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CHEMISTRY ** This course meets the 1 hr. Chemistry requirement for Florida license renewal. ** BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION AUTHORED BY: Multiple Authors COURSE CODE: C022 CONTACT HOURS: 2 COURSE LEVEL: Intermediate Continuing Education Unlimited 6231 PGA Blvd / Suite 104, #306 / Palm Beach Gardens, FL 33418 888-423-8462 / General Fax: 561-775-4933 / Answer Sheet ONLY Fax: 561-775-4948 / www.4CEUINC.com PROVIDER #s: Florida: 50-2256 | California: 0001 | ASCLS P.A.C.E.: 511 COURSE OBJECTIVES 1. Discuss the background information of cardiac biomarkers, listing the features of a good biomarker and general history. 2. List the Biomarkers of Myocardial Injury reviewed in this course and identify specifics for each marker. 3. List the Biomarkers for Inflammatory Processes reviewed in this course and identify specifics for each marker. 4. List the Biomarkers of Cardiac Stress reviewed in this course and identify specifics for each marker. COPYRIGHT INFO: RIGHTSHOLDERS CEUINC LICENSE INFO: LABORATORY This course is based off of 3 open access articles. Authors: 1.) Sadip Pant, et al, 2.) Anthony McLean and Stephen Huang, and 3.) Daniel Chan and Leong Ng Copyrights: 2010 ‐ 2012 Publications: BMC Medicine Journal & InTech Open CA Department of Health: Florida Board of Clinical Lab: ASCLS P.A.C.E.® Our courses are accepted by: AMTIE, AMT, ASCP, CA, FL, LA, ND, NV, MT, RI, TN, WV ** If you do not see your organization, state, or licensing agency listed above it does not mean that the credits will be unacceptable. Most licensing bodies accept credits, so please check directly with them for acceptance of our courses.** PERMISSIONS These are Open Access articles distributed under the terms of the Creative Commons Attribution Licenses 2.0 and 3.0 (http://creativecommons.org/licenses/by/2.0) (http://creativecommons.org/licenses/by/3.0/us/) permits unrestricted use, distribution, and reproduction in any medium, for any purpose, provided the original work is properly cited. Access the main articles directly: Intechopen.com – Cardiac Biomarkers BiomedCentral.com – Cardiac Biomarkers in ICU PHLEBOTOMY Most licensing bodies accept credits. Please check with them directly for acceptance of our course credits. OTHER MEDICAL DISCIPLINES BiomedCentral.com – Biomarkers in Acute Myocardial Infarction Many medical licensing bodies will accept credits issued by valid licensed providers of other disciplines. Please check directly with the state, agency, or organization that issued your license for acceptance of our credits. ARTICLE REPRODUCTION Any article reproduction falls under the guidelines of the Creative Commons License. Copyright is retained by the original author(s) and proper, citation must be kept intact. Reproduction requires that integrity is maintained and its original authors, citation details, and publisher are identified. 0001 50‐2256 511 ii ** CEUINC is approved as a provider of continuing education programs in the clinical laboratory sciences by the ASCLS P.A.C.E.® Program. ** www.4CEUINC.com Last Revised 11/09/12 Continuing Education Unlimited 6231 PGA Blvd , Ste 104 / #306 Palm Beach Gardens, FL 33418 General Fax: 561-775-4933 / Answer Sheet Only Fax: 561-775-4933 Phone: 561-775-4944 / Web: www.4CEUINC.com Thanks for choosing CEUINC for your continuing education needs! We strive to offer you current course material at the most cost effective price. If you have comments or suggestions, be sure to add them to your evaluation – we appreciate them. If you like our courses pass them on to a coworker or friend. READ BEFORE COMPLETING MATERIAL GENERAL: 1.) Check your reading material to make sure that it contains the correct course(s) you ordered. 2.) Carefully read the material before completing your quiz packet. All answers are within the reading material. With few exceptions, quiz questions typically follow in order of the reading. 3.) Courses must be completed within 1 year of purchase date, unless otherwise specified. 4.) All of your records are available to you on our website for 4 years. If you don’t have a login to access your records, please contact our office and we will give you that information. Please do not create a 2nd profile! 5.) When sharing your materials with a coworker, be sure to pass on both the reading material and the quiz. HOME STUDY COURSES: 1.) 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Please remember to save or print the document before completing your quiz. Once you complete your quiz you will be permanently locked out of that record. Per copyright law, you can print one copy of each online course. 2.) Quizzes can be printed out if you’d like to work offline. Once you are done, simply transfer your results to the active, online quiz and click “Score”. You will receive immediate feedback of your results. “SITE-BASED” GROUPS: 1.) Coordinators should mail all “Pay As You Go” answer sheets to our facility as a group once per month. 2.) We mail certificates once per month according to the schedule furnished to the educational coordinator. 3.) Be sure to fill in your course code on the Pay As You Go (PAYG) answer sheets. 4.) If you have the online login to your profile, you may purchase online quizzes rather than mail in an answer sheet. This will allow you to immediately print your certificate of completion and will save time & money. ALERT: iii Please make a copy of your answer sheets before mailing them! When faxing your answer sheets, make a note of the date and time you sent them! This safeguards you in the event that your answer sheet does not reach its destination. www.4CEUINC.com Continuing Education Unlimited 6231 PGA Blvd , Ste 104 / #306 Palm Beach Gardens, FL 33418 Last Revised 11/09/12 General Fax: 561-775-4933 / Answer Sheet Only Fax: 561-775-4933 Phone: 561-775-4944 / Web: www.4CEUINC.com FREQUENTLY ASKED QUESTIONS Q. Your phones are often busy, how can I reach you? A. Because we have a small staff, the most efficient way would be to Schedule a Call Back by clicking the button on the Home Page of our website. You will then be able to select a convenient time for our staff to call you back. Q. What course completion date goes on my certificate? A. The date that we receive your answer sheet in our office. Q. I need my certificate dated on a certain day how can I be sure that this will happen? A. 1.) 