and ANP. ProANP is secreted in equimolar
for GDF-15 >1800 ng/l; p < 0.001) (Figure 3) , amounts to ANP but it is larger, has a longer half-
but GDF-15 was not associated with mortality life, has fewer nonspecific binding interactions,
at 24 h. GDF-15 had a c-statistic for mortality and is less actively excreted than ANP, making it
of 0.75 which was similar to those of established an attractive marker of activation of the ANP sys-
markers cardiac cTnT (0.67) and NT-proBNP tem [112,113] . Assays for the detection of proANP
(0.79), and provided additional prognostic infor- can be limited by proANP fragmentation pre-
mation in patients already risk stratified by cTnT venting appropriate antibody binding, and assays
and NT-proBNP. GDF-15 levels rose immedi- with antibodies directed against the midregional
ately after reperfusion with fibrinolytics and then area of proANP (MR-proANP) are considered to
decreased while remaining elevated above base- be most reliable [113,114] . While NT-proANP has
line for 5 days after reperfusion, but there was previously been shown to have prognostic value
no difference in GDF-15 levels among patients in STEMI [115,116] , only recently has a reliable
with or without STRes at 60 min arguing against assay for MR-proANP become available [113] .
reperfusion and washout inducing a rise in GDF- Midregional area of proANP was evaluated
15 levels. In addition to the prognostic informa- with NT-proBNP 3–5 days following a MI in
tion provided by baseline GDF-15 levels, elevated 983 patients (79.7% STEMI, 79.4% received
levels at 90 min were also associated with 1-year fibrinolytics, and 12.4% underwent primary PCI)
mortality and elevated levels at 1 day and 5 days enrolled in the LAMP study who were followed for
showed a nonsignificant trend towards increased a median of 343 days. NT-proBNP levels peaked
1-year mortality [110] . on day 2 and then decreased and plateaued, while
In a subsequent prospective study of MR-proANP levels peaked on day 1, decreased on
1142 patients with acute MI (45% STEMI), GDF- day 2, and increased again on day 3. MR-proANP
15 levels measured on day 3–5 were associated levels were more elevated in patients with estab-
with an increase in death or heart failure during lished risk factors for cardiovascular disease and
a median follow-up of 1.4 years, with a slightly females, but there was no difference among

