BIOMARKERS

JANTUNG

Ima Arum L
History

MARKERS OF
CARDIAC NECROSIS
What is Myocardial Infarction?
Myocardial ischemia results from the reduction of coronary
blood flow to an extent that leads to insufficiency of oxygen
supply to myocardial tissue

When this ischemia is prolonged & irreversible, myocardial
cell death & necrosis occurs ---this is defined as:
myocardial infarction


Patogenesis Aterosklerosis
Biochemical Changes in Acute Myocardial
Infarction
(mechanism of release of myocardial markers)
ischemia to myocardial muscles (with low O
2
supply)

anaerobic glycolysis

increased accumulation of Lactate

decrease in pH

activate lysosomal enzymes

disintegration of myocardial proteins

cell death & necrosis




release of intracellular
contents to blood
BIOCHEMICAL
MARKERS

clinical manifestations
(chest pain)

ECG
changes

Diagnosis of Myocardial Infarction

SHOULD depend on THREE items
(as recommended by WHO)

1- Clinical Manifestations
2- ECG
3- Biochemical Markers
Perfect Cardiac Marker
Early appearance

Accurate, specific, precise

Readily available, fast results

Cost-effective
Markers of Cardiac Necrosis
CREATIN KINASE (CK)

Enzim di berbagai jaringan, konsentrasi tinggi di otot
untuk energi metabolisme.

Ada 2 subunit : B dan M
isoform CK-MB, CK-BB, CK-MM

Konsentrasi CKMB tertinggi di sel otot jantung dan otot
skelet

Dilepaskan dalam serum 48 jam setelah onset
Kembali normal setelah 3 hari

CKMB
Isoenzim CK

Meningkat 4 - 8 jam setelah infark
puncak 12-24 jam kemudian

Persiapan sampel darah :
- serum/ plasma heparin/ plasma EDTA
- tidak boleh hemolisis
- bila tidak langsung diperiksa
serum disimpan beku
- sampel stabil 24 jam pada suhu 4
0
C
atau 1 jam pada suhu ruang

Cardiac Markers


Release kinetics of cardiac markers in AMI
Early, rapid, transient release of Myoglobin
Delayed, sustained release of Troponin T
Compared with CK and CK-MB
25
20
15
10
5
0
1 3 5 7 10
days after onset of AMI
multiples of reference range
Myoglobin
LD
CK-MB
Troponin I
Troponin T
038
Figure of CPK, AST ( GOT ), and LD level after myocardial
infarction (means of values for 200 patiens). Note that the CPK
rise is earliest, the LD rise is latest, and the LD elevations are
present longer than those of CPK and AST ( GOT ).
LDH
Enzim mengkatalisis perubahan reversibel
laktat ke piruvat

Tersebar luas dalam macam2 jaringan
peningkatan LDH sangat tidak spesifik
LDH meningkat pada kelainan sirkulasi (syok)

Ada 5 isoenzim LDH : LDH1-5
Miokard dan eritrosit kaya LDH1

Miokardium mengandung lebih banyak LDH1
infark miokard rasio LDH1 : LDH2 >1

LDH
Spesimen darah :
- Tidak boleh hemolisis
( eritrosit mengandung banyak LDH
spesimen darah hemolisis ringan
LDH meningkat )

- Segera dipisahkan jadi serum/ bekuan
cegah pengeluaran LDH intrasel

- LDH dalam serum stabil 2 hari pada suhu 4
0
C
- LDH rusak bila dibekukan

TROPONIN
Merupakan protein kontraktil di filamen serabut otot
jantung
Unit kontraktil otot skelet : filamen tipis dan tebal
Troponin terdapat dalam filamen tipis , fungsi :
mengontrol proses kontraksi

Kompleks Troponin terdiri dari 3 protein :
- Troponin-C ( cTnC )
- Troponin-T ( cTnT )
- Troponin-I ( cTnI )

Kerusakan miokard troponin dilepas ke darah

Troponin T
Tropomyosin
Actin
Troponin I
Troponin C
Head-to-Tail Overlap
of Tropomyosin
The Troponin complex: three unrelated proteins
Troponin I, C and T which interact synergistically
In the absence of Ca++, the Troponin complex and
Tropomyosin inhibit myosin actin interaction
Troponin T in the myocardium is different from
Troponin T in skeletal muscle
The Troponin complex
046
TROPONIN
Half-life biologik dan kecepatan peningkatan kadar cTnT
di serum sama dengan cTnI (2-4 jam).
Ukuran molekul cTnT lebih besar dari cTnI kadar cTnT
di serum lebih lambat menjadi normal (14 hr)

Patogenesis pelepasan Troponin : kerusakan miokard
(infark, miokarditis, kardiomiopati).

