CARDIAC BIOMARKERS IN MI

Dr. Ishrat Rawoot

INTRODUCTION
• Biomarkers - biological parameters that can be
objectively measured and quantified as
indicators of normal biologic processes,
pathogenic processes, or responses to a
therapeutic intervention.
• Typically thought of as disease process
screening, diagnosing, or monitoring tools,
biomarkers may also be used to determine
disease susceptibility and eligibility for specific
therapies.
CARDIAC BIOMARKERS
• Cardiac biomarkers - protein components of cell
structures that are released into circulation when
myocardial injury occurs.
• Play a pivotal role in the diagnosis, risk
stratification, and treatment of patients with chest
pain and suspected acute coronary syndrome (ACS)
as well as those with acute exacerbations of heart
failure.
• Central to the new definition of acute myocardial
infarction (AMI) put forward by the American
College of Cardiology and the European Society of
Cardiology.
CHARACTERISTICS OF AN IDEAL CARDIAC MARKER
• High sensitivity: Abundant in cardiac tissue
• High specificity: Absent from non-myocardial tissue Not
detectable in blood from non-diseased subjects
• Release: Rapid release for early diagnosis
Long half-life in blood for late diagnosis
• Analytical: Cost effective
Short turnaround
time Precise
Accurate
• Clinical : Ability to influence therapy and so improve
patient outcome
Validated by clinical studies
Categories of Biomarkers of Cardiovascular Risk*
Biomarkers associated with various pathophysiological
processes associated with acute myocardial infarction.
CLINICAL UTILITY-BASED CLASSIFICATION OF CARDIAC
BIOMARKERS
GLYCOGEN PHOSPORYLASE ISOENZYME BB
• Glycogen phosphorylase (GP) catalyses the first step
in glycogenolysis in which glycogen is converted to
glucose- 1-phosphate, utilizing inorganic phosphate.
• The physiological form of GP is a dimer, which is
composed of two identical subunits.
• Three different GP isoenzymes have
been described in human tissues: GPLL (liver),
GPMM(muscle), and GPBB (brain).
• Although isoenzymes BB and MM are found in the
heart, GPBB is predominant.
• However, tissue concentrations of GPBB in the heart
and brain are comparable raising issues with
specificity.
GLYCOGEN PHOSPORYLASE ISOENZYME BB
• In cardiomyocytes, GP is a/w glycogen and the
sarcoplasmatic reticulum and forms a macromolecular
complex, the sarcoplasmatic reticulum glycogenolysis
complex.
• With the onset of tissue hypoxia, GP is thereby converted
from a particulate, structurally bound form into a soluble,
cytoplasmatic form.
• A high GPBB concentration gradient is immediately
formed in the perisarcoplasmatic reticulum compartment
and GPBB is released from cardiomyocytes upon an
increase in the cell membrane permeability.
• Early marker for detection of ischemic myocardial
damage. GPBB levels increase between 1 - 4h from chest
pain onset and return to the reference interval within 1–2
days after AMI onset.
 FATTY ACID BINDING PROTEIN
• FABPs are relatively small (15kDa) intracellular proteins,
abundantly produced in tissues having active fatty acid
metabolism - heart, liver, intestine.
• Bind long-chain fatty acids reversibly and noncovalently.
• The H-FABP isoform produced mainly in cardiomyocytes
also, to a lesser extent, in skeletal muscle, distal tubular
cells of the kidney, specific parts of the brain, lactating
mammary glands, and placenta .
• Not found in circulation (plasma concentration <5 μg/l)
under nonpathological conditions.
• H-FABP secretion into the interstitial space may be
mediated by increased permeability of the myocardial
cell membrane associated with severe ischemia.
FATTY ACID BINDING PROTEIN
• Sequential H-FABP monitoring by only two samples,
at admission and 1h after admission, can reliably
diagnose AMI within 1h.
• In addition, 100% of non-AMI can be excluded with
no false-negative results.
• LIMITATIONS:
- lack of complete cardiac specificity,
- relatively small diagnostic window of 24–30h after
the acute event,
- probability of falsely increased values in patients
with renal insufficiency.
ISCHEMIA-MODIFIED ALBUMIN
• Albumin loses its ability to bind transitional metals like
copper, cobalt, nickel in its N terminus region as it
undergoes conformational change because of ischemia.
• This alteration most likely caused by hypoxia, acidosis, free
radical injury or energy-dependent membrane disruption.
• This decrease in binding capacity can be measured by
addition of a specified amount of cobalt to the patient’s
serum followed by a colorimetric assay that determines the
amount of unbound cobalt.
• This assay reported to be positive within minutes of
ischemia, peaking within 6h, and remains elevated for up
to 12h, thus allowing detection before the development of
myocardial necrosis [as evidenced by normal levels of
creatinine kinase isoenzyme (CK-MB), troponin and,
myoglobin]
ISCHEMIA-MODIFIED ALBUMIN
• The albumin cobalt binding test has been approved by the
FDA for use as a rule-out marker for acute myocardial
ischemia.
• The optimum cut-off for IMA, for ruling out ACS, is
85kU/l and the higher values of 100kU/l or more can be
used for risk stratification.
