cardiac bio markers are important diagnostic and prognostic tool in acute coronary syndrome. several new emerging bio markers are coming with more sensitivity and specificity.

1. CARDIAC
BIOMARKERS IN
ACS
DR MAHENDRA
CARDIOLOGY,JIPMER
1

2. Biomarker- definition
 “A characteristic that is objectively measured and evaluated as an indicator
of normal biological processes or pharmacologic responses to a
therapeutic intervention”
 Specificity- 1. Analytical specificity 2. Diagnostic specificity1
 Analytical specificity of a biochemical marker depends not only on avoiding
any methodological cross reactivity with other biologically related
molecules, but also on biological characteristics of the marker as well,
showing no other tissue sources, even in trace amounts or under
pathological conditions, in addition to the anatomic or histologic target
1.Saah AJ et al, Ann Intern Med 126:91-94; 1997
2

3. Ahmad MI et al, Biomarkers in Acute Myocardial Infarction. J Clin Exp Cardiolog 3:222 ;2012
3

4. Timeline of development of cardiac
biomarkers for ACS
Pankaj G, et al. Intern Emerg Med 12:147–155; 2017
4

5. 5

6. 6

7. TROPONINS
 Proteins that regulate interaction between actin and myosin in cardiac and
skeletal muscle
 Troponin C – synthesized in both cardiac and skeletal muscle
 Troponin I and Troponin T isoforms- highly specific and sensitive to cardiac
myocytes, so known as cardiac troponins(cTn)
 Plasma half life of cTn- 2 hours
 92-95% troponin attached to actin thin filament of sarcomere and only 5-
8% remain unbound in cytoplasm
 Unbound cTn- Early releasable Troponin Pool (ERTP)- immediately
released following myocyte injury
7

8.  cTn subunits are detectable in the peripheral circulation when damage to
the cardiac myocyte first leads to the release of cytoplasmic cTn, which
accounts for 3% to 5% of cTnI and 7% of cTnT levels
 Latency period for necrosis and troponin release is 2 hours, so needs to be
repeated at 6-9 hours interval
 Reaches peak concentration in 12-24 hours
 cTn remains detectable for days (4–7 days for cTnI and 10–14 days for
cTnT)
 Cleared by reticuloendothelial system
8

9.  Measurement of troponin in blood has a dual role:
1. abnormally high concentrations are indicative of AMI
2. mildly abnormal concentrations suggest increased short-term risk
for a future cardiac event
 Independent predictor of early postoperative cardiovascular complications
following non-cardiac surgery and early predictor of short-term mortality in
vascular surgery patients as well as a predictor of MI and death after
CABG
9

10. 10
Antman EM, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary
syndromes. N Engl J Med 1996;335:1342-9

11. Falahati A et al, Implementation of serum cardiac troponin I as marker for detection of acute
myocardial infarction. Am Heart J 137(2):332-7; 1999
11

12. Highly sensitive troponin
 The definition of high-sensitivity cTn is not clearly established, but last
generation assays can detect cTn in approximately 95% of normal
individuals
 New 5th generation hs-cTn T and I assays which can detect troponin at
concentrations 10- to 100-fold lower than conventional assays
 Increases the sensitivity of cTn in the first few hours after coronary
occlusion
 The negative predictive value(NPV)of hs-cTn assays is 95% for AMI
exclusion when patients are tested on arrival at the ED
 These hs-cTn assays have allowed the diagnostic cutoff to be lowered to
the level of the 99th percentile or lower while maintaining precision at a CV
of <10%
12

13. 13
Pankaj G, et al. Intern Emerg Med 12:147–155; 2017

14. 14

15. 15
Pankaj G, et al. Intern Emerg Med 12:147–155; 2017

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D. del Val Martin et al. / IJC Metabolic & Endocrine 8 (2015) 20–23

17. CK-MB
 Cardiac muscle has higher CKMB levels (25–30%) compared with skeletal
muscle (1%), which is mostly CKMM
 Measurement of CKMB, CKMB fraction or CKMB/CKMM ratio was a more
specifIc marker for AMI
 The initial CK-MB rise occurs 4 to 9 hours after the onset of chest pain
induced by myocardial injury
 The level peaks at 24 hours, and returns to baseline at 48 to 72 hours
 One advantage of CK-MB over other markers is that it remains elevated
for longer periods and it is easier to detect reinfarction using serial CK-MB
measurements
17

