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Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
Cardiac Biomarkers.ppt
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Cardiac Biomarkers.ppt

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  • 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 <ul><li>Present background scientific information concerning cardiac biomarkers including current and historical markers
 </li></ul><ul><li>Present information about the medical use and utility of cardiac biomarkers </li></ul><ul><li>Identify CKMB and TI results in situations where false-positive and false-negative possibilities should be entertained

 </li></ul><ul><li>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

 </li></ul><ul><li>Inform audience briefly about ongoing clinical trials regarding use of cardiac biomarkers
 </li></ul>
  • 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 <ul><li>Triad of Chest pain, ECG manifestations and elevations of biomarkers of cardiac injury </li></ul><ul><ul><li>Chest Pain: highly variable and subjective </li></ul></ul><ul><ul><li>ECG: Objective ST or T-wave changes </li></ul></ul><ul><ul><li>Biomarker elevations: Objective data defining ACS/AMI, Right? </li></ul></ul><ul><ul><ul><li>sometimes </li></ul></ul></ul>
  • 5. What biomarkers are good for: <ul><li>Diagnosing AMI/ACS </li></ul><ul><li>Detecting myocardial damage whether due to AMI or other cardiac process </li></ul><ul><li>Risk-stratifying patients </li></ul><ul><li>Commenting on Prognosis </li></ul><ul><ul><li>In ACS, pre and post PCI/reperfusion therapy </li></ul></ul><ul><ul><li>CHF </li></ul></ul><ul><ul><li>Renal Disease </li></ul></ul><ul><li>Stressing interns, confusing residents and worrying cardiology fellows </li></ul>
  • 6. Which Biomarkers? CK (CPK) CK-MB Troponin-I/T LD (LDH) Myoglobin ALT/AST Others
  • 7. Creatine Kinase <ul><li>Creatine kinase (CK/CPK) is an enzyme expressed in a number of tissues. </li></ul><ul><li>Function: it catalyses the conversion of creatine to phosphocreatine degrading ATP to ADP </li></ul><ul><li>(In cardiac as well as other tissues, phosphocreatine serves as an energy reservoir for the rapid regeneration of ATP) </li></ul><ul><li>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 </li></ul><ul><li>CK-BB occurs mainly in tissues, rarely of any significance in the bloodstream </li></ul><ul><li>Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%) </li></ul><ul><ul><li>Sensitive lab tests can pick up these low levels of CK-MB from skeletal muscle </li></ul></ul><ul><li>The myocardium has CK-MM at 70% and CK-MB at ~30% </li></ul><ul><li>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 </li></ul>
  • 8. CK <ul><li>Needs >two-fold increase with simultaneous increase in CK-MB to be diagnostic for MI </li></ul><ul><li>May be problematic for use in patients with very little muscle mass </li></ul><ul><li>Increases 4-6 hours after onset of MI </li></ul><ul><li>Peak activity is at 18 to 24 hours </li></ul><ul><li>Usually has returned to baseline levels by 36 hours </li></ul><ul><li>False positive (for MI) CK elevation can be seen in: </li></ul><ul><ul><li>Significant skeletal muscle injury </li></ul></ul><ul><ul><li>Significant CNS damage (Stroke/Trauma) </li></ul></ul><ul><ul><li>Occasionally from GI, renal, urologic disease </li></ul></ul><ul><li>*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 </li></ul>
  • 9. CK-MB <ul><li>High specificity for cardiac tissue </li></ul><ul><li>Begins to rise 4-6 hours after onset of infarction </li></ul><ul><li>Peaks at about 12 hours </li></ul><ul><li>Returns to baseline at 24-36 hours </li></ul><ul><li>Can be used to indicate early re-infarction if level normalizes and then increases again </li></ul><ul><li>Lab test is for mass, not activity; mass assays are reported to be more sensitive. </li></ul><ul><li>False positive (for MI) CK-MB elevation can be seen in: </li></ul><ul><ul><li>Significant skeletal muscle injury </li></ul></ul><ul><ul><li>*Cardiac injury for reason other than MI </li></ul></ul><ul><ul><ul><li>Cardioversion, Defibrillation (ACLS CPR/ICD firing) </li></ul></ul></ul><ul><ul><ul><li>Blunt chest trauma (MVA/Sports injuries) </li></ul></ul></ul><ul><ul><ul><li>Cardiac AND non-cardiac surgical procedures </li></ul></ul></ul><ul><ul><ul><li>Cocaine abuse (vasospasm, tachycardia, perfusion/demand mismatch) </li></ul></ul></ul><ul><ul><ul><li>Non often elevated in myocarditis, unless severe </li></ul></ul></ul>