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If you are sharing materials, one person will buy the “complete course” package and each of the others will purchase an “answer sheet only” or “online quiz only” packet. Please be sure you have BOTH the reading material and the quiz packet if you’re sharing. Prices are subject to change, please check before ordering. Q. How long will it take for my certificate to arrive if I’m sending my answers by mail? A. We can’t give an exact date because of variations in mail delivery time, however, we ask that you allow 3-4 weeks from the time you mail it to us until your certificate to arrives in your mailbox. You may also consider email delivery or online quiz completion for faster turnaround. Q. May I print out an online course? A. Yes, you may print 1 copy of an online course. Copyright laws do not allow more than one copy to be printed! Q. Where can I find additional information out about a course? A. Basic course information is located on the course cover. Additional information is located on the 2nd page of each course. Q. What are your most popular courses? A. Currently our most popular courses remain the Unlimited Online Course Package and our Combination Courses. Q. Does CEUINC offer group discounts or group packages? A. Yes. We require at least 5 participants and a person to act as the educational coordinator for the group. Discount amounts depend on the number of participants and the course or package chosen. Please check our website for details. ALERT: Please make a copy of your answer sheets before mailing them! When faxing your answer sheets, make a note of the date and time you sent them! This safeguards you in the event that your answer sheet does not reach its destination. iv www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION Category: Chemistry | Contact Hours: 2 | Course Code: C022 1.) Measurement of cardiac biomarkers is used to help diagnose, risk stratify, monitor and manage people with suspected acute coronary syndrome (ACS) and cardiac ischemia. A. True B. False 2.) ____________ is/are the first biomarkers that were used. A. Troponin B. Myoglobin C. AST & LDH 3.) ________ is a sensitive marker of acute myocardial infarction A. CK-BB 6 B. CK-MB C. CK-MM 4.) A single elevated Troponin alone is not sufficient to make the diagnosis of AMI. A. True B. False 5.) The sensitivity for troponin testing 8-12 hours after symptom onset is ________. A. 33% B. 75% C. approaching 100% 6.) Renal failure can elevate a cardiac troponin level. A. True B. False 7.) Myoglobin usually returns to normal after an AMI by ________. A. 6 hours B. 24 hours C. 7 days 8.) As an inflammatory marker, CRP is used mainly as a prognostic test to predict the patient’s risk of a future cardiac event. A. True B. False 9.) Myeloperoxidase in leukocytes plays a central role in atherosclerotic plaque rupture. A. True B. False v www.4CEUINC.com BIOMARKERS OF ACUTE MYOCARDIAL INFARCTION - QUIZ PAGE 2 - 10.) Atherosclerotic risk increases progressively with an increasing concentration of homocysteine levels. A. True B. False 11.) BNP, having a half-life of __________, is cleared by cells containing BNP receptors, whereas NT-proBNP, which is cleared by the kidney, has a longer half-life of _________________. A. 10 minutes, 6 hours B. 20 minutes, 60-120 minutes C. 3 hours, 2 days 12.) The clearest clinical benefit of the application of BNP and NTproBNP has been the diagnosis and prognosis of heart failure by evaluating the severity of _________________in the patient. A. liver failure B. renal failure C. congestive heart failure (CHF) *****LAST QUESTION **** vi www.4CEUINC.com TABLE OF CONTENTS INTRODUCTION .......................................................................................... 1 Background ............................................................................................. 1 Features of a Good Biomarker.................................................................. 3 Classes of Cardiac Biomarkers .................................................................... 3 Biomarkers of Myocardial Injury .............................................................. 4 Creatine kinase-MB .................................................................................. 4 Cardiac troponins (cTn)............................................................................. 5 Myoglobin [2] .......................................................................................... 9 Fatty acid binding proteins (FABPs) .......................................................... 10 Biomarkers for Inflammatory Processes ................................................ 11 C-Reactive Protein ................................................................................. 11 Myeloperoxidase (MPO) [2, 4] ................................................................... 12 Homocysteine ........................................................................................ 12 Ischemia Modified Albumin ...................................................................... 13 Matrix Metalloproteinases ........................................................................ 13 Pregnancy Associated Plasma Protein Alpha ............................................... 13 Placental Growth Factors ......................................................................... 14 Biomarkers of Cardiac Stress ................................................................. 14 Natriuretic peptides (NP) ......................................................................... 