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Cardiac biomarkers


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this ppt will give a detailed review of cardiac biomarkers

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  • "9th International Conference on Biomarker” welcomes all the attendees, speakers, sponsor’s and other research expertise from all over the world which is going to be held during October 26 -28, 2017 in Osaka, Japan. We are very much honoured to invite you all to exchange and share your views and experience on the Biomarkers Congress 2017. Oncology & Cancer has evolved into one of the most dynamic specialties in medicine. Biomarkers Congress 2017, in the hands of clinical investigators, provide a dynamic and powerful approach to understanding the spectrum of diseases with obvious applications in analytic epidemiology, biomarkers and clinical research in disease prevention, diagnosis, and disease management. Cancer biomarkers have the additional potential to identify individuals susceptible to disease. For more details:
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Cardiac biomarkers

  1. 1.  Chairman Dr. K.V.Venkteswaran, Professor, Dept. of Veterinary Pharmacology and Toxicology, MVC, Chennai Members Dr. S.Selvasubramanian, Professor, Dept. of Veterinary Pharmacology and Toxicology, MVC, Chennai Dr.P.S.L.Sesh, Assistant Professor, Dept. o VeterinaryBiochemistry, MVC, Chennai
  2. 2. “A biomarker is a substance used as anindicator of a biologic state”. Morrow and de lomos three criteriafor biomarkers› Accurate repeated measurements at reasonable cost› Must provide additional information› Should aid treatment
  3. 3. HEART FAILURE Heart failure a major and growing health problem appears to result not only from cardiac overload or injury but also from complex interplay among genetic, inflammatory and biological changes acting on cardiac myocytes, the cardiac interstitium or both.ACUTE MYOCARDIAL INFARCTION A sudden occlusion of a coronary artey by thrombus or by embolisation causes an acute myocardial infarction.
  4. 4.  Cardiac biomarkers are protein molecules released into the blood stream from damaged heart muscle Since ECG…… inconclusive ….biomarkers !!!!!?????myocardial injury These biomarkers have a characteristic rise and fall pattern Dr. Jaikanth
  5. 5.  High cardiac specificity Pharmacokinetics of cardiac biomarker Easy diagnosis Marker should play a designed role in the treatment and management of clinical subject
  6. 6.  1954 - SGOT (AST) 1955 - LDH 1960 - CPK 1972 - CPK isoforms by Electrophoresis 1975 - CK - MB by immunoinhibition 1975 - Myoglobin 1985 - CK - MB Mass immunoassay 1989 - Troponin T 1992 - Troponin I
  7. 7.  Biomarkers of myocardial injury › markers of myocardial necrosis › markers of myocardial ischemia Biomarkers of haemodynamic stress Inflammatory and prognostic Biomarkers
  8. 8.  Markers of myocardial necrosis › Creatine kinase – MB › Myoglobin › Cardiac troponins• Markers of myocardial ischemia Ischemia Modified Albumin (IMA) Heart-type fatty acid binding protein (H-FABP) Dr. Jaikanth
  9. 9. Zones of Ischemia Injury and Infarction withTransmural and Subendocardial Infarction
  10. 10. Creatine kinase (CK/CPK) is an enzyme expressed in a number of tissues. Function: it catalyses the conversion of creatine to phosphocreatine degrading ATP to ADP The CK enzyme consists of two subunits, B (brain type) or M (muscle type), Making three different isoenzymes: CK-MM, CK-BB and CK-MB CK-BB occurs mainly in tissues, rarely of any significance in the bloodstream Skeletal muscle expresses CK-MM (98%) and low levels of CK- MB (1%) The myocardium has CK-MM at 70% and CK-MB at ~30%
  11. 11.  High specificity for cardiac tissue Begins to rise 4-6 hours after onset of infarction Peaks at about 12 hours Returns to baseline at 24-36 hours Can be used to indicate early re-infarction if level normalizes and then increases again