AMI kadar cTnI meningkat 2-8 jam onset
tergantung luas, letak infark, vaskularisasi koroner
normal setelah 7 hr.

CARDIAC BIOMARKER

NATRIURETIC
PEPTIDES
Natriuretic Peptides
Present in two forms, atrial (ANP) and brain
(BNP)
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
Came to market in 2000 based on data from
many studies, primarily the Breathing Not
Properly (BNP) study
Prospective study of 1586 patients presenting
to the ER with acute dyspnea
The predictive value of BNP much superior to
previous standards including radiographic,
clinical exam, or Framingham Criteria
BNP
BNP has also shown utility as a prognostic
marker in acute coronary syndrome
It is associated with increased risk of death at
10 months as concentration at 40 hours post-
infarct increased
Also associated with increased risk for new or
recurrent MI
PROGNOSTIC MARKERS
AND MARKERS OF RISK
STRATIFICATION
Prognostic Markers and Markers of
Risk Stratification

C-reactive protein
Myeloperoxidase
Homocysteine
Glomerular filtration rate

C-Reactive Protein
Multiple roles in cardiovascular disease have
been examined
Screening for cardiovascular risk in otherwise
healthy men and women
Predictive value of CRP levels for disease
severity in pre-existing CAD
Prognostic value in ACS
C-Reactive Protein
Pentameric structure consisting of five 23-kDa
identical subunits
Produced primarily in hepatocytes
Plasma levels can increase rapidly to 1000x
baseline levels in response to acute
inflammation
Positive acute phase reactant
C-Reactive Protein
Binds to multiple ligands, including many
found in bacterial cell walls

Once ligand-bound, CRP can:
Activate the classical compliment pathway
Stimulate phagocytosis
Bind to immunoglobulin receptors

C-Reactive Protein:
Risk Factor or Risk Marker?
CRP previously known to be a marker of high
risk in cardiovascular disease
More recent data may implicate CRP as an
actual mediator of atherogenesis
Multiple hypotheses for the mechanism of
CRP-mediated atherogenesis:
Endothelial dysfunction via NO synthesis
LDL deposition in plaque by CRP-stimulated
macrophages
CRP and CV Risk
Elevated levels predictive of:
Long-term risk of first MI
Ischemic stroke
All-cause mortality
Myeloperoxidase
Released by activated leukocytes at elevated
levels in vulnerable plaques
Predicts cardiac risk independently of other
markers of inflammation
May be useful in triage of ACS (levels elevate
in the 1
st
two hours)
Also identifies patients at increased risk of CV
event in the 6 months following a negative
troponin
NEJM 349: 1595-1604

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
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
Homocysteine
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
Treatment includes supplementation with
folate, B6 and B12
Glomerular Filtration Rate
The relationship between chronic kidney
disease and cardiovascular risk is
longstanding
Is this the result of multiple comorbid
conditions (such as diabetes and
hypertension), or is there an independent
relationship?
Glomerular Filtration Rate

Recent studies have sought to identify whether
creatinine clearance itself is inversely related
to increased cardiovascular risk, independent
of comorbid conditions
Glomerular Filtration Rate
Go, et al performed a cohort analysis of 1.12
million adults in California with CKD that were
not yet dialysis-dependent
Their hypothesis was that GFR was an
independent predictor of cardiovascular
morbidity and mortality
They noted a strong independent association
between the two


NEJM 351: 1296-1305
Glomerular Filtration Rate
Reduced GFR has been associated with:
Increased inflammatory factors
Abnormal lipoprotein levels
Elevated plasma homocysteine
Anemia
Arterial stiffness
Endothelial dysfunction