14 ST2 ...................................................................................................... 16 Other Biomarkers .................................................................................. 16 REFERENCES ............................................................................................. 16 vii www.4CEUINC.com **** THIS PAGE INTENTIONALLY LEFT BLANK **** viii www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 INTRODUCTION Acute coronary syndrome (ACS) is a group of potentially life-threatening disorders resulting from insufficient blood flow to the heart caused by the narrowing or blockage of one or more blood vessels to the heart; the conditions included in this group range from unstable angina to acute myocardial infarction (AMI) and are usually characterized by chest pain, upper body discomfort with pain in one or both arms, shoulders, stomach or jaw, shortness of breath, nausea, sweating or dizziness.[1] ACS is caused by rupture of a plaque that results from atherosclerosis. Plaque rupture causes blood clot (thrombus) formation in coronary arteries, which results in a sudden decrease in the amount of blood and oxygen reaching the heart. Cardiac ischemia is caused when the supply of blood reaching heart tissue is not enough to meet the heart's needs. The root causes of both ACS and cardiac ischemia are usually atherosclerosis and buildup of plaque, resulting in severe narrowing of the coronary arteries or a sudden blockage of blood flow through these arteries. Angina is caused by a decrease in the supply of blood to the heart. When blood flow to the heart is blocked or significantly reduced for a longer period of time (usually for more than 30-60 minutes), it can cause heart cells to die and causes an acute myocardial infarction.[1] Acute myocardial infarction (AMI) is a leading cause of death and disability throughout the world. Accurate and rapid diagnosis is essential to a positive outcome. Measurement of cardiac biomarkers helps to assist in making a proper diagnosis. BACKGROUND Cardiac biomarkers: substances that are released into the blood when the heart is damaged or stressed. Measurement of these biomarkers is used to help diagnose, risk stratify, monitor and manage people with suspected acute coronary syndrome (ACS) and cardiac ischemia. [1] Cardiac biomarkers (CB) have become increasingly accurate over the past 50 years for evaluating cardiac abnormalities. Initially, with the focus on myocardial infarction (MI), the use of creatinine kinase-MB (CKMB) (first described in 1972) was a major step forward in the development of a highly cardiac-specific biomarker. The introduction of cardiac troponin (cTn) assays in 1989 was the next major advance, and subsequent refinement of the assays now has the definition of acute myocardial infarction (AMI) centered on it. This progression ironically has brought considerable difficulties to the critical care physician who deals with multiorgan failure rather than the patient presenting to the emergency department with chest pain or single-organ pathology. The recent use of high-sensitivity (hs) cTn, replacing the fourth-generation cTn assays can further compound these diagnostic challenges. Moving beyond a sole focus on myocardial infarction, the search for alternative and supplementary serum markers to assist in unraveling the presence, severity, and type of cardiac injury has been intense (Figure 1). While cardiac ischemia/infarction is the most 1 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 Figure 1: The Development of Cardiac Biomarkers ADM, adrenomedullin; BNP, B-type natriuretic peptide; CAM, cell adhesion molecule; CKMB, creatine kinase-MB; CRP, C-reactive protein; cTn, cardiac troponin; H-FABP, human fatty-acid binding protein; HSP, heat shock protein; IL, interleukin; IMA, ischemia-modified albumin; INFg, interferon g; LP-LPA2, lipoprotein-associated phospholipase A2; PAPP, pregnancy-associated plasma protein; ROS, reactive oxygen species; sCD40L, soluble CD40 ligand. 2 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 prevalent cause of cardiac injury with biomarker development reflecting this, the search for more meaningful biomarkers now also include CBs for inflammatory processes and myocardial wall stress (as a result of pressure or volume overload) where evaluation extends beyond myocardial necrosis. The important role of C-reactive protein (CRP) is as a prognostic marker for an inflammatory process, while natriuretic peptides are now accepted as clinically useful markers of cardiac stress. In the critical care setting, the challenge of confounding (multiple) factors at times brings about interpretation difficulties. When the heart is the only organ involved, diagnostic clarity and guidance in clinical management decisions is present (as is seen in the emergency department or cardiac ward), but in the intensive care unit (ICU) setting this scenario does not always hold true. Even when possible multiple organ involvement is present, however, an understanding of the commonly used cardiac biomarkers can still be very helpful for cardiac evaluation in the critically ill patient. Table 1. General History of Cardiac Biomarkers [2] DECADE 1950s BIOMARKER AST, LDH These enzymes are released in varying amounts by dying myocytes, however, they lack sensitivity and specificity for cardiac muscle necrosis. 1960s CPK Total CK, known to be released during muscle necrosis, was designed as a fast, reproducible spectrophotometric assay. 