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Enzymes in action:

Myocardial Infarction
Lopez, Amier Dayle
Lucero, Celina Roxanne
Macatangay, Neon
Mallillin, Nikko
Marcelino, Jonhenryk

Objectives:
At the end of the discussion, the students must be able to:
1. Define enzymes and myocardial infarction.
2. Describe the biochemical events that lead to MI.
3. Enumerate the different diagnostic enzymes.
4. Define isoenzymes and their roles in the diagnosis of
MI.
5. Describe the initial rise, peak and descent of enzyme
serum levels in accordance with the duration of the
disease, from onset onwards.

Objectives:
5. Discuss the importance of enzyme assays in the
diagnosis of MI.
6. Enumerate the non-enzymatic proteins that are of
diagnostic to MI.
7. Enumerate the different enzymes that have therapeutic
value to MI and describe their mechanisms of action.
8. Enumerate the anti-thrombotic drugs that can be used
for MI and describe their mechanisms of action.
9. Define reperfusion injury and its relation to
thrombolytic therapy.

What are enzymes?


Enzymes are biological catalysts that
enhance the rate of metabolic processes
taking place in living cells without altering any
significant change to the cells involved.
MAIN FUNCTIONS:
Increase rate of chemical reactions
Regulate metabolic reactions

What is myocardial
infarction?
It is a heart attack that is caused by a
decrease in the hearts blood flow
that results to ischemia of the
myocardial tissue.
In most cases, patients suffer from
myocardial infarction due to an occlusion
of a coronary blood vessel by a
thrombus.

Causes and risk


factors
Atherosclerosis

- Diabetes Mellitus

Obesity

- Illegal Drugs (Cocaine)

Smoking
Carbon monoxide
poisoning
Age

- Family history
- Male
- High level of LDL
- Hypertension

BIOCHEMICAL EVENTS
OF MYOCARDIAL
INFARCTION

TISSUE DAMAGE IN
MI

TISSUE DAMAGE IN
MI

How do enzymes
assist AMI?
CARDIAC MARKERS:
Aspartate Aminotransferase (AST)
Aspartate + -ketoglutarate Oxaloacetate +
Glutamate
One of the enzyme used to diagnose MI
It is not specific for heart damage.
Proved less than ideal
DIAGNOSTIC WINDOW:
Rise: 6-8 hours
Peak: 24 hours
Normal: 5 days

CARDIAC MARKERS
Lactate Dehydrogenase, LDH
Lactate + NAD+ Pyruvate + NADH + H+
Catalyst for the interconversion of lactate and pyruvate
LDH-1 isoenzyme is normally in the heart muscle.
Widely distributed in the body with highest activities in
the heart, liver, skeletal muscles, and red blood cells

DIAGNOSTIC WINDOW:
Rise: 12-24 hours
Peak: 48-72 hours
Normal: 10-14 days

!! Not specific for MI. !!

CARDIAC MARKERS
Creatine Kinase, CK-MB
Creatine + ATP Creatine Phosphate + ADP
Very sensitive indicator of AMI
Levels increase within 3-12 hours of the onset of
chest pain.
DIAGNOSTIC WINDOW:
Rise: 4-6 hours of an MI
Peaks at 24 hours
Normal: after 48 72 hours

CARDIAC MARKERS
Troponin
Contractile protein, not found in serum.
Released only when myocardial necrosis occurs.
Most sensitive and specific for myocardial infarction.
DIAGNOSTIC WINDOW:
Levels rise for 2-6 hours after an MI, and remain elevated
for 4-10 days.
Peak time: 12 hours
CARDIAC TROPONINS served as a marker of all heart
muscle damage

CARDIAC MARKERS
Myoglobin, Mb
High when there is muscle tissue damage
but has a low specificity for MI.
Responds very rapidly, rising and
normalizing earlier than Troponin or CK-MB.
Urine myoglobin level rises within 1-4 hours
from the onset of chest pain.

What are
isoenzymes?
One of a group of enzymes that catalyze
the same reaction but are differentiated
by variations in physical properties.

Isoenzymes could either be tissue


specific or species specific that are
present in serum and other biological
fluids and tissues.

ISOENZYMES
CK has three isoenzymes:
CK-BB (CK-1), CK-MB (CK-2), CK-MM (CK-3)

CK-MB (CK-2, hybrid type)


CK-MB is the most significant isoenzyme of CK
for MI
Found in skeletal and cardiac muscles
Elevation is considered the most specific
indicator of myocardial damage, particularly AMI.

