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Myocardiac markers

Myocardiac markers



cardiac markers

cardiac markers



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    Myocardiac markers Myocardiac markers Presentation Transcript

    • Myocardial Injury Detection Dr. B. K. Iyer
    • Myocardial injury
      • Irreversible injury typically requires 30 minutes of ischemia
      • Chronic o 2 deficiency makes cells more resistant
      After 30-60 min, cell death starts 80% of cells at risk die within 3 hours Almost 100% by 6 hours of ischemia
      • Time to diagnosis and therapy is critical
      • Myocardial Survival
      100 50 0 Fraction of ischemic cells already dead 0 1 2 3 4 5 6 Hours of Ischemia
      • Time to diagnosis and therapy is critical
      • Spectrum of ischemia
        • No Symptoms
      • NON-Q MI
      • Q-WAVE MI
      Crescendo Angina ANGINA
    • Acute coronary syndrome
      • Term describing spectrum of ischemic changes
    • MI Diagnosis - WHO criteria
      • History of ischemic type of chest discomfort
      • Evolutionary ECG changes
      • Rise and fall in serum cardiac  markers
    • MI Diagnosis - WHO criteria
      • Limitations
      • 1/3 of patients with AMI do not present with chest pain
      • Only ½ present with Q waves or ST elevation
      • ½ of patients with suggestive chest pain have non-diagnostic ECG.
      • With use of new markers, additional 1/3 are diagnosed to have MI.
      • Perioperative MI and post PCI MI - Symptoms may be absent and ECG changes may be non specific.
    • Myocardial injury markers
    • Cardiac Markers
      • Cardiac markers = intracellular macromolecules [proteins] which mark myocardial injury.
      • Choice of biochemical cardiac marker
        • Which marker(s) to offer?
        • Do ideal markers differ in varying circumstances?
        • Is one marker enough?
        • What is the turnaround time?
      • Significance of positive markers without clinical picture of “MI”
    • Criteria of Ideal marker
      • Found only in tissue of interest
      • High gradient to allow early detection
      • Detection of marker must enable intervention that prevents or minimizes effects of disease
      What is an ideal cardiac marker?
    • Ideal cardiac marker
      • Good specificity - detects only cardiac damage
      • Optimal sensitivity and detectable while damage is reversible or preventable
      • Correlates with amount of injury and enables prognosis prediction
      • No single marker meets all needs
        • Previous concept --‘Cardiac Enzymes’
        • Now = Non-enzymatic markers
      • Cheap, rapidly measurable and easy to detect
    • Myocardial contents
      • Myocardial proteins
      Myoglobin Actin, Myosin Troponin LDH CK, AST
    • Myocardial contents
      • With cell death, holes develop in cell membrane
      • Contents leak dependent on size, solubility
        • Small, cytoplasmic markers leak fast
        • Larger, complexed markers released slowly
      • Standard teaching - markers only released with irreversible injury
      • Because markers are proteins, will not leak with ischemia
      • Marker release = cell death
    • Myocardial contents
      • Concentration gradient also important
      • High gradient between serum and cells allows early detection
      • Low gradient makes test insensitive to myocardial injury
    • Myocardial injury markers Cardiac enzymes Non enzymes
      • Troponins
      • Others
    • Which markers?
      • Joint group of laboratorians, cardiologists, emergency med physicians published in July 1999 (clin chem 1999;45:1104-1121)
    • Which markers?
      • Recommend early marker (+ by 6 hrs) and more definitive late marker (high specificity)
      • Rapid change marker myoglobin as best early marker especially to detect reinfarction
        • Isoforms also possible choice
      • However, myoglobin detection has serious limitation
        • What is that?
      • Low concentration gradient between serum and cells
    • Which markers?
      • Cardiac Troponin I or Troponin T popular as definitive marker
        • But, this is not a early marker
      • Direct relation between level of Troponins, risk (up to about 2 ng/ml)
    • Clinical significance
      • Myocardial markers can detect smaller amounts of damage than clinical criteria
      • Numerous studies show patients with “unstable angina” and positive markers have high incidence of cardiac events in follow-up
      • Negative markers indicate low risk patients
      • Relative risk with positive markers averages 6:1 compared to negative
      • Higher for Troponin T than Troponin I
    • Clinical significance
      • With diagnostically confirmed ECG, markers not needed for diagnosis but for monitoring progress.
