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Similar to The Past, Present, and Future of Cardiac Biomarkers
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The Past, Present, and Future of Cardiac Biomarkers
- 1. The Past, Present, and Future of Cardiac Biomarkers Presented By: Curtis Beebe, B.S., Medical Laboratory Science Intern Heritage University
- 2. OBJECTIVES AT THE END OF THIS PRESENTATION THE LEARNER WILL BE ABLE TO: 1. EXPLAIN WHETHER TESTING FOR CARDIAC BIOMARKERS IS WARRANTED OR NOT BASED ON CLINICAL SYMPTOMS USING TWO JUSTIFIABLE REASONS. 2. NAME ONE UNIQUE ADVANTAGE OR DISADVANTAGE FOR FIVE OF THE CARDIAC BIOMARKERS PRESENTED WITH 80% ACCURACY. 3. PREDICT WHETHER RESULTS WILL BE INCREASED OR DECREASED FOR FIVE OF THE CARDIAC BIOMARKERS THAT WERE PRESENTED BASED ON CLINICAL SYMPTOMS.
- 3. ACRONYMS ACS: ACUTE CORONARY SYNDROME CHF: CONGESTIVE HEART FAILURE NSTEMI: NON-ST-T WAVE ELEVATION MYOCARDIAL INFARCTION STEMI: ST-T WAVE ELEVATION MYOCARDIAL INFARCTION UAP: UNSTABLE ANGINA PECTORIS AMI/MI: ACUTE MYOCARDIAL INFARCTION CAD: CORONARY ARTERY DISEASE LDI: LACTATE DEHYDROGENASE ISOENZYMES CK/CK-MB: CREATINE KINASE/MB FRACTION
- 4. WHAT IS A BIOMARKER? BIOLOGICAL MOLECULE THAT IS MEASURABLE CELLS PROTEINS GENES HORMONES MANY ARE CLINICALLY USEFUL AND THEY ENCOMPASS A MYRIAD OF DIFFERENT BIOLOGICAL PROCESSES
- 5. WHY DO THE VALUES CHANGE IN CELL DAMAGE? ANAEROBIC RESPIRATION INHIBITION OF MEMBRANE TRANSPORT ELECTROLYTE IMBALANCE LYSOSOMAL ENZYMES MEMBRANE INTEGRITY
- 6. WHAT CAN CARDIAC BIOMARKERS REVEAL? CONGESTIVE HEART FAILURE (CHF) A CONDITION IN WHICH THE HEART IS UNABLE TO PROVIDE SUFFICIENT BLOOD FLOW TO THE BODY ACUTE CORONARY SYNDROME (ACS) ENCOMPASSES CONDITIONS IN WHICH THE HEART CAN NOT FUNCTION PROPERLY OR DIES
- 7. WHY DO THEY MATTER? RISK ASSESSMENT/PREVENTION DIAGNOSIS THERAPY PROGNOSIS ABOUT 1/3 OF DEATHS IN THE WORLD ARE DUE TO CARDIOVASCULAR DISEASE, OF WHICH A GREAT PROPORTION IS CORONARY ARTERY DISEASE 15% DIRECTLY DUE TO AMI
- 8. WHAT TRAITS ARE NEEDED? HIGH SENSITIVITY HIGH CONCENTRATION IN MYOCARDIUM AFTER MYOCARDIAL INJURY RAPID RELEASE FOR EARLY DIAGNOSIS LONG HALF-LIFE IN BLOOD FOR LATE DIAGNOSIS HIGH SPECIFICITY ABSENT IN NON-MYOCARDIAL TISSUES NOT DETECTABLE IN BLOOD OF NON-DISEASED SUBJECTS ANALYTICAL CHARACTERISTICS MEASURABLE BY COST-EFFECTIVE ASSAY SIMPLE TO PERFORM RAPID TURNAROUND TIME SUFFICIENT PRECISION AND TRUENESS CLINICAL CHARACTERISTICS ABILITY TO INFLUENCE THERAPY ABILITY TO IMPROVE PATIENT OUTCOME
- 9. WHO DIAGNOSTIC CRITERIA FOR AMI CURRENTLY IN THE 3RD GENERATION REQUIRES RISING AND FALLING LEVELS OF CARDIAC TROPONINS “MYOCARDIAL CELL DEATH DUE TO PROLONGED ISCHEMIA” DIAGNOSIS TODAY REQUIRES A RISE AND/OR FALL OF BIOMARKER VALUES (PREFERABLY TROPONIN) WITH ONE VALUE ABOVE THE 99TH PERCENTILE THE RISE/FALL PATTERN DISTINGUISHES BETWEEN ACUTE AND CHRONIC DISORDERS
- 12. PATHOLOGICAL DEFINITION CLASSIFIED AS ACUTE, HEALING, OR HEALED ACUTE-PRESENCE OF PMNS HEALING-PRESENCE OF MONONUCLEAR AND FIBROBLAST CELLS, NO PMNS HEALED-SCAR TISSUE WITH NO CELLULAR PRESENCE ACUTE STAGE TO HEALED STAGE TYPICALLY REQUIRES 5-6 WEEKS
- 13. QUESTION 1 TRUE OR FALSE: A RISE AND/OR FALL PATTERN WITH AT LEAST ONE VALUE ABOVE THE 99TH PERCENTILE UPPER REFERENCE LIMIT OF CARDIAC TROPONINS IS DIAGNOSTIC FOR MI ACCORDING TO THE WHO CRITERIA. FALSE. THIS IS ONE REQUIREMENT, BUT THE WHO ALSO REQUIRES ONE OF THE FOLLOWING FOR DIAGNOSIS: 1) SYMPTOMS OF ISCHEMIA 2) NEW OR PRESUMED NEW SIGNIFICANT CHANGES IN THE ST-T WAVE SEGMENT 3) EVIDENCE OF THROMBUS VIA ANGIOGRAPHY 4) IMAGING EVIDENCE OF NEW LOSS OF VIABLE MYOCARDIUM OR REGIONAL WALL MOTION ABNORMALITY 5) ST-T WAVE CHANGES CONSISTENT WITH MI