• Studies on the use of IMA in patients with chest pain in
the ED have found sensitivities that ranged from 71 to
98%, and specificities of 45–65%, with a NPV of 90–
97% for ACS.
• Thus, the main limitation of IMA at the present
time is its low specificity.
 MYOGLOBIN
• Heme protein found in all striated muscle fibers, accounts
for about 2% of both skeletal and cardiac tissue mass.
• Due to small molecular weight, it is rapidly released
during skeletal muscle injury and cardiac tissue
necrosis.
• This is unlike larger molecules like creatine kinase and its
isoform CK-MB (released more slowly after an AMI).
• Myoglobin typically rises 2–4 h after onset of infarction,
peaks at 6–12 h, and returns to normal within 24–36 h.
• Released in a pulsatile manner, so serial testing with
early presentation may be needed.
• Has an excellent Negative Predictive Value (99.9 vs.
95% for CK-MB) if determined early enough to onset of
symptoms, generally within the first hour.
 MYOGLOBIN
• Level at which myoglobin becomes indicative of an AMI,
ranges from 50 - to 120 mg/ml.
• Lacks cardiospecificity as many noncardiac-related
factors, such as skeletal muscle or neuromuscular
disorders, strenuous exercise, renal failure, intramuscular
injections, and CABG, can elevate serum myoglobin levels.
• Specificity of myoglobin tests in the ∆sis of AMI can be
increased by monitoring an additional marker, carbonic
anhydrase III (CA-III).
• Normal range for CA-III is 13–29 mg/l. A serum myoglobin
concentration > 110 mg/l together with a myoglobin/CA-
III ratio ≥ 3.21 is considered abnormal and indicative of
AMI.
• Although myoglobin is not the perfect cardiac marker for
diagnosing AMI, it is the earliest significant indicator of
breakdown of myocardial cells.
CK-MB
• CK-MB has 3 dimeric isoenzymescomprising total
CK activity; CK-MM, CK-MB,and CK-BB isoenzymes,
of which CK-MB is mainly cardiac specific.
• While CK-MM is predominantly seen with striated
muscle and myocardium, CK-MB only constitutes 0–3%
of CK in skeletal muscle and is elevated in myocardial
disease.
• CK-MB isoenzyme comprises around 20% of total CK
in myocardial tissue damage versus that of normal
individuals whereby one would find it constituting
around 1% in this tissue)
CK-MB
• The relative index calculated by the ratio of CK-
MB (mass)/total CK x 100 can assist in
differentiating false-positive elevations of CK-MB
arising from skeletal muscle (such as in muscular
dystrophy or crush injury) and renal failure.
• Relative index - useful only when both total CK
and CK-MB levels are increased.
• Ratio < 3 - consistent with skeletal muscle source.
• Ratio > 5 - indicative of a cardiac source.
• Ratio between 3 and 5 represent a gray zone. No
definitive diagnosis can be established without serial
determinations to detect a rise.
CK-MB
• One advantage of CK-MB is a shorter half-life in the
circulation - useful for gauging the timing of an MI (a
normal CK-MB with an elevated troponin level could
represent a small MI or an MI that occurred several
days ago)
• For diagnosing reinfarction in a patient who had an MI
in the past week.
CARDIAC TROPONINS
• Troponin is a complex of three regulatory proteins,
namely TnC (18 kD), TnI (26 kD), and TnT (39 kD),
that form the thin filaments of muscle fibers and
regulate the movement of contractile proteins in muscle
tissue.
• For both cTnT and cTnI, the definition of an abnormally
increased level is a value exceeding that of 99% of a
reference control group.
• Assays that have a level of imprecision (i.e., coefficient
of variation) < 10% at the specific 99th percentile cut
off are optimal for clinical practice.
• In patients with MI, cTnT and cTnI first begin to rise by
approximately 3 hours after the onset of chest pain.
STRUCTURE OF THE
CARDIAC TROPONIN-
TROPOMYOSIN COMPLEX
AND THE FORMS OF
TROPONIN RELEASED
FOLLOWING
MYOCARDIAL NECROSIS.
Whilst most cardiac troponin (cTn) is
bound to the myofibril, ~2–4% and ~
6–8% of cTnI and cTnT respectively
exist either unbound in the cytosol,
or loosely bound to sarcomere.
cTnT primarily appears in blood
as a mixture of free-forms and
the T:I:C ternary complex, whilst
cTnI appears predominantly as
the I:C binary complex.
CARDIAC TROPONINS
• Genes encoding skeletal and cardiac isoforms of TnC
are identical; thus, no structural difference exists
between them.
• However, the skeletal and cardiac subforms for TnI and
TnT are distinct, and immunoassays have been designed
to differentiate between them with no cross-reactivity.
CARDIAC TROPONINS
• Because of continuous release from a degenerating
contractile apparatus in necrotic myocytes, elevations in
cTnI may persist for 7 to 10 days after MI; elevations in
cTnT may persist for up to 10 to 14 days.
• Lack of standardization between cTnI assays means test
results from different assays are not comparable, leading
to a debate regarding the application of cut-off points
and their subsequent interpretation.
• Assays for cTnT have a sensitivity of up to 100% for
myocardial damage within 4–6 h after an AMI, and for
cTnI have a sensitivity of up to 100% by 6 h after an
AMI
ROLE OF TROPONINS IN RENAL FAILURE

