BIOCHEMICAL MAKERS OF CARDIAC DISEASE

Learning Objectives

What are Cardiac Markers Enumerate different cardiac markers Importance/Role of different biochemical

markers in the diagnosis of Acute MI

Cardiac Marker

A cardiac marker is a clinical labaratory test useful in detection of AMI or a minor myocardial injury.

ACUTE MYOCARDIAL INFARCTION

Ischaemic necrosis of myocardium Major cause: Atherosclerotic CAD with

super- imposed thrombosis

ACUTE MYOCARDIAL INFARCTION

AMI- PRECIPITATING FACTORS

• No precipitating factors identified in majority of cases

• Modest or usual exertion : 18% • Heavy physical exertion : 13% • Surgical procedure : 06% • Rest : 51% • Sleep : 08%

Diagnosis Of Acute Myocardial Infarction

Clinical history Evolutionary changes in ECG

Initial ECG : Positive in 50% of AMI cases Serial tracings : Sensitivity is above 75%

Abnormal cardiac enzymes/ proteins WHO Criteria : Two out of three

positive for diagnosis of AMI

CLINICAL HISTORY

Chest Pain Its character? tight", "heavy",

"constricting" Its location? typically retrosternal, Its duration? "prolonged", i.e. at least

20 minutes, and usually much longer.

BIOMARKERS OF CARDIAC INJURY

Cardiac Enzymes

Creatine Kinase (CK)

Lactate dehydrogenase(LD)

Aspartate aminotransferase(AST)

Cardiac Proteins

Troponin-I, Troponin-T

Myoglobin

Serum Creatine Kinase (CK) (Reference Range: 25 - 192 U/L)

Non specific for diagnosis of AMI present in :

Skeletal muscle Heart muscle Brain and other tissues

Isoenzyme: Different molecular forms of proteins with the same catalytic activity

CK has Two polypeptide subunits M & B and has three isoenzymes:

CK‑MM (or CK‑1) in skeletal muscle CK‑MB (or CK‑2) in cardiac muscle

CK‑BB (or CK‑3) in brain tissue

Distribution of CK activity

Total CK

Plasma CK activity 97% by CK-MM<3% by CK-MB

Starts to rise 3-8 hrs post chest pain Peak 12-24 hrs return to normal 3-4 days not specific

CK-MB (CK-2)

• Current ‘gold standard’Diagnosis of Acute MIReperfusion injuryReinfarction

• Starts to rise 3-6 hrs post chest pain

• Peak 10-24 hrs

• Return to normal 2-3 days

• Minor myocardial injury not detected

CK-MB (CK-2)

• Concentration in myocardium is 20 times more than in skeletal muscle

• Plasma activityNormal <6% of total CKIn MI >6 % of total CK

• Methods of detectionElectrophoresisImmunoinhibitionTwo site immunoassay i.e CK-MB mass

CK-MB (CK-2)

• SamplingSensitivity <50% if one sample is takenSensitivity >98% if serial sampling at 0, 6h,12h, 24 hSpecificity 100%

• Other causes of raised plasma activity of CK-MBCardiac proceduresCrush syndromeMajor surgeryRhabdomyolysisSevere exercise

AST(Aspartate Aminotransferase)

• Starts to rise 7-9 hrs post chest pain

• Peak 24-48 hrs

• Return to normal in 4-6 days

• Not specific

Serum LD (lactate dehydrogenase)

• Cytoplasmic enzyme - all tissues, highest in muscle, liver, kidneys, RBCs.

• Timing• Starts to rise 8-12 hrs post chest pain• Peak 72-144 hrs• return to normal 8-14 days

• Not specific for Ac. MI

Isoenzymes of lactate dehydrogenase

LD Isoenzyme 1 2 3 4 5

Subunit structure H4 H3M H2M2 HM3 M4

Normal serum + ++ + trace trace

Heart muscle ++ + trace - -

Liver - - - + ++

Skeletal muscle - - - + ++

MI : Flipping (LD1 to LD2 >1)

Cardiac Proteins

• Serum Myoglobin

• Cardiac Troponin T (cTnT)

• Cardiac Troponin I (cTnI)

Serum Myoglobin

• Haem containing protein of cardiac and skeletal muscles

• Earliest detectable marker

• Analytical methods: Unable to distinguish tissue of origin

• Rise Pattern• Released from myocardium: within 1-2 hrs

• Peak levels: 4-8 hours

• Revert to normal: 1 day

• Role in diagnosis of AMI• During early 4 hrs, when CK-2 still within the range

• Sensitivity (90-100%), Specificity (60-90%)

