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Cardiac Biomarkers: Definitions, Use and Utility Herbert A. Hartman III, M.D. Resident, Internal Medicine University Hospitals/Case Medical Center – PowerPoint PPT presentation

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Title: Cardiac Biomarkers: Definitions, Use and Utility?


1
Cardiac Biomarkers Definitions, Use and
Utility?
  • Herbert A. Hartman III, M.D.
  • Resident, Internal Medicine
  • University Hospitals/Case Medical Center
  • PGY-3 Senior Talk

2
Objectives
  • Present background scientific information
    concerning cardiac biomarkers including current
    and historical markers?
  • Present information about the medical use and
    utility of cardiac biomarkers
  • Identify CKMB and TI results in situations where
    false-positive and false-negative possibilities
    should be entertained??
  • Describe the associations between TI, CKMB and CK
    in patients with suspected acute coronary
    syndrome as compared to patients with enzyme
    elevations in non-ACS situations by using
    examples??
  • Inform audience briefly about ongoing clinical
    trials regarding use of cardiac biomarkers?

3
Definitions
  • A biomarker is a substance used as an indicator
    of a biologic state. It is a characteristic that
    is objectively measured and evaluated as an
    indicator of normal biologic processes,
    pathogenic processes, or pharmacologic responses
    to a therapeutic intervention.--Wikipedia
  • Cardiac markers are substances released from
    heart muscle when it is damaged as a result of
    myocardial infarction.
  • --Wikipedia
  • Note As will be discussed, it has been shown
    that cardiac markers can be released from
    cardiac tissue as a result of damage from
    processes other than MI

4
Diagnosis of Acute Myocardial Infarction
  • Triad of Chest pain, ECG manifestations and
    elevations of biomarkers of cardiac injury
  • Chest Pain highly variable and subjective
  • ECG Objective ST or T-wave changes
  • Biomarker elevations Objective data defining
    ACS/AMI, Right?
  • sometimes

5
What biomarkers are good for
  • Diagnosing AMI/ACS
  • Detecting myocardial damage whether due to AMI or
    other cardiac process
  • Risk-stratifying patients
  • Commenting on Prognosis
  • In ACS, pre and post PCI/reperfusion therapy
  • CHF
  • Renal Disease
  • Stressing interns, confusing residents and
    worrying cardiology fellows

6
Which Biomarkers?
  • CK (CPK)
  • CK-MB
  • Troponin-I/T
  • LD (LDH)
  • Myoglobin
  • ALT/AST
  • Others

7
Creatine Kinase
  • Creatine kinase (CK/CPK) is an enzyme expressed
    in a number of tissues.
  • Function it catalyses the conversion of creatine
    to phosphocreatine degrading ATP to ADP
  • (In cardiac as well as other tissues,
    phosphocreatine serves as an energy reservoir for
    the rapid regeneration of ATP)
  • The CK enzyme consists of two subunits, B (brain
    type) or M (muscle type), Making three different
    isoenzymes CK-MM, CK-BB and CK-MB
  • CK-BB occurs mainly in tissues, rarely of any
    significance in the bloodstream
  • Skeletal muscle expresses CK-MM (98) and low
    levels of CK-MB (1)
  • Sensitive lab tests can pick up these low levels
    of CK-MB from skeletal muscle
  • The myocardium has CK-MM at 70 and CK-MB at 30
  • CK therefore, lacks specificity for cardiac
    damage and needs to be augmented with the MB
    fraction and Relative Index (RI) to indicate true
    cardiac damage

8
CK
  • Needs gttwo-fold increase with simultaneous
    increase in CK-MB to be diagnostic for MI
  • May be problematic for use in patients with very
    little muscle mass
  • Increases 4-6 hours after onset of MI
  • Peak activity is at 18 to 24 hours
  • Usually has returned to baseline levels by 36
    hours
  • False positive (for MI) CK elevation can be seen
    in
  • Significant skeletal muscle injury
  • Significant CNS damage (Stroke/Trauma)
  • Occasionally from GI, renal, urologic disease
  • elevations of CK secondary to non-cardiac causes
    have been noted to increase following a flatter
    curve, rising and disappearing at a slower pace
    that a cardiac source