- 14. THE TASK AT HAND DIFFERENT BIOMARKERS ARE ELEVATED IN DIFFERENT CLINICAL SITUATIONS
- 15. THERE’S A LONG HISTORY ASPARTATE AMINOTRANSFERASE IN LATE 1950’S CREATINE KINASE IN 1960’S LACTATE DEHYDROGENASE LD1 IN 1970’S CREATINE KINASE MB-FRACTION IN 1972
- 16. CREATINE KINASE (1960’S) MYOCARDIUM CONTAINS A SPECIFIC AMOUNT INCREASES WITHIN 4-8 HOURS AFTER MI PEAKS AT 18-24 HOURS BASELINE AFTER 48-72 HOURS
- 17. LACTATE DEHYDROGENASE LD1 (1970’S) DETECTS CARDIAC DAMAGE LONG AFTER MI APPEARS IN 4-6 HOURS, REMAINS ELEVATED FOR 4-14 DAYS NOT SPECIFIC FOR CARDIAC MYOCYTES INCREASED IN: LEUKEMIA, ANEMIA, MYOGLOBINURIA, MUSCULAR DYSTROPHY, RENAL DISEASE, CARCINOMA
- 18. CK-MB (1970’s) CAN DETECT REINFARCTION BETWEEN 3-10 DAYS OF FIRST EPISODE SERUM LEVELS ARE BASELINE BY 72 HOURS SENSITIVITY ONLY 50% AT 3 HOURS AND 80% AT 8 HOURS LIMITED BY INCOMPLETE SPECIFICITY STILL VALUED FOR REINFARCTION AND UAP
- 19. QUESTION 2 RELATIVE TO CK-MB, ONE OF THE MAIN REASONS LACTATE DEHYDROGENASE WAS USEFUL AS A CARDIAC BIOMARKER WAS: A. THEY WERE DETECTABLE IN DIAGNOSTIC CONCENTRATIONS SOONER B. THEY REMAINED ELEVATED FOR AN EXTENDED PERIOD OF TIME C. THEY WERE HIGHLY SPECIFIC FOR CARDIAC MYOCYTE DAMAGE
- 20. WHAT MARKERS ARE TESTED FOR TODAY CARDIAC TROPONINS BRAIN-TYPE NATRIURETIC PEPTIDE NT-PROBNP
- 21. THE TROPONIN COMPLEX TROPONIN COMPLEX CONSISTS OF CTNT, CTNI, AND CTNC ONLY CTNI AND CTNT ARE TESTED IN THE LAB ENCODED BY DIFFERENT GENES BOTH ARE PRESENT IN STRIATED CONTRACTILE APPARATUS AND CYTOSOL THE CYTOSOLIC CONCENTRATION OF EACH ISOFORM DIFFERS
- 22. CARDIAC TROPONINS CTNT AND CTNI SERVE AS THE STANDARD FOR DIAGNOSIS OF MI PER EUROPEAN SOCIETY OF CARDIOLOGY & AMERICAN COLLEGE OF CARDIOLOGY DETECTABLE FOR A LONGER TIME APPEAR 3-4 HOURS AFTER MI PEAK 12-48 HOURS AFTER ABNORMAL FOR 7-14 DAYS INDICATE MYOCARDIAL NECROSIS
- 23. HS-TROPONIN INCREASE IN FALSE-POSITIVES TROPONINS STILL WON’T BE DETECTED IMMEDIATELY FOLLOWING ISCHEMIA STILL EARLIER DETECTION OF MI COMPARED TO CURRENT METHODS AS EARLY AS MYOGLOBIN CAN BE DETECTED
- 24. IS THERE ALWAYS A HEART PROBLEM WITH INCREASED CTN? RENAL ISSUES CHRONIC KIDNEY DISEASE (CKD) AFFECTS 15% OF THE US
- 25. BNP INCREASED IN CONGESTIVE HEART FAILURE RELEASED DUE TO BIOMECHANICAL STRESS BRAIN-TYPE NATRIURETIC PEPTIDE <100 NG/L: HF IS HIGHLY UNLIKELY (NPV 90%) >500 NG/L: HF IS HIGHLY LIKELY (PPV 90%)
- 26. NT-PROBNP THE N-TERMINAL END OF THE INACTIVE PROHORMONE BNP STUDIES HAVE SHOWN <300 NG/L: HF HIGHLY UNLIKELY (NPV 99%) >450 NG/L IN PATIENTS UNDER 50: HF IS HIGHLY LIKELY >900 NG/L IN PATIENTS OVER 50: HF IS HIGHLY LIKELY HIGH PROGNOSTIC VALUE
- 27. NT-PROBNP OR BNP? BNP IS A SUPERIOR MARKER BOTH HAVE DECREASED PERFORMANCE WITH INCREASING PATIENT AGE AND SEX (MORESO WITH NT-PROBNP)
- 28. ACTIVITY GET INTO GROUPS OF 2-3 PEOPLE CHOOSE 3 OF THE FOLLOWING AND WRITE DOWN AS MANY ADVANTAGES OR DISADVANTAGES AS YOU CAN FOR EACH, THEN WE’LL SHARE 1. LACTATE DEHYDROGENASE 2. CREATINE KINASE 3. CREATINE KINASE MB FRACTION 4. TROPONINS 5. BNP 6. NT-PROBNP 7. HIGH-SENSITIVITY TROPONIN TESTING
- 29. WHAT’S NEXT? HEART-TYPE FATTY ACID BINDING PROTEIN (H-FABP) GLYCOGEN PHOSPHORYLASE ISOENZYME BB (GPBB) SUPPRESSION OF TUMORIGENICITY 2 (ST2) MICRORNA
- 30. HEART-TYPE FATTY ACID BINDING PROTEIN CYTOPLASMIC PROTEIN INVOLVED IN THE UPTAKE OF FATTY ACIDS INTO MYOCARDIUM PRESENT IN A VERY HIGH CONCENTRATION IN MYOCARDIUM (5 MG/G TISSUE) RELEASED DURING ISCHEMIA HAS PROGNOSTIC VALUE ELEVATED WITHIN 2 HOURS, BASELINE 12-24 HOURS
