Lecture 5

Infarction The process by which necrosis results from ischemia is called infarction Ischemic necrosis of myocardial cells is one of the commonest cause of death in industrialized countries.

Pathology Atherosclerosis Narrowing of arterial lumen Reduced coronary blood supply Clinical manifestations Chest pain

Diagnosis History ECG Biomarkers

WHO classification of MI 2/3 these criteria: Ischemic symptoms EKG changes. Increased serum markers.

ECG

CARDIAC PROFILE TEST ENZYMES Creatinine Kinase –MB(CK-MB) Lactate Dehydrogenase(LDH 1 and 2) Aspartate Aminotransferase(AST)/Serum Glutamate Oxaloacetate Transaminase(SGOT) Alanine Aminotransferase(ALT)/ Serum Pyruvate Transaminase(SGPT) PROTEINS Myoglobin Troponin LIPID PROFILE CHOLESTEROL TRIGLYCERIDE HDL LDL

AST found in all tissue, especially the heart, liver, and skeletal muscles It catalyzes the transfer of the amino group of aspartic acid to alpha-ketoglutaric acid to form oxaloacetic acid and glutamic acid Reference range: < 35 U/L in male and < 31 in female Considerations in AST assays -Serum is the best specimen -Hemolyzed samples must be avoided -Muscle trauma like intramuscular injections, exercise, or surgical operation can significantly increase AST levels

Clinical significance  Myocardial infarction  In myocardial infarction, AST levels are usually 4-10 times the upper limit of normal  These develop within 4-6 hours after the onset of pain  Peak on the 24 th – 36 th hour  Usually normalize on the 4 th or 5 th day  Muscular dystrophy  Hepatocellular disorders  Skeletal muscle disorders

LACTATE DEHYDROGENASE (LDH) Catalyzes the reversible oxidation of lactate to pyruvate Used to indicate AMI Is a cytoplasmic enzyme found in most cells of the body, including the heart Not specific for the diagnosis of cardiac disease

Distribution of LD isoenzymes LD1 and LD2 (HHHH, HHHM) Fast moving fractions and are heat-stable Found mostly in the myocardium and erythrocytes Also found in the renal cortex LD3 (HHMM) Found in a number of tissues, predominantly in the white blood cells and brain LD4 and LD5 (HMMM, MMMM) Slow moving and are heat labile Found mostly in the liver and skeletal muscle

Considerations in LD assays Red cells contain 150 times more LDH than serum, therefore hemolysis must be avoided LDH has its poorest stability at 0°C Clinical Significance In myocardial infarction, LD increases 3-12 hours after the onset of pain Peaks at hours and remain elevated for days In MI, LD1 is higher than LD2, thus called “flipped” LD pattern

flipped LDH An inversion of the ratio of LD isoenzymes LD 1 and LD 2 ; LD 1 is a tetramer of 4 H–heart subunits, and is the predominant cardiac LD isoenzyme; Normally the LD 1 peak is less than that of the LD 2, a ratio that is inverted–flipped in 80% of MIs within the first 48 hrs DiffDx. LD flips also occur in renal infarcts, hemolysis, hypothyroidism, and gastric CA

Increased levels of LD Trauma Megaloblastic anemia Pulmonary infarction Granulocyte leukemia Hemolytic anemia Progressive muscular dystrophy (PMD)

CREATINE KINASE (CK) Is a cytosolic enzyme involved in the transfer of energy in muscle metabolism Catalyzes the reversible phosphorylation of creatine by ATP -Is a dimer comprised of two subunits, resulting in three CK isoenzymes The B, or brain form The M, or muscle form

isoenzymes CK-BB (CK1) isoenzyme Is of brain origin and only found in the blood if the blood-brain barrier has been breached CK-MM (CK3) isoenzyme Accounts for most of the CK activity in skeletal muscle CK-MB (CK2) isoenzyme Has the most specificity for cardiac muscle It accounts for only 3-20% of total CK activity in the heart Is a valuable tool for the diagnosis of AMI because of its relatively high specificity for cardiac injury Established as the benchmark and gold standard for other cardiac markers

Clinical Significance -In myocardial infarction, CK will rise 1-3 hours after the onset of pain -Peaks at hours and returns to normal on the third day -CK is the most specific indicator for myocardial infarction (MI) Ratio of CK-MB/ total CK activity (specificity) CK-MB mass instead of activity (sensitivity)

Raised levels of CK Progressive muscular dystrophy Polymyositis Acute psychosis Alcoholic myopathy Hypothyroidism Malignant hyperthermia Acute cerebrovascular disease Trichinosis and dermatomyositis Exercise and intramuscular injections causes CK elevations Normal Value: a. Male – IU/mL b. Female – IU/mL

Myoglobin Non specific marker Frequently elevated in other conditions Most useful when not detected Can not be used alone for the diagnosis of MI.

Troponins Proteins that regulate muscle contraction T & I are specific for cardiac muscles

Cardiac troponins: 1.Troponin C: binds with calcium. 2.Troponin T: binds with tropomyosin. 3.Troponin I: inhibits contraction.

Troponin T & I  Require myocardial necrosis for release from sarcomere.  Early rise (4-12 hours after symptom).  Peak hours (sensitivity is 100%).  Continuous release up to days

 Myocardial infarction: elevation of serum troponin T/I >0.1. (AHA)  Negative troponin and normal EKG, mortality 1%.  Negative troponin and ischemic EKG: mortatity 4% at 1 month.  Troponin and EKG changes complementary.  Problems with TnI: variability of assays.  Complement clinical risk factors and EKG changes.