9
CK-MB
  • High specificity for cardiac tissue
  • Begins to rise 4-6 hours after onset of
    infarction
  • Peaks at about 12 hours
  • Returns to baseline at 24-36 hours
  • Can be used to indicate early re-infarction if
    level normalizes and then increases again
  • Lab test is for mass, not activity mass assays
    are reported to be more sensitive.
  • False positive (for MI) CK-MB elevation can be
    seen in
  • Significant skeletal muscle injury
  • Cardiac injury for reason other than MI
  • Cardioversion, Defibrillation (ACLS CPR/ICD
    firing)
  • Blunt chest trauma (MVA/Sports injuries)
  • Cardiac AND non-cardiac surgical procedures
  • Cocaine abuse (vasospasm, tachycardia,
    perfusion/demand mismatch)
  • Non often elevated in myocarditis, unless severe

10
Troponin
  • Troponin is a complex of three regulatory
    proteins that is integral to non-smooth muscle
    contraction in skeletal as well as cardiac muscle
  • Troponin is attached to the tropomyosin sitting
    in the groove between actin filaments in muscle
    tissue
  • Troponin has three subunits, TnC, TnT, and TnI
  • Troponin-C binds to calcium ions to produce a
    conformational change in TnI
  • Troponin-T binds to tropomyosin, interlocking
    them to form a troponin-tropomyosin complex
  • Troponin-I binds to actin in thin myofilaments to
    hold the troponin-tropomyosin complex in place
  • Thus far, studies have failed to find a source of
    Troponin-I outside the heart, but have found some
    Troponin-T in skeletal muscle
  • Because of its increased specificity, our lab
    uses Troponin-I

11
More about Troponin
  • Laboratory range definition
  • Cutoff is set at 99th percentile of a normal
    reference population, variation of less than 10
  • Since troponin levels are virtually undetectable
    in normal subjects, this 99th percentile
    corresponds to lt0.06
  • -heparin in sample can result in lowered values

12
Troponin Use
  • Troponin-I levels begin to rise 2-3 hours after
    onset of MI and roughly 80 of patients with AMI
    will have positive values at 3 hours
  • Elevations in Troponin-I and Troponin-T can
    persist for up to 10 days after MI
  • Therefore it has good utility for retrospectively
    diagnosing AMI
  • Remember, CK-MB returns to baseline by 48 hours
  • Troponin release can also be precipitated by
    other conditions that cause myocardial damage

13
Troponin Influence on Prognosis
  • Since normal people have virtually nil levels of
    troponin in serum, it is thought that detectable
    levels indicate chronic disease even if not acute
    myocardial damage
  • Degree of elevation of Troponin value can give
    prognostic information
  • Some data suggest that the 72-96 hour peak TI
    value correlates with infarct size. This is not
    necessarily true with other biomarkers

14
Lab Details
  • Run in chemistry section of UH lab on sample of
    patient serum
  • Red top tube (you may need to draw for yourself
    someday)
  • Type of chemistry reaction
  • CK/CK-MB Radioimmunoassay
  • Troponin Immunoassay
  • An immunoassay is a biochemical test that
    measures the concentration of a substance in
    serum or urine, using the reaction of a specific
    antibody (often monoclonal Ab) or antibodies to
    bind to its antigen. To determine a numerical
    result (as in cardiac biomarkers), the response
    of the fluid being measured must be compared to
    standards of a known concentration. One of the
    most common methods is to label either the
    antigen or the antibody with an enzyme (EIA),
    radioisotope (RIA), magnetic labels (MIA) or
    fluorescence.

