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ACUTE MYOCARDIAL INFARCTION

Acute myocardial infarction is defined as death or necrosis of myocardial cells. The diagnosis of AMI was established by WHO in 1979, requiring the presence of two or more of the following criteria: 1. History of severe and prolong chest pain 2. Unequivocal electrocardiographic (ECG) changes such as persistent Q or QS waves and evolving injury lasting longer than 1 day and 3. Unequivocal initial increase and subsequent decrease in activity of enzymes collected on serial basis.

Because of the emergence of new biochemical marker such as cardiac troponin (cTn), the European Society of Cardiology (ESC) and American college of Cardiology (ACC) redefined the criteria for diagnosis of AMI: 1. Typical increase and gradual decrease of troponin or more rapid increase and decrease of creatin kinase CK-MB with at least on of the following: Ischemic symptoms Development of pathologic Q waves on the ECG ECG changes indicative if ischemic Coronary artery intervention 2. Pathologic finding of an AMI The more and new guidelines place more emphasis on biochemical markers, particularly cTn, as the entry criteria for AMI detection relative to CK-MB because this assay has higher clinical and analytic sensitivity for detection of myocardial damage.

CARDIAC BIOMARKER
BIOMARKER Is a substance used as an indicator of a biologic state. It is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. CARDIAC MARKERS Are substances (enzyme) released from heart muscle when it is damaged as a result of myocardial infarction.

The importance of biomarkers: 1. Diagnosing acute myocardial infarction (AMI) 2. Detecting myocardial damage whether due to AMI or other cardiac process 3. Risk-stratifying patients 4. Commenting on Prognosis 5. Stressing interns, confusing residents and worrying cardiology fellows

The important biomarkers in diagnosis of acute myocardial infarction, AMI:

1. Creatine kinase (CK), total activity 2. CK-MB isoenzyme, mass 3. CK-MB isoforms and isoforms ratio 4. Myoglobin (Mb) 5. Cardiac troponin I (cTn I) 6. Cardiac troponin T (cTn T) 7. Lactate dehydrogenase (LDH) 8. AST/ALT

Enzymes in the myocardial cells:


Enzyme Creatine kinase Description consists of two subunits, B (brain type) or M (muscle type), Making three different isoenzymes: CK-MM, CK-BB and CK-MB Found in cytosol of all human cells Have 2 subunit which are H (heart) and M (muscle); combine to form 5 isoenzymes of LD. Ubiquitous small-size heme protein released from all damaged tissues Increases often occur more rapidly than TI and CK Not utilized often for AMI assessment because of its very rapid metabolism (short plasma half-life) causing short burst increases that are difficult to assess clinically its lack of specificity for cardiac tissue. Physiological functions Responsible for regeneration of ATP

Lactate dehydrogenase

Catalyze the reduction of pyruvate to lactate using NAD

Myoglobin -

Oxygen binding protein

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 tropomyosin sitting in the groove between actin filaments in muscle tissue Troponin has three subunits, TnC, TnT, and TnI

Troponin

Troponin-C binds to calcium ions to produce a conformational change in TnI Troponin-T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex Troponin-I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place Catalyze the transfer of an amino group between aspartic acid and pyruvate to form oxaloacetate and alanine Its effect is reversible cleavage of its substrate into two compound without hydrolysis. It convert the fructose-1,6diphosphate to dihydroxyacetone phosphate and G3P

Aspartate aminotransferase (AST) Aldolase -

Used as surrogate markers of cellular damage in the past. Very non-specific so not used for assessment of myocardial damage any longer An enzyme of the lyase group Aldolase is present most significantly in skeletal and heart muscle. Damage to skeletal muscle produces high serum levels of aldolase, particularly in the case of progressive muscular dystrophy.

CURRENT CARDIAC MARKERS


CREATINE KINASE Creatine kinase (CK/CPK) is an enzyme expressed in a number of tissues. Function: it catalyses the conversion of creatine to phosphocreatine degrading ATP to ADP

Creatine kinase isoenzymes In the cells, the cytosolic CK enzymes consists of two subunits which can be either B (brain types) or M ( muscle type). There are therefore three different isoenzymes: CK1=CK-BB=brain type CK2=CK-MB=cardiac type CK3=CK-MM=muscle type Skeletal muscle express CK-MM (98%) and low level of CK-MM at 70% and CK-MB at 25-30%. Diagnostic uses: Clinically, creatine kinase is assayed in blood tests as a marker of myocardial infarction. In myocardial infarction, it begins to rise in 4-8 hours and reaches its maximum level in 12-24 hours and return to normal level after two or three days. Normal level: Male: 38-174 U/L Female: 26-140U/L CK-MB (CK2) ISOFORMS The primary indicator (gold standard) used to diagnose a heart attack because it exists in the highest amount in the heart. If CK-Mb makes up more than 5% of total CK level, a heart attack is suspected. The CK-MB fraction exists in two isoforms called 1 and 2 identified by electrophoretic methodology. If one part of CK-MB (CK-MB2) is greater than another part (CK-MB1) by ratio of 1.5 or more, then this is indicative that a heart attack has occurred.