patients with STEMI or NSTEMI. In a subgroup

of patients with discordant levels of NT-proBNP 16
and MR-proANP, there was no difference in GDF-15 <1200 ng/l
outcomes, and after multivariate analysis, both GDF-15 1200–1800 ng/l
MR-proANP and NT-proBNP were associated GDF-15 >1800 ng/l
with increased mortality with similar results
12
(HR: 3.87; p = 0.005 and HR: 3.25; p < 0.0005,
respectively). MR-proANP but not NT-proBNP
was independently associated with heart failure
Mortality (%)
requiring hospitalization, but there was no differ-
ence among markers in terms of the risk of recur- 8
rent MI. MR-proANP and NT-proBNP each
generated a c-statistic of 0.83 for mortality, but
MR-proANP did offer incrementally improved
prognostic information when patients were already
4
stratified by NT-proBNP, suggesting that although
ANP and BNP are both natriuretic peptides, they
may provide different prognostic information [112] .
MR-proANP has also been shown to be useful and
superior to NT-proBNP (c-statistic 0.73 vs 0.68) 0
in identifying patients with LV dysfunction (EF
<50%) after a STEMI [114] . 0 1 2 3 4 5 6 7 8 9 10 11 12
Time (months)
Soluble ST2
ST2 is a member of the IL-1 receptor family Figure 3. Cumulative probability of mortality according to growth-
that exists in transmembrane (ST2L) and sol- differentiation factor-15 level at presentation.
uble (sST2) forms [117] . Both forms of ST2 are GDF-15: Growth-differentiation factor-15.
Reproduced from [110] , with permission from the European Society of Cardiology.
upregulated in cardiac myocytes in response to
myocardial strain and volume overload and lev- recurrent MI or stroke. Elevation of sST2 and/or
els of sST2 have been shown to increase post NT-proBNP above the median, when added to
MI [118] . It was recently discovered that ST2 is a the TIMI risk score, provided additional infor-
receptor for IL-33, and that ST2L/IL-33 signal- mation about patient risk, especially in a subset
ing is cardioprotective via antihypertrophic and of patients with a TIMI Risk Score <4 [46] .
antifibrotic pathways. Soluble ST2 attenuates In a small study of 100 patients with a MI
the cardioprotective effects of IL-33 by acting and LV dysfunction (90% STEMI), higher
as a decoy receptor and preventing binding of levels of sST2 were associated with greater LV
IL-33 to transmembrane ST2L [117,119] . dysfunction at baseline and 24 weeks of follow-
In a substudy of 810 patients with STEMI up, and with larger infarct volume. Changes
in the TIMI 14 and ENTIRE-TIMI 23 trials, in sST2 over 24 weeks correlated with changes
levels of sST2 peaked at 12–24 h following pre- in left ventricular end diastolic volume index
sentation, and sST2 at presentation was associ- (LVEDVI), suggesting a role for ST2 signal-
ated with 30-day mortality (adjusted OR: 1.77; ing in post-MI cardiac remodeling. sST2 levels
p = 0.047) and heart failure, but not recurrent were correlated with aldosterone levels and treat-
MI. sST2 levels were weakly correlated with ment of patients with the aldosterone antagonist
levels of cTnI and BNP suggesting a distinct eplerenone reduced indices of adverse remodel-
mechanism for sST2 release [120] . ing in those with high sST2 levels [121] . Although
Among 1239 patients from the CLARITY- this may suggest that ST2 signaling is related to
TIMI 28 trial, in contrast to NT-proBNP, base- signaling via the RAAS and earlier in vivo exper-
line sST2 levels were independent of age, gender, iments showed that ST2L/IL-33 signaling can
hypertension, prior MI, prior CHF (markers of block cardiomyocyte hypertrophy induced by
chronic LV stress) and minimally related to renal angiotensin II (AT-II) [117] , other in vivo experi-
function. sST2 was also less correlated with ments failed to corroborate ST2 expression in
LVEF than was NT-proBNP. Elevated sST2 response to AT-II stimulation or treatment with
levels were associated with a significant increase angiotensin receptor blockers [118] , and an ana
in the risk of CV death or CHF (OR: 1.94 per 1 lysis of ST2 levels in the PRAISE-2 study did
SD increase in log sST2; p = 0.003), but not with not reveal a correlation between blood levels of