  12. 12.  CK-MB now measured via a highly sensitive monoclonal antibody assay Immunological Sandwich technique using two Abs for different epitopes of CK –MB molecule The first Ab is rendered immobile on a matrix (e.g. CrO2 particles) The second Ab conjugate to an enzyme (β- galacto- sidase) Separated bound sandwiches are reacted with their substrate (e.g. Chlorophenol β- Red Galactopyranoside) Liberated end product chlorophenol is measured spectrophotometrically and is proportionate to CK-MB amount (not the activity)
  13. 13.  The CK-MB isoforms may also be analyzed using high- voltage electrophoresis The ratio of MB2/MB1 is calculated MB2 released from heart muscle and converted to MB1 A level of MB2 > or = 1 and a ratio of MB2/MB1 > 1.5 indicates myocardial injury A result is positive if MB2 is elevated and the ratio is more than 1.5
  14. 14.  False positive (for MI) CK-MB elevation can be seen in: › Significant skeletal muscle injury › The MB fraction is determined to be expressed during the process of muscle regeneration › Cardiac injury for reason other than MI  Defibrillation  Blunt chest trauma  Cocaine abuse The search for cardiac specificity continues…
  15. 15.  Small-size heme protein found in all tissues mainly assists in oxygen transport It is released from all damaged tissues Increases often occur more rapidly than TI and CK Released from damaged tissue within 1 hour Normal value: 17.4-105.7 ng/ml Timing: › Earliest Rise: 1-3 hrs › Peak 6-9 hrs › Return to normal: 12 hrs
  16. 16.  Acute myocardial infarction Skeletal muscle damage, muscular dystrophy, inflammatory myopathies Renal failure, severe uremia Shock and trauma
  17. 17.  Rapid monitor of success of thrombolytic therapy Negative predictor of MIDRAWBACKS Due to poor specificity, myoglobin levels do not always predict myocardial injury Not utilized often for AMI/cardiac damage assessment because of its very rapid metabolism
  18. 18.  Troponin is a complex of three regulatory proteins that is integral to non-smooth muscle contraction in skeletal as well as cardiac muscle Troponin is attached to the tropomyosin sitting in the groove between actin filaments in muscle tissue Troponin has three subunits, TnC, TnT, and TnI › Troponin-C has calcium binding ability and has no diagnostic value › Troponin-T binds the troponin tropomyosin complex, › Troponin-I is an inhibitory protein
  19. 19.  Less than 5% in cytosol Troponin levels begin to rise 2-3 hours after onset of myocardial injury Elevations in Troponin-I and Troponin-T can persist for up to 10 days after MI Remember, CK-MB returns to baseline by 48 hours Thus far, studies have failed to find a source of Troponin-I outside the heart, but have found some Troponin-T in skeletal muscle
  20. 20. NEJM 2002;Vol.346,No.26:2079-82
  21. 21. Conditions commonly associated with cardiac troponin elevations Arrhythmias Congestive heart failure Coronary artery disease Coronary vasospasm Critically ill patient Hypertension Myocarditis Pericarditis Pulmonary embolism Pulmonary hypertension, severe Renal failure Sepsis/septic shock Sepsis-related myocardial dysfunction Systemic inflammatory diseases Trauma
  22. 22.  Troponin T and I are not detected in healthy individuals Significant increase in Troponins reflects myocardial necrosis ACC/ESC has defined increase in Troponins as a measurement above 99th percentile value of reference group To reduce false-positive outcomes, CV of 10% at decision limit is recommended
  23. 23. • TropT (Roche Diagnostics, Germany)• Trop I (Siemens Healthcare Diagnostics)• Troponin T › 99th percentile limits - 0.01 ng/mL › assay ranges - 0.01-25 ng/mL (Troponin I) › 99th percentile limits -0.04 ng/mL › assay range -0.04-40 ng/mL• Reference limits based on the 99th percentile for a healthy population are 0.01 ng/mL (Troponin T) and 0.04 ng/mL (Troponin I)
  24. 24. They used the concentration of 0.04 ng per mL as the upper reference limit and established the diagnosis of myocardial infarction if one value of more than 0.04 ng per mL was documented, combined with a rise or fall in the value of 30% or more within 6 hours after admission.Patients with troponin rises benefit more from Glycoprotein IIb IIIa inhibitors such as, Abciximab Eptifibatin Clopidogrel
  25. 25.  Most commonly used in dogs and catsClinical conditions Congestive heart failure Percardial disease Doxorubicin toxicity Gastric dilatation and volvulus etc,.