  • 10. Troponin <ul><li>Troponin is a complex of three regulatory proteins that is integral to non-smooth muscle contraction in skeletal as well as cardiac muscle </li></ul><ul><li>Troponin is attached to the tropomyosin sitting in the groove between actin filaments in muscle tissue </li></ul><ul><li>Troponin has three subunits, TnC , TnT , and TnI </li></ul><ul><ul><li>Troponin-C binds to calcium ions to produce a conformational change in TnI </li></ul></ul><ul><ul><li>Troponin-T binds to tropomyosin, interlocking them to form a troponin-tropomyosin complex </li></ul></ul><ul><ul><li>Troponin-I binds to actin in thin myofilaments to hold the troponin-tropomyosin complex in place </li></ul></ul><ul><li>Thus far, studies have failed to find a source of Troponin-I outside the heart, but have found some Troponin-T in skeletal muscle </li></ul><ul><li>Because of it’s increased specificity, our lab uses Troponin-I </li></ul>
  • 11. More about Troponin <ul><li>Laboratory range definition: </li></ul><ul><ul><li>Cutoff is set at 99th percentile of a normal reference population, variation of less than 10% </li></ul></ul><ul><ul><li>Since troponin levels are virtually undetectable in normal subjects, this 99th percentile corresponds to <0.06 </li></ul></ul><ul><ul><li>-heparin in sample can result in lowered values </li></ul></ul>
  • 12. Troponin Use <ul><li>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 </li></ul><ul><li>Elevations in Troponin-I and Troponin-T can persist for up to 10 days after MI </li></ul><ul><li>Therefore it has good utility for retrospectively diagnosing AMI </li></ul><ul><li>Remember, CK-MB returns to baseline by 48 hours </li></ul><ul><li>Troponin release can also be precipitated by other conditions that cause myocardial damage </li></ul>
  • 13. Troponin Influence on Prognosis <ul><li>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 </li></ul><ul><li>Degree of elevation of Troponin value can give prognostic information </li></ul><ul><ul><li>Some data suggest that the 72-96 hour peak TI value correlates with infarct size. This is not necessarily true with other biomarkers </li></ul></ul>
  • 14. Lab Details <ul><li>Run in chemistry section of UH lab on sample of patient serum </li></ul><ul><li>Red top tube (you may need to draw for yourself someday) </li></ul><ul><li>Type of chemistry reaction: </li></ul><ul><ul><li>CK/CK-MB: Radioimmunoassay </li></ul></ul><ul><ul><li>Troponin: Immunoassay </li></ul></ul><ul><li>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 . </li></ul>
  • 15. Other Biomarkers <ul><li>LD (LDH) </li></ul><ul><ul><li>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 . </li></ul></ul><ul><li>Myoglobin </li></ul><ul><ul><li>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. </li></ul></ul><ul><li>ALT/AST </li></ul><ul><ul><li>Used as surrogate markers of cellular damage in the past. Very non-specific so not used for assessment of myocardial damage any longer </li></ul></ul><ul><li>H-FABP </li></ul><ul><ul><li>Heart-type fatty acid binding protein </li></ul></ul><ul><ul><li>Kinetically similar to myoglobin but more specific to cardiac tissue which contains a greater percentage of this protein than skeletal muscle </li></ul></ul><ul><ul><li>May also have role in prediction- prognosis in patients with NSTEMI </li></ul></ul><ul><ul><li>Current studies ongoing to further evaluate its utility </li></ul></ul>
  • 16. UH Laboratory CK ( U/L) Normal Range: 0-215 CKMB ( ng/mL) RELATIVE INDEX- RI (%MB OF CK) CKMB <7 and RI <4% :Negative CKMB <7 and RI >4% :Equivocal CKMB >=7 and RI <4% :Equivocal CKMB >=7 and RI >4% :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. >0.5 NG/ML: CONSISTENT WITH CARDIAC DAMAGE, INCREASED CLINICAL RISK AND MYOCARDIAL INFARCTION.
