Cardiac Markers PH 167 PDF

upcph Cardiac Damage and Function Raycha Lei Concess M. Rama-Sabandal, RMT, DAP&E, MPH Department of Nutrition COLLEGE OF PUBLIC HEALTH UNIVERSITY OF THE PHILIPPINES MANILA SEAMEO TROPMED Philippines Regi...

upcph Cardiac Damage and Function Raycha Lei Concess M. Rama-Sabandal, RMT, DAP&E, MPH Department of Nutrition COLLEGE OF PUBLIC HEALTH UNIVERSITY OF THE PHILIPPINES MANILA SEAMEO TROPMED Philippines Regional Centre for Public Health, Hospital Administration, Environmental and Occupational Health Outline I. Review on the anatomy and physiology of the heart II. Brief Pathophysiology of Atherosclerosis III. Cardiac Damage (ACS vs CHF) IV. Markers for Cardiac Damage A. For ACS B. For CHF C. For CVD Risk Session Outcomes: Describe the anatomy of the heart Explain the origin of general symptom of cardiac disease Identify risk factors for coronary heart disease Discuss the features of an ideal cardiac marker Describe the clinical utility/diagnostic significance of each cardiac marker Review of Heart Anatomy and Physiology Average human adult heart weights ~325 g in men and 275 g in women Pericardium – sac which encloses it 4 chambers of the heart: LA, RA, LV, RV Cardiac wall has 3 layers: Epicardium – outer most layer; the coronary arteries (supply blood to the cardiac wall) are located Myocardium – middle layer; contains bundles of straited muscle fibers Endocardium – inner layer; continuous with the This Photo by Unknown Author is licensed endothelium of blood vessels under CC BY-NC-ND Most susceptible to myocardial ischemia Review of Heart Anatomy and Physiology Muscle fibers of the myocardium: Their alternating contraction and relaxation generate the “pumping” work of the heart Contain the contractile proteins: actin and myosin Contain troponins à regulate contraction Cardiac cycle – has two intervals (systole, diastole) Controlled by cardiac conducting system Electrocardiogram (ECG) – records the changes in electrical potential and is a graphic tracing of the variation in electrical potential caused by the excitation of the heart muscle Cardiovascular Diseases Two of the most common CVDs that rely on a biochemical (i.e. biomarker) diagnosis: acute ischemic disease à acute myocardial infarction (AMI) is the most severe form heart failure à AKA congestive heart failure (CHF) Epidemiology In the Philippines (PSA, 2022): Ischemic heart diseases were the leading cause of death with 29,442 cases or 18.7 percent of the total deaths in the country from Jan-Apr 2022. 1. Acute Myocardial Infarction Occurs when there is imbalance of supply and demand for oxygen in myocardium à injury to and the eventual death of myocytes Necrosis/cell death in myocardium: When blood supply is blocked for more than a few minutes, many/most myocytes in the affected region die Lesser severity: may be missed or be called angina (stable to unstable) Angina: a condition marked by severe pain in the chest, often also spreading to the shoulders, arms, neck Stable angina – activity induced chest pain Acute Coronary Syndrome (ACS) Refers to all ischemic events in the heart, ranging from: Cell death/necrosis No cell death Acute myocardial Angina infarction ST segment elevation myocardial infarction (STEMI) the ECG typically shows elevation of a portion called the ST segment in severe form of AMI Non-ST segment elevation myocardial infarction (NSTEMI or non-STEMI) Partial loss of coronary perfusion (may lead to necrosis if severe) but the magnitude of cell death is generally less; ECG does not show elevation of the ST segment Acute Coronary Syndrome (ACS) Refers to all ischemic events in the heart, ranging from: No cell death Partial necrosis Complete necrosis Angina NSTEMI STEMI Cell death/necrosis Acute myocardial infarction  ECGs from a patient with AMI The sequence is: (A) normal, (B) hours after infarction, the ST segment becomes elevated, (C) hours to days later, the T wave inverts and the Q wave becomes larger, (D) days to weeks later, the ST segment returns to near normal, and (E) weeks to months later, the T wave becomes upright again, but the large Q wave may remain. Patients with STEMI usually will develop Q waves on their ECG à Q-wave MI Atherosclerosis: major cause of ACS Disease caused by a plaque (deposit of fatty material) being formed on the inner lining of the coronary arteries that feed the surface of the heart à contributes to significant narrowing of the artery’s lumen Plaques are vulnerable to rupture that results in the formation of a platelet- and fibrin-rich thrombus leading to myocardial infarction