1970s CPK isoforms by electrophoresis, CK-MB by immunoinhabition, Myoglobin CK isoenzymes were discovered: MM, MB, BB fractions. MB fraction was noted to be elevated in AMI. Myoglobin is released from all damaged tissues, but more rapidly than CKMB. 1980s CM-MB Mass immunoassay. Troponin T Troponin I 1990s FEATURES OF A GOOD BIOMARKER A good biomarker should have several characteristics to be useful: 9 9 9 9 9 9 High sensitivity and specificity Have a rapid rise and fall pattern after ischemia Perform reliably and uniformly Easy to perform, with rapid turnaround time of <60 minutes Plays a role in clinical management Correlation between blood level and extent of injury CLASSES OF CARDIAC BIOMARKERS The search for clinically useful CBs has resulted in a large number of circulating plasma substances being investigated. These can be broadly grouped into three major categories: inflammatory, acute muscle injury, and cardiac (hemodynamic) stress (Figure 2). 3 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 BIOMARKERS OF MYOCARDIAL INJURY Cardiac markers are used in the diagnosis and risk stratification of patients with chest pain and suspected acute myocardial infarction. The main markers that can be used to determine myocardial injury are: CK-MB, Cardiac Troponins, Myoglobin, and Fatty Acid Binding Proteins (FABP). CREATINE KINASE‐MB When first described in 1972, the electrophoresis methods required for separation of the cardiac isoenzymes had a low analytical specificity. Later, an immune-inhibition method resulted in a useful clinical test and so creatine kinase-MB (CK-MB), in combination with aspartate transaminase (AST) and lactate dehydrogenase (LDH), became the triad of biomarkers used for the diagnosis of AMI in the 1970s. CK-MB is a sensitive marker of MI, but a single measurement on presentation has a low sensitivity. Lack of specificity is also a problem where 10% of patients that experience chest pain with an elevated CK-MB have a normal cardiac troponin level (cTn). It should be noted that it is also present in small amounts in skeletal muscle so a large muscle injury can produce a positive CK-MB isoenzyme. Cardiac injury, for reasons other than AMI, can also produce a positive CK-MB including: defibrillation, blunt chest trauma, and cocaine abuse. [5] CK-MB Interpretation: [1] 9 CKMB is detectable within 3-6 hours after the onset of chest pain during an AMI 9 CKMB peaks at 12-24 hours 9 CKMB returns to normal by 48-72 hours CK-MB to total CK Relative Index (CKMB x 100/total CK): [1] 9 If the CKMB is elevated and the relative index is >2.5 to 3, heart damage is likely 9 If the CKMB is elevated and the relative index is <2.5, skeletal muscle (rather than cardiac muscle) damage is likely 4 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 CARDIAC TROPONINS (cTn) Troponins are a family of proteins found in both skeletal and heart muscle, consisting of three different types: troponin C, troponin I (cTnI), and troponin T (cTnT).[1] These proteins together regulate muscular contractions and control the calciummediated interaction of actin and myosin. [1, 2] Troponin C exists in all muscle tissue, while troponins I and T are specific for the heart. Although normally present in undetectable amounts in the blood, when there is damage to the heart, cTnI and cTnT will be released into the circulation. The greater the heart damage, the higher the troponin values will be. [1, 4] Because troponin C is found in all tissues, it is not used to diagnose heart related anomalies. Table 2. Cardiac Troponins at a Glance [2] Cardiac Troponin: 9 Cardiac troponins (cTn) are detectable 2-4 hours after heart injury occurs 9 Cardiac troponins typically peak around 12-16 hours in most cases [2, 3, 4] 9 Cardiac troponins typically remain elevated for 10-14 [1, 4, 5] [1, 5] A single elevated Troponin alone is not sufficient to make the diagnosis of AMI. It’s recommended that serial test samples should be collected at a minimum up to 12 hours or longer after symptoms began. 4-6 hours is the typical time used between blood draws when collecting a series of samples to see if AMI has occurred. Although each lab may establish their own draw schedule criteria for a troponin workup, the physician is looking for the typical rise and fall of the values seen in a cardiac event. The sensitivity for troponin testing after symptom onset is 33% at 0-2 hours, 50% at 2-4 hours, 75% at 4-8 hours and approaching 100% at 8-12 hours. The specificity is 5 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 close to 100%, however, it should be noted that troponin elevations have been reported in a variety of clinical scenarios other than AMI (see list below). Cardiac Troponin I (cTnI) vs. Cardiac Troponin T ( cTnT) 9 Both cardiac troponin I (the inhibitory component) and cardiac troponin T (the tropomyosin-binding component) have cardio-specific isoforms not found in skeletal muscle, making them highly specific markers of myocardial damage. 9 Both are released from a necrotic myocardium (ischemic and nonischemicinduced) as intact proteins and degradation products. 9 cTnT is a slightly larger than cTnI and remains elevated longer after an AMI. [10] 9 In standard cTn assays, cTnT is found more often in renal patients than cTnI. [3,10] For proper diagnosis, it’s important that the clinician have a good understanding of the assay used in their institution, including analytical quality and limitations since methodologies can differ. Although increasing sophistication of the troponin assay has resulted in fewer false-negatives and false-positives, it should be noted that the presence of cTn autoantibodies in the blood, marked hemolysis, and other medical etiologies can on occasion produce inaccurate results. Importance of Serial Troponin Testing Because the release of cardiac troponin into the circulation follows a distinct rise and fall pattern, levels should be checked at presentation (baseline) and again at two additional time intervals so the most accurate data can be obtained to determine whether an AMI occurred. Specifically, if the cardiac troponin value is rising over time, this is indicative of an AMI; if levels are declining, this may indicate that an infarction has occurred sometime in the recent preceding period. If the troponin level does not rise and the clinical picture does not indicate AMI, then a heart attack can be ruled out. Detectable cardiac troponin measurements