- 31. GLYCOGEN PHOSPHORYLASE ISOENZYME BB 1 OF 3 ISOENZYMES AND PRODUCED IN THE BRAIN AND HEART A STUDY OF 61 PATIENTS PRESENTING SYMPTOMS OF ACS, (37 MI, 24 UAP), FOUND 90.1% OF PATIENTS HAD INCREASED GP-BB CONCENTRATIONS 1 HOUR AFTER CHEST PAIN AND 100% AFTER 4-5 HOURS AT 6 HOURS, 95.5%-100% SENSITIVITY, 94-96% SPECIFICITY TROPONINS AT ≥3 HR: >95% SENSITIVITY, 100% SPECIFICITY
- 33. SOLUBLE ST2: SUPPRESSION OF TUMORIGENICITY 2 A PROTEIN IN THE INTERLEUKIN FAMILY BOTH BOUND AND SOLUBLE VERSIONS, SST2 AND ST2L PROVIDES DATA REGARDING CHF, LIKE NT-PROBNP/BNP PROGNOSTICALLY VALUABLE
- 34. WHAT IS MICRORNA? RNA STRAND THAT IS 19-25 NUCLEOTIDES LONG RESPONSIBLE FOR GENE REGULATION BY INTERACTING WITH 3’- UTR OF MESSENGER RNA FOUND IN EVERY CELL BUT HAS ORGAN AND CELL SPECIFIC EXPRESSION PATTERNS
- 35. THE IMPORTANT ONES SO FAR MIRNA-1: SPECIFIC FOR STEMI MIRNA-21: FIBROBLASTS MIRNA-28: ONLY IN CARDIOMYOCYTES MIRNA-29: NECROSIS MIRNA-126: REPAIR MIRNA-133: MYOBLASTS MIRNA-208: SPECIFIC FOR STEMI
- 36. WHAT WE LEARNED ULTIMATELY THE GOAL IS TO USE MULTIPLE BIOMARKERS TO DETERMINE THE PRESENCE, CAUSE, AND EXTENT OF DAMAGE TO CARDIAC TISSUE LD, CK, AND CK-MB WERE USED AGES AGO BUT HAVE BEEN REPLACED BY THE TROPONINS TROPONINS ARE THE CURRENT STANDARD FOR DIAGNOSIS OF MYOCARDIAL INFARCTION GPBB, H-FABP, SST2, AND MIRNA HAVE THE POTENTIAL TO IMPROVE THE DIAGNOSIS AND TREATMENT OF PATIENTS SUSPECTED OF AN ADVERSE CARDIAC EVENT
- 37. GPBB 1-3 HOURS 2-3 DAYS ++++ ++++ MIRNA VARIABLE VARIABLE ++++ ++++
- 38. REFERENCES 1. Rosalki S, Roberts R, Katus H, Giannitsis E, Ladenson J, Apple F. Cardiac biomarkers for detection of myocardial infarction: perspectives from past to present. Clinical Chemistry. 2004;50(11):2205–13. DOI: 10.1373/clinchem.2004.041749. 2. Dolci A, Panteghini M. The exciting story of cardiac biomarkers: from retrospective detection to gold diagnostic standard for acute myocardial infarction and more. Clinica Chimica Acta. 2006;369(2):179-187. DOI: 10.1016/j.cca.2006.02.042 3. Granger C, Povsic T. Another biomarker for risk assessment in acute myocardial infarction? Journal of the American College of Cardiology. 2014;64(16):1708-1710. DOI: 10.1016/j.jacc.2014.06.1200. 4. Nigam P. Biochemical markers of myocardial injury. Indian Journal of Clinical Biochemistry. 2007;22(1):10–17. DOI: 10.1007/BF02912874. 5. Jaffe A, Babuin L, Apple F. Biomarkers in acute cardiac disease: the present and the future. Journal of the American College of Cardiology. 2006;48(1):1-11. DOI: 10.1016/j.jacc.2006.02.056. 6. Schulte C, Zeller T. Microrna-based diagnostics and therapy in cardiovascular disease-summing up the facts. Cardiovasc Diagn Ther. 2015 Feb;5(1):17– 36. DOI: 10.3978/j.issn.2223-3652.2014.12.03. 7. Viswanathan K, Kilcullen N, Morrell C, Thistlethwaite S, Sivananthan M, Hassan T, et al. Heart-type fatty acid-binding protein predicts long-term mortality and re-infarction in consecutive patients with suspected acute coronary syndrome who are troponin-negative. J Am Coll Cardiol. 2010;55(23). DOI: 10.1016/j.jacc.2009.12.062. 8. Thygesen K, Alpert JS. Universal definition of myocardial infarction. J Am Coll Cardiol [internet]. 2007; Available from: http://content.onlinejacc.org/article.aspx?articleid=1138690 9. Ewald B, Ewald D, Thakkinstian A, Attia J. Meta‐analysis of b type natriuretic peptide and n‐terminal pro b natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction. Intern Med J. 2008;38(2):101–13. DOI: 10.1111/j.1445- 5994.2007.01454.x. 10. Ladenson J. Reflections on the evolution of cardiac biomarkers. Clin Chem. 2012;58(1):21–4. DOI: 10.1373/clinchem.2011.165852. 