ST2 and AT-II [122] . Although there may be a 18%; p = 0.006), cardiogenic shock (18 vs
link between the ST2/IL-33 and RAAS systems, 5%; p = 0.04), and cardiac death (13 vs 0%;
both appear to be mediated by different mecha- p = 0.008) [132] .
nisms. It remains unclear if ST2 is a marker of Due to its vasoconstrictor properties, ET-1
risk or is itself a risk factor that could be targeted is a potential mediator of the no-reflow phe-
with therapy [46] . nomenon associated with adverse events after
reperfusion [133] . In a subgroup of 128 patients in
Endothelin-1 & C-terminal the LIPSIA-N-ACC trial, ET-1 levels were mea-
pro‑endothelin-1 sured prior to and immediately after primary
Endothelin-1 (ET‑1) is a 21 amino acid peptide PCI, and no reflow was assessed by angiographic
with potent vasoconstrictor properties found in parameters during PCI and cardiac magnetic
endothelial, pulmonary, intestinal, and renal resonance imaging 1–4 days after PCI. Patients
cells. There are 3 human endothelins (ET-1, with ET-1 levels greater than the median of 7.14
ET-2 and ET-3), but ET-1 is the isopeptide that pg/ml pre-PCI had significantly higher rates of
circulates in the greatest concentration [123] . ET-1 TIMI flow 0, higher rates and a larger extent of
may also have immunologic and inflammatory late MVO on MRI, and lower LVEF. Patients
functions [124] as well as direct electrophysiologic with ≤30% STRes had higher levels of ET-1
effects on myocardium [125] . ET-1 is difficult to compared with those with >30% STRes, and
measure directly because it is inherently unstable patients with no-reflow also had larger increases
with a half-life of 1–2 min, and binding to vari- in ET-1 after PCI than those with good reflow
ous receptors and plasma proteins and cleavage [134] . In another small prospective observational
by endopeptidases interferes with accurate and study of 51 STEMI patients treated with either
reliable measurement. ET-1 is derived from a primary PCI or rescue PCI, admission ET-1
larger 212 amino acid peptide called pre-proET-1, was most strongly associated with no-reflow
which is cleaved into bigET-1 (which is subse- (OR: 2.76; p = 0.03), although absolute differ-
quently cleaved at the level of tissues into ET-1), ences between patients with or without reflow
and a variety of proET-1 fragments, including were small [135] .
C-terminal proET-1 (CT-proET‑1). Unlike ET-1, In the LAMP study, CT-proET-1 was com-
CT-proET-1 is stable for 4–6 h and is not affected pared with NT-proBNP in 983 patients present-
by receptor or protein binding [126] . Early stud- ing with MI (80% STEMI) who were followed
ies of ET-1 in MI revealed that it rises within for a median of 343 days. While ET-1 peaks at
6 h [127] , and that higher levels are associated with 6 h after symptom onset, returning to baseline
increases in heart failure, cardiogenic shock [128] , within 24 h, CT-proET-1 levels peaked at 2 days
mortality [129] and myocardial fibrosis [130] . before reaching a plateau, which persisted for at
In a prospective cohort study of 186 STEMI least 5 days (end of the study). No significant
patients, ET-1 ≥0.632 pg/ml prior to primary differences were found in CT-proET-1 levels
PCI was strongly correlated with 30-day adverse between patients with STEMI and NSTEMI,
outcomes and was associated with an OR of but levels were significantly higher in women,
6.8 (p < 0.0001) for both 30-day mortality patients with a history of prior MI, hypertension
and 30-day MACE (including Killip score ≥3, or heart failure and those with higher Killip class
NYHA class IV CHF, and death), although on presentation. After multivariate analysis, log
ET-1 levels in this study were significantly lower CT-proET-1 was associated with a HR of 6.82
compared with others. Female gender, Killip (p < 0.001) for the risk of death or heart failure
class ≥3, longer duration of time from symp- during follow-up, while log NT-proBNP, was
tom onset to treatment, and reduced LVEF were only associated with a HR of 2.62 (p < 0.001).
correlates of an elevated admission ET-1 level, Both CT-proET-1 and NT-proBNP had a c-sta-
but ET-1 was not associated with the success of tistic of 0.76 for death or heart failure during
reperfusion [131] . In another prospective obser- follow-up, but the combination of both biomark-
vational study of 110 STEMI patients treated ers yielded a superior c-statistic of 0.81. Levels
with primary PCI, ET-1 measured 24 h after of CT-proET-1 and NT-proBNP were associated
symptom onset greater than the median value with each other, suggesting a possible common
of 2.94 pg/ml was associated with reduced mechanism for their release [136] .
LVEF (51 vs 60; p = 0.003), less STRes (57 vs These results are similar to a smaller study
96%; p = 0.002), and increased rates of major of 30 patients (67% of whom had STEMI)
complications during the 3-month follow-up where CT-proET-1 measured at 3 days was
period including ventricular tachycardia (44 vs associated with increased adverse events during

