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Cardiac Biomarkers: Ella Melissa L. Pembimbing: Dr. Dr. Tinny E. H., SPPK (K)
Cardiac Biomarkers: Ella Melissa L. Pembimbing: Dr. Dr. Tinny E. H., SPPK (K)
Cardiac Biomarkers: Ella Melissa L. Pembimbing: Dr. Dr. Tinny E. H., SPPK (K)
Ella Melissa L.
Pembimbing:
Dr. dr. Tinny E. H., SpPK(K)
1
Introduction
Heart disease is an affliction intimately tied to high technology
Technology has had a causal role, in part by allowing people to
live longer, and in part by enabling a sedentary and overly
consumptive lifestyle.
Diagnosis & treatment of heart disease also depend heavily on
advanced technology, including electrophysiologic, imaging,
catheterization, surgical and clinical laboratory modalities.
Major laboratory applications in cardiac
disease:
1. Measurement of proteins present in cardiac myocytes
indicates recent damage to cardiac muscle used mainly for
the diagnosis and management of ischemic events (ACS).
Although many different markers of ischemic damage have
been used in the past, at the time of writing the most
important markers by far are cardiac troponin I and cardiac
troponin T.
2. Measurement of substances that are damaging to the coronary
arteries, or at least have proven association with coronary heart
disease, is used to assess risk and select appropriate preventive
measures
The most important laboratory risk factors are lipids
Of the many other substances that could be: homocysteine
(Hcy) and C-reactive protein (CRP)
1. Kualitatif:
Positif T C
T C
Negatif
T C
Gagal
2. Kuantitatif:
Menggunakan easy reader.
Konsentrasi hasil dalam ng/ml.
Nilai normal:
< 1 ng/ml (whole blood)
< 0,8 ng/ml (plasma/ serum)
Myoglobin
Myoglobin is a heme-containing protein that binds oxygen
within cardiac and skeletal muscle; only a single form is
common to both muscle types
Having a molecular weight of only 18 kDa, myoglobin apparently
leaks from damaged cells more rapidly than other proteins
Following MI elevated myoglobin may be detectable in plasma
before CK-MB or cTn.
Typically, myoglobin peaks about 6 hours after MI and
returns to baseline after 24 hours.
Although myoglobin may offer some advantage in early
detection of myocardial damage, its value is limited by its
lack of specificity.
Carbonic Anhydrase III
Carbonic anhydrase III (CA III) is an enzyme present in skeletal
but not in cardiac muscle, hence it can serve as a sort of
“negative” cardiac marker
It is released from damaged muscle at a fairly fixed ratio to
myoglobin
Thus myoglobin is a more specific indicator of myocardial
damage when its ratio to CA III is also elevated
Glycogen Phosphorylase
Glycogen phosphorylase (GP) is a widely distributed enzyme
that catalyzes the first step in glycogenolysis
A dimer of identical subunits, it has three characterized
isoenzymes: GPLL (liver), GPMM (muscle), and GPBB (brain)
GPBB is also expressed in myocardium, as well as other tissues,
but it is not found in skeletal muscle
The potential usefulness of GPBB is that it appears to be
released earlier than other markers, and may in fact be
released under conditions of reversible ischemia that do not
give rise to comparable elevations in other markers
(Rabitzsch, 1995; Krause, 1996)
However, comparisons with modern cTn assays have been
limited and not particularly encouraging (Lang, 2000)
Heart Fatty Acid–Binding Protein
Heart fatty acid–binding protein (HFABP) is a LMW (15 kDa)
protein that is a relatively early marker of myocardial damage,
with kinetics similar to that of myoglobin
It is not cardiac specific and therefore does not seem to offer
advantages over myoglobin
However, the ratio of myoglobin to HFABP is much lower in heart
than in skeletal muscle and may have diagnostic applicability
Myosin
Myosin makes up the thick filament of the muscle contractile
apparatus and is composed of a pair of heavy chains (200
kDa) and one pair each of type I and type II light chains (20–
26 kDa)
Several of these components have been examined as cardiac
markers (Katus, 1988; Uji, 1991; Ravkilde, 1994; Ravkilde,
1995)
It has not been possible to achieve complete cardiac
specificity with myosin, and it is not clear that it would offer
any important advantages
Ischemia-Modified Albumin
Ischemia-modified albumin (IMA) is a unique type of cardiac
marker (FDA approved in 2003) that is not a protein released
from damaged myocytes (Bar-Or, 2000; Bar-Or, 2001;
Christenson, 2001; Bhagavan, 2003).