      • Guidelines suggest need for 2 markers, though rationale not given for late presentation
      • Role of new early markers (such as glycogen phosphorylase b, Human fatty acid binding protein)
    • Myocardial markers
      • Troponin markers
      • Found only in muscle - predominantly bound to myofibers; small fraction free
      • Troponin complex – C , I , T
        • C – Binds Ca++
        • I – binds to actin; inhibit actin-myosin interaction
        • T – binds to Tropomyosin
      TnI Actin Tropomyosin TnC TnT
    • Myocardial markers
      Troponin Myoglobin CK, AST LDH Normal
      • 0 6 12 18 24 2 3 4 5 6 7 8 9 10
      • Days
      • Hours
    • Myocardial markers
    • Sensitivity
      • 10
      Size of Myocardial Infarction (grams
      • 0.01
      • 100
      • 0.001
      • 1
      • 0.1
      • ECHO
      • CK,
      • AST
      • CK-
      • MB
      • TROPONIN
      • ECG
    • Sensitivity Wasimuddin et al. Crit Care Med, 1994 6 557 PAIN < 30 min NO ECG CHANGE 16 551 PAIN > 30 min OR ECG CHANGE 49 312 PAIN > 30 min, ECG CHANGE 20 1420 ANY CHEST PAIN % MI NUMBER CATEGORY
    • Sampling frequency
      • Guidelines suggest 0, 3, 6, 9, 12 hr after presentation for both early and late marker
      • If positive, may discontinue after 9 hr specimen
      • Currently, not clear if late marker should be measured at 3 hr or not
      • Always recommend at least 2 determinations
    • Cardiac protein changes with thrombolysis / Reperfusion
      • Guidelines suggest use of markers at baseline, 90 minutes to detect reperfusion, but do not offer specific cut points to determine reperfusion
      • Increase also depends on infarct size, time since onset
      RELATIVE CONCENTRAITON TIME AFTER INFARCTION Successful thrombolysis Normal MI, unsuccessful thrombolysis
    • MI  >48 hrs
      • CK MB may have returned to normal
      • Tn I or Tn T preferred
        • (Tn I 5-10 days & Tn T 5-14 days)
      • Reinfarction
        • CK MB isoforms / Myoglobin
        • Normalizes by 24 hrs ; Myoglobin less specific
    • MI  >48 hrs
      • Baseline sample in EDTA – preserved activity for days
        • >72 hrs – CK MB may be used
        • > 50%     above mean of 2 preceding values
        • > 25%      if on the downslope  
    • Release mechanism
      • FENG et al., A J clin pathol 1998;110:70
      • Induced coronary stenosis in 12 pigs, compared to 5 controls
      • Measured TROPONIN, MYO, CK MB
      • Studied myocardium by biopsy and autopsy with gross, micro, histochemistry
      • With stenosis, 8 pigs had necrosis, 4 no necrosis (only em lesions)
    • Release mechanism
      • All markers went up after induction of ischemia in both groups;
      • Only TROPONIN significantly higher than control in necrosis and ischemia (higher in former)
    • Myocardial markers
    • Myoglobin
      • Not specific for cardiac muscle
      • Found in skeletal, cardiac muscle
      • Small size allows early detection, rapid clearance
      • Heme  protein and hence seen in-
        • skeletal muscle injury
        • renal failure
      • Useful in early diagnosis of AMI
    • Creatine kinase
      • Sensitive detector of AMI, available in most hospitals
      • Found mainly in striated muscle, brain (does not cross blood-brain barrier)
      • Much more per gm of tissue in skeletal compared to cardiac muscle
      • Relatively high gradient (2000x plasma in cardiac)
    • Creatine kinase
      • Disadvantages: 
        • Low specificity ;
        • High false positivity
          • Muscle Diseases, Muscle trauma & Vigorous exercise
          • Alcohol / Diabetes Mellitus
          • Convulsions
          • Pulmonary Embolism
          • Thyroiditis   
          • Surgery, Catheterisation, CVA 
          • Rhabdomyolysis
    • CK MB
      • Trace form in all muscle; 1-2% in skeletal, 15-20% in cardiac
      • Higher in skeletal in neonates, chronic muscle injury, respiratory muscles
      • Different assays; results not interchangeable
      • Dimer: M & B monomers
      • CK- 1: BB; neural & mesenchymal tissue
      • CK- 2: MB; muscle (<1%); heart (<40%)
      • CK- 3: MM; heart (60 - 80%); muscle (>99%)
    • CK MB isoforms
