Cardiac Biomarkers

Cardiac Biomarkers

  • Cardiac biomarkers are substances that are released into the blood when the heart is damaged or stressed.

Biomarkers 

  • diagnose, 
  • risk stratify, 
  • monitor
  • manage people with suspected acute coronary syndrome (ACS) and cardiac ischemia

Biomarker

It reflects the severity or presence of some disease state.
 
More generally a biomarker  can be used as an indicator of a particular disease state or some other physiological state of an organism.

What is Myocardial Infarction?

  • Myocardial ischemia (insufficient blood flow to the heart muscle via the coronary arteries) results from the reduction of coronary blood flow to an extent that leads to insufficiency of oxygen supply to myocardial tissue
  • When this ischemia is prolonged & irreversible, myocardial cell death & necrosis (premature cell death) occurs —this is defined as: 

   myocardial infarction

Biochemical Changes in Acute Myocardial Infarction
(mechanism of release of myocardial markers)

Biochemical Changes in Acute Myocardial Infarction

Cardiac Biomarker Release Patterns

Cardiac Marker Release Patterns

“Perfect” Cardiac Biomarker

  • Early appearance
  • Accurate, specific, precise
  • Readily available, fast results
  • Cost-effective

Acute myocardial infarction and unstable angina

Biomarkers of necrosis

  • 1.Myoglobin
  • Myoglobin has long  been used as muscle damage indicator, but its generalised distribution in all muscles has limited its specificity.
  • Myoglobin is a 17.8 KD heme protein found in the cytoplasm of cardiac and skeletal muscle cells that rises most rapidly after myocardial injury but is not cardiac specific
  • Myoglobin levels are frequently elevated inpatients who have renal failure, skeletal muscle injury, trauma, and other diseases.
  • Mean increase within 2 H peaks at 6-9 H)
  • Level returns to normal in 12-36 H.
  • Normal value: 17.4-105.7 ng/ml
  • Timing:
    • Earliest Rise: 1-3 hrs
    • Peak 6-9 hrs
    • Return to normal: 12 hrs

Advantage

  • Provides earliest detection of AMI
  • Best marker to exclude AMI if patient presents within 4 hrs of symptom onset
  • Useful to detect reinfarction

Disadvantage

  • Elevations not specific to cardiac muscle injury
  • Concentration elevated in patients with renal insufficiency

Acute myocardial infarction and unstable angina

  • Creatinine Kinase
  • CK is found in Skeletal/Brain/Heart Muscle.
  • Formed from two Dimer M and B (Mol wt 40 KD)
  • Three different isozyme MM,MB,BB
  • The MB isozymes is predominantly found in heart and rises after MI at about 4-8 H.
  • Good marker for  MI diagnosis at early stage.
  • Concentration often returns to normal within three days.

Biomarkers of necrosis

  • Creatine-Kinase MB :
  • CK-MB is an enzyme present primarily in cardiac muscle. 
  • released rapidly after myocardial injury and is more cardiac-specific than Myoglobin. 
  • Before the use of troponin, CK-MB was the gold standard for the biochemical diagnosis of AMI. CK-MB is released early during AMI, and it plays an important role in defining infarct size, infarct expansion, and reinfarction
  • Creatine-Kinase MB Isoforms
  • The CK-MB fraction exists in two isoforms called 1 and 2 identified by electrophoretic methodology. The ratio of isoform 2 to 1 can provide information about myocardial injury
  • Studies suggested that cahnges in the ratios of these isomorphs ( MB2/MB1, MM3/MM1) might provide reliable early markers for myocardial damage.
  • An isoform ratio of 1.5 or greater is an excellent indicator for early acute myocardial infarction. 
  • However, the disadvantage of this method is that it is skilled labor intensive because electrophoresis is required, and large numbers of samples cannot be run simultaneously nor continuously. 
  • False positive results with congestive heart failure and other conditions can occur.
  • Normal values
    • CK 21-240 u/L
    • MB 0-5 ng/ml
  • Timing
    • Earliest Rise: 4-8 hrs
    • Peak: 12-24 hrs
    • Return to normal: 3-4 days