11. Chan D, Ng L. Biomarkers in acute myocardial infarction. BMC Med. 2010;8(1):34. DOI: 10.1186/1741-7015-8-34. 12. Shortt CR, Worster A, Hill SA, Kavsak PA. Comparison of hs-cTnI, hs-cTnT, hFABP and GPBB for identifying early adverse cardiac events in patients presenting within six hours of chest pain-onset. Clin Chim Acta. 2013 Apr 4;419:39–41. DOI: 10.1016/j.cca.2013.01.008. 13. Lippi G, Mattiuzzi C, Comelli I, Cervellin G. Glycogen phosphorylase isoenzyme BB in the diagnosis of acute myocardial infarction: a meta-analysis. Biochem Med (Zagreb). 2013 Jan 2;23(1):78–82. DOI: 10.11613/BM.2013.010.
- 39. 14. Thygesen K, Alpert J, Jaffe A, Simoons M, Chaitman B, White H, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(20):2551–67. DOI: 10.1093/eurheartj/ehs184. 15. Stacy SR, Suarez-Cuervo C, Berger Z, Wilson LM, Yeh H-C, Bass EB, et al. Role of troponin in patients with chronic kidney disease and suspected acute coronary syndrome. Annals of Internal Medicine. 2014 7 Oct;161(7):502–12. DOI: 10.7326/M14-0746. 16. Maynard SJ, Menown IB, Adgey AA. Troponin T or troponin I as cardiac markers in ischaemic heart disease. Heart. 2000 Apr 6;83(4):371–3. 17. Apple FS, Wu AHB, Mair J, Ravkilde J, Panteghini M, Tate J, et al. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clinical Chemistry. 2005;51(5):810–24. DOI: 10.1373/clinchem.2004.046292. 18. French JK, White HD. Clinical implications of the new definition of myocardial infarction. Heart. 2004 Jan 4;90(1):99–10 19. Rognoni A, Cavallino C, Lupi A, Secco G, Veia A, Bacchini S, et al. Novel biomarkers in the diagnosis of acute coronary syndromes: the role of circulating mirnas. Expert Review of Cardiovascular Therapy. 2014;12(9):11191124. DOI: 10.1586/14779072.2014.953483. 20. Cheng Y, Tan N, Yang J, Liu X, Cao X, He P, et al. A translational study of circulating cell-free microrna-1 in acute myocardial infarction. Clin Sci. 2010 Jul 4;119(2):87–95. DOI: 10.1042/CS20090645. 21. Nazemiyeh M, Sharifi A, Amiran F, Pourafkari L, Taban Sadeghi M, Namdar H, et al. Relationship between prohormone brain natriuretic peptide (nt-probnp) level and severity of pulmonary dysfunction in patients with chronic congestive heart failure. J Cardiovasc Thorac Res. 2015 Jan 4;7(1):24–7. DOI: 10.15171/jcvtr.2015.05. 22. Peetz D, Post F, Schinzel H, Schweigert R, Schollmayer C, Steinbach K, et al. Glycogen phosphorylase bb in acute coronary syndromes. Clin Chem Lab Med. 2005;43(12):1351–8. DOI: 10.1515/CCLM.2005.231. 23. Members A, Steg P, James S, Atar D, Badano L, Lundqvist C, et al. Esc guidelines for the management of acute myocardial infarction in patients presenting with st-segment elevation the task force on the management of st-segment elevation acute myocardial infarction of the european society of cardiology (esc). Eur Heart J. 2012;33(20):2569–619. DOI: 10.1093/eurheartj/ehs215. 24. Peetz D, Post F, Schinzel H, Schweigert R, Schollmayer C, Steinbach K, et al. Glycogen phosphorylase bb in acute coronary syndromes. Clin Chem Lab Med. 2005;43(12):1351–8. DOI: 10.1515/CCLM.2005.231. 25. Januzzi J. St2 as a cardiovascular risk biomarker: from the bench to the bedside. J Cardiovasc Transl Res. 2013;6(4):493–500. DOI: 10.1007/s12265-013-9459-y. 26. Ciccone M, Cortese F, Gesualdo M, Riccardi R, Nunzio D, Moncelli M, et al. A novel cardiac bio-marker: st2: a review. Molecules. 2013;18(12). DOI: 10.3390/molecules181215314. REFERENCES CONTINUED