ISOENZYMES
NV: 15-160 U/L (Male), 15-130 U/L
(Female), CK-MB =<6% of total CK
After the onset of MI,CK-MB begin to
rise within 4-8 hours, peaks at 12-24
hours, and returns to normal in 48-72
hours, with CK-MB >6% of the total CK.

ASSAYS
Oliver-Rosalki
Most commonly used method
pH: 6.8; 340nm
CK

Creatine Phosphate + ADP Creatine + ATP


HK

ATP + Glucose ADP + Glucose-6-Phosphate


G-6-PD

Glucose-6-phosphate + NADPH+ 6-phosphogluconate + NADPH

ISOENZYMES
AST has two isoenzyme fraction:

Cytoplasmic AST (predominant)


Mitochondrial AST
NV: 5-37 U/L
After the onset of MI, AST rises within 68 hours, peaks at 24 hours, and return
to normal in 5 days.

ASSAYS
Karmen Method
Most commonly used
Uses malate dehydrogenase (MD)
pH: 8.8
AST

Aspartate + -ketoglutarate oxaloacetate + glutamate


MD
+

Oxaloacetate + NADH + H malate + NAD+

ISOENZYMES
five isoenzymes: LD1, LD2,
LD3, LD4, LD5

LD has

LD1 (HHHH) = 17-17%


Found in heart, RBCs, and kidneys
Relatively abundant in cardiac muscle

LD2 (HHHM) = 27-37%


Found in heart, RBCs, and kidneys
Greater than I1 and the major LD
isoenzyme in healthy individuals

ISOENZYMES

NV: 100-225 U/L


After the onset of MI, LD begin to
rise within 10-24 hours, peaks at
48-72 hours, and remains elevated
for 10 days.

ASSAYS
Wacker Method
Commonly used method
340nm
LDH

Lactate + NAD+ Pyruvate + NADH + H+

The Rise, Peak, and


Descent of Serum
Levels
ENZYME

RISE

PEAK

NORMALIZE

CK

4-6 hours

12-24 hours

48-72 hours

AST

6-8 hours

24 hours

5 days

LD

10-12 hours

48-72 hours

10 days

The Rise, Peak, and


Descent of Serum
Levels
Serum levels in the episode of
myocardial infarction from its onset.

The Rise, Peak, and


Descent of Serum
Levels

Anti- thrombotic
drugs for MI
Aspirin
An essential element in the management of patients
with MI because of its ability to inhibit platelet
thromboxane A2 synthesis.

It is rapidly absorbed in the stomach and upper


small intestine, reaching appreciable plasma
levels in 20 min and platelet inhibition in
approximately 60 min.
The anti-platelet effect lasts for the life of
the platelet (9-10 days).

Anti- thrombotic
drugs for MI
Depyridamol
-A pyrimidopyrimidine compound with
antithrombic and vasolidating
properties.

It activates the enzyme adenylate


cylase by a prostacyclin-mediated
effect on the platelet membrane.

Anti- thrombotic
drugs for MI
At a more physiological concentrations,
dipyridamole increases plasma adenosine
levels by inhibiting its uptake from vascular
endothelium and erythrocytes, thereby
enhancing platelet adenyl cyclase activity.

Anti- thrombotic
drugs for MI
Bivalirudin
inhibits thrombin.
It is utilized for anticoagulation to patients
with unstable angina who are undergoing
PTCA.

Heparin
Amplifies the activity of antithrombin III
Prevents the conversion of fibrinogen to fibrin.
Prevents re-accumulation of a clot after
spontaneous fibrinolysis.

Anti- thrombotic
drugs for MI
Enoxaparin
Enhances the inhibition of
thrombin through elevating the
antithrombin III activity.

What is reperfusion
injury?
Reperfusion Injury
This condition occurs when blood supply on a
particular tissue or area of a tissue has been cut off
causing damage to tissue.
Damage may vary depends on the intensity
of the infarct.

WHAT IS THROMBOLYTIC
THERAPY?
This method is the most successful way
of reducing the severity of the
damage caused by the myocardial
infarction.
It removes the dangerous clots in the
blood vessels through an injection of
clot-dissolving medications.

THERAPEUTIC ENZYMES:
THROMBOLYTIC DRUGS
These enzymes are considered treatment for
acute MI.
Thrombolytic Drugs are used to lyse (dissolve)
blood clots (thrombi) thru tPA (Tissue
plasminogen activator) streptokinase by
forming a cleaved product called plasmin.

THERAPEUTIC ENZYMES:
THROMBOLYTIC DRUGS
Plasmin is a proteolytic enzymes that is
capable of breaking the structural integrity
of blood clots.
That is why thrombolytic drugs are also
called plasminogen activators
or fibrinolytic drugs.