that remain unchanged over time may be cause to seek an alternative diagnosis. Troponin Note: [1] Troponin levels should never be used as the sole test to diagnose an AMI, as other disease states may also cause an elevation. A positive troponin should always fit the clinical picture of the patient as well as correlate with other clinical testing such as: 9 9 9 9 9 6 Clinical symptoms for AMI Additional lab testing EKG changes Imaging studies such as echocardiogram Stress testing www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 CTN as a Diagnostic Marker [3] The central consideration in the interpretation of an elevated serum cTn is that it is a marker of myocardial damage, but on its own it does not determine the etiology of the damage. cTnT and cTnI demonstrate similar diagnostic abilities in the detection of myocardial damage despite analytical differences. The criteria for diagnosing an AMI are a rising or falling pattern of blood troponin levels in association with clinical presentation of myocardial ischemia. An international taskforce th Figure 3. Visual example of the 99 percentile cutoff of the upper comprising of the reference limit Source: Challenges & Pragmatic Approaches in Troponin Testing ( Abbott) American Heart Association, World Health Foundation, European Society of Cardiology, and the American College of Cardiology Foundation (AHA/WHF/ESC/ACCF) recommends a cutoff value set at the 99th percentile of the upper reference limit (URL), or the concentration at which the assay achieves a coefficient of variation of 10% if that exceeds the 99th percentile (Figure 3). Clinical features of AMI include classical symptoms, EKG changes, regional wall motion abnormalities, or imaging evidence of new loss of viable myocardium. In the absence of these features, an alternative cause of the troponin elevation and myocardial damage should be sought (see list below). Additional, Non‐AMI Conditions commonly associated with elevated cardiac troponin: [2, 3, 5] 9 Arrhythmias* 9 Aortic dissection* 9 Acute heart failure* 9 Burns, especially those affecting >25% of the body surface 9 Cardiac contusion 7 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 9 Cardiomyopathy 9 Chemotherapy (adriamycin, 5-flurouracil, Herceptin) 9 Coronary vasculitis 9 Coronary vasospasm* 9 Critically ill patients (especially diabetes, respiratory failure, etc.) 9 Drug toxicities 9 Extreme exertion 9 Hypertension* 9 Infiltrative diseases (amyloidosis, hemochromatosis, sarcoidosis, and scleroderma) 9 Inflammatory diseases 9 Myocarditis 9 Pulmonary embolus, severe pulmonary hypertension 9 Radiofrequency ablation* 9 Renal failure 9 Rhabdomyolysis with cardiac injury 9 Sepsis and septic shock 9 Severe neurological disorders 9 Trauma including the following: surgery, ablations, pace maker insertion, implantable defibrillator placement, defibrillator shocks, cardioversion, endomyocardial biopsy, cardiac surgery 9 Transplant vasculopathy * Elevations of cTn in the absence of overt ischemic heart disease or in the patient with normal coronary arteries include those patients with myocardial ischemia from noncoronary disease, and by definition come into the MI type II classification. Certain conditions result in chronic elevations of cTn, including chronic renal failure, chronic heart failure, stable CAD, marked left ventricular wall hypertrophy, and aortic stenosis. The timing of cTn elevations becomes increasingly important with the development of more sensitive assays and an understanding of the manner in which cTn is released from the damaged myocytes. The less sensitive cTn assays require more pronounced elevations, while the newer hs-cTn assay requires smaller elevations to be considered positive. When the initial cTn level is not elevated, then serial measurements at specified intervals are necessary. If the second sample is still not elevated but clinical suspicion of an AMI remains high, then an additional sample at 12-24 hours should be considered. 8 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 High Sensitivity Cardiac Troponin (hs‐cTn) The introduction of high sensitivity cardiac troponin testing has helped improve precision dramatically, has enhanced sensitivity, and reduced the time to diagnose AMI in the acute setting. In most current scenarios with standard troponin testing methodologies, patients present with chest pain and have a baseline, 6 hr, and 12 hour (or similar) troponin testing series run before a definitive diagnosis can be made. With the hs-cTn testing, that time can be cut down to as little as 3 hours in some cases. Cutting down the diagnostic time can help patients who are not having a cardiac event get discharged earlier, while instituting the proper treatment more rapidly for those patients that are having a cardiac event. It should be noted here that improvement in diagnostic accuracy & sensitivity can sometimes result in a lower specificity with more patients testing positive with the hs-cTn tests. Cardiac troponin as a prognostic marker [2, 3] Elevated cTn is associated with poor prognosis in patients with acute ischemia. In addition to its use in the diagnosis of AMI, an elevated troponin level can identify patients at increased risk for adverse cardiac events. Specifically, data from a study indicated that an elevated troponin level in patients without ST-segment elevation (on an EKG) is associated with a nearly 4-fold increase in the cardiac mortality rate. Lim and colleagues also found that an elevated cTn in critically ill patients predicted a 2.5 times increased risk of death and an increased length of stay in ICU of 3 days and an increased general hospital stay of 2.2 days. MYOGLOBIN [2] Myoglobin is a heme protein found in both skeletal and heart muscle. Although myoglobin levels are not specific for heart damage, they rise very early in an acute myocardial infarction, making them useful for the early, provisional diagnosis. Myoglobin levels are usually drawn upon arrival