and ischemic stroke Considered a chronic inflammatory disease as a result of damages in the endothelium of blood vessels Atherosclerosis Many therapies are now oriented towards (1) inhibition of thrombosis, (2) fibrinolysis, (3) platelet aggregation, (4) inflammation Irreversible cardiac injury consistently occurs when the occlusion is complete for at least 15-20 minutes Most of the damage occurs within the first 2 to 3 hours Atherosclerosis Restoration of coronary blood flow within the first 60 to 90 minutes results in the maximal salvage of tissue, but treatment even up to 4 to 6 hours is associated with increased survival. Treatment: Patients with STEMI: thrombolysis (clot dissolving agents), percutaneous coronary intervention (PCI) Patients with NSTEMI: combination of: coronary revascularization (PCI or other), + anticoagulant, antiplatelet, anti-inflammatory agents Atherosclerosis Precipitating Factors – elements that contribute to the occurrence of the disorder At the onset of AMI, the following precipitating factors have been observed for patient activities: Heavy exertion 13% Modest or usual exertion 18% Surgical procedure 6% Rest 51% Sleep 8% Role of Clinical History in Diagnosis of ACS Prodromal history of angina – abdomen à misdiagnosis of indigestion 40-50% of patients with AMI Severe pain but rarely Discomfort radiates to the intolerable pain of an ACS shoulder, upper extremities, Described as: constricting, neck, jaw (left side) crushing, oppressing, compressing With previous angina: more Something sitting on or severe, longer, not relieved squeezing sensation on the by rest chest Felt behind the sternum, Older individuals, diabetics spreading frequently to both and women: w/o pain / sides of the chest (left side); nonspecific symptoms often radiates down left arm May begin in the upper Role of Cardiac Biomarkers Cardiac biomarker biochemical compound whose measurement is useful in detecting cardiac disease, such as AMI or myocardial injury Usefulness in detecting AMI, Usefulness in detecting the biomarker: myocardial injury: Must be released rapidly Persist in the circulation for from the heart à circulation several days à more time Provide sensitive and specific window for patients to be diagnostic information diagnosed Analytical assays: rapid, can measure low concentrations in blood Diagnosis of AMI In 1950s: Use of cardiac In 1986: WHO produced a biomarkers used for criteria for AMI diagnosis diagnosis of AMI started Two of the following Aspartate aminotransferase must be met: (AST) History of chest pain Lactate dehydrogenase Changes in ECG (LD) Elevation of serial Total creatine kinase (CK) α-hydroxybutyrate cardiac biomarkers (x2 than normal) Cardiac injury occurs in many disease processes, beyond MI 2. Congestive Heart Failure (CHF) Condition in which the heart has lost its ability to pump Findings depend on many enough blood to the body’s factors such as tissues Clinical characteristics of the patient Encompasses a wide spectrum Extent and rate at which of clinical conditions: the heart’s performance A primary impairment in pump becomes abnormal function (after a large AMI) Cause of the heart disease Increased cardiac stiffness Concomitant co- Unable to sustain life without morbidities external support Part of the heart that is New York Heart Association affected by abnormal (NYHA) classification à often functioning used to functionally stage CHF patients 2. Congestive Heart Failure (CHF) Severity of impairment ranges from mild (manifested clinically only during stress) – to advanced (cardiac pump function is unable to sustain life w/o external support) Signs and symptoms are not specific à an objective test for heart failure would be extremely useful Ideally, the biomarker would increase progressively with increasing severity of disease and not be increased/decreased in conditions that mimic CHF; its assay must be rapid.  