  26. 26. 120 animals were examined in emergency with cardiac troponin assays, First group= ctni less than .15ng/ml Second group= ctni .15-1 ng/ml Third group= ctni more than 1 ng/mlPrognosis grave in second and third group
  27. 27.  A novel marker of ischemia, is produced when circulating serum albumin contacts ischemic heart tissues IMA can be measured by the albumin cobalt binding (ACB) assay that is based on IMAs inability to bind to cobalt Mechanism- due to structural change in the amino terminal end of albumin IMA levels rise within 6 hours remain elevated for 12 hours
  28. 28. Drawbacks IMA levels raised in non- cardiac ischemia Modification to n- terminal end may also be induced by extracellular hypoxia, acidosis etc,Conclusion FDA in 2010 has approved a multimarker approach for using the combination of ECG, the cTnI, and the IMA levels achieving a sensitivity of 95% for ACS
  29. 29. Heart-type fatty acid binding protein (H-FABP) H-FABP is a very stable abundant [138] low molecularweight protein (14–15 kDa) in the cytoplasm of myocardial cells Appearing as early as 90 min after symptom onset and peaking within 6 h Parameters of kinetic release make it an ideal candidate both for early assessment or exclusion of AMI and for the measurement of a recurrent infarction
  30. 30.  A study by Puls et al › the negative predictive value (NPV) of H-FABP was an impressive 100% › its Positive predictive value was 41% which was greater than that of both cTnT (29%) and NT-proBNP (19%). The myoglobin/heart FABP ratio has been used to differentiate between heart muscle and skeletal muscle injury Cardiodetect Dr. Jaikanth
  31. 31.  The natriuretic peptides (NP) are a group of structurally similar but genetically distinct peptides. NPs are identified as regulatory diuretic-natriuretic substances responsible for salt and water homeostasis Lowers blood pressure.
  32. 32.  The NP family includes ANP : -atrial natriuretic peptide (28 a.a.) N-terminal proANP (98 a.a.) BNP : brain natriuretic peptide (32 a.a.) N-terminal proBNP (76 a.a.) CNP : C-type natriuretic peptide (22 and 53 a.a.)
  33. 33. Fig. Schematic representation of the ANP and BNP precursors with sequencenumbering defining low-molecular-mass forms, N-terminal forms and high-molecular-mass precursors
  34. 34.  ANP is released primarily in response to atrial wall stretching and intravascular volume expansion. BNP is mainly secreted by the ventricles CNP is found predominantly in the brain and also synthesized by vascular endothelial cells
  35. 35.  originally isolated from porcine brain Subsequently also isolated from human heart Circulating levels of BNP are raised in patients with cardiovascular or renal disease More important than ANP in heart failure Greatest proportion of circulating BNP is thought to come from the ventricles (left)
  36. 36.  Synthesis
  37. 37. Three receptors for natriuretic peptides : Natriuretic peptide receptor -A Natriuretic peptide receptor -B Natriuretic peptide receptor -CNPR-A and NPR-B NPR-A and NPR-B are particulate guanylyl cyclases that catalyses the conversion of GTP to c-GMP NPR-C They lack the guanyl cyclase domain and may influence the target cell function through inhibitory guanine nucleotide (Gi) protein, and they likely also act as clearance receptors for circulating peptides.
  38. 38. NPR-A and NPR-B NPR- A is the most abundant type in large blood vessels NPR-B predominate in the brain Both receptors are present in the adrenal glands and the kidney Affinity for NPR-A : ANP > BNP > CNP for NPR-B : CNP > BNP > ANP
  39. 39. Action of Atrial Natriuretic Peptide at Target Cells
  40. 40.  ANP and BNP concentrations increase in response to volume expansion and pressure overload of the heart ANP and BNP have been shown to be physiological antagonists of the effects of (1) angiotensin II on vascular tone (2) aldosterone secretion (3) renal-tubule sodium reabsorption (4) vascular-cell growth
  41. 41. Figure . Physiology of the natriuretic-peptide family
  42. 42.  Clearance factors for natriuretic peptides NPR-C and neutral endopeptidaseEndopeptidase Neutral endopeptidase inactivates all three natriuretic peptides Present within renal tubular cells and vascular cells
  43. 43. Conditions or factors commonly associated with B-typenatriuretic peptide or N-terminal-pro-B-type natriuretic peptideelevations Age Arrhythmias Cardiomyopathy: hypertrophic, ischemic, or dilated Congestive heart failure Coronary artery disease Gender Hypertension Left ventricular diastolic dysfunction Pulmonary embolism Renal failure Right heart failure Right ventricular overloading: fluid, or pressure overloading Sepsis or septic shock Sepsis-related myocardial dysfunction
  44. 44.  Prospective study of 1586 patients presenting to the emergency department with acute dyspneaOutcomes of the study The predictive value of BNP much superior to previous standards including radiographic, clinical exam, or Framingham Criteria Bnp cut point was fixed at 100pg/ml and it showed 90% sensitivity and 80% specificity for diagnosing heart failureVeterinary field Chronic left ventricular systolic and diastolic dysfunction Cardiac vs non- cardiac dyspnoea Recent development of ELISA kits for canine and feline NTproBNPby Guildhay Ltd (www. guildhay.