  • 17. Timing Summary DURATION PEAK ONSET TEST 6-8 days 24-48 hours 6-12 hours LDH 24 hours 6-7 hours 1-4 hours Myoglobin Up to 10 days 18-24 hours 3-12 hours Troponins 36-48 hours 18-24 hours 3-12 hours CK/CK-MB
  • 18. Elevated cardiac biomarkers in non-ACS situations <ul><li>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 </li></ul><ul><li>Some as previously described with CK and TI </li></ul><ul><li>Others: sepsis , hypovolemia, atrial fibrillation , PE, HF, myocarditis, myocardial contusion, renal failure and tachycardia </li></ul><ul><li>In patients with low pre-test probability of CHD or ACS, increased cardiac biomarkers may skew analysis and diagnosis causing “tunnel vision” </li></ul>
  • 19. Elevated cardiac biomarkers in non-ACS situations <ul><ul><li>Situations of prolonged myocyte ischemia--cell membrane breaks down releasing myofibril cell components into the bloodstream </li></ul></ul><ul><ul><ul><li>Tachy/bradyarrhythmias (reduced diastolic coronary filling time), </li></ul></ul></ul><ul><ul><ul><li>prolonged/profound hypotension, HF-acute and chronic, pulmonary hypertension </li></ul></ul></ul><ul><ul><li>CPR/Cardiac contusion </li></ul></ul><ul><ul><li>Electrical Cardioversion/ICD firing </li></ul></ul><ul><ul><li>PE, pericarditis, myocarditis </li></ul></ul><ul><ul><li>Sepsis (SIRS)-- secondary both to hypotension as well as direct effects of inflammatory mediators and myocardial oxygen demand-supply mismatch) </li></ul></ul><ul><ul><li>Apical Ballooning syndrome-- “Takotsubo Cardiomyopathy” </li></ul></ul><ul><ul><li>Chemotherapy, e.g. Adriamycin, Herceptin </li></ul></ul><ul><ul><li>Toxins, cocaine </li></ul></ul><ul><ul><li>Extreme exertion--Marathons, ultramarathons, Military basic training </li></ul></ul><ul><ul><li>LVH--leads to subendocardial ischemia by increased O2 demand from increased mass </li></ul></ul><ul><ul><li>HF--discussed separately </li></ul></ul>
  • 20. Biomarkers in Renal Failure <ul><li>CAD is highly prevalent in patients with end-stage renal disease and patients on dialysis. </li></ul><ul><ul><li>HTN and DM are very prevalent in this population </li></ul></ul><ul><ul><li>ESRD itself as well as dialysis change normal homeostatic mechanisms for lipids, calcium and electrolytes </li></ul></ul><ul><ul><li>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. </li></ul></ul><ul><ul><li>Possible reasons parallel those for HF: </li></ul></ul><ul><ul><ul><li>significant LVH , endothelial dysfunction, loss of cardiomyocyte membrane integrity and possibly impaired renal excretion </li></ul></ul></ul>
  • 21. Biomarkers in Renal Failure <ul><ul><li>Increasing evidence suggests that chronically elevated troponin levels indicate a worse long-term prognosis for cardiovascular outcomes in this patient population </li></ul></ul><ul><ul><li>False positives have been reported with use of troponin-T in ESRD patients but not as much with troponin-I </li></ul></ul><ul><ul><li>CK: plasma concentrations are elevated in 30-70% of dialysis patients at baseline, likely secondary to skeletal myopathy, intramuscular injections and reduced clearance </li></ul></ul><ul><ul><li>CK-MB: 30-50% of dialysis patients exhibit an elevation in the MB fraction >5% without evidence of myocardial ischemia </li></ul></ul><ul><ul><li>Therefore, the most specific marker for suspected AMI in ESRD patients is Troponin-I with an appropriate sequential rise </li></ul></ul>
  • 22. Biomarkers in Heart Failure <ul><li>It has been reported that small elevations in TI are chronically found in patients with heart failure, without current symptoms of ischemia </li></ul><ul><li>In these studies, the presence of TI remained an independent predictor of death </li></ul><ul><li>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% P<0.001 (data from Peacock et al. reference at end) </li></ul><ul><li>The presumed mechanism of cardiac troponin release in HF is from </li></ul><ul><ul><li>myocardial strain-volume and pressure overload of both ventricles causing excessive wall tension leading to decreased subendocardial myocyte perfusion. </li></ul></ul><ul><ul><ul><li>There is a correlation of elevated BNP and TI release </li></ul></ul></ul><ul><ul><li>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 </li></ul></ul>