- 40. LET’S TAKE THE QUIZ!
- 41. QUIZ ANSWERS 1. False 2. BNP, NT-proBNP, sST2 3. D 4. 1-3 hours 5. Troponin-Increased BNP-Normal sST2-Normal H-FABP-Increased LD1-Increased 6. Yes because: dyspnea is a symptom of MI, NSTEMI may be present, R/O any heart damage, could be UAP or any other acute coronary syndrome, age.
Editor's Notes
- 1. A physician sees a 30 year old patient whom, upon examination, explains that he has been experiencing chest tightness, dyspnea, and always seems to be tired, especially when walking up stairs. He also says he has had a cough that won’t seem to go away. Most of these symptoms started about two weeks ago and have progressed since, but he thought he simply had a cold that would resolve itself over time. The patient states he has never smoked and follows healthy eating habits.
- Anaerobic respiration: lactic acid builds up in the cell due to oxygen deprivation, pH decreases Inhibition of membrane transport: There’s simply not enough ATP production to support ATP-dependent membrane transport Membrane integrity: Lysosomal enzymes: the decreased pH causes the release of proteolytic enzymes which destroy intracellular structures and cause cleavage of membrane bound proteins. This process causes the release of both cytosolic proteins and structurally bound proteins. Cytosolic proteins are released first and are dependent on the amount of circulation to the affected area. Bound proteins are released second and their values are independent of the circulation reaching affected cells.
- Congestive heart failure: heart is unable to pump sufficiently to maintain sufficient blood flow for the body. A multitude of disease states are responsible. There are two types: left-side failure and right-side failure. Both can cause pleural effusion. Acute coronary syndrome: myocardial infarction (NSTEMI/STEMI), hemodynamic stress, inflammation, vascular damage, acute atherosclerosis, and unstable angina pectoris3 Left-side is more common and includes more pulmonary related symptoms: labored breathing, cyanosis, “rales and crackles” when breathing, pulmonary edema, wheezing, dyspnea. Right-side includes more vascular symptoms: edema, ascites and liver enlargement. Acute myocardial infarction: necrosis of cardiac tissue due to a blockage of blood flow, perhaps embolism, plaque, etc. Angina: an experience of chest pain due to the narrowing of the coronary arteries. Stable Angina Pectoris: chest pain occurring regularly due to exercise, meals, etc., that is predictable. This is the type often associated with MI Unstable Angina Pectoris: Chest pain that occurs but isn’t regular or predictable. It changes in pain level, intensity, frequency, etc. It can precede MI but, in patients diagnosed with this, there is often no elevation of any cardiac biomarkers. NSTEMI: Non ST-T Wave Elevation Myocardial Infarction. No elevation in the ST-T wave of an ECG Coronary Artery Disease (CHD): part of a group of diseases including Stable Angina, Unstable Angina, MI, and sudden coronary death as a group of diseases. Coronary Artery disease is the most common of the group. Basically, it’s atherosclerosis in a coronary artery. In 2011, it was the most common cause of death globally with over 7 million deaths, accounting for 12.8% of all worldwide deaths.23 Also, about 20% of individuals over 65 have CAD. Relative to MI, the arteries are damaged not blocked. Can anyone tell me some sort of process where the heart muscle dies?