2. Congestive Heart Failure (CHF) New York Heart Association Functional Classification Used to Classify the Extent of Heart Failure* NYHA Class Symptoms I Cardiac disease, but no symptoms and no limitation in ordinary physical activity (e.g., shortness o breath when walking, climbing stairs, etc.) II Mild symptoms (mild shortness o breath and/or angina) and slight limitation during ordinary activity III Marked limitation in activity due to symptoms, even during less- than-ordinary activity (e.g., walking short distances [20- 100m]). Comfortable only at rest. IV Severe limitations; experiences symptoms even while at rest (mostly bedbound patients) *as of April 2013 Recommended specific laboratory and clinical tests for patients with suspected heart failure cTnI or cTnT determination is recommended if the clinical presentation is suggestive of ACS - ACC/AHA/Heart Failure Society of America and the European Society of Cardiology Cardiac Markers Principle behind serum Detection of cardiac biomarkers of cardiac proteins in plasma provides damage: insight into the: Cell death releases Occurrence intracellular proteins Extent from myocardium à circulation Timing of MI ^All critical for proper medical management  upcph Markers for ACS Cardiac Markers Initial markers Current markers Other markers SGOT Troponin I Myoglobin LD Troponin T Heart-type CK-MB Fatty Acid- Binding Protein Ischemia- Modified Albumin Cardiac Markers First cardiac markers (used in clinical practice): Glutamic oxaloacetic transaminase (GOT) Lactate dehydrogenase Creatine Kinase  Initial Cardiac Markers AKA aspartate transaminase (AST) First cardiac markers: Became widely used in the diagnosis of MI Glutamic shortly after its discovery oxaloacetic transaminase Cons: ↑ FN rate, labor-intensive nature of its Lactate assay, short window of AST elevation dehydrogenase AST was replaced by lactate dehydrogenase as the Creatine Kinase marker of choice  Initial Cardiac Markers More sensitive marker of MI (vs AST) Remains elevated for significantly longer after MI (up to two First cardiac markers: weeks) Glutamic Cons: ↓ specificity to cardiac muscle oxaloacetic LD is involved in glycolytic pathway à takes place in nearly all cells transaminase in the body Lactate Also ↑ in other conditions (e.g. cancer, anemia) dehydrogenase 5 LD isomers: Creatine Kinase LD1 – myocardium LD5 - skeletal muscle and liver To differentiate: LD1:LD2 ratio à 0.75 after 24-48 hours the onset of symptoms of MI and remains elevated up to 2 weeks à MI related elevation Typically, this ratio is lesser among those without MI  Initial Cardiac Markers Like LD, CK is found in nearly all cells in the body However, CK catalyzes the conversion of creatine to First cardiac markers: creatine phosphate à greatly upregulated in the muscle Glutamic cells and brain oxaloacetic transaminase Damage in these tissues (brain and muscle) à rapid ↑ in plasma CK Lactate dehydrogenase In AMI, serum CK levels were found to exceed normal range within 6-8 hours, reaches a peak of 2-10x by 24 Creatine Kinase hours, then declines to normal range after 3-4 days Primary means of enzymatic detection of AMI for years: [plasma CK] > 2x normal à correlate with MI; together with elevated AST and LDH  Initial Cardiac Markers High levels are found in striated muscles ↓ specificity of CK for MI marker, in spite of its high First cardiac markers: sensitivity Glutamic ↑ levels: stroke, pulmonary disease, chronic alcoholism, oxaloacetic transaminase after strenuous exercise Lactate 3 cytoplasmic isoenzymes of CK dehydrogenase Dimers: combination of subunits (M: muscle, B: brain) Creatine Kinase CK-MM – ↑ in muscle injury CK-BB – ↑ in brain injury CK-MB – ↑ in myocardial damage 15-30% is found in the heart  Initial Cardiac Markers Serum CK-MB First cardiac markers: increases at 4-6 hours after the onset of MI Glutamic oxaloacetic symptoms and quickly drop to normal levels transaminase after 2-4 days Lactate dehydrogenase Considered most reliable serum maker of MI Creatine Kinase and is still widely used today Due to its higher specificity, and rapid elevation after MI symptom Initial Cardiac Markers These 3 cardiac markers was the cornerstone of post-MI management for several decades: AST – for intermediate presentation LD – for late presentation CK – for early presentation However, since they are not specific to myocardium and to myocardial injury à extensive research lead to the discovery of more tissue-specific cardiac biomarker Troponins (Tn) Complex of three proteins (regulatory proteins) that bind to the thin filaments of cardiac muscles Regulators of actin and myosin TnT and TnI are nearly absent from normal serum – many healthy individuals have undetectable levels à cardiac muscle-specific isoform TnC = present in both cardiac and skeletal muscles binds calcium ions that regulate muscle contractions Reference value: < 0.1 ng/mL (< 0.1 µg/L) Troponins (Tn) Diagnostic Significance: Most important marker for cardiac injury (AMI) Since they are derived from myocardium Levels in the blood may elevate after AMI attack in the absence of CK-MB elevations Cardiac Troponins: a. Troponin T (TnT) b. Troponin I (TnI) Structure of Troponins Figure 34-4 Structure of cardiac troponin (cTn) complex