15
Other Biomarkers
  • LD (LDH)
  • Used in the past along with aminotransferases to
    diagnose AMI. LD is non-specific for cardiac
    tissue, which contains LD-1. However, pancreas,
    kidney, stomach tissue and red cells also contain
    LD-1. In the setting of AMI, LD rises at about 10
    hours, peaks at 24-48 hours, and remains elevated
    for up to 8 days.
  • Myoglobin
  • Ubiquitous small-size heme protein released from
    all damaged tissues. Increases often occur more
    rapidly than TI and CK. Not utilized often for
    AMI/cardiac damage assessment because of its very
    rapid metabolism (short plasma half-life) causing
    short burst increases that are difficult to
    assess clinically, as well as its lack of
    specificity for cardiac tissue.
  • ALT/AST
  • Used as surrogate markers of cellular damage in
    the past. Very non-specific so not used for
    assessment of myocardial damage any longer
  • H-FABP
  • Heart-type fatty acid binding protein
  • Kinetically similar to myoglobin but more
    specific to cardiac tissue which contains a
    greater percentage of this protein than skeletal
    muscle
  • May also have role in prediction- prognosis in
    patients with NSTEMI
  • Current studies ongoing to further evaluate its
    utility

16
UH Laboratory
  • CK (U/L) Normal Range 0-215
  • CKMB (ng/mL)
  • RELATIVE INDEX- RI (MB OF CK)
  • CKMB lt7 and RI lt4 Negative
  • CKMB lt7 and RI gt4 Equivocal
  • CKMB gt7 and RI lt4 Equivocal
  • CKMB gt7 and RI gt4 Positive
  • TROPONIN I
  • LESS THAN 0.07 NG/ML NEGATIVE
  • 0.07 - 0.5 NG/ML CONSISTENT WITH POSSIBLE
    CARDIAC DAMAGE AND POSSIBLE INCREASED CLINICAL
    RISK.
  • gt0.5 NG/ML CONSISTENT WITH CARDIAC DAMAGE,
    INCREASED CLINICAL RISK AND MYOCARDIAL INFARCTION.

17
Timing Summary
18
Elevated cardiac biomarkers in non-ACS situations
  • The ACC/AHA task force states that clinical
    evidence of myocardial ischemia is necessary in
    addition to biochemical evidence because
    biochemical markers can be elevated in numerous
    other physiologic scenarios
  • Some as previously described with CK and TI
  • Others sepsis, hypovolemia, atrial fibrillation,
    PE, HF, myocarditis, myocardial contusion, renal
    failure and tachycardia
  • In patients with low pre-test probability of CHD
    or ACS, increased cardiac biomarkers may skew
    analysis and diagnosis causing tunnel vision

19
Elevated cardiac biomarkers in non-ACS situations
  • Situations of prolonged myocyte ischemia--cell
    membrane breaks down releasing myofibril cell
    components into the bloodstream
  • Tachy/bradyarrhythmias (reduced diastolic
    coronary filling time),
  • prolonged/profound hypotension, HF-acute and
    chronic, pulmonary hypertension
  • CPR/Cardiac contusion
  • Electrical Cardioversion/ICD firing
  • PE, pericarditis, myocarditis
  • Sepsis (SIRS)-- secondary both to hypotension as
    well as direct effects of inflammatory mediators
    and myocardial oxygen demand-supply mismatch)
  • Apical Ballooning syndrome-- Takotsubo
    Cardiomyopathy
  • Chemotherapy, e.g. Adriamycin, Herceptin
  • Toxins, cocaine
  • Extreme exertion--Marathons, ultramarathons,
    Military basic training
  • LVH--leads to subendocardial ischemia by
    increased O2 demand from increased mass
  • HF--discussed separately