10-month follow-up. In this small study, levels of ADM are secreted in equimolar amounts, and
CT-proET-1 at admission were higher in patients measurement of MR-proADM allows indirect
with NSTEMI as compared with STEMI, but measurement of circulating ADM levels [142] .
this difference disappeared by day 3 and may In one early study, ADM levels were not
reflect differences in time to presentation among strongly associated with risk of death and reduced
NSTEMI and STEMI patients and rising LVEF during 24 months of follow-up [148] . In
CT-proET-1 levels in the first 48 h after onset another small prospective case control study of
of a MI. CT-proET-1 was able to risk stratify 15 patients, ADM levels measured within the first
patients at 4 months following a MI, but not at 24 h were associated with acute hemodynamic
admission when levels of CT-proET-1 were still changes, including elevations in pulmonary
rising [137] . capillary wedge pressure, right atrial pressure,
Endothelin receptor blocking medications and pulmonary artery pressure, and ADM lev-
have been evaluated in a variety of cardiovascular els remained elevated in patients who developed
diseases including heart failure and pulmonary clinical heart failure [145] . These results were sup-
hypertension. Recent data from experimental ported by another small prospective case control
models suggest that the endothelin type A and study of 31 patients where admission ADM levels
B receptor antagonist bosentan and other novel were associated with worsening heart failure and
endothelin receptor antagonists are effective in reduced LVEF. In this same study, ADM levels
reducing infarct size [124,138] and arrhythmia [125] 12–24 h after admission were associated with a
after MI. One randomized clinical trial is cur- lower systemic vascular resistance measured by
rently ongoing to evaluate the effect of endothe- invasive hemodynamic monitoring, suggesting
lin receptor blockade in patients with STEMI a potential cardioprotective role [146] . In a larger
(see clinicaltrials.gov identifier NCT00502528). cohort of 113 patients, ADM measured 2 days
after the onset of symptoms was associated with
Adrenomedullin & midregional worsening symptomatic heart failure and was
pro‑adrenomedullin the only noninvasive parameter associated with
Adrenomedullin (ADM) is a 52 amino acid 25-month mortality (RR: 1.04; p = 0.014) [149] .
peptide that is present within most tissues, and More recent studies of ADM in STEMI patients
which shares significant sequence homology have revealed that ADM is produced and secreted
with calcitonin gene related peptide and amy- by the myocardium after a MI, especially in
lin [139–141] . ADM is present in high concentra- patients with LV dysfunction [150] .
tions in vascular endothelium and is secreted MR-proADM was assessed as a prognostic
by endothelial cells in response to a variety of biomarker in the LAMP study (80% STEMI)
stimuli [141] . A 185 amino acid precursor mol- 3–5 days after the onset of chest pain. Higher
ecule pre-pro-adrenomedullin is cleaved into levels of MR-proADM were found in patients
ADM, pro-adrenomedullin N-terminal 20 who were older, female, with a history of prior
peptide (PAMP), proADM (45–92), and adreno- MI, heart failure or hypertension, with a higher
tensin [142] . ADM circulates primarily as an Killip class, and with higher creatinine, but
immature, carboxy-terminal glycine-extended there was no difference among levels in STEMI
peptide which is converted to mature ADM via or NSTEMI. MR-proADM levels were corre-
enzymatic reactions [141] . It is a potent vasodi- lated with NT-proBNP levels and both were
lator involved in the homeostasis of vascular associated with a higher risk of death or heart
tone, but has a multitude of other effects in failure in logistic and Cox regression models
multiple organs via increases in cyclic AMP, (OR: 4.22; p = 0.02 for MR-proADM and 3.20;
including natriuresis, diuresis, and GI, repro- p < 0.0001 for NT-proBNP). The c-statistics for
ductive, and endocrine functions [140,141,143,144] . MR-proADM and NT-proBNP were similar at
In the setting of acute MI, ADM levels rapidly 0.77 and 0.79, respectively, but the combina-
increase within hours, peak on days 1–2, and tion of both biomarkers yielded a superior high
then decline, remaining elevated for at least 1–3 c-statistic of 0.84 (p < 0.001). In patients who
weeks [145–147] . Direct assays for ADM are lim- were stratified by NT-proBNP below or above
ited by its short half-life, instability, and binding the median, use of MR-proADM quartiles pro-
to other plasma proteins [142] . ProADM (45–92), vided further information about future risk,
also known as midregional pro-adrenomedullin especially in those with NT-proBNP greater
(MR-proADM), is more stable than ADM, has than the median of 914 pmol/l [151] . In a smaller
no known biological function, and is more eas- study of 30 patients (20 of whom had STEMI),
ily measurable than ADM. MR-proADM and patients with a MR-proADM level above the