The mitochrondrial creatine kinase isoenzymes: Picture show Mitochrondrial and cytoplasmic isoenzyme of creatine kinase. In the motochrondria, mitCK catalyze the formation of creatine phosphate; it is transported to the cytoplasm for storage of high-energy phosphate bonds. With muscle contraction, cytoplasmic CK catalyze the formation of ATP.

In addition to those three cytosolic CK isoforms, there are two mitochrondrial creatine kinase isienzymes: The ubiquitous CKMT1 (present in non-muscle tissues) The sarcomeric CKMT2 (present in sarcomeric skeletal and cardiac) While mitochrondrial creatine kinase is directly involved in formation of phosphor-creatine from mitochrondrial ATP, cytosolic CK regenerate ATP from ADP. This happens at intracellular sites where ATP is used in the cell.

Electrophoresis of Creatine kinase Electrophoresis is the migration of charged molecules in a media upon application of an electric field. The rate of migration depends on the charged of the molecule, its molecular mass and the strength of the electric field. Usually electrophoresis is used for the separation of protein. The most commonly used matrix is agarose. Agarose is used mostly for the separation or larger macromolecules, including proteins and their complexes. Protein can be visualized after electrophoresis by treating the gel with a stain such as Coomassive blue. The picture show the pattern of migration of different creatine kinase isoenzymes. The molecules being sorted are dispensed into a well in the gel material. The gel is placed in an electrophoresis chamber, which is then connected to a power source. When the electric current is applied, the larger molecules of CK isoenzyme move more slowly through the gel while the smaller molecules move faster and further away from the negative charge. The different sized molecules of CK isoenzymes form distinct bands on the gel. The picture also show the normal pattern of CK isoenzyme migration and also the pathologic condition that suggest AMI.

A gel electrophoresis

LACTATE DEHYDROGENASE An enzyme that catalyzes the conversion of lactate to pyruvate. This is an important step in energy production in cells. Many different types of cells in the body contain this enzyme. Some of the organs relatively rich in LDH are the heart, kidney, liver, and muscle.

Increase absorption of UV maximum at 340 nm Serum LDH-isoenzyme patterns are determined by the agar gel electrophoresis and quantitative determination by densitometry.

Lactate dehyrogenase isoenzyme LDH-1 (4H) LDH-2 (3H1M) LDH-3 (2H2M) LDH-4 (1H3M) LDH-5 ( 4M)

Locations In the heart In the reticuloendothelial system In the lungs In the kidneys In the liver and striated muscle

LDH-2 is usually the predominant form in the serum. A LDH-1 higher than LDH-2 suggests AMI The picture beside show a various pattern of LDH serum electrophoresis. From the picture the normal pattern and pathologic pattern (AMI) can be compared and determined.

TROPONIN Troponin is a protein that is integral to muscle contraction in skeletal and cardiac muscle but not smooth muscle. Troponin is attached to the protein tropomyosin and lies within the groove between actin filament in the muscle tissue.

The function of troponin: When the muscle cell is stimulated to contract by an action potential calcium channel open in the sarcoplasmin reticulum and release calcium into the sarcoplasm. Some of this calcium attaches to troponin, causing a conformational changes that moves tropomyosin out of the way so that the cross bridges can attach to actin and produce muscle contraction.

Individual subunits serve different functions: Troponin C: binds to calcium ions to produce a conformational changes in troponin. Troponin T: binds to tropomyosin, interlocking them to form a troponin-troponyosin complex. Troponin I: binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place.

Diagnostic use: certain subtype of troponin ( cardiac troponin I and T) are very sensitive and specific indicators of damage to the heart muscle (myocardium).it is important to note that cardiac troponins are marker of all heart muscle damage, not just myocardial infarction.