at a hospital, and then every 2 to 3 hours thereafter for several cycles. A persistently normal myoglobin level can rule out heart muscle damage. Although an elevated myoglobin can suggest an AMI has occurred, an elevated troponin level is required to make a definitive diagnosis because myoglobin can also be elevated in many other conditions. Myoglobin: [1] 9 Levels are detectable within 2-3 hours 9 Peaks within 8-12 hours 9 Typically returns to normal by 24 hours unless massive or ongoing injury occurs Myoglobin Facts: [1] 9 Myoglobin is not specific to cardiac tissue 9 Rises and falls more rapidly than troponin 9 A negative result essentially rules out cardiac issues, however, a positive result must be confirmed by a troponin level 9 Myoglobin level correlates to the size of the cardiac infarct 9 [7] www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 Limitations of Myoglobin Since myoglobin lacks specificity for cardiac tissue it should always be run in conjunction with a troponin level to determine cardiac related elevations. Elevated levels of myoglobin are also seen in many different scenarios, including: trauma, excessive muscle exertion, rhabdomyolysis, surgery, shock, renal failure, etc. [7] Figure 4. Normal Rise & Fall Patterns for Biomarkers of Myocardial Injury Dashed, horizontal orange line represents the upper limit of normal for the reference population (defined as the 99th percentile). Source: American Heart Assoc. FATTY ACID BINDING PROTEINS (FABPs) Journal March 28, 2011 Fatty acid binding proteins (FABPs) are transport proteins that carry fatty acids and other lipophilic molecules like eicosanoids and retinoids across the membranes. They occur in nine different isoforms in a predictable tissue distribution, with Heart-type FABP (H-FABP) as one of them. It has been found that H-FABP may perform better and reach its upper reference limit sooner than either myoglobin or troponin and is released during both ischemia and necrosis. A number of enzyme immunoassays are available for H-FABP testing. Its relation to ischemia and prognosis for adverse events is likely to expand testing in the near future. Heart-type FABP (H-FABP): [2, 9] 9 Released from damaged cell within 1-3 hours of pain onset 9 Peaks at approximately 6-8 hours 9 Returns to normal by 12-24 hours 10 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 BIOMARKERS FOR INFLAMMATORY PROCESSES Inflammation plays a role in both progression and repair of cardiac damage. In progression, acute coronary syndromes are caused by vulnerable plaques. It is thought that inflammation is one of the driving forces that cause plaques to rupture triggering a cascade of events which leads to coronary artery occlusion. Inflammation is also present in ‘phase 2’ of cardiac wound healing after a cardiac event. Cardiac wound healing after an AMI can be divided into four phases: phase 1 begins with the actual death of myocytes commencing within 6 hours and continuing for up to 4 days; phase 2 is that of an inflammatory response beginning 12-16 hours after onset of ischemia; phase 3 is when granulation tissue begins forming at the infarct border zone; and phase 4 consists of remodeling and repair and begins at 2-3 weeks, persisting for up to a year. Although a number of immune mediators, including cytokines, autoantibodies to myosin and tropomyosin, interferon (IFN)-g, etc. have been closely studied, clinically useful circulating inflammatory biomarkers to accurately assist in the diagnosis and prognosis of AMI are still in their infancy. Creactive protein (CRP), Myeloperoxidase (MPO), Matrix Metalloproteinases (MMP), Pregnancy Associated Protein A (PAPPA), Placenta Growth Factor (PGF) are reviewed here and are the most promising inflammatory markers at this time. C‐REACTIVE PROTEIN C- reactive protein (CRP) was so named because it was first discovered as a substance in the serum of patients with acute inflammation that reacted with the C(capsular) polysaccharide of pneumococcus. Discovered by Tillett and Francis in 1930, it was initially thought that CRP might be a pathogenic secretion as it was elevated in people with a variety of illnesses including cancer, however, the discovery of hepatic synthesis demonstrated that it is a native protein produced in the body. CRP is a non-specific test used to detect inflammation when there is a high suspicion of tissue injury or infection somewhere in the body. One of the downfalls of this test is that it cannot determine where the inflammation is or what condition is causing it. Although CRP is not diagnostic of any one condition, it can be used in conjunction with clinical signs and symptoms and other testing to evaluate an individual for coronary injury. In addition to being an inflammatory marker prior to a cardiac event occurring, it’s also shown to have a rapid increase in synthesis within hours after tissue injury or infection suggesting that it also contributes to host defense and that it is part of the innate immune response. There are two different tests for CRP. The standard test measures a much wider range of CRP levels (10-1000 mg/L) but is less sensitive in the lower ranges. It is usually ordered when infection or chronic inflammatory diseases are suspected. The high-sensitivity CRP (hs-CRP) test can more accurately detect lower concentrations of the protein (0.05 to 10 mg/L) making it more sensitive. The hs-CRP is more useful than the standard CRP test in predicting a healthy person's risk for cardiovascular disease. [1] 11 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 As an inflammatory marker, CRP is used mainly as a prognostic test to predict the patient’s risk of a future cardiac event. The American Heart Association has defined risk groups as follows: 9 9 9 9 Low risk: less than 1.0 mg/L Average risk: 1.0 to 3.0 mg/L High risk: above 3.0 mg/L. For values > 10 mg/L, there should be a search initiated for an obvious source of infection or inflammation. MYELOPEROXIDASE (MPO) [2, 