Table 3. Other novel biomarkers in ST-elevation myocardial infarction.
536
Biomarker Biochemical role Outcomes assessed Ref.
2+ [176–181]
Review
IMA Normal component of human sera. In vivo binding of Co to albumin is Elevated levels correlate with 1-year mortality and in-hospital CHF,
reduced in the setting of ischemia by way of a controversial and incompletely and weakly correlate with an increased composite of adverse
understood mechanism cardiovascular outcomes
sCD40L Cell surface protein that binds CD40 and is highly involved in immune Mixed results: some studies finding elevated levels associated with [182–188]
function and inflammation. CD40–CD40L signaling has been demonstrated increases in death, MI and CHF, other studies without any clear
to induce proinflammatory cytokines in vascular smooth muscle cells, and be relationship
involved in platelet aggregation at the site of ruptured atherosclerotic
Waks & Scirica
plaques. After CD40–CD40L interaction, CD40L is cleaved from the cell and
circulates in soluble form as sCD40L
MPO Proinflammatory, leukocyte-produced enzyme that generates free radicals Elevated levels associated with in-hospital adverse events and death [189–192]
and oxidants, and interferes with endothelial homeostasis by consuming during 1- or 5-year follow-up. Elevated levels also associated with
nitric oxide. Implicated in coronary artery plaque destabilization failed fibrinolysis, impaired microcirculation after reperfusion and
lower LVEF at 6 months
MMPs Family of numerous zinc-dependent endopeptidases involved in extracellular Different MMPs likely have different prognostic implications. [193–195]
matrix degradation. Implicated in adverse myocardial remodeling and Absolute plasma levels of MMPs as well as their change over time
coronary artery plaque destabilization after STEMI may both have important associations with LVEF.
Pharmacologic inhibition of MMPs after STEMI did not improve LV
remodeling or 90-day clinical outcomes
PAI-1 Protein released from platelets and vascular endothelium that neutralizes Large increases during the acute phase of a STEMI are associated [196,197]
tissue-type plasminogen activator and reduces the effectiveness with increased rates of 30-day CHF and mortality. Release may be
of fibrinolysis blunted by ACE inhibitors
IL-6 Proinflammatory cytokine that increases levels of CRP Elevated baseline levels correlate with elevated CRP and are [71,193,198]
associated with adverse 90-day outcomes, and a modest increase in
2-year and 3-year adverse outcomes
IL-10 Anti-inflammatory cytokine Lower levels after primary PCI associated with increased in-hospital [186,199]
Future Cardiol. (2011) 7(4)

death or heart failure, but elevated levels prior to PCI also associated
with increased 30-day mortality
SAA Hepatically produced acute-phase inflammatory protein Elevated levels at presentation are not independently associated [87,200]
with 5-year cardiovascular mortality, but elevated levels 24 h after
STEMI are associated with increased cardiac death and lower LVEF
at 6 months
MRP-8/14 Proinflammatory modulator of calcium signaling, arachidonic acid Elevated levels 30 days after ACS are associated with an increased [201]
metabolism and neutrophil trafficking risk of cardiovascular death or MI at 2 years
ACS: Acute coronary syndrome; CHF: Congestive heart failure; CRP: C-reactive protein; GFR: Glomerular filtration rate; IMA: Ischemia-modified albumin; LDL: Low-density lipoprotein; Lp PLA 2: Lipoprotein-associated
phospholipase A 2; LV: Left ventricle; LVEF: Left ventricular ejection fraction; MACE: Major adverse cardiovascular event; MI: Myocardial infarction; MMP: Matrix metalloproteinase; MPO: Myeloperoxidase;
MRP: Myeloid-related protein; OPG: Osteoprotegerin; PAI-1: Plasminogen activator inhibitor-1; PCI: Percutaneous coronary intervention; PTX: Pentraxin; RANK: Receptor activator of NF-kB; RANKL: Receptor activator of
NF-kB ligand; SAA: Serum amyloid A; sCD40L: Soluble CD40 ligand; STEMI: ST-elevation myocardial infarction; TpP: Thrombus precursor protein; TWEAK: TNF-like weak inducer of apoptosis.

Table 3. Other novel biomarkers in ST-elevation myocardial infarction (cont.).
Biomarker Biochemical role Outcomes assessed Ref.
TpP Soluble polymer of fibrin that is the precursor to insoluble fibrin clots Elevated levels correlate with increased 10-month composite of [202]
death, MI or recurrent ischemia requiring revascularization
Lp PLA 2 Pro- and anti-inflammatory mediator expressed in vulnerable Levels at 30 days but not at baseline are associated with increased [203]