THERAPEUTIC ENZYMES:
THROMBOLYTIC DRUGS
There are three major classes of Fibrinolytic
drugs:
Tissue plasminogen activator (tPA)
Streptokinase
Urokinase
While drugs in these three classes all have the
ability to effectively dissolve blood clots, they
differ in their detailed mechanisms in ways that
alter their selectivity for fibrin clots.

tPA
Tissue plasminogen activator produces clot lysis
through the following sequence:
tPA binds to fibrin on the surface of the clot
Activates fibrin-bound plasminogen
Plasmin is cleaved from the plasminogen
associated with the fibrin
Fibrin molecules are broken apart by the
plasmin and the clot dissolves

Streptokinase
It is not a protease and has no enzymatic
activity; however, it forms a complex with
plasminogen that releases plasmin.
Unlike tPA, it does not bind preferentially to clotassociated fibrin and therefore binds equally
to circulating and non-circulating
plasminogen.
Therefore, SK produces significant
fibrinogenolysis along with clot fibrinolysis

Urokinase
It is synthesized by the kidney
that directly converts plasminogen
to active plasmin.
This therapeutic enzyme act as
thrombolytic agent in the treatment
of severe or massive deep venous
thrombosis, pulmonary embolism,
myocardial infarction, and occluded
intravenous or dialysis cannulas.

THERAPEUTIC ENZYMES:
THROMBOLYTIC DRUGS
It is important to note that the efficacy of
thrombolytic drugs depends on the age of
the clot.

Older clots have more fibrin cross-linking


and are more compacted; therefore, older
clots are more difficult to dissolve.

THERAPEUTIC ENZYMES:
THROMBOLYTIC DRUGS
For treating acute myocardial
infarction, the thrombolytic drugs
should ideally be given within the
first 2 hours.
Beyond that time, the efficacy
diminishes and higher doses are
generally required to achieve desired
lysis.

SUMMARY
Myocardial Infarction is the irreversible necrosis
of heart muscle secondary to prolonged ischemia.
Atherosclerosis leads to myocardial infarction
that forms large thrombus in the artery which will
inhibit normal blood flow into the heart.
Diagnostic Enzymes: (CARDIAC MARKERS)
Aspartate Aminotransferase (AST)
Lactate Dehydrogenase (LDH)
Creatine Kinase, CK-MB
Troponin
Myoglobin

SUMMARY
Isoenzymes are group of enzymes that
catalyze the same reaction but with different
variation in physical properties.
Order and Appearance:
Myoglobin (1-4 hours)
Troponin (2-6 hours)
CK-MB (4-6 hours)
AST (6-8 hours)
LD (10-24 hours)

SUMMARY
Different assays are used for the measurement
of enzyme levels in the serum.
Troponin and Myoglobin are proteins that are
not enzymatic in nature but can still help in
diagnosing MI.
Anti-thombotic drugs for myocardial infarction:
Aspirin
Depyridamol
Bivalirudin
Heparin
Enoxaparin

SUMMARY
Reperfusion Injury occurs when the blood
supply to an area of tissue is cut off.

Therapeutic enzymes
(Thrombolytic/ Fibrinolytic drugs)
Tissue plasminogen activation (tPA)
Streptokinase
Urokinase

REFERENCES
Murray, R. K., Bender, D. A. et. al. 2009. Harpers
Illustrated Biochemistry. 28th ed. United States of
America: McGraw-Hill Companies. 122-123, 126-128.
Harvey, R. A. 2010. Lippincotts Illustrated Reviews:
Biochemistry. 5th ed. Lippincott Williams and Wilkins.
Unknown. 1990. Acute Myocardial Infarction: Setting
Priorities for Effectiveness Research. Washington DC:
National Academy Press. 5-6.
Biswanger, H. 2011. Practical Enzymology. 2nd Ed.
Wiley-VCH Verlag and Co.

REFERENCES
Rodriguez, M. T. T. 2014. Clinical Chemistry Review Handbook
for Medical Technoloogists.
Klabunde, R. 2009. Cardiovascular pharmacology concepts.
Retrieved from:http
://www.cvpharmacology.com/thrombolytic/thrombolytic.htm
Nordqvist, J. 2013. What is Anterosclerosis. Medical News
Today. Retrieved from:
http://www.medicalnewstoday.com/articles/247837.php
Becker, R. Myocardial Infarction. Retrieved from:
http://www.rjmatthewsmd.com/Definitions/
myocardial_infarction.htm
Zafari, M. and Yang, E. 2014. Antithrombic Agents. Medscape
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