Normal range: cTNT: < 0.1 ng/mL nTNI: < 0.4 ng/mL

Detection of cardiac troponin: Cardiac troponin T and I are measured by immunoassay methods. An immunoassay is a biochemical test that measures the concentration of a substances in a biological fluid using the reaction of an antibody antigen interaction.

The assay takes advantage of the specific binding of an antibody ton its antigen. Detecting the quantity of antibody or antigen can be achieved by a variety of methods. One of them is to label either the antigen antibody. The label may consist of an enzyme immunoassay, radioisotope or fluorescence.

Troponin will begin to increase following myocardial infarction eithin (2-4) hours. Approximate peak 12 hours, about the same time framne as CK-MB. Troponin will remain elevated longer than CK up to 5 to 9 days for troponin I and up to 2 weeks for troponin T.

MYOGLOBIN Myoglobin is a protein found in skeletal and cardiac muscle which binds oxygen.

Clinical interpretations: Serum concentrations of myoglobin rise above the reference values as early as 1 hours after the occurrence of an AMI with peak activity in the range of 4 to 12 hours. Myoglobin is cleared rapidly and has a reduced clinical sensitivity after 12 hours. The role of myoglobin in the detection of AMI is within the first 0 t0 4 hours. The time period in which the CK-2 and cardiac troponin are still within their normal values. A negative myoglobin can help to rule out myocardial infarction.it is elevated even before CK-MB. However, it is not specific for cardiac muscle, and can be elevated with any form of injury to skeletal muscle. Serum myoglobin levels were measured in normal subjects and patients by means of a newly developed radioimmunoassay. Myoglobin ranged between 6 and 85 ng/ml.

ASPARTATE TRANSAMINASE
Aspartate transaminase (AST) also called serim glutamic oxaloacetic transaminase or aspartate aminotransferase is enzyme associated witH liver parenchymal cells.

Aspartate transaminase isoenzymes Two isoenzymes are present in humans: GOT1 - the cytosolic isoenzyme derives mainly from red blood cells and heart. GOT2 - the mitichrondrial isoenzyme is predominantly present in liver.

Clinical significance: It is raised in acute liver damage. It is also present in red blood reds and cardiac muscle and may be elevated due to those sources as well. Clinical interpretation: The serum activity of AST begins to rise about 6 to 12 hours after myocardial infarction and usually reaches its maximum value in about 24 to 48 hours. It is usually return to normal 4 to 6 days after the infarction. AST was defined as biochemical marker for the diagnosis of acute myocardial infarction. This was the first used. However the used of AST for such a diagnosis is now redundant and has been superseded by the cardiac troponins. AST is commonly measured clinically as part of diagnostic liver function tests. A maximum increase of 20 times normal usually indicates severe viral hepatitis, severe trauma. A high level of 10 to 20 times normal may indicate a heart attack or alcoholic cirrhosis of the liver.

SUMMARY ON IMPORTANT CARDIAC MARKERS

Test CK-MB

Sensitivity and specitivity It is relatively specific when skeletal muscle damage is not present LDH is not as specific as troponin This was the first used but it is not specific The most sensitive and specific test for myocardial damage. Troponin is a super marker for myocardial injury. Low specificity for myocardial infarction

Normal range Immunoassay CK-MBmass < 6% Electrophoresis method: CK-MB (<4% - 6%) 105 250 IU/L 10 35 U/L cTNT: < 0.1 ng/mL nTNI: < 0.4 ng/mL

Rise in

Approximate peak 12 25 hours

Returns normal 2 3 days

4 8 hours

LDH AST Troponin

6 - 12

72 hours 24 48 hour

10 days 4 6 days

2 4 hours

12 hours

5 9 days

Myoglobin

< 100 g/L

One hour

4 12 hours

Reduced after 12 hours

OTHER RECENT CARDIAC MARKERS:

C-REACTIVE PROTEIN (CRP)

CRP is a protein found in serum or plasma at levels during a inflammatory processes. It is a sensitive marker of acute and chronic inflammation and infection. CRP levels are useful in predicting the risk for the thrombotic event such as blood clot causing MI. CRP level normally found in serum is (0.1 2.5 mg/L). Patients who have persistent CRP level between 4 and 10 mg/L, with clinical evidence of low-grade inflammation, should be considered to be at risk for thrombosis.

HOMOCYSTEINE
Homocysteine is an amino acid. According to the American Heart Association, too much homocysteine in the blood is related to a higher risk of coronary heart disease, stroke, and peripheral vascular disease, and that it may also have an effect on atherosclerosis. The normal fasting level for plasma is 5-15 micromol/L.

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