• Troponins are the biomarker of choice for detecting

cardiac injury in patients with renal failure, including
those with end-stage renal disease (ESRD) receiving
long-term dialysis.
• The Global Use of Strategies to Open Occluded
Coronary ArteriesIV (GUSTO-IV) trial found that
elevated troponin levels predicted short-term prognosis
regardless of creatinine clearance.
• Patients of ESRD with elevated troponin levels had an
increased risk of death after 1, 2, and 3 years of follow-
up, and increases in troponin levels in ESRD patients
showed a 2- to 5-fold increase in mortality.
SALIENT FEATURES OF TROPONIN
• Fast results and diagnosis
• Improved diagnostic sensitivity and specificity.
• Prognostic indicator
• Detects perioperative MI
• Can predict cardiovascular risk
• Useful in detecting reinfarction
• Point of care availability
• Useful as a single marker
The 99th percentile diagnostic cut-off for cardiac troponin (cTn) assays. A hypothetical case of an acute
coronary syndrome is shown to illustrate the evolution of cTn assay precision and sensitivity. The
diagnostic cut-off for cTnI assays in 1995 was ≥ 1.5 ng/mL, in 2003 > 0.10 ng/mL and in 2007 > 0.04 ng/mL.
The increasing sensitivity of the assays meant that very small concentrations of cTn could be detected,
thus the 99th percentile decision limit had to be lowered. The 99th percentile quantitatively represents a
value at which 1 person in 100 will have a false positive result. Any concentration of cTn detected within
the 99th percentile decision limit suggests a ‘normal’ result. Any concentration value which falls outside
this decision limit indicates a ‘positive’ cTn and substantiates a possible AMI.
When patients with STEMI undergo reperfusion, as depicted in the
dashed blue and red curves, the cardiac biomarkers are detected
sooner and rise to a higher peak value but decline more rapidly, which
results in a smaller area under the curve and limitation of infarct size.
Biochemical Markers of Myocardial Necrosis
CRITERIA FOR MYOCARDIAL INJURY
The term myocardial injury should be used when there is evidence of elevated
cardiac troponin values (cTn) with at least one value above the 99 th percentile
upper reference limit (URL). The myocardial injury is considered acute if there
is a rise and/or fall of cTn values.
 CLINICAL CLASSIFICATION OF
MYOCARDIAL NFARCTION
based on pathological, clinical, and prognostic differences,
along with different treatment strategies.

Myocardial Myocardial Myocardial Myocardial Myocardial

infarction type 1 infarction type 2 infarction type 3 infarction type 4 infarction type 5

