1. CARDIAC BIOMARKERS - I
Hussein A. Abid
Iraqi Medical Laboratory Association
Scientific Affairs & Cultural Relations
Training and development center
Lecture: 3
Date: 07/08/2018
2. BIOMARKER
• Is a substance used as an indicator of a biologic state
• It is characteristic and found only in tissue of interest
• It is objectively measured
• It is elevated as an indicator of normal biologic processes,
pathogenic processes, or pharmacologic responses to a
therapeutic intervention
• Detection of marker must enable intervention that prevent
or minimize effects of disease
3. CARDIAC MARKERS
• Intracellular macromolecules (proteins) released from a heart
muscle when it is damaged as a result of myocardia infarction
(MI).
• They found in the blood.
• They are normally present at all times, however, they are
significantly elevated during a damage of the heart muscle.
• They include: aspartate aminotransferase (AST or GOT),
troponin I & T (TnI, TnT), creatine kinase MB (CK-MB),
myoglobin (Mb), lactate dehydrogenase (LDH), B-type natriuretic
peptide (BNP), C-reactive protein (CRP), myeloperoxidase
(MPO) and ischemic modified albumin (IMA).
4. CRITERIA OF IDEAL CARDIAC
MARKER
• Good specificity: detects only cardiac damage
• Optimal sensitivity and detectable while damage is
reversible or preventable
• Correlates with amount of injury and enables prognosis
prediction
• No single marker meets all needs
• Cheap, rapidly measurable and easy to detect
5. CARDIAC MARKERS HISTORY
• 1954 – GOT (AST)
• 1955 – LDH
• 1960 – CK
• 1972 – CK isoforms by electrophoresis
• 1975 – CK-MB by immunoinhibition
• 1975 – Myoglobin
• 1985 – CK-MB mass immunoassay
• 1989 – Troponin-T
• 1992 – Troponin-I
6. CLASSIFICATION
ACCORDING TO USE
Obsolete markers:
Aspartate transaminase (AST or GOT)
Lactate dehydrogenase (LDH) and lactate dehydrogenase isoenzymes
Current markers and test panels:
Creatine kinase (CK) and muscle-brain creatine kinase (CK-MB)
Troponin T (TnT) and Troponin I (TnI)
Myoglobin (Mb)
Markers under assessment with potential for clinical use:
CK-MB isoforms
High sensitivity C-reactive protein (hs-CRP)
B-type (formerly brain) natriuretic peptide (BNP)
7. CLASSIFICATION ACCORDING TO THE
TYPE OF CARDIAC PROBLEM
• Cardiac markers could be classified as:
Myocardial injury markers:
Markers of myocardial necrosis: CK-MB, myoglobin and troponin
Markers of myocardial ischemia: IMA and H-FABP
Hemodynamic stress markers: natriuretic peptides
Inflammatory and prognostic markers: hs-CRP, sCD40L
and homocysteine
8. MYOCARDIAL CONTENTS
• With cell death, holes develop in cell membrane.
• Contents leak depend on size and solubility:
Small, cytoplasmic markers leak fast
Larger, complexed markers released slowly
• Markers only released with irreversible injury.
• Because markers are proteins, will not leak with ischemia.
• Marker release means cell death.
9. MYOCARDIAL CONTENTS
• Concentration gradient also important.
• High gradient between serum and cell allows early
detection.
• Low gradient makes test insensitive to myocardial injury.
• Myocardial injury markers:
1. Cardiac enzymes: CK and its isoforms such as CK-
MB, LDH, AST.
2. Non-enzyme markers: Troponins and others.
10. WHICH MARKERS?
• Recommended early marker (+ by 6 hrs.) and more
definitive late marker (high specificity).
• Rapid change marker myoglobin as best early marker
especially to detect re-infarction.
o Isoforms also possible choice.
• However, myoglobin detection has serious limitations such
as:
o Low concentration gradient between serum and cells.
11. WHICH MARKERS?
• Cardiac troponins I and T popular as definitive markers.
• But, this is not an early marker.
• Direct relation between level of troponins and risk (up to
about 2 ng/ mL).
12. CLINICAL SIGNIFICANCE
• Myocardial markers can detect smaller amounts of
damage than clinical criteria.
• Numerous studies show patients with “unstable angina”
and positive markers have high incidence of cardiac events
in follow-up.
• Negative markers indicate low risk patients.
• Relative risk with positive markers average is 6:1 compared
to negative.
• Higher for troponin T than troponin I.
13. CLINICAL SIGNIFICANCE
• With diagnostically confirmed ECG, markers not needed for
diagnosis but monitoring progress.
• Guidelines suggest need for 2 markers, though rationale
not given for late presentation.
• Role of new early markers (such as glycogen phosphoryl-
ase b, Human fatty acid binding protein)
14. REVIEW
• Cardiac markers are biomarkers measured to evaluate
heart function.
• Most of the early markers identified were enzymes, and as
a result, the term "cardiac enzymes" is sometimes used.
• However, not all of the markers currently used are
enzymes.
• Cardiac markers or cardiac enzymes are proteins that leak
out of injured myocardial cells through their damaged cell
membranes into the bloodstream.