4] Leukocytes play a central role in atherosclerotic plaque rupture. Myeloperoxidase (MPO) is a hemoprotein that is abundantly expressed in polymorphonuclear cells (neutrophils) and is secreted during their activation. It has been found that MPO in leukocytes may activate metalloproteinases and inactivate plasminogen activator inhibitor. Leukocytes also consume nitric oxide catalytically, causing vasoconstriction and endothelial dysfunction. MPO has been found in atherosclerotic plaques and is believed to participate in the initiation and progression of cardiovascular diseases as it possesses potent proinflammatory properties that may contribute directly to tissue injury. It’s been noted that after an AMI, MPO peaks early then decreases substantially over time. In a study consisting of patients diagnosed with heart disease or unspecified chest pain, considerably higher MPO concentrations were demonstrated on admission even though an initial troponin test was negative. Those same patients later had a positive troponin result after 6 hours. This may suggest that levels of MPO possess remarkably high sensitivity during the early presentation of chest pain. MPO has been approved by the FDA as a cardiac biomarker when used in conjunction with clinical history and other tools to evaluate the patients with chest pain and at high risk for coronary artery disease. [2] HOMOCYSTEINE Homocysteine is a protein amino acid found in the plasma. Elevated levels have been associated with a number of disease states, including increased cardiovascular disease risk. Deficiencies of the vitamins folic acid (B9), pyridoxine (B6), and B12 (cobalamin) can lead to high homocysteine levels. Supplementation with pyridoxine, folic acid, B12, or trimethylglycine (betaine) reduces the concentration of homocysteine in the bloodstream. Elevations also occur in homocystinuria, a rare genetic disease which is linked to an increased risk of pulmonary embolism, stroke and cardiovascular disease. [6, 11] Homocysteine can be considered to be an independent risk factor for the development of cardiovascular disease. [7] Atherosclerotic risk increases progressively with an increasing concentration of homocysteine levels. Measurement should be used to predict future risk assessment, but not used as a routine 12 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 assessment of cardiac risk.[6] Although normal ranges will vary from lab to lab, the average upper reference limit is usually around 11μmol/L. ISCHEMIA MODIFIED ALBUMIN The ischemia modified albumin (IMA) using the albumin cobalt binding test (ACB) is an FDA cleared test used for assessment of myocardial ischemia. It’s typically ordered along with or following a troponin test and an EKG to provide the physician added information if the initial troponin test is negative and the EKG is not definitive. IMA measured within 24 hours of an AMI is a strong and independent predictor of cardiac outcome at 1 year and may help identify those requiring more aggressive medical management. IMA has low specificity and therefore can result in false positives. [1, 2] According to labtestsonline.org, this test is no longer available although scientists do continue to study the marker for new ways to use it in risk stratification. [1] MATRIX METALLOPROTEINASES Matrix Metalloproeinases (MMP) are a family of nine zinc-dependent endopeptidases required for structural integrity of the extracellular matrix (ECM) proteins, including those in the myocardium. Elevated levels and over-expression of circulating matrix metalloproteinase-9 (MMP-9) is frequently seen in changing or remodeling tissues and has been demonstrated in patients with established coronary artery disease (CAD). [2] In a study of patients with AMI, tissue inhibitors of metalloproteinases (TIMP-1) and MMP-9 correlated with EKG parameters of left ventricular (LV) dysfunction and remodelling after AMI and identified patients at risk of subsequent LV remodeling and associated with severe extensive CAD. Since only limited information has been studied about this biomarker to date, it’s too early to use as a successful predictor of cardiac disease, however, studies do point to a future role for this marker. [2] PREGNANCY ASSOCIATED PLASMA PROTEIN ALPHA PAPP-A is a high-molecular-weight, zinc-binding metalloproteinase, which acts as a specific protease of IGF binding protein-4 (IGFBP-4). Pregnancy associated plasma protein alpha (PAPP-A) was originally identified in the serum of pregnant women, with PAPP-A being produced by the placenta. Only recently has PAPP-A been identified in non-placental tissue. [2] There is histological evidence, using specific monoclonal antibodies, that PAPP-A is abundantly expressed in both eroded and ruptured coronary plaques, but not in stable plaques. Furthermore, accumulating evidence suggests that PAPP-A may play a pivotal role in the development of atherosclerosis and subsequent plaque instability in acute coronary patients. PAPP-A is markedly elevated in the earliest hours after the onset of cardiac symptoms in patients with ST segment elevations (on EKG) during myocardial infarction (STEMIs) who are treated with heparin and primary percutaneous coronary intervention. In animal studies, heparin administration is 13 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 associated with a significant increase in PAPP-A levels, presumably because of the detachment of PAPP-A from the vessel wall. Much more studies are needed, but this may become a new biomarker for inflammatory plaque development in coronary artery disease in the future. [2] PLACENTAL GROWTH FACTORS Placental growth factor (PGF) is a member of the vascular endothelial growth factor (VEGF) subfamily which is primarily responsible for angiogenesis, vasculogenesis, during embryo development. PGF expression has also been found in atherosclerotic lesions and is associated with plaque formation and neovascular growth. PGF was recently shown that it is