- The most debilitating manifestation of coronary artery disease is MI. This sets the precedent for the importance of finding biomarkers that are detectible sooner after the initial event, are detectible longer, and that show specificity for the type, location, and cause of the damage. Currently, there aren’t any single biomarkers, or combinations thereof, that have achieved this feat. Yet as scientists, we push forward diligently (maybe assiduously; It’s a better word but they may not know), in the hopes that serendipity is on our side. Risk Assessment:
- What physiological reasons determine a biomarkers unique characteristics?4 Location in the cell. Cytosolic molecules are released immediately following cellular damage whereas structurally bound molecules are released later. Molecular weight. Smaller molecules diffuse faster than larger molecules. Half-life. Smaller molecules tend to be eliminated more rapidly than larger molecules. Relationship to blood flow. The cytosolic molecules are heavily affected by the relative difference between blood flow in the necrotic region and non- necrotic region. This difference in blood flow does not affect structurally bound molecules.
- Myocardial infarction is cell necrosis due to ischemia; where ischemia is defined as an imbalance between perfusion supply and demand.8,12 Following this imbalance are various symptoms including: combinations of chest, upper extremity, jaw, or epigastric discomfort with or without exertion.8 These symptoms last at least 20 minutes and are often accompanied by dyspnea (trouble breathing), syncope (fainting), diaphoresis (sweating), or nausea.8 The symptoms are also diffuse and can easily be misdiagnosed as some other disorder unrelated to ischemia. Myocardial infarction can also be present without any noticeable symptoms, only identified by EKG, biomarkers, or imaging techniques.8,12 Interpreting clinical symptoms in order determine the correct diagnosis therefore is incredibly difficult and the heart can continue to sustain damage while the physician determines the cause. Correct diagnosis requires rapid, specific, and sensitive testing. According to WHO, the specific pathology of myocardial infarction is “myocardial cell death due to prolonged ischemia”.8 It’s important to understand that cell death is not immediate after ischemia occurs, but takes, at minimum, 20 minutes. Complete necrosis of affected affected tissue requires 2-4 hours depending on collateral circulation.
- Retrieved from “Third universal definition of myocardial infarction.” (14) Worldwide, about 3 million are diagnosed with NSTEMI each year and 4 million with STEMI An ECG measures the electrical activity of the heart. The P, Q, R, and S-wave reflect depolarization of the heart which means an influx of calcium ions right before the myocytes contract, first the atria (P-wave), then the ventricles (QRS-wave). Electrical activity is generated by the sinoatrial node in the atria and the atrioventricular node in the ventricles. The T-wave represents repolarization of the ventricles. Repolarization is in the negative direction since it is the opposite of depolarization but the peak is positive because the direction of repolarization is in the opposite direction as depolarization. In the way that two negatives multiplied together is a positive number. STEMI represents complete blockage of on or more coronary arteries and is the most damaging (all affected cells will die); NSTEMI is a milder form. This is important because non-ST-wave elevation won’t be diagnosed as MI right away (the ECG may look normal), leading to increased importance on biomarkers.
- There may be more than one type present in a single patient. The definition includes only necrosis due to ischemia. Necrosis due to other causes is not termed MI.8
- These definitions are incredibly important because not only determining the presence or absence of MI but also the stage, prognosis, and treatment need to be determined. Remember that the clinical timing may not always correspond to the pathological timing, (i.e., there may still be clinical signs when the heart is in the healing/healed phase).
- False. This is one criteria but also required is one of the following: MI consistent symptoms, or imaging of MI, or evidence of thrombus, or ST-T wave changes consistent with MI.
- This figure shows the characteristic disease process that eventually ends with myocardial necrosis and dysfunction.16 Today we have markers that are highly sensitive and highly specific for heart damage (e.g., the troponins and BNP). The disconcerting fact is that this process was underway long before the damage actually occurred.16 With UAP, the defining feature is no elevation in biomarkers.
- GDF-15: Growth Differentiation Factor 15 ST2
- Not specific for the heart. Is found in all muscle and an increase can easily be mistaken for cardiac damage when only skeletal damage occurred. Also, dilutions make the accuracy of the test much lower in the lab.(Per Darlene)
- There are 5 isoenzymes. Normally they are in a specific order from highest to lowest concentration. The heart is rich in LD1 and LD2 whereas the liver is rich in LD3, LD4, LD5.4 LD2 is also found in serum and an increased ratio of LD1/LD2 represents heart damage. Peaks at 72 hours.
- Each unit (gram) of myocardium releases a specific amount of CK into circulation and the amount is related to the extent of the damage.1 However, in contrast to total CK, MB was much more specific and sensitive for cardiac damage as 25% of CK in myocytes was MB and the rest MM. This cemented its place as a much more useful marker than total CK. Detection of re-infarction wasn’t practical with LD due to its long detection period. The more rapid detection (per test methods, which were electrophoresis and immunoinhibition4, allowed medical decisions to be made sooner, patients without MI could be discharged in 1 day versus the traditional 3, and treatment could begin sooner for those with confirmed MI. There is only one CK-MB isoform within muscle but upon release into circulation modification occurs to create two, MB1 (the modified form) and MB2 (the tissue form).4 The differentiation of MB1/MB2 however, offers no advantage to total CKMB testing.4
- The answer is B. They remained elevated for 4-14 days, in contrast to the 2-3 day elevation of CK-MB.3 However, the detection window was 4-8 hours, just like CK-MB. And LD is not highly specific for cardiac damage. This trait decreased its diagnostic role as a biomarker.