20
Biomarkers in Renal Failure
  • CAD is highly prevalent in patients with
    end-stage renal disease and patients on dialysis.
  • HTN and DM are very prevalent in this population
  • ESRD itself as well as dialysis change normal
    homeostatic mechanisms for lipids, calcium and
    electrolytes
  • Like HF patients, it has been found that ESRD
    patients nay have low levels of troponin
    elevations chronically without evidence of
    myocardial damage, although the mechanism and
    significance are not known.
  • Possible reasons parallel those for HF
  • significant LVH, endothelial dysfunction, loss of
    cardiomyocyte membrane integrity and possibly
    impaired renal excretion

21
Biomarkers in Renal Failure
  • Increasing evidence suggests that chronically
    elevated troponin levels indicate a worse
    long-term prognosis for cardiovascular outcomes
    in this patient population
  • False positives have been reported with use of
    troponin-T in ESRD patients but not as much with
    troponin-I
  • CK plasma concentrations are elevated in 30-70
    of dialysis patients at baseline, likely
    secondary to skeletal myopathy, intramuscular
    injections and reduced clearance
  • CK-MB 30-50 of dialysis patients exhibit an
    elevation in the MB fraction gt5 without evidence
    of myocardial ischemia
  • Therefore, the most specific marker for
    suspected AMI in ESRD patients is Troponin-I with
    an appropriate sequential rise

22
Biomarkers in Heart Failure
  • It has been reported that small elevations in TI
    are chronically found in patients with heart
    failure, without current symptoms of ischemia
  • In these studies, the presence of TI remained an
    independent predictor of death
  • On the same note, a positive TI in a hospitalized
    patient with ADHF is associated with a higher
    in-hospital mortality 8 vs. 2.7 Plt0.001 (data
    from Peacock et al. reference at end)
  • The presumed mechanism of cardiac troponin
    release in HF is from
  • myocardial strain-volume and pressure overload of
    both ventricles causing excessive wall tension
    leading to decreased subendocardial myocyte
    perfusion.
  • There is a correlation of elevated BNP and TI
    release
  • myocyte death- continued wall tension and other
    mediator stimulation (sympathetic stimulation,
    increased renin-AII system, inflammatory
    cytokines) is thought to lead to progressive
    myocyte apoptosis and cardiac dysfunction

23
Case 1
  • 62 yo male with PMH of HTN x20 years, DM II x 10
    years presents with 2 hours of mid-sternal chest
    pain radiating to left arm and jaw, with
    associated SOB and diaphoresis. He was given O2,
    ASA 325mg and SL NTG en-route by EMS. Upon
    arrival to ED his CP is 5/10, somewhat relieved
    by the nitro, His ECG shows TWI in v2-v6. BP
    150/100, P115, R18, 96 2L NC

24
Case 1 Discussion
  • What is your pre-test probability for ACS before
    you get cardiac biomarkers in this patient?
  • Which biomarkers to you think will be positive at
    this time? In 12 hours?
  • Will you wait for the biomarker results to start
    treatment for ACS?

25
Timing Revisited
26
Case 2
  • 55 yo female with no significant PMH but positive
    FHx for early MI in her brother at 48 years, and
    her father at 56 years, presents with
    mid-epigastric pain episodes lasting 1hr each,
    off and on for the last 24 hours after her labor
    Day BBQ (1st episode 24hrs ago), and she thinks
    her right arm is tingly. The last episode was 2
    hours ago, but the pain is gone now. The ED gave
    her 1 nitropaste, 81mg asa x4 and Lovenox
    1mg/kg, as well as Zofran and Morphine. Her ECG
    shows TWI in lead II. Pulse is 100. Other VS WNL.

27
Case 2 Discussion
  • What is your pre-test probability of ACS in this
    patient and how are you going to utilize your
    blood tests?
  • Obviously the ED physician felt this was likely
    to be ACS, do you agree?
  • If her troponin comes back as 0.07 with a normal
    CK and CK-MB what will you do?

28
UH Laboratory
  • CK (U/L) Normal Range 0-215
  • CKMB (ng/mL)
  • RELATIVE INDEX- RI (MB OF CK)
  • CKMB lt7 and RI lt4 Negative
  • CKMB lt7 and RI gt4 Equivocal
  • CKMB gt7 and RI lt4 Equivocal
  • CKMB gt7 and RI gt4 Positive
  • TROPONIN I
  • LESS THAN 0.07 NG/ML NEGATIVE
  • 0.07 - 0.5 NG/ML CONSISTENT WITH POSSIBLE
    CARDIAC DAMAGE AND POSSIBLE INCREASED CLINICAL
    RISK.
  • gt0.5 NG/ML CONSISTENT WITH CARDIAC DAMAGE,
    INCREASED CLINICAL RISK AND MYOCARDIAL INFARCTION.

29
Case 3
  • 73 yo AAM presents to clinic for routine HF
    check. By office scale he has gained 10 since
    last visit 2 months ago. He admits to sleeping
    upright and has1block DOE. He denies angina/chest
    pain. In-office ECG is notable for strain
    pattern. He is diagnosed with HF exacerbation and
    direct admitted. AMI panel is drawn and CK is
    250, MB is 8, TI is 1. BNP is 3500. 2nd TI is 1.2
    and 3rd is 1.1. He is hypertensive but stable.

30
Case 3 Discussion
  • What is the likely explanation for this patients
    elevated cardiac biomarkers?
  • How do you plan to manage this patient from here?
    Does he need to be in the CICU? Does he need
    further enzyme studies?

31
Case 4
  • 44 yo AAF with ESRD secondary to HTN on dialysis
    (HD x 7 years) presents with chest pain at
    dialysis. Her end-HD BP was 190/100 and she
    reports a headache. ECG shows Q-waves in the
    inferior leads but no acute changes. She got her
    flu shot at dialysis today. You draw AMI panel
    and CK is 300, MB 15, RI 4 and TI is 1.13

32
Case 4 Discussion
  • If her serial enzymes stay at the same levels
    what is her general Cardiovascular prognosis?
  • Given the story, what other findings do you
    expect on her ECG?
  • What is the likely physiological mechanism for
    her elevated CK? Her TI?
  • She refuses cath. What is the best, simplest way
    to attenuate her cardiovascular mortality?

33
References
  • Zethelius, B. et al. Use of multiple Biomarkers
    to Improve the Prediction of Death from
    Cardiovascular Causes. NEJM 20083582107-16.
  • Peacock, F. et al. Cardiac Troponin and Outcome
    in Acute Heart Failure. NEJM 20083582117-26.
  • Brunwald, E. Biomarkers in Heart Failure. NEJM
    20083582148-59
  • Foy, A and Weitz, H. When to Suspect a
    false-positive cardiac troponin. Resident and
    Staff Physician 200854(4)32-36.
  • Jaffe, A. Troponins, creatine kinase, and CK
    isoforms as biomarkers of cardiac injury.
    Up-To-Date. 2008.
  • Henrich, W. Serum cardiac enzymes in patients
    with renal failure. Up-To-Date. 2008.
  • Gibson, C. Elevated serum cardiac troponin
    concentration in the absence of an acute coronary
    syndrome. Up-To-Date. 2008.

34
Objectives
Cardiac Biomarkers Definitions, Use and Utility?
  • Present background scientific information
    concerning cardiac biomarkers including current
    and historical markers
  • Present information about the medical use and
    utility of cardiac biomarkers
  • Identify CKMB and TI results in situations where
    false-positive and false-negative possibilities
    should be entertained??
  • Describe the associations between TI, CKMB and CK
    in patients with suspected acute coronary
    syndrome as compared to patients with enzyme
    elevations in non-ACS situations by using
    examples??
  • Inform audience briefly about ongoing clinical
    trials regarding use of cardiac biomarkers?
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