Creatine Kinase-MB

Advantage

  • 90% accuracy for detecting myocardial necrosis within 4-6 hours after onset
  • Readily available
  • Good for detecting re-infarction

Disadvantage

  • Levels don’t start to rise for 4 hrs after onset
  • Other conditions can cause elevations

Acute myocardial infarction and unstable angina

TROPONINS

  • Troponin is a regulatory complex of protein and comprises three proteins.( Trop T 39 kd, Trop I 26.5kd, Trop C 18kd)
  • Troponin T (cTnT) and troponin I (cTnI) control the calcium-mediated interaction of actin and myosin
  • Troponin C distributed through all the muscles.
  • cTnI completely specific for the heart
  • cTnT released in small amounts by skeletal muscles, though clinical assays do not detect skeletal TnT
  • Cardiac troponins
  • Cardiac troponins and tropomyosin form the thin filament component of the contractile structure in striated muscle.
  • The preferred biomarker for the diagnosis of acute MI
  • Troponins are released following irreversible ischemic myocardial cell injury and remain elevated for a prolonged time.
  • no clinical difference between TnT and TnI in diagnosing cardiac necrosis (cardiac and skeletal isoforms of both)

Cardiac troponins:

  • In renal dysfunction may be attributable to:
  • decreased renal clearance
  • Increased release from cytoplasm because of the loss of membrane integrity
  • TnT is more frequently elevated than TnI
  • However, an acute increase from baseline troponin levels may be associated with increased mortality.
  • Therefore, baseline troponin levels, in such cases are helpful when differentiating between acute and chronic elevations in cardiac troponins.
  • Should not be used alone to diagnose myocardial infarction.
  • Troponin levels may be elevated in patients who have myocarditis, pericarditis, decompensated heart failure,and septicshock.
  • Normal: 0-0.3 ng/ml
  • Timing
    • Earliest rise: 3-4 hrs
    • Peak: 10-24 hrs
    • Return to Normal: 1-3 wks

Advantage

  • Troponin T and I can detect MI, ACS and 
  • Troponin T and I more sensitive than CK-MB
  • Allows earlier and longer window to identify MI and ACS

Disadvantage

  • False positives can occur with rheumatoid arthritis and renal failure patients
  • Not good to detect reinfarction

Lactate dehydrogenase (LD)

  • LD activity is measured by monitoring absorbance at λ = 340 nm (NADH)
  • Methods can be P → L or L → P
    • But. . .reference range is different
  • Total LD activity has poor specificity

Sensitivity and specificity of LD-1

  • Sensitivity and specificity of the LD 1:2 “flip”, or LD-1 > 40% of total, are 90+% within 24 hours of MI, but. . .
    • May be normal for 12 or more hours after symptoms appear (peak in 72-144 hours)
    • May not detect minor infarctions
  • Elevations persist for up to 10 days
  • Even slight hemolysis can cause non-diagnostic elevations in LD-1
    • Normal value: 100-220U/L

Congestive Heart Failure

> It is the inability of the heart to provide sufficient pump blood flow
Brain and atrial natriuretic peptide and heart failure:

  • BNP & ANP are neuro-endocrine hormones, produced and secreted by the ventricles, that participate in fluid homeostasis by:
  • increase urine volume and urine sodium excretion
  • vascular smooth muscle relaxation
  • inhibition of the renin-angiotensin-aldosterone system and sympathetic nervous system

