Clinical chemistry of myocardial infarction week 2 Flashcards Preview

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1

What 2 types of plasma proteins are there?

1. those at high concentrations that are specific to blood and have a functional role in blood (albumin, carrier proteins, immune proteins, proteins of blood coagulation)

2. those at low levels that are relased form the cells due to normal cell turnover and have no fxn in blood

In disease, there is an increased release of intracellular proteins into the plasma (e.g. heart enzyme levels in the case of MI)

2

What parameters are observed when detecting enzyme levels after MI?

  • tissue specificiy of enzyme
  • time of appearance
  • time of disappearance
  • detection level (sensitivity)
  • availability of specific tests

3

What are isoenzymes? What are the benefits of using isoenzyme levels as diagnostic tool? How may isoenzymes be separately detected?

Isoenzymes are enzymes that catalyze the same rxn but differ slightly in amino acid composition since they arise from different gene loci. These aa differences do not affect enzyme fxn but allow the enzymes to be separately identified-tissue specificity

Diagnostic value: Different organs may contain characteristic proportions of isoenzymes, thus, 
isoenzyme levels in blood may serve to identify the site of tissue damage.

Many isoenzymes comprise of different subunits in various combinations (enzyme complex, have quaternary structure)
Diagnostic value: The amino acid composition, thus the net charge of these subunits are different, 
consequently, the net charge of the enzyme complex 
will also be different--> Electrophoretic separation of 
these isoenzymes is possible.

4

What is the composition of creatine kinase (CK) What are the isoenzymes and in what tissues are they predominant?

CK is a dimer with 2 types of subunits: M (short for muscle) and B (for brain) named after where they were first isolated. The subunits can be combined in 3 different ways:

composition     name     tissue origin

BB                    CK1             brain, bowel

MB                   CK2            myocardium

MM                   CK3            skeletal mm and myocardium

 

Skeletal muscle: CK3 + 0-2% CK2

Myocardium: 85% CK3 + 15% CK2

No other tissue expresses as much CK2 as myocardium does. Therefore, elevation of CK2 is specific to myocyte necrosis

 

 

 

 

5

Why else is CK-MB sensitive for dection of MI? (has to do with timing of appearance and disappearance)

CK-MB is sensitive for detection of MI because it begins to appear within blood within 2 days. Additionally, it is sensitive for detection of re-infarction because it begins to fall after about a day. So if levels rise again, indicative of another MI

6

What rxn does lactate dehydrogenase (LDH) catalyze? What are its isoenzymes? Where are the isoenzymes located? How/when may LDH be used to diagnose MI? How may it be used to diagnose liver congestion and skeletal mucle dystrophy?

LDH catalyzes this reversible rxn :

lactate + NAD pyruvate + NADH

LDH is a tetramer containing 2 kinds of subunits: H (stands for heart) and M (stands for muscle). The 2 subunits can be combined in 5 different ways.

Because LDH1 and LDH2 are both found in RBCs and myocardium but LDH1 is more abundant in skeletal muscle and LDH2 is more abundant in RBCs, the ratio of LDH1/LDH2 is calcuated for MI. If the ratio is greater than 1, it is indicative of heart muscle damage. (please see slide 19 of notes)

Assays for these isoenzymes can be done within 30 minutes to an hour after MI.

Increased levels of LDH5 is indicative of liver congestion and skeletal muscle dystrophy.

7

What other enzyme may be used to diagnose MI? Among the isoenzymes used to diagnose MI, which is the most specific? When do CK2 and LDH1/2 ratios appear and when do they peak?

AST (aspartate aminotranferase) may also be used to detect MI. This along with CK and LDH levels are commonly determined in the dx of MI especially when EKG is difficult to interpret due to previous heart disease.

CK2 is the most specific to the dx of MI. It appears 3-8 hours after the episode of chest pain and peaks within 24 hours and then returns back to normal levels. Note that detection of CK2 sub-isoforms may also be used to diagnose MI.

LDH1/2 ratio is diagnostic btwn 12-24 hours after chest pain and then returns to normal levels. 

8

What subunits of troponin may be used to diagnose MI? When are they elevated and for how long do they stay elevated? May they be used to determine re-infarction?

There are 3 subunits of troponin: Tn-T (binds to tropomyosin to stabilize troponin complex), Tn-I (inhibits actin and myosin binding), and Tn-C (binds Ca2+ to allow for myosin and actin binding). There are cardiac isoforms of both Tn-T (cTn-T) and Tn-I (cTn-I). Note the word isoform is being used instead of isoenzyme bc troponin is not an enzyme

There are two isoforms of cardiac Tn-T, Tn-T1 and Tn-T2, in adult cardiac tissue. It is thought that the two isoforms are a result of alternative mRNA splicing. Serum levels of Tn-T2 increase within 4 hours of MI and remain high for up to 14 days. The appearance of Tn-T2 in serum is 100% sensitive and 95% specific for detection of MI. 

Elevated serum levels of cardiac isoform of Tn-I is also predictive of adverse outcomes of unstable angina or MI. cTn-I is elvated 4 hours after MI and stays elevated for 7 days in 68% of pts.

Bc troponin levels stay elevated for so many days (esp Tn-T2) they are not sensitive for detection of re-infarction (cannot be detected for at least 2 weeks). However, these tests are very sensitive for initial detection of MI bc cardiac troponin levels are normally undetectable. 

9

How does sensitivity of Tn-T for detection of MI compare to EKG, CK, and CK-MB? How can myoglobin be used?

EKG: detects 5-10 g of tissue damage (substantial amount of tissue)

CK: 0.2 g of tissue

CK-MB: 0.02 g of tissue

Tn-T: 0.003 g of tissue

Remember that other proteins levels may also be detected to confirm dx: LDH, AST. Myoglobin is not specific bc there is a vast amount of skeletal muscle that contains myoglobin. However, myoglobin can be used to detect the extent of damage. 

10

What 2 enzymes are used as therapeutic agents for MI? How do they work? What is a drawback to these therapies?

Blood clots formed in MI can be dissolved by plasmin. However, plasmin circulates in the blood in its inactive form, plasminogen. Plasminogen can be activated by:

streptokinase: from streptococcus

tissue plasminogen activator (t-PA)

These enzymes activate fibrinolysis by activing plasminogen to the active enzyme, plasmin. The resultant plasmin degrades insoluble fibrin. 

The drawback to these therapies is that the enzymes are removed from circulation very rapidly so high doses must be used.