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 O2 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 bloodBIOCHEMICAL

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 onsetKembali 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 40 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

01 3 5 7 10

days after onset of AMI

multiples of reference range

MyoglobinLDCK-MBTroponin ITroponin T

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 ).

LDHEnzim 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 : LDH1-5Miokard dan eritrosit kaya LDH1

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

LDHSpesimen 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 40 C - LDH rusak bila dibekukan

TROPONINMerupakan 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

TropomyosinActin

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

TROPONINHalf-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 1st 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

SELAMAT BELAJAR