15. REVIEW
• Until the 1980s, the enzymes SGOT and LDH were used to
assess cardiac injury.
• Now, the markers most widely used in detection of MI are
MB subtype of the enzyme creatine kinase and cardiac
troponins T and I as they are more specific for myocardial
injury.
• Note: An ECG still remains the most specific diagnostic
tool in evaluating the patient with chest pain however, the
initial ECG may be negative/non-diagnostic in > 40% of
AMI cases
16. REVIEW
• Note: the perfect cardiac marker test, with a 100% early
sensitivity + 100% specificity in diagnosing an AMI, does
not exist different cardiac marker tests are used in varying
combinations.
Why it is done?
• Cardiac enzymes levels help diagnose chest pain or other
signs and symptoms of a heart attack.
17. REVIEW
Limitations:
• Depending on the marker, it can take between 2 to 24
hours for the level to increase in the blood.
• Additionally, determining the levels of cardiac markers in
the laboratory takes time. Cardiac markers are therefore
not useful in diagnosing a myocardial infarction in the acute
phase. The clinical presentation and results from an ECG
are more appropriate in the acute situation.
19. ASPARTATE TRANSAMINASE (AST)
• Also called Glutamic Oxaloacetic Transaminase (GOT or
SGOT, as serum GOT).
• It is widely distributed in tissues but highest levels is found
in liver, heart, skeletal muscles and RBCs.
• It catalyzes the reversible transfer of an α-amino group
between aspartate and glutamate and, as such, is an
important enzyme in amino acid metabolism (it provide a
source of oxaloacetate for Krebs cycle).
20. ASPARTATE TRANSAMINASE (AST)
• Normal values (8 – 20 U/ L).
• Raised by 6 – 8 hours.
• Peak by 18 – 24 hours.
• Returned to normal by 4 – 5 days.
21. LACTATE DEHYDROGENASE (LDH)
• Lactate dehydrogenase (LDH, or LD) is an enzyme that is
found in almost all body tissues but only a small amount of
it is usually detectable in the blood.
• It usually stays contained within the tissues cells. When
cells are damaged or destroyed, however, they release
LDH into the bloodstream, causing blood levels to rise.
• For this reason, LDH is used as a general marker of
injury to cells.
22. LACTATE DEHYDROGENASE (LDH)
Function
• Lactate dehydrogenase catalyzes the interconversion of
pyruvate and lactate with concomitant interconversion of
NADH and NAD+.
• It converts pyruvate, the final product of glycolysis to
lactate when oxygen is absent or in short supply. This
reaction is known as anaerobic homolactic fermentation
and is an important way to regenerate NAD+ to allow
glycolysis to continue .
23. LDH ISOENZYMES
• LDH functions as a tetramer and is made of two kinds of
subunits, H and M, each of which are encoded by a
different gene. This results in 5 different isoenzymes (2
homotetramers and 3 heterotetramers).
• The M subunit is found predominantly in anaerobic tissues
including skeletal muscle and liver. The H subunit is more
commonly found in tissues with a ready source of oxygen
and that metabolize lactate including the heart and the
brain.
24. LDH ISOENZYMES
1. LDH-1 (4H) – in the heart
2. LDH-2 (3H1M) – in the reticuloendothelial system
3. LDH-3 (2H2M) – in the lungs
4. LDH-4 (1H3M) – in the kidneys
5. LDH-5 (4M) – in the liver and striated muscle
• Usually LDH-2 is the predominant form in the serum. A
LDH-1 level higher than the LDH-2 level (a "flipped
pattern"), suggests myocardial infarction.
25. LDH MEASUREMENT
Sample:
• Serum sample is used
Source of error:
• Strenuous exercise can cause temporary elevations in LDH
• Hemolysis of blood can cause false positives
Interpretation:
• Elevated levels of LDH and changes in the ratio of the LDH
isoenzymes usually indicate some type of tissue damage.
Usually LDH levels will rise as the cellular destruction begins,
peak after some time period, and then begin to fall.
26. LDH RESULT INTERPRETATION
Cardiac disease:
• It can be used as a marker of myocardial infarction. Following a
myocardial infarction, levels of LDH will rise within 24 to 48
hours, peak at 3-4 days and remain elevated for up to 10 days.
• In this way, elevated levels of LDH can be useful for determining
if a patient has had a myocardial infarction if they come to
doctors several days after an episode of chest pain.
• LDH level is directly proportional to the infraction size.
• Note: LDH level can be elevated in other cardiac disease such
as Myocarditis and rheumatic fever
27. LDH RESULT INTERPRETATION
Non-cardiac disease: elevated levels of LDH may be seen in the
following conditions:
• Hemolytic anemia and pernicious anemia but it decrease with
treatment.
• Liver disease: LDH increase in liver disease (mainly LD4 and LD5) but
not as much as GOT and GPT. Toxic hepatitis and carcinoma of liver
cause high elevation while Viral hepatitis and obstructive jaundice
cause moderate elevation
• Muscular dystrophy: It increase in patients with progressive muscle
dystrophy especially in early and middle stage of the disease then it
decreases with progression of the disease
• Some cancers (especially lymphoma and leukemia) as cancer cells
have a high rate of turnover with destroyed cells leading to an elevated
LDH activity.