  • 23. Case 1 <ul><li>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 </li></ul>
  • 24. Case 1 Discussion <ul><li>What is your pre-test probability for ACS before you get cardiac biomarkers in this patient? </li></ul><ul><li>Which biomarkers to you think will be positive at this time? In 12 hours? </li></ul><ul><li>Will you wait for the biomarker results to start treatment for ACS? </li></ul>
  • 25. Timing Revisited DURATION PEAK ONSET TEST 6-8 days 24-48 hours 6-12 hours LDH 24 hours 6-7 hours 1-4 hours Myoglobin Up to 10 days 18-24 hours 3-12 hours Troponins 36-48 hours 18-24 hours 3-12 hours CK/CK-MB
  • 26. Case 2 <ul><li>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. </li></ul>
  • 27. Case 2 Discussion <ul><li>What is your pre-test probability of ACS in this patient and how are you going to utilize your blood tests? </li></ul><ul><li>Obviously the ED physician felt this was likely to be ACS, do you agree? </li></ul><ul><li>If her troponin comes back as 0.07 with a normal CK and CK-MB what will you do? </li></ul>
  • 28. UH Laboratory CK ( U/L) Normal Range: 0-215 CKMB ( ng/mL) RELATIVE INDEX- RI (%MB OF CK) CKMB <7 and RI <4% :Negative CKMB <7 and RI >4% :Equivocal CKMB >=7 and RI <4% :Equivocal CKMB >=7 and RI >4% :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. >0.5 NG/ML: CONSISTENT WITH CARDIAC DAMAGE, INCREASED CLINICAL RISK AND MYOCARDIAL INFARCTION.
  • 29. Case 3 <ul><li>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. </li></ul>
  • 30. Case 3 Discussion <ul><li>What is the likely explanation for this patient’s elevated cardiac biomarkers? </li></ul><ul><li>How do you plan to manage this patient from here? Does he need to be in the CICU? Does he need further enzyme studies? </li></ul>
  • 31. Case 4 <ul><li>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 </li></ul>
  • 32. Case 4 Discussion <ul><li>If her serial enzymes stay at the same levels what is her general Cardiovascular prognosis? </li></ul><ul><li>Given the story, what other findings do you expect on her ECG? </li></ul><ul><li>What is the likely physiological mechanism for her elevated CK? Her TI? </li></ul><ul><li>She refuses cath. What is the best, simplest way to attenuate her cardiovascular mortality? </li></ul>
  • 33. References <ul><li>Zethelius, B. et al. Use of multiple Biomarkers to Improve the Prediction of Death from Cardiovascular Causes. NEJM 2008;358;2107-16. </li></ul><ul><li>Peacock, F. et al. Cardiac Troponin and Outcome in Acute Heart Failure. NEJM 2008;358:2117-26. </li></ul><ul><li>Brunwald, E. Biomarkers in Heart Failure. NEJM 2008;358:2148-59 </li></ul><ul><li>Foy, A and Weitz, H. When to Suspect a false-positive cardiac troponin. Resident and Staff Physician 2008;54(4):32-36. </li></ul><ul><li>Jaffe, A. Troponins, creatine kinase, and CK isoforms as biomarkers of cardiac injury. Up-To-Date. 2008. </li></ul><ul><li>Henrich, W. Serum cardiac enzymes in patients with renal failure. Up-To-Date. 2008. </li></ul><ul><li>Gibson, C. Elevated serum cardiac troponin concentration in the absence of an acute coronary syndrome. Up-To-Date. 2008. </li></ul>
  • 34. Objectives: <ul><li>Present background scientific information concerning cardiac biomarkers including current and historical markers </li></ul><ul><li>Present information about the medical use and utility of cardiac biomarkers </li></ul><ul><li>Identify CKMB and TI results in situations where false-positive and false-negative possibilities should be entertained

 </li></ul><ul><li>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

 </li></ul><ul><li>Inform audience briefly about ongoing clinical trials regarding use of cardiac biomarkers
 </li></ul>Cardiac Biomarkers: Definitions, Use and Utility


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