      • After relase, CK MB cleaved by removing single amino acid, changing charge
      • Half-life of tissue isoform = only 3 hours
      • Differentiates acute from chronic or remote muscle injury; not cardiac specific
    • Troponin
      • New standard for detection of myocardial injury
      • Normally negligible levels in circulation
        • > 20 times in injury
      • Can detect even minor degrees of myocardial damage
      • Release from fibrils causes high levels for many days
      • For tni and tnt, differences between cardiac and skeletal muscle forms
    • Troponin significance
      • Several studies suggest positive tn at presentation associated with poorer prognosis
      • Not clear if related to other variables
        • Larger infarct,
        • Delayed presentation
    • Troponin
      • Troponins – ‘False positivity’ 
        • Non – ischemic cardiac injury
        • End stage heart failure
        • Non-ischemic cardiomyopathy
        • Myocarditis
        • Skeletal muscle problems (1st generation assays)
        • Muscular dystrophy,Injury, Myositis,
        • Polymyositis
        • Fibrin clots
        • Heterophil antibody
        • Renal Failure 
    • Troponin T (TnT)
      • Cardiac-like form found in fetal skeletal muscle
      • About 6% cytosolic, detectable earlier than tni
      • Second generation assay detects less damage than tni
      • One assay manufacturer
    • Troponin I (TnI)
      • Found only in cardiac muscle
      • Only about 2% cytosolic, later detection than tnt
      • No standardization; different assays produce different results, detection limits
    • Tn in renal failure
      • Elevated TnT seen commonly in renal failure (up to 50%)
      • High TNI seen occasionally
      • Patients with tn have high likelihood of cardiac death in year after detection
      • ? Higher likelihood for TNI
    • Problems with TnI
      • Different forms of troponin I found in serum (free, bound, and forms of bound)
      • Cannot confirm troponin results with any other assay since it is more “sensitive”
      • Different manufacturer’s assays variably measure these
      • No standardization, making comparison between labs difficult
      • In assays, fibrin may trap labeled antibody
      • Patients with ua / mi often on heparin, preventing full use of fibrinogen
      • Residual fibrinogen may form fibrin in instrument, causing false positive results
      • Rheumatoid factor, autoantibodies may cause false positive with some assays
      Problems with TnI
    • New Markers
      • Early rising markers provide potential for early diagnosis
      • Heart Fatty Acid Binding Protein(h FABP)
      • Combined with myoglobin, gives specificity 
      • Useful for estimating infarct size after reperfusion
      • Longer window (MHC return normal = 14 days) 
      • Glycogen Phosphorylase Isoenzyme BB (GPBB)
    • Early markers of cardiac injury
    • Early markers
      • Since treatment of patients with thrombolytic therapy is more beneficial when started earlier after AMI, there is currently a lot of interest in defining those plasma marker proteins that permit an early and sensitive detection of AMI.
      • Non-enzymatic cardiac proteins are being used as early diagnostic markers of acute myocardial injury abundantly
      • What are these early markers?
    • hFABP
      • Heart Fatty acid-binding protein (hFABP; 15 kDa) and Myoglobin (17 kDa) belong to the early biochemical cardiac markers and they represent the soluble cytoplasm of cardiomyocytes.
      • Due to their small size (15 and 17.8 kDa, respectively), they are released into plasma in significant amounts within 3 h of the onset of AMI, while plasma concentrations usually return to normal within 24 h [1–4].
    • hFABP
      • These characteristics allow:
        • Early confirmation of AMI,
        • Monitoring of coronary recanalisation or reinfarction, and
        • Early estimation.
      • What is significance of hFABP?
        • Cytosolic protein involved in intracellular transport of FAs
        • Aids metabolism of FA within myocyte
        • Related with muscle FA oxidation capacity
    • Is hFABP new?
      • Is it new?