atherosclerotic plaques cardiovascular risk. Levels decrease with statin therapy
PTX3 Inflammatory marker in the PTX family (including CRP) that is highly Elevated levels correlate with 3-month mortality better than levels [204,205]
expressed in cardiac endothelial cells and that may have of CRP
cardioprotective effects
OPG Decoy receptor for RANKL, which prevents binding of RANKL to its usual Elevated levels correlate with long-term mortality and [206]
receptor RANK. Implicated in atherosclerosis and inflammation hospitalization for CHF
Cystatin C Cysteine protease inhibitor, which is superior to creatinine as a surrogate Elevated levels correlate with increased in-hospital mortality and [207]
of GFR 6-month re-hospitalization for CHF
Soluble TWEAK Circulating member of the TNF family Elevated levels correlate with increased 30-day MACE [208]
CXCL16 Chemokine involved in the inflammatory response and uptake of Elevated levels correlate with increased death, CHF and [209]
oxidized LDL re-hospitalization for MI over 81 months
Fetuin-A Hepatically produced, anti-inflammatory glycoprotein Decreased levels correlate with increased 6-month mortality [210]
Myotrophin NF-kB modulating protein Elevated levels correlate with increased 1-year MACE [211]
ACS: Acute coronary syndrome; CHF: Congestive heart failure; CRP: C-reactive protein; GFR: Glomerular filtration rate; IMA: Ischemia-modified albumin; LDL: Low-density lipoprotein; Lp PLA 2: Lipoprotein-associated
phospholipase A 2; LV: Left ventricle; LVEF: Left ventricular ejection fraction; MACE: Major adverse cardiovascular event; MI: Myocardial infarction; MMP: Matrix metalloproteinase; MPO: Myeloperoxidase;
MRP: Myeloid-related protein; OPG: Osteoprotegerin; PAI-1: Plasminogen activator inhibitor-1; PCI: Percutaneous coronary intervention; PTX: Pentraxin; RANK: Receptor activator of NF-kB; RANKL: Receptor activator of
NF-kB ligand; SAA: Serum amyloid A; sCD40L: Soluble CD40 ligand; STEMI: ST-elevation myocardial infarction; TpP: Thrombus precursor protein; TWEAK: TNF-like weak inducer of apoptosis.
www.futuremedicine.com
Established & novel biomarkers in ST-elevation myocardial infarction
Review
537
median of 0.67 nmol/l had an approximate already decreasing by the time of admission,
threefold increase in the risk of death, recurrent and those with anterior MI and/or who had
MI, need for revascularization, CHF, syncope, less successful reperfusion were noted to have
or need for CPR, although MR-proADM lev- a second PAPP-A peak at 24–48 h. Patients
els at 4 months were not associated with worse with an admission PAPP-A >10 mIU/l had
outcomes [137] . significantly higher rates of cardiovascu-
There is interest in a potential therapeutic role lar death or nonfatal MI by 12 months (45
for ADM in MI, as experimental animal models vs 15–20%; p = 0.049), and patients with a
have demonstrated that ADM infusion can limit second, late peak in PAPP-A were also signifi-
infarct size and reperfusion injury [152–154] , and cantly more likely to have death or nonfatal MI
decrease pathologic cardiac remodeling after a in the following 12 months (53.8 vs 20.4%;
MI [155,156] . The first pilot human trial of ADM p = 0.016) [162] . In another study primar-
administration in 10 patients with STEMI was ily of STEMI patients treated with primary
recently carried out and was associated with PCI using a newer PAPP-A assay, levels were
reduced pulmonary capillary wedge pressure and elevated in 95% of patients presenting within
pulmonary artery pressures, increased cardiac 6 h of symptom onset or within 2 h of primary
index and improvement in infarct size and wall PCI. PAPP-A levels peaked approximately 6 h
motion in the infracted area of myocardium at after symptom onset, and about 40 min after
3 months of follow-up. These results should be PCI, before rapidly normalizing within 10 h
interpreted with caution, however, as there was [161] . PAPP-A levels rise significantly after PCI
no control group for comparison [157] . or fibrinolysis, but increase to a greater extent
with PCI possibly due to increased mechanical
Pregnancy-associated plasma protein A disruption of unstable/ruptured plaques [166] .
Pregnancy-associated plasma protein A In a study of 314 patients with STEMI, a
(PAPP-A) is a zinc-binding metalloproteinase PAPP-A in the highest quartile (>35.8 mIU/l)
originally identified in the sera of pregnant was associated with a HR of 2.19 (p = 0.02) for
women, which activates IGF-1 by degrading death, but there was no significant difference in
the IGF-1 inhibitors IGF-binding proteins 4 the rate of the composite of death or recurrent
and 5 [158] . PAPP-A is present in many tissues MI over a median follow-up of 3 years [167] .
throughout the body, has been implicated in Data suggest that treatment with high
the pathogenesis of atherosclerosis [158] , and is dose statins can reduce circulating levels of
highly expressed in unstable/recently ruptured, PAPP-A [168] , and human and animal data
but not in stable, coronary artery plaques [159,160] . suggest that use of heparin in the treatment of
IGF-1 is thought to mediate atherosclerosis by STEMI may increase circulating levels [163] . It
increasing smooth muscle migration, promot- appears that PAPP-A circulates differently in
ing the release of proinflammatory cytokines, ACS than in pregnancy, and this has signifi-
and increasing macrophage/foam cell uptake of cant implications for the development of newer
LDL cholesterol in atherosclerotic plaques [158] . PAPP-A assays [158] .
Levels of PAPP-A are higher in patients with
ACS (and in NSTEMI vs STEMI [161]) than in Other novel biomarkers
patients with stable angina or healthy controls, Numerous other markers of coagulation, inflam-
and are generally correlated with levels of CRP, mation and myocardial damage are currently
although not universally [159,162,163] . PAPP-A has being studied in STEMI and are summarized
been shown to be prognostic in patients with in Table 3. As with other novel biomarkers, their
MI [159,162,164] , although one study, using differ- role in STEMI and other disease states remains
ent assays for PAPP-A, has called into question to be clarified.
the utility of PAPP-A as a marker in the early
phase of STEMI [165] . Future perspective
The kinetics of PAPP-A release following a Cardiac biomarkers are integrated into clinical
STEMI were evaluated in 62 patients (87% of practice when they improve diagnosis, enhance
whom were reperfused, primarily with fibri- risk stratification, provide treatment implica-
nolytics) via serial monitoring of PAPP-A lev- tions, or can be used to monitor therapy. This
els. PAPP-A levels peaked 1 h after admission, is best illustrated by the case of troponin in
and then rapidly normalized within 12–24 h. non-ST-elevation ACS, where it is critical to
Patients with delayed presentations often diagnosis, carries important prognostic infor-
did not have a PAPP-A peak, as levels were mation and identifies a population of patients