upregulated in all forms of atherosclerotic lesions and has been shown to induce the following: 9 Vascular smooth muscle cell growth 9 Recruits macrophages into atherosclerotic lesions 9 Pathological angiogenesis Plasma PGF levels are an independent inflammatory biomarker of poor outcome in patients with suspected acute cardiac syndrome. A single initial measurement of plasma PGF appears to extend the predictive and prognostic information gained from traditional inflammatory markers. Look for future studies on this biomarker. [2] BIOMARKERS OF CARDIAC STRESS Certain external factors, such as CHF, pulmonary hypertension, or renal disease, can exert mechanical or chemical stress on the heart making the patient more prone to cardiac events. NATRIURETIC PEPTIDES (NP) One of the best known biomarkers of biomechanical stress is the B-type Natriuretic Peptide (BNP). Secreted by the ventricles in response to cardiomyocytes under tension, BNP binds and activates receptors causing reduction in systemic vascular resistance, central venous pressure and natriuresis. BNP has been studied extensively and provides prognostic information following an AMI. This biomarker has a short half-life but is released with the N-terminal portion of the pro-BNP peptide (NTproBNP), a peptide much more stable in serum and can be measured easily. The understanding of its biochemistry is far from complete, in particular posttranslational metabolism of the peptides, which may affect accurate determination of the levels of active BNP. [4] Both peptides are accepted markers for cardiac dysfunction, while elevated levels of either of these peptides are associated and are equally useful as an aid in the diagnosis of CHF. The natriuretic peptides are cleared by the kidneys, and the hypervolemia and hypertension characteristic of renal failure enhance the secretion and elevate the levels of BNP, especially the NT-pro-BNP. There is also a moderate increase in the level of circulating BNP with increasing age, presumably in relation to myocardial fibrosis or renal dysfunction, which are both common in the elderly. Pulmonary hypertension from a variety of causes may increase the plasma level of BNP. The level varies inversely with the body-mass index. All of these physiological conditions 14 www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 and disease states must be taken into consideration in the interpretation of natriuretic peptides in individual patients. Assays for BNP and NT-pro-BNP are commercially available, and these biomarkers of heart failure are the most widely tested; such testing is recommended in current guidelines. [12] BNP, having a half-life of 20 minutes, is cleared by cells containing BNP receptors, whereas NT-proBNP, which is cleared by the kidney, has a longer half-life (60-120 minutes); this explains the higher circulating concentrations compared with BNP. The obvious clinical applications of BNP and NT BNP have led to the development of fully automated assays for both; some understanding by the clinician of the specific assay used is important, because some immunoassays cannot differentiate between active and inactive forms. For example, some assays actually measure a mixture of both BNP and NT-proBNP, whereas various breakdown products of BNP may be included in the assay. [3] Clinical application of BNP/NT-proBNP: The clearest clinical benefit of the application of BNP and NTproBNP has been the diagnosis and prognosis of heart failure by evaluating the severity of congestive heart failure (CHF) in the patient. Application in the emergency department is based on studies where a serum BNP level > 100 pg/ml was demonstrated to diagnose congestive heart failure (CHF) with a sensitivity of 90% and specificity 73%. Similar diagnostic accuracy was identified with NT-proBNP, with a level of 500 ng/ml.[3] NTproBNP should not be used as a standalone test to diagnose cardiac stress since although its generally more specific, it’s less sensitive and can be affected by renal insufficiency causing elevated concentrations that no longer correlate to the true degree of cardiac stress.[6] Numerous factors may contribute to the measurement BNP level in the serum in a single patient (Figure 5). Figure 5. 15 Factors Contributing to Circulating BNP Levels www.4CEUINC.com BIOMARKERS IN ACUTE MYOCARDIAL INFARCTION COURSE # - C022 ST2 ST2 is an IL1-receptor-like protein which was found to be elevated in the serum of hearts under mechanical stress. ST2 signals the presence and severity of cardiac repair and tissue fibrosis, which occurs in response to AMI, acute coronary syndrome, or heart failure. ST2 turned out to be the target for an Interleukin called IL-33 which seems to have a cardioprotective role, and only appears when myocytes are under biomechanical stress. It is thought that ST2/IL33 interaction also reduces the atherosclerotic burden. Post AMI though, it correlates somewhat with NTproBNP, and both of these biomarkers predict death risk at six months after MI or heart failure risk. [4] OTHER BIOMARKERS Currently, various other biomarkers are being studied, including many not listed here. The goal is to identify markers that have a high specificity and sensitivity for the heart. Prognostic markers, as well as, diagnostic markers are equally important in patient care. REFERENCES 1.) http://labtestsonline.org 2.) Intechopen.com – Cardiac Biomarkers 3.) BiomedCentral.com – Cardiac Biomarkers in ICU 4.) BiomedCentral.com – Biomarkers in Acute Myocardial Infarction 5.) Cardiac Biomarker PPT Presentation 6.) http://www.arupconsult.com 7.) http://www.labcorp.com 8.) http://www.questdiagnostics.com 9.) http://www.randox.com/brochures/pdf%20brochure/lt242.pdf 10.) http://www.aacc.org/resourcecenters/archivedprograms/expert_access/2010/HighSensitivity Troponin/Documents/hsTropPresentation.pdf 11.) http://en.wikipedia.org/wiki/Homocysteine 12.) http://www.columbia.edu/itc/hs/medical/pathophys/cardiology/2009/WR24.pdf 16 www.4CEUINC.com