18. Myoglobin
 Small cytoplasmic heme protein found in all muscles
 Earliest marker to rise after AMI (2hrs from onset of chest pain)due to its
small size and high cytoplasmic content
 Increases within 1 to 3 hrs in the setting of myocardial necrosis, peaks
within 6 to 9 hrs, and may become normal in 24 hrs
 A single myoglobin measurement at presentation has been shown to have
a sensitivity of 70% and a NPV of 97.4% for predicting AMI among patients
with suspected ACS
 Myoglobin has limited specificity for myocardial necrosis in patients who
have renal insufficiency and skeletal muscle trauma
18

19. 19
Chan and Ng BMC Medicine 2010, 8:34

20. H-FABP
 Heart-type fatty acid-binding protein (H-FABP) is a cytosolic, low-
molecular-weight protein involved in fatty acid transport and metabolism
 Although it is expressed in high levels in the myocardium, small quantities
also can be found in the brain, kidney, and skeletal muscle
 H-FABP displays a very early raise after an AMI (i.e., increased
concentrations can be detected as soon as 30 min after the onset of an
ischemic episode)
 Peaks in blood after ~6–8 hrs and returns to baseline values after 24–30
hrs
 It is unsuitable as a test for patients presenting >6 hrs from onset of
symptoms due to rapid renal clearance

20

21.  H-FABP has also been shown to independently predict mortality in patients
with ACS
 When added to troponin for risk stratification, a negative troponin and H-
FABP level < 5.8 mcg/L was associated with zero mortality at six months1
 A negative troponin but H-FABP level > 5.8 mcg/L was associated with a
4.93-fold increase in risk of death and 7.93-fold increase in risk if troponin
was positive and H-FABP > 5.8 mcg/L
21
1.Kilcullen N et al, J Am Coll Cardiol 2007, 50:2061-2067

22. ISCHAEMIA MODIFIED ALBUMIN
 On exposure to ischemic conditions, the N-terminus of albumin is
damaged, which makes it unable to bind metals
 IMA levels in the blood increase within minutes of the onset of ischemia
and return to normal within 6–12 hrs
 So, IMA has been implicated in the detection of acute ischemia prior to
necrosis
 One study of patients with suspected ACS found that IMA had a better
NPV for ACS of 92% than the combination of CK-MB, myoglobin, and
cTnT (86%), and the use of all 4 biomarkers together resulted in an NPV of
95% 1
22
1. Lee YW et al, Clin Chim Acta. 2007 Sep;384(1-2):24-7

23. CRP
 Acute phase protein produced by the hepatocyted in response to
stimulation by IL-6
 High CRP levels (10–15 mg/L)  strong indicator of long-term future
cardiac events
 In patients with MI treated with thrombolysis, high CRP levels (226 mg/L)
 associated with an increased risk of death within the first 6 months of
the infarct event
 In NSTEMI, increased CRP values are independent prognostic markers of
recurrent nonfatal myocardial infarction or cardiac death (GUSTO IV,
PROVE IT-TIMI 22)
23

24. Pro-inflammatory markers
 IL-6 and TNF-α
 Ischemia and reperfusion of infarcted myocardium results in induction of
these cytokines
 IL-6 negative inotropic effect mediated through myocardial nitric oxide
synthase
 TNF-α  cardio-inhibitory cytokine that depresses cardiac contractility
either directly or through induction of nitric oxide synthase.
24

25. Markers of plaque destabilization
 Metalloproteinases- Myeloperoxidase and PaPPA
 In post-acute coronary syndrome  MPO levels higher than median
predicted future death and MI at one year
 After an AMI, MPO levels peak early, then decrease over time and do not
correlate with troponin or the neutrophil count
 It is not affected by fibrinolytic therapy
 PaPPA  proatherosclerotic metalloproteinase which is highly expressed
in unstable plaques and their extracellular matrices
 PaPPA > 2.9 mIU/L predicts a 4.6- fold increase in risk of cardiovascular
death, MI or revascularisation even without a raised troponin
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26. Markers of myocyte rupture
 CD40L is a cytokine belonging to the TNF-α family and CD40 is its
receptor
 CD40L is up-regulated on platelets within fresh thrombus
 Platelet derived growth factor(PDGF)
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27. GDF-15
 GDF-15 is a stress-responsive member of the transforming growth factor-b
cytokine superfamily
 High levels of GDF-15 have been found to be an independent predictor for
yearly mortality rate and the use of invasive strategy, and they add
prognostic value to current cardiac biomarkers, including BNP, cTnT, and
TIMI score
 GDF-15 is not specific for cardiovascular disorders and has been found to
be elevated in a variety of malignancies (prostate, colon, glial)
27