  45. 45. ANP and BNP infusion Decrease renin and aldosterone concentration Increase urinary sodium and water excretion Neutralendopeptidase inhibitor Nesiritide is a new drug that is a synthetic BNP that vasodilates vessels and serves as a potent diuretic agent
  46. 46. BNP for Rx of decompensated heart failure Nesiritide (h-BNP) R I S S D S M S K G R L G G H F R S C R C S K V L G S P K M V Q G S 32 amino acid sequence Recombinant technology using E-coNOTE: hBNP affects assay for BNP, but can still use proBNP or one of the proANP assays
  47. 47. C-reactive proteinMyeloperoxidaseHomocysteine
  48. 48.  CRP is an acute-phase protein produced by the liver Pentameric structure consisting of five 23- kDa identical subunits Plasma levels can increase rapidly to 10000x levels High-sensitivity CRP (hs-CRP) assays
  49. 49.  CRP previously known to be a marker of high risk in cardiovascular disease More recent data may implicate CRP as an actual mediator of atherogenesisMechanism of CRP-mediated atherogenesis: Once ligand-bound, CRP can: › Activate the classical compliment pathway › Stimulate phagocytosis › Bind to immunoglobulin receptors › Endothelial dysfunction via ↑ NO synthesis › ↑LDL deposition in plaque by CRP-stimulated macrophages
  50. 50. Clinical Uses › Screening for cardiovascular risk in otherwise “healthy” individuals › Predictive value of CRP levels for disease severity in pre-existing Coronary artery diseaseElevated levels predictive of • Long-term risk of first MI • Ischemic stroke
  51. 51. Limitations of CRP Low specificity No evidence that lowering CRP levels decreases CV riskIndustry and FDA staff guidelines 2005 had given clinical cut off value as less than 1 mg/l as safe levels with hs-CRP tests CRP Risk for CVD Less than 1.0 mg/L Low 1.0-2.9 mg/L Intermediate Greater than 3.0 mg/L High
  52. 52.  MPO is an enzyme that aids white blood cells in destroying bacteria and viral particles MPO catalyzes the conversion of hydrogen peroxide and chloride ions (Cl-) into hypochlorous acid MPO is released in response to infection and inflammation EPIC Norfolk StudySugiyama Am J Pathology 2001
  53. 53.  MPO leads to oxidized LDL cholesterol › Oxidized LDL is phagocytosed by macrophages producing foam cells MPO leads to the consumption of nitric oxide › Vasoconstriction and endothelial dysfunction MPO can cause endothelial denuding and superficial platelet aggregation MPO indicates activated immune cells › Activated immune cells and inflammation lead to unstable plaque Inflammatory plaque is inherently less stable › Thin fibrous cap/fissured/denuded
  54. 54.  In august 2005, FDA approved the first MPO assay, Cardio MPO tm developed by Prognostix,inc. The test is a sandwich enzyme immuno assay Normal plasma MPO levels are 51- 633pmol/ml
  55. 55. Progression of Biomarkers in ACS STABLE CAD PLAQUE RUPTURE UA/NSTEMI STEMI MPO MPO MPO TnI CRP ICAM D-dimer TnT IL-6 sCD40L IMA Myoglobin PAPP-A FABP CKMB Inflammation has been linked to the development of vulnerable plaque and to plaque ruptureACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segmentelevation myocardial infarctionAdapted from: Apple Clinical Chemistry March 2005
  56. 56.  Intermediary amino acid formed by the conversion of methionine to cysteine Moderate hyperhomocysteinemia occurs in 5- 7% of the population Recognized as an independent risk factor for the development of atherosclerotic vascular disease and venous thrombosis Can result from genetic defects, drugs, vitamin deficiencies
  57. 57.  Homocysteine implicated directly in vascular injury including: › Intimal thickening › Disruption of elastic lamina › Smooth muscle hypertrophy › Platelet aggregation Vascular injury induced by leukocyte recruitment, foam cell formation, and inhibition of NO synthesis Normal levels less than 6micro mol/l
  58. 58.  Elevated levels appear to be an independent risk factor, though less important than the classic CV risk factors Treatment includes supplementation with folate, B6 and B12
  59. 59. Stefan Blankenberg, MD; Renate Schnabel, MD; Edith Lubos, MD, et al., Myeloperoxidase Early Indicator of Acute Coronary Syndrome andPredictor of Future Cardiovascular Events 2005
  60. 60.  Send the comments of this ppt to for further enhancement of my presentationsDr. Jaikanth
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