- Picture is from reference 11.
- The TnC, TnI, and TnT complex is located on the striated muscle contractile apparatus.16 Each is encoded by a separate gene and therefore is distinguishable from the others.16 Although most of the complex is bound to striated muscle there is also a small cytosolic pool for TnI (2.8-4.1%) and TnT (6-8%).1,16 This trait leads to differences in detection, both rapidity and duration, between the two isoforms.1,16 Rapid release of the cytosolic TnT pool occurs first following ischemia. Followed by the release of the entire complex from the myofibrils.16 The larger TnT cytosolic pool leads to biphasic release kinetics whereas the TnI release kinetics are monophasic due to its smaller cytosolic pool.16 At its most basal level, the myocardium contracts when calcium concentration increases, and relaxes when the calcium concentration falls. Contractile Process: TnI blocks myosin binding sites on the actin filament; a change in action potential opens calcium ion transporters and some calcium binds TnC; this releases the TnI from the myosin binding sites; myosin binds and generates force to contract the muscle filament. (Remember that TnT binds to tropomyosin in the actin filament to anchor the complex).
- Released from the cytosolic pool first due to necrosis, later released from the structural pool.5 Expressed almost exclusively from the heart as they are part of the contractile apparatus.14 They indicate myocardial necrosis but don’t reveal the underlying mechanism. Excellent specificity and sensitivity, some studies have found ****sensitivities as high as _____ and specificities as high as ______, better than all previous markers.16 Why don’t we test for both isoforms in the lab? Roche diagnostics holds a patent on the cTnT immunoassay test method so it comes down to cost. A very important point regarding troponin is that it doesn’t discriminate between ischemic damage from non-ischemic damage. All raised troponin can provide is whether or not necrosis has occurred.4
- One of the main disadvantages is that in part of the population, predominantly the elderly, have an elevated troponins due to chronic heart failure or chronic kidney disease. False-positives are always a problem with high sensitivity tests. With high-sensitivity testing it takes 2-4 hours to detect troponins after MI or some other event.6 Diagnosis of MI requires one value outside of the 99th percentile. Remember that the WHO requires the troponin rise/fall pattern as well as one other criteria to diagnose MI.
- This is the biggest disadvantage to cTn.22 The troponins are also elevated in renal disease, especially End Stage Renal Disease. cTnT is more valuable in this respect, being elevated in 30-70% of patients with ESRD. cTnI is elevated in about 5% of the same patients.5 So depending on the patient cTn can be useful in diagnosing various disorders unrelated to MI. With cTnT being more useful in patients with renal disorders.
- Introduced as a pro-peptide and then cleaved by the enzyme corin.5 BNP is secreted by the ventricles in response to increased cardiomyocyte stretching and ventricular pressure and it binds to receptors that cause a reduction in systemic vascular resistance, central venous pressure, and natriuresis (increase in sodium excretion will decrease the extracellular volume and pressure on the heart). Suggestive of CHF (heart can’t pump enough blood to supply the needs of the body), not necrosis.
- Interestingly, some proBNP circulates regardless of cardiac damage and current tests likely detect this irrelevant amount. proBNP normal values are different depending on physiological variables (e.g., age, sex, comorbidities). Women and older individuals have higher normal values, obese have lower values. This increases the difficulty in determining if a cardiac event has actually occurred. Although when combined with cTns, the diagnostic and prognostic value can be synergistic. The caveat is values that fall in the middle ranges. proBNP can be elevated in other disorders as well including: right-sided heart failure, sepsis, volume overload, stroke, and left-ventricular hypertrophy.5
- BNP is superior to NT-proBNP in the diagnosis of congestive heart failure.9 Although the age-related and sex related differences make the clinical value of BNP results more difficult to determine. In a meta-analysis regarding heart failure, BNP had a sensitivity of 85% and specificity of 84%.9
- We’ll do this as a group for 5 minutes and then share answers with the rest of the group. I haven’t decided whether to use poster paper and then just have them bring up the sheets so I can present them. I think it’ll take too long to have each group explain what they wrote.
- So one downside that occurs so far is the time between any cardiac event and the possibility of detecting troponins or other cardiac markers. A large amount of damage could occur in those first few hours. Also, differentiating Unstable Angina Pectoris from Non-Coronary Chest Pain can’t be done with troponin or any other current marker.6 ST2: is involved in the cardial remodeling pathway. It also helps in determining mortality and prognosis. It’s unrelated to the natriuretic peptides, and as such is able to offer additional information when coupled with the NPs.
- Clinically useful in patients that are troponin negative (indicating something other than MI). Highly concentrated in the myocardium.12 Together with troponin it has a high prognostic value. Troponin negative people with increased H-FABP represent the moderate risk patients.