      • No, usefulness of hFABP for detection of AMI has been known since 1988 but extensive clinical studies after that have proven its significance
    • FA metabolism depends on Transport Uptake Delivery to intracellular sites of β -oxidation The insoluble FA bound to special carriers to enhance their rate of transport and cellular uptake Plasma triglycerides serve to supplement FA transport Plasma albumin augments circulatory transport by increasing FA binding sites and binding of non-esterified FAs Fatty acid metabolism
    • FABP types
      • Intestine
      • Liver
      • Cardiac muscle [10-30%]
      • Skeletal muscle
      • Adipocytes
      • Kidney
      • Brain
      • Retina
      • Myelin
      • FABP levels
      FABP levels in AMI and UAP at admission and one hour later
      • Comparison of FABP and CPK levels
    • Why is hFABP earlier?
      • In conclusion, plasma cardiac Troponin T concentration at 48 h after infarction can be used to distinguish MI, whereas H-FABP concentration at 3 h can be used for stratification of risk according to infarct size.
      • Why so?
      Pflügers Arch – Eur J Physiol (2000) 439:416–422
    • Why is hFABP earlier?
      • In contrast to hFABP and myoglobin, cardiac Troponin T is a protein that is structurally bound to the myofibrillar structure and hence it needs to dissociate before it can be detected in the blood
      • Besides, due to the small size, hFABP and Myoglobin can cross the endothelial cell barrier directly whereas Troponin must be transported through lymph drainage [like CK-MB]
    • Is hFABP earlier than myoglobin?
      • In contrast to myoglobin, hFABP has 4 times higher concentration gradient.
      • Thus, whilst both are released almost simultaneously, the percentage rise in hFABP is much sharper and higher.
        • Peak rise in hFABP = 30 fold vis-à-vis 15 fold with myoglobin
    • Why is hFABP more specific than myoglobin?
      • As compared to the amount of myoglobin present in the myocardium, double that amount is present in the skeletal muscle
      • In contrast to this myoglobin distribution, for hFABP only 10-50% of the myocardial amount is present in the skeletal muscle.
    • Does hFABP detect stable angina also?
      • As compared to the AMI and unstable angina, stable angina does not require acute intervention but bed rest principally
      • In contrast, episodes of unstable angina are like mini infarctions and hence more essential to establish faster.
      • Whether the test for hFABP is positive or not in unstable angina depends upon the amount of cell necrosis that occurs.
    • Is hFABP testing an ELISA test?
      • There are ELISA tests for the detection of hFABP but an immunochromatographic test to detect hFABP is faster.
      • At a predefined position, there are hFABP specific antibodies which react with hFABP if present in the blood sample to give visible proof.
    • What is sensitivity in hFABP testing?
      • This is a measure for the percentage of infarcts from the test detects.
      • The higher the number, the better it is.
      • A sensitivity of 100% would be ideal.
      • Sensitivity is calculated by setting the number of detected infarcts [TP = true positive] in relation to the number of infarcts not detected [FN= false negative]
      • Sensitivity % = TP/[TP+FN] x 100
    • Can false positives occur in hFABP testing?
      • Yes, there are 2 conditions where false positives can occur while testing for hFABP
        • Excessive physical activity – due to damage to skeletal muscle cells and release of hFABP with subsequent rise in the levels of hFABP;
        • Renal insufficiency – when deficient kidneys are not able to flush out the normal levels of hFABP presented for excretion by release from the skeletal muscles and subsequent increase in levels.
    • In case of false +ve with hFABP, what is done?
      • Retesting after half an hour or one hour
      • If the second test yields darker line, this is more likely then that an infarction has occurred.
    • What is specificity in hFABP testing?
      • This is a measure for how often a non-infarction is correctly recognized as such.
      • The higher the number, the better it is and a sensitivity of 100% would be ideal.
      • Specificity is calculated by setting the number of detected non-infarctions [TN=true Negative] in relation to the number of non-infarctions incorrectly detected as infarctions [FP=false positive]
      • Sensitivity % = TN/[TN+FP] x 100
    • Can false negatives occur in hFABP testing?
      • Yes, especially in the diagnostic early window period due to individual differences in the infarction process.
      • Hence, althought the test has a very high sensitivity [over 90%], it cannot be said to have absolute reliability.
      • For that matter, there are no medical tests with 100% reliability.
    • Any medications interfere with hFABP testing?
      • No interference is known to date with detection of hFABP.
    • Emerging Markers
      • Brain Natriuretic Peptide (BNP)
        • Predictor of mortality,progressive CHF & recurrent MI in ACS (STEMI,NSTEMI,UA)
      • Carbonic anhydrase III isoenzyme
        • Improves specificity & sensitivity of myoglobin