CARDIAC BIOMARKERS

BY
DR. FARYAL HUSNAIN
PGR CHEMICAL PATHOLOGY

10/18/20 10:19 AM
AMI
 Acute myocardial infarction (AMI) is one of the major causes of
mortality and morbidity worldwide
 About 10% of patients who are admitted to emergency departments with
chest pain every year are diagnosed with heart attack.
 AMI is a condition that can be due to ischemic heart disease or coronary
artery disease in conjunction, and it becomes manifest when an
atherosclerotic plate ruptures and a developing thrombus occludes the
coronary artery totally or partially, restricting blood access to the heart
 NEW CRITERIA

Based on ESC/ACC’s redefinition of MI (2017)

Typical rise and fall of Troponin or CKMB with one of the
following:
 Symptoms of acute myocardial ischemia;
 New ischemic electrocardiographic (ECG) changes;
 Development of pathological Q waves;
 Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality in a pattern consistent with an ischemic etiology;
 Identification of a coronary thrombus by angiography including intracoronary
imaging or by autopsy.
 IDEAL MARKER TO DETECT
AMI
High concentration in myocardium
Absence from non-myocardial tissues
High sensitivity & specificity in circulation
Rapid release into blood following myocardial injury
Remains in blood several days to allow detection
Blood levels correlate with extent of myocardial injury &
prognosis
Rapid, simple & automated commercial assays available
 OLDER BIOMARKERS
 LDH
 Used in the past along with aminotransferases to diagnose AMI. LD is non-
specific for cardiac tissue, which contains LDH. However, pancreas, kidney,
stomach tissue and red cells also contain LDH. In the setting of AMI, LD rises at
about 10 hours, peaks at 24-48 hours, and remains elevated for up to 8 days.
 False positives are not uncommon in the measurement of LDH and its
isoenzymes. Major pitfalls include hemolysis of the blood sample, hepatic
congestion due to CHF, and skeletal muscle damage
OLDER BIOMARKERS
 ALT/AST
 Used as surrogate markers of cellular damage in the past. Very non-
specific so not used for assessment of myocardial damage any longer
 H-FABP
 Heart-type fatty acid binding protein
 Kinetically similar to myoglobin but more specific to cardiac tissue
which contains a greater percentage of this protein than skeletal muscle
 Current studies ongoing to further evaluate its utility
CREATINE KINASE
 Creatine kinase (CK/CPK) is an enzyme expressed in a
number of tissues. It catalyzes the reversible transfer of
high-energy phosphate from ATP to creatine, facilitating
storage of energy in the form of phosphocreatine.
CKMB
 The CK enzyme consists of two subunits, B (brain type) or
M (muscle type), Making three different isoenzymes: CK-
MM, CK-BB and CK-MB
 CK-MM found mostly in skeletal muscles
 CK-MB found mostly in the heart muscle
 CK-BB found mostly in brain tissue
 CK-MB is found in cardiac muscle and is used as a Cardiac
biomarker
CK-MB
 Increases 4-6 hours after onset of MI
 Peak activity is at 18 to 24 hours
 Usually has returned to baseline levels by 36 hours
CK-MB
 Determination of CK–MB isoenzyme has a 98% predictive value for
myocardial necrosis with a positive enzyme profile and a 100% negative
predictive value for the absence of necrosis with a normal profile.
 The clinician must have access to a quality-controlled laboratory
capable of determining CK and CK–MB isoenzymes rapidly and with
an acceptable degree of reproducibility.
 Because of the short serum half-life of CK–MB, blood sampling must
begin within 48 hours (and preferably within 24 hours) of symptoms.
 Serum sampling should be obtained at first contact and at 8- to 12-hour
intervals for 48 hours to observe the characteristic appearance, peak,
and disappearance of CK– MB. Serial sampling is emphasized and
single values in the emergency room setting are inadequate to exclude
myocardial injury.
CK-MB
 Patients seen more than 48 hours after symptoms
should have determination of lactic dehydrogenase
 Clinical judgment must be exercised in the rare
instance where CK–MB is elevated in the absence
of obvious myocardial necrosis.
CK-MB
 When the diagnosis of acute MI is strongly entertained,
CK–MB levels should be determined in spite of normal CK
levels. Small infarctions may release significant levels of
CK–MB with normal total CK.
 Because of the rapid rise and fall of CK–MB levels after a
myocardial infarction, it is useful to sample CK–MB again
at 8- to 12-hour intervals following recurrent post-MI chest
pain in order to detect infarct extension.
CK-MB
 False positive (for MI) CK-MB elevation can be seen in:
 Significant skeletal muscle injury
 *Cardiac injury for reason other than MI
 Cardioversion, Defibrillation
 Blunt chest trauma (Sports injuries)
 Cardiac AND non-cardiac surgical procedures
 Cocaine abuse (vasospasm, tachycardia, perfusion/demand mismatch)
 Not often elevated in myocarditis, unless severe
 Significant CNS damage (Stroke/Trauma)
CK-MB
False Positive also seen in:
Marathon runners
Chronic renal failure
Hypothyroidism
 LIMITATION OF CKMB
FP incidents in perioperative patients without
cardiac injury
MI detection not timely enough for thrombolytic
intervention. MB peaking takes >12h
 MB INDEX