- GPBB is an enzyme involved in cellular metabolism and dissociates from glycogen during ischemia, within the first hours of onset.12,22 For MI: Myoglobin at 6 hours: 85-95% sensitivity22 CK-MB mass: 71.4%-91.3% sensitivity22 For UAP: GPBB: large increase in 93.9% of patients22 Myoglobin: increased in 66.7%22 cTnT: 33.8%22 CK-MB: 55.0%22 So cTnT wasn’t very useful in diagnosing UAP but was able to determine patients who were negative for MI incredibly well. The enzymes are GP-MM, GP-BB, and GP-LL (skeletal muscle, brain and heart, liver, respectively).22 Multiple studies have obtained similar results (e.g., reference 24).
- Notice that a 3-4 fold increase in GPBB is present within 1 hour of the start of MI whereas troponin takes roughly 4-5 hours to be helpful. Also notice the lack of an increase in the early stages of MI and the continual relative increase in GPBB.
- sST2 can be used in the prognosis of CHF (highly specific), similar to BNP and ANP, not for necrosis (MI).25 When used alongside NT-proBNP, more information regarding prognosis can be determined. High sST2/high NT-proBNP=worst prognosis; low sST2/high NT-proBNP=moderate; low sST2/NT-proBNP=worst prognosis; this means it provides information independent of NT-proBNP It also provides prognostic information that is independent of traditional risk factors regarding a second cardiac event. Not powerful enough to be used independently in the diagnosis of any disease states. It has effects on apoptosis, inflammation, fibrosis, and remodeling. This is the reason it is useful in prognosis (i.e., it indicates state and healing process of the heart). ST2 ligand is IL-33 which is able to inhibit hypoxia induced apoptosis, infarct volume, and fibrosis of affected tissue. IL-33 is activated by ST2L wherea sST2 acts as a decoy receptor and prevents activation.
- miRNA is a short oligonucleotide that negatively (post-transcriptionally) regulates mRNA by promoting degradation or repression. Each miRNA has target sites on hundreds of genes.6 It’s estimated that over 60% of human genes are regulated by miRNA.6 Research shows that up and down regulation of cell/organ specific miRNA is altered in different fields of cardiac disease and polymorphisms in the miRNA regulation pathway are associated with certain disease states.6 Extraordinarily stable in circulating blood.6,19 Potential strategies for how to use them: construct molecules that mimic their function, construct anti-sense oligonucleotides that are extremely specific and will make targets dysfunctional, and overexpress miRNA of interest that is downregulated in specific disease processes.19
- What if we could determine what kind of damage the heart endured, if heart cells are undergoing remodeling due to a cardiac event that was undetected, if tissue fibrosis is occurring, what cells were specifically damaged and what the surrounding tissue is doing about it? That’s all possible with miRNA. Unlike troponin, some miRNAs are able to enter the urine and could provide new means for cardiomyopathy detection.19 Importantly, in a study on 332 patients with suspected ACS, miRNAs were compared to hs-cTn. The researchers found that in all patients various miRNAs were upregulated, including those patients that had a negative hs-cTn.19 miRNA-1 Cells that underwent necrosis from a coronary occlusion increase expression of miR-1 (which is pro-apoptotic in cells under oxidative stress).6 Increased plasma concentration in patients with STEMI, but only a very slight increase in other cardiac dysfunction.22 This is the most abundant miRNA in the heart and is heart and muscle specific.23 In one study, there was a 60-fold increase of miRNA-1 in urine at 24 hours that returned to normal after 7 days. This was true for patients presenting with STEMI.19 miRNA-21 is upregulated shortly after ischemia but is down-regulated before cell death occurs; it’s also thought to be involved in fibroblast proliferation.6 miRNA-28 is only expressed in cardiomyocytes and released upon cell death, therefore is highly specific for cardiac events.6 The miRNA-29 family is expressed in cells adjacent to necrotic cardiomyocytes.6 miRNA-126 is involved mainly with the reparative phase.6 miRNA-133 enhances myoblast differentiation and proliferation.6 Peak at 2h following MI.19 miRNA-208B expressed in the heart but undetectable in healthy individuals and individuals without MI. In one study, it was detected upon myocyte injury in 100% of patients within 4 hours. Troponin T was released as well, whereas Troponin I was unaffected.19 Specific for STEMI. Within 12 hours, the concentration increased 3000-fold.19 Although another study had similar findings, there wasn’t a statistical advantage over troponin T.19 miRNA changes occur with any type of cellular stress, although the specific miRNA differs for each. All that needs to be done is find the correct miRNA for the type of damage being considered. miRNA also has the potential as a therapeutic target.
- Ultimately, the goal is to use multiple biomarkers to characterize a cardiac disorder and therefore improve treatment. This can provide clinicians with the ability to tailor therapy or even prevent an adverse cardiac event from occurring in the first place.11 We also learned that the important qualities of a good indicator are: specificity, sensitivity, and analytical and clinical characteristics.