Serum Troponins

Structural proteins inside myocyte Troponin-C: binds calcium and initiates

contraction Troponin-T: binds troponin complex to

the tropomysin strand Troponin-I: inhibits contraction in the

resting state. > 90% in myofibrils & 3-6% in cytoplasm

Serum Troponins

Troponin-T: • increased 3-8 hr post chest pain• peak 1- 4 days• increased for up to 14 days Troponin-I:• increased 3-8 hr post chest pain• peak 1-2 days• returns to normal 5days• More specific & sensitive as compared to cTnT Both specific for myocardium

Brain Natriuretic Peptide (BNP) • Synthesized in myocardium • Associated with poor prognosis• Have potential to complement standard

cardiac markers• Requires versatile and applicable

analytical assays

Emerging Cardiac Risk Factors

• C-Reactive Protein

• Lipoprotein (a)

• Fibrinogen

• Homocysteine

The Four Big Ones

Possible future Markers

• BB isoenzyme of glycogen phosphorylase

• Acute phase proteins

• Selectin P

• Fibrin/FDP

Cardiac Makers : summary

Cardiac Enzymes & Protein contribute in:

• Diagnosis of acute MI

• Estimate of quantity of infarcted tissue

• Assessment of re-infarction

• Monitoring treatment

• Prognosis

MONITORING TREATMENT

Successful coronary reperfusion following

intravenous thrombolytic treatment results

More rapid rise in plasma Proteins

Earlier peaks in enzyme activities

HEART FAILURE

Complex clinical syndrome structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject bloodCharacterized by specific symptoms &signs

• Dyspnea • Fatigue• Fluid retention.

ANP & BNP

Secreted from Atria and ventricles In response to

Volume expansion Possibly increased wall stress.

Plasma concentrations are increased Heart failure (HF) Asymptomatic left ventricular dysfunction Symptomatic left ventricular dysfunction

Biochemical Tests Heart failure (HF)

Serum electrolytes and creatinine Baseline to follow when initiating-diuretics and/or ACEI Liver function tests Hepatic congestion Fasting blood glucose Diabetes mellitus Thyroid function tests Over the age of 65 Atrial fibrillation Hypothyroidism Thyrotoxicosis

Biochemical Tests

Iron studies (ferritin and TIBC) Hereditary hemochromatosis (HH)

Evaluation for pheochromocytoma Thiamine, carnitine, and selenium levels Plasma Atrial Natriuretic

Peptide(ANP) Plasma Brain Natriuretic Peptide

(BNP)

CARDIAC MARKERS

Which of the following Cardiac markers have the high specificity for cardiac injury

  a) Globulin b) CK-MB mass assay   c) Total CK d) AST e) LDH

CARDIAC MARKERS

A serum Troponin T concentration is of most value to the patient with a myocardial infarction when:

Sample being drawn within 3 to 6 hours of the onset of symptoms

The CK-MB has already peaked and returned to normal concentrations

The myoglibin concentrations is extremely elevated

The Troponin I concentration has returned to normal concentration

CARDIAC MARKERS

A normal myoglobin concentration 8 hours after onset of symptoms of a suspected myocardial infraction will:

Essentially rule out acute myocardial infraction Provide a definitive diagnosis of acute myocardial

infarction Must be interpreted with careful consideration of

the Troponin T concentration Give the same information as the total CK-MB

CARDIAC MARKERS

After myocardial infarction CPK rises within   30 minutes Four Hours Twelve hours 24 hours

CARDIAC MARKERS

Which of the following Cardiac markers have the high specificity for cardiac injury

a. CK-MB assay b. Troponin I c. Total CK d. AST e. LDH

CARDIAC MARKERS

In acute coronary syndrome trop T better reflects myocardial damage and peaks at 1-2 hours 6-12 hours 12-24 hours 24-48 hours 36-72 hours

 

CARDIAC MARKERS

Four hours after abdominal surgery a 65 years old male was found to have some equivocal ECG changes and markedly raised serum CK (> 1500 U/L). Which of the following cardiac markers would be the most specific investigations to rule out myocardial infarction in this patient: CK-MB activity measurement CK-MB mass measurement CK-MM activity measurement Myoglobin estimation in the blood Estimation of Cardiac Troponin T.

CARDIAC MARKERS

A 64 year old man was admitted to coronary care unit with history of central chest pain for last 8 hours. ECG on admission indicated changes of MI including Q wave. Which of the following enzymes do you expect to raise maximum in this patient?

a) AST  b) CKMM  c) LDH  d) CKMB   e) CKBB

A 40 years old farmer was admitted to the hospital with chest pain which had developed during the afternoon. He gave history of spending 4 hours digging in his fields. There were no specific signs of myocardial infarction on the ECG. He was kept in acute coronay unit for 48 hours. How you interpret his lab results.

Answer

Although Creatinine kinase (CK-NAC) activity is increased but normal CK-MB shows no cardiac injury. Total cholesterol levels and LDL-cholesterol can be measured in non-fasting individuals and recent food intake affects total cholesterol concentration less than 1.5%. However, serum triglyceride can increase markedly after eating.