Brain Natriuretic Peptide

  • Brain natriuretic peptide (also known as B-type natriuretic peptide ) is a 32-amino-acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of myocytes (heart muscles cells) in the ventricles.
  • At the time of release, a co-secreted 76 amino acid n-terminal fragment (NT-proBNP) is also released with BNP.
  • BNP binds to its receptor in a similar fashion to ANP but with 10-fold lower affinity. The Biological half life of BNP however, is twice as long as that of ANP.
  • Tests showing elevated levels of BNP or NT-proBNP in the blood are used as a diagnosis of heart failure and may be useful to establish prognosis in heart failure, as both markers are typically higher in patients with worse outcome.
  • Both BNP and NT-proBNP have been approved as a marker for acute CHF. The plasma concentrations of both BNP & ANP are increased in patients with asymptomatic and symptomatic left ventricular dysfunction.
  • Brain natriuretic peptide was originally identified in extracts of porcine brain, but in humans it is produced mainly in the cardiac ventricles.
  • Normal Value: 0 – 80 ng/L
  • In Congestive Heart Failure : Brain natriuretic peptide is measured.
  • Disadvantage:
  • baseline BNP levels increase with age and are higher in women than in men
  • To establish appropriate reference ranges, the distribution of BNP in different populations still needs to be determined.

Biomarker indicators of MI

  • Troponin is preferred biomarker for dx of MI 
  • cTnT or cTnI > 99th %ile on any determination 
  • CK-MB > 99th %ile on two successive
    measurements

New Biomarkers

  • Serum Amyloid
  • sCD40 Ligand
  • Cytokines
  • Oxidized LDL
  • Ischemia Modified Albumin
  • Choline
  • Unbound Free Fatty Acid
  • Nourin

Prognostic Biomarkers

  • C-reactive protein
  • Myeloperoxidase
  • Homocysteine
  • Glomerular filtration rate

C-Reactive Protein

  • Multiple roles in cardiovascular disease have been examined
    • Screening for cardiovascular risk in otherwise “healthy” men and women
    • Predictive value of CRP levels for disease severity in pre-existing CAD
    • Prognostic value in ACS
  • Pentameric structure consisting of five 23-kDa identical subunits
  • Produced primarily in hepatocytes
  • Plasma levels can increase rapidly to 1000x baseline levels in response to acute inflammation 
  • “Positive acute phase reactant”
  • CRP and CV Risk :-
  • Elevated levels predictive of:
    • Long-term risk of first MI
    • Ischemic stroke
    • All-cause mortality

Myeloperoxidase

  • Released by activated leukocytes at elevated levels in vulnerable plaques
  • Predicts cardiac risk independently of other markers of inflammation
  • identifies patients at increased risk of CV event in the 6 months following a negative troponin

Homocysteine

  • Intermediary amino acid formed by the conversion of methionine to cysteine
  • Moderate hyperhomocysteinemia occurs in 5-7% of the population
  • Recognized as an independent risk factor for the development of atherosclerotic vascular disease and venous thrombosis
  • Can result from genetic defects, drugs, vitamin deficiencies, or smoking 
  • Homocysteine implicated directly in  vascular injury including:
    • Intimal thickening
    • Disruption of elastic lamina
    • Smooth muscle hypertrophy
    • Platelet aggregation
  • Vascular injury induced by leukocyte recruitment, foam cell formation, and inhibition of NO synthesis

Glomerular Filtration Rate

  • The relationship between chronic kidney disease and cardiovascular risk is long standing
  • Is this the result of multiple comorbid conditions (such as diabetes and hypertension), or is there an independent relationship?
  • Recent studies have sought to identify whether creatinine clearance itself is inversely related to increased cardiovascular risk, independent of comorbid conditions
  • Reduced GFR has been associated with:
    • Increased inflammatory factors
    • Abnormal lipoprotein levels
    • Elevated plasma homocysteine
    • Anemia
    • Arterial stiffness
    • Endothelial dysfunction

Other Biochemistry Notes :-

Carbohydrate Metabolism

VITAMIN PYRIDOXINE AND BIOTIN

Vitamin A

VITAMIN D

Pyrimidine metabolism

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