28. 28

29. COPEPTIN
 Copeptin is the more stable surrogate of arginine vasopressin (AVP)
 Post AMI, vasopressin  (1) increases peripheral vasoconstrictor activity
thus increasing afterload and ventricular stress
(2) increases protein synthesis in myocytes leading to hypertrophy
(3) vasoconstriction of coronary arteries
 At presentation, copeptin level of < 14 pg/ml and a Trop T level of < 0.01
 rules out a myocardial infarction with NPV of 99.7%
 CHOPIN trial Adding copeptin to cTnI allowed safe rule out of AMI with a
NPV of99% in patients presenting early with a suspected ACS
 Lack of specificity (elevated in sepsis)
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30. CYSTATIN-C
 Cysteine protease inhibitor involved in the catabolism of proteins
 This protein is synthesized in all nucleated cells at a constant rate, and is
freely filtered by the glomerulus with no reabsorption into the blood
 Cystatin C is less influenced by other factors like diet, muscle mass, or
body constitution
 Measurement of cystatin-C substantially improves the early risk
stratification of a large population with suspected or confirmed non-ST
elevation ACS
 More recent studies confirm that cystatin-C concentration is independently
correlated with cardiovascular risk, including myocardial infarction and
cardiovascular death
30
Jernberg T et al, Circulation. 2004;110:2342-2348

31. 31
Jernberg T et al, Circulation. 2004;110:2342-2348

32. Neutrophil gelatinase-associated
lipocalin (NGAL)
 NGAL is a glycoprotein of 25 kDa
 Serum NGAL level was significantly higher in the NSTE-ACS group
compared to the control group (112.3±49.6 ng/mL vs. 58.1±24.3 ng/mL,
p<0.001)
 There was a significant positive correlation between serum NGAL levels
and the GRACE (r=0.533 and p<0.001), SYNTAX (r=0.395 and p=0.006),
and Gensini risk scores (r=0.575 and p<0.001)
 The intermediate-high SYNTAX (>22) group had statistically significantly
higher serum NGAL levels compared to the low SYNTAX (≤22) group
(143±29.5 ng/mL vs. 98.7±43.2 ng/mL, p=0.001)
32
Soylu et al. Serum NGAL level in NSTE-ACS, Anatol J Cardiol 2015; 15: 450-5

33. Micro RNAs
 MicroRNAs (miRNAs) are non-coding RNA fragments of 22 nucleotides
with a key role in the regulation of mRNA coding for key proteins in the
maintenance of cell integrity
 Levels of miR-1, -133a, -133b, and miR-499-5p  increased in the hours
following infarction
 miR-122 and miR-375 decreased in their plasma levels
33
D'Alessandra et al .Eur Heart J (2010) 31 (22) 2765-2773

34. OTHER MARKERS
 Choline  enzymatic product of phospholipase D
 Phospholipase D, is involved in endothelial dysfunction, and is considered
a marker of plaque instability, as well as a marker of severe myocardial
ischemia, and has been associated with elements of the metabolic
syndrome
 F2 isoprostanes  biologically active product of arachidonic acid
metabolism
 Elevated levels found in smokers, dyslipidemia, unstable angina
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35.  Point of care cardiac markers:
If standard laboratory testing exceeds a maximum 60-minute turn-
around time (the average being 65–128 min) or 25% of decision time, then a
POC device (with an average turn-around time of 15–26.5 min) should be
implemented
 Current AHA guidelines for cTn measurement recommend testing on
presentation and again at 8–12 hrs post symptom onset
 National Academy of Clinical Biochemistry recommends an early marker at
0–6 hrs and a definitive marker at 6–9 hrs post-presentation
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36. 36
Roffi M, et al (2015) 2015 ESC Guidelines for the management of acute coronary syndromes in
patients presenting without persistent ST-segment elevation. Eur Heart J 37:ehv320

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