MB Index = (CKMB /total CK) x 100

Rationale for using MB Index
Using CKMB alone often yields False Positive
results
Combined use with MB Index helps to rule-out
patients with skeletal muscle injury
Recommended Cut Off: 6%
 MYOGLOBIN AS CARDIAC
MARKER

Small-size heme protein released from all

damaged tissues. Increases often occur
more rapidly than TI and CK. Not utilized
often for AMI/cardiac damage assessment
because of its very rapid metabolism (short
plasma half-life) causing short burst
increases that are difficult to assess
clinically, as well as its lack of specificity
for cardiac tissue.
MYOGLOBIN & CKMB IN TYPICAL
MI

3 samples drawn within 2 h

240 120 300 240

Myo 220
210 Myo 105 270
CKMB 200
CKMB 240
Myo (n g /m L )

180 90 180
Myo = 45 at 1h 210

C K M B (n g /m L )
160
150 = 87 at 2 h 75
180 140
120 60 150 120

100
90 45 120
80
90
60 30 60
60
40
30 15
30 20
0 0 0 0
0 15 30 45 60 75 90 105 120 0 180 360 540 720 900 1080 1260 1440 1620 1800

Time(min) Time(min)
 TROPONINS

Regulatory proteins in
striated muscle
 Cardiac specific forms
 Troponin T (TpnT)
 Troponin I (TpnI)
TROPONINS
 Troponin is a complex of three regulatory proteins that is integral to
non- smooth muscle contraction in skeletal as well as cardiac muscle
 Troponin is attached to the protein tropomyosin and lies within the
groove between actin filaments in muscle tissue. In a relaxed muscle,
tropomyosin blocks the attachment site for the myosin crossbridge,
thus preventing contraction.
 When the muscle cell is stimulated to contract by an action potential,
calcium channels open in the sarcoplasmic membrane and release
calcium into the sarcoplasm. Some of this calcium attaches to
troponin, which causes it to change shape, exposing binding sites for
myosin (active sites) on the actin filaments. Myosin's binding to actin
causes crossbridge formation, and contraction of the muscle begins
 Thus far, studies have failed to find a source of Troponin-I outside
the heart, but have found some Troponin-T in skeletal muscle
TROPONINS
 Troponin-I levels begin to rise 2-3 hours after onset of MI
and roughly 80% of patients with AMI will have positive
values at 3 hours
 Elevations in Troponin-I and Troponin-T can persist for up
to 10 days after MI
 Therefore it has good utility for retrospectively diagnosing
AMI as, CK-MB returns to baseline by 48 hours
 DEFINING INCREASED TROPONIN
Tpn T and I are not detected in healthy persons

Significant Tpn reflects myocardial necrosis

Detectable Tpn but no  CKMB may indicate

microinfarction
ACC/ESC defined Tpn as a measurement above 99th
percentile value of reference group
To reduce false-positive outcomes, CV of 10% at decision
limit is recommended
 SHORTCOMINGS OF TROPONINS

 cardiac troponin reflects myocardial injury but

do not indicate its mechanism
 Not synonymous with MI or ischemic mechanism of injury.
Pursue other etiologies of myocardial injury
 Likely reflects irreversible injury
 Tpn after heart surgery; can’t differentiate injury caused by
MI from procedural-induced injury
HS-TROP-I
 HS Troponin-I assays have been introduced in an
effort to improve detection of MI
 These assays are able to detect much lower
concentrations of the troponin protein thereby
shortening time interval to identify MI
 Our reference range for HS-Trop-I is <0.03ng/ml
 IFCC & NACB GUIDELINES
Early marker to be performed in ED
  within 6 h, e.g. myoglobin. Good for r/o AMI

Definitive marker
 6-12 h, sensitive & specific, e.g. TpnT, TpnI,HS-Troponin
Perform both CKMB and Tpn’s for a period of time to
understand the difference in Tns vs CKMB
 BIOMARKERS IN RENAL
FAILURE
False positives have been reported with use of
troponin-T in ESRD patients but not as much with
troponin-I
CKMB plasma concentrations are elevated in 30-
70% of dialysis patients at baseline, likely secondary
to skeletal myopathy, intramuscular injections and
reduced clearance
CK-MB: 30-50% of dialysis patients exhibit an
elevation in the MB fraction >5% without evidence
of myocardial ischemia
 Therefore, the most specific marker for suspected
AMI in ESRD patients is Troponin-I with an
appropriate sequential rise
 CARRY HOME MESSAGE
Myocardial Infarction has been redefined with
inclusion of Biomarkers (new) as essential
component of diagnosis
CK-MB is no longer the ideal cardiac marker,
however, its use should be continued in conjunction
with Trops
CK-MB should be assayed alongwith total CK for
calculation of MB Index
Troponins I,HS-Trop-I should be the cardiac marker
of choice for diagnosis, evaluation of severity and
monitoring.