Type 4a

Type 4b

Type 4c
MYOCARDIAL INFARCTION TYPE 1
• MI caused by atherothrombotic coronary artery disease (CAD)
and usually precipitated by atherosclerotic plaque disruption
(rupture or erosion) is designated as a type 1 MI.
 MYOCARDIAL INFARCTION TYPE 2
• The pathophysiological mechanism
leading to ischaemic myocardial
injury in the context of a mismatch
between oxygen supply and demand
has been classified as type 2 MI .
• By definition, acute atherothrombotic
plaque disruption is not a feature of
type 2 MI.
• In pts with stable known or presumed
CAD, an acute stressor such as an
acute GI bleed with a precipitous drop
in Hb, or a sustained tachyarrhythmia
with clinical manifestations of
myocardial ischaemia, may result in
myocardial injury and a type 2 MI.
MYOCARDIAL INFARCTION TYPE 3
• Patients can manifest a typical presentation of myocardial
ischaemia/infarction, including presumed new ischaemic ECG
changes or ventricular fibrillation, and die before it is possible to
obtain blood for cardiac biomarker determination; or
• the patient may succumb soon after the onset of symptoms before
an elevation of biomarker values has occurred. Such patients are
designated as having a type 3 MI, when suspicion for an acute
myocardial ischaemic event is high, even when cardiac biomarker
evidence of MI is lacking.
 CRITERIA FOR PCI-RELATED MI ≤48 h AFTER THE INDEX
PROCEDURE (TYPE 4A MI)
• Coronary intervention-related MI is arbitrarily defined by an elevation of cTn
values > 5 times the 99th percentile URL in pts with normal baseline values.
• In pts with elevated pre-procedure cTn in whom cTn level are stable (≤
20% variation) or falling, postprocedure cTn must rise by >20%. However,
absolute post-procedural value must still be at least five times the 99th
percentile URL. In addition, one of the following elements is required:
 New ischaemic ECG changes;
 Development of new pathological Q wavesa
 Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality in a pattern consistent with an ischaemic aetiology;
 Angiographic findings consistent with a procedural flow-limiting complication
such as coronary dissection, occlusion of a major epicardial artery or a side
branch occlusion/thrombus, disruption of collateral flow, or distal
embolization.b
 STENT/SCAFFOLD THROMBOSIS ASSOCIATED
WITH PERCUTANEOUS CORONARY INTERVENTION
(TYPE 4B MYOCARDIAL INFARCTION)
• A subcategory of PCI-related MI is stent/scaffold thrombosis, type 4b MI, as
documented by angiography or autopsy using the same criteria utilized for
type 1 MI.
• It is important to indicate the time of the occurrence of the stent/scaffold
thrombosis in relation to the timing of the PCI procedure.
• The following temporal categories are suggested: acute, 0–24 h; subacute, >
24 h to 30 days; late, > 30 days to 1 year; and very late > 1 year after stent/
scaffold implantation
 RESTENOSIS ASSOCIATED WITH PERCUTANEOUS
CORONARY INTERVENTION (TYPE 4C MYOCARDIAL
INFARCTION)
• Occasionally MI occurs and—at angiography, in-stent restenosis, or
restenosis following balloon angioplasty in the infarct territory—is the
only angiographic explanation since no other culprit lesion or
thrombus can be identified.
• This PCI-related MI type is designated as type 4c MI, defined as focal
or diffuse restenosis, or a complex lesion associated with a rise and/or
fall of cTn values above the 99th percentile URL applying, the same
criteria utilized for type 1 MI.
MYOCARDIAL INFARCTION ASSOCIATED WITH CABG
(TYPE 5 MYOCARDIAL INFARCTION)
• It should be recognized that ST-
segment deviation and T wave
changes are common after CABG due
to epicardial injury - not reliable.
• ST-segment elevation with reciprocal
ST-segment depression or other
specific ECG patterns - more reliable
finding of potential ischaemic event.
• Marked isolated elevation of cTn
values within the 48 h post-op period,
even in the absence of ECG/angio or
other imaging evidence of MI,
indicates prognostically significant
cardiac procedural myocardial injury.
RECURRENT MYOCARDIAL INFARCTION

• Incident MI is defined as the individual’s first MI. When features of

MI occur in the first 28 days after an incident
event, the second event is not counted as a new MI for
epidemiological purposes.
• If characteristics of MI occur after 28 days following an incident MI,
it is considered to be a recurrent MI.
 RE -INFARCTION
• The term re-infarction is used clinically for an acute MI that occurs within
28 days of an incident or recurrent MI.
• Should be considered when ST elevation ≥1 mm recurs or new
pathognomonic Q waves appear in at least two contiguous leads,
particularly when a/w ischaemic symptoms.
• Re-elevation of ST can also be seen in threatened myocardial rupture or in
cases of pericarditis, and should lead to additional diagnostic evaluation.
• If re-infarction suspected from clinical signs or symptoms following the
initial MI, an immediate measurement of cTn is recommended.
• 2nd sample to be taken 3–6 h later or, earlier with more sensitive cTn assays.
• If the cTn concentration elevated, but stable or decreasing at the time of
suspected re-infarction, the diagnosis of re-infarction requires a > 20%
increase of the cTn value in the second sample. If the initial cTn conc is
normal, the criteria for new acute MI apply.
High-sensitivity cardiac troponin as a quantitative marker. AMI acute myocardial
infarction, CAD coronary artery disease, CHF congestive heart failure, HI healthy individual, LVH left
ventricular hypertrophy, PEpulmonary embolus, SAB Staphylococcus aureus bacteraemia. The lower
the level of hs-cTn, the higher the negative predictive value (NPV) for the presence of AMI. The
higher the level of hs-cTn, the higher the positive predictive value (PPV) for the presence of AMI.
Levels just above the 99th percentile have a low PPV for AM
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