who may benefit from an early invasive manage- Financial & competing interests disclosure
ment strategy. In STEMI, no cardiac biomarker Benjamin M Scirica has received research grants and
has demonstrated a similar degree of clinical honoraria from AstraZeneca, Daiichi-Sankyo, Merck,
utility, and measurement of biomarkers should Schering-Plough, Bristo-Myers Squibb, Johnson and
not delay rapid reperfusion therapy. In fact, the Johnson, Bayer Healthcare, Novartis and Gilead, and
12-lead ECG remains the most important ‘bio- is a consultant to or on the advisory board of Gilead,
marker’ in STEMI. Future research into the use Shionegii and Arena Pharmaceuticals. The authors
of biomarkers in STEMI are unlikely to funda- have no other relevant affiliations or financial involve-
mentally change the current paradigm regard- ment with any organization or entity with a financial
ing diagnosis and initial treatment strategies of interest in or financial conflict with the subject matter
STEMI, however, continued investigation may or materials discussed in the manuscript apart from
identify biomarkers that improve late prognosis those disclosed.
and that can then identify specific therapies that No writing assistance was utilized in the production
may modify that risk. of this manuscript.
Executive summary
n Current cardiac biomarkers have limited clinical utility in diagnosing an ST-elevation myocardial infarction (STEMI), but may be of
considerable use for both short and long-term risk stratification after a STEMI.
n Current guidelines recommend measurement of troponin in all patients with a STEMI, and consideration of measuring natriuretic
peptides and/or C-reactive protein.
n Over the last few years there has been explosive growth in the discovery and clinical application of novel cardiac biomarkers for risk
stratification in patients who have had a STEMI, but few have become firmly established in clinical practice and most are unlikely to
change the current paradigm regarding rapid diagnosis and initial treatment strategies.
n Novel cardiac biomarkers target a wide variety of surrogates for hemodynamic stress, coagulation, inflammation and myocardial
damage, but none are entirely specific to myocardial infarction.
n Novel cardiac biomarkers demonstrate the most promise in improving the ability of clinicians to estimate a patient’s risk of
complications after a STEMI, and in the future may allow clinicians to identify at-risk individuals and prescribe specific novel therapies to
modify this risk.
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Established and novel

Cardiac biomarkers assist in the diagnosis of and risk stratification in acute

Despite considerable advances in the manage- cTn

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changes in gene expression and has a different

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