Rather, the test detects a variant form of albumin with a
reduced affinity for metal ions near the N-terminus
The variant is measured by a spectrophotometric determination
of Co++ binding
The theoretical advantage of this test is that it detects ischemia
before irreversible cell damage occurs
The change in albumin appears to occur within minutes of
ischemia and lasts for about 6 hours
The test clearly is not specific for cardiac ischemia, but appears to
have a clinical sensitivity of 80%–90% for ACS at the time of
presentation — greater than that of the ECG (Roy, 2004; Sinha,
2004)
Homocysteine
Intermediary amino acid formed by the conversion of
methionine to cysteine
Moderate hyperhomocysteinemia occurs in 5-7% of the
population
Recognized as an independent risk factor for the
development of atherosclerotic vascular disease and venous
thrombosis
Can result from genetic defects, drugs, vitamin deficiencies,
or smoking
Homocysteine implicated directly in vascular injury including:
◦ Intimal thickening
◦ Disruption of elastic lamina
◦ Smooth muscle hypertrophy
◦ Platelet aggregation
Vascular injury induced by leukocyte recruitment, foam cell
formation, and inhibition of NO synthesis
Elevated levels appear to be an independent risk factor,
though less important than the classic CV risk factors
Screening recommended in patients with premature CV
disease (or unexplained DVT) and absence of other risk
factors
Hcy has traditionally been measured by chromatographic
techniques (Vester, 1991; Ubbink, 1999; Frick, 2003; Arndt,
2004).
A method using enzymatic adenosylation followed by
immunoassay has been automated on the Abbott IMx
analyzer (Shipchandler, 1995)
And purely enzymatic methods suitable for automation have
also been introduced (Tan, 2000; Huijgen, 2004; Roberts,
2004).
Markers of Congestive
Heart Failure
CARDIAC NATRIURETIC PEPTIDES
Present in two forms, atrial (ANP) and brain (BNP)
BNP is used clinically because it exists in a much wider range
of concentrations in varying clinical settings, making it easier
to measure
Natriuretic Peptides
Both ANP and BNP have diuretic, natriuretic and hypotensive
effects.
Both inhibit the renin-angiotensin system and renal
sympathetic activity
BNP is released from the cardiac ventricles in response to
volume expansion and wall stress
BNP Assay
Approved by the FDA for diagnosis of cardiac causes of
dysnpea
Currently measured via a rapid, bedside immunofluorescence
assay taking 10 minutes
Especially useful in ruling out heart failure as a cause of
dyspnea given its excellent negative predictive value
BNP test had the following
characteristics for diagnosis of HF:
sensitivity 90%, specificity 76%,
positive predictive value 79%, and
negative predictive value 89%
(Maisel, 2002).
BNP levels decline when effective
therapy for HF is instituted, and so
the test may be used to monitor
the course of treatment (Cheng,
2001; Faggiano, 2009; Novo,
2009).
proBrain Natriuretic Peptide, NT
Other Potential Biomarkers
1. C-Reactive Protein
Acute phase reactant
CRP is considered to be marker of the atherosclerotic
process (chronic & acute atherosclerotic processes involve
an inflammatory component)
2. Choline
Choline released after stimulation by phospholipase D during
ischemia and has been touted as a test of prognosis in ACS
patients with chest discomfort without increases in cTn
At present, there is no standardized assay & no reference
interval studies or consistent assay validations
3. sCD40 Ligand
A transmembrane protein related to tissue
necrosis factor (TNF)-alpha.
It has multiple prothrombotic and
proatherogenic effects.
Shown to be predictor of events after ACS
presentations.
4. Myeloperoxidase
Released when neutrophils aggregate &
thus may indicate an active
inflammatory response in blood vessels.
It has been shown to be elevated
chronically when chronic CAD is
present.
An assay has been cleared by the FDA
for prognostic use in high risk patients
with ACS.
5. Oxidized LDL
Has been attributed a key role in the
development of atherosclerosis.
Some have correlated malondialdehyde
LDL with the development of
atherosclerosis.
Direct identification with Ab suggests that
oxidized LDL may be released from
vessels & co-localize with Lpa after acute
events.
6. Pregnancy-Associated Plasma Protein
A
PAPP-A is metalloproteinase that is
thought to be expressed in plaques that
are prone to rupture.
Present concerning its use in ACS.
7. Lipoprotein-Associated Phospholipase A2
(LpPLA2)
LpPLA2 is a phospholipase associated with
LDL & is thought to be an inflammatory
marker.
It is synthesized by monocytes &
lymphocytes.
It has been shown to improve prediction
of events in patients without prior AMI.
8. Placental Growth Factor
Placental growth factor is an angiogenic
chemoattractant protein-1.
Placental growth factor is thought to provide