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

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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

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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

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Which Biomarkers?

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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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.

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Timing Summary
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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

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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

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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

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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

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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

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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

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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?

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Timing Revisited
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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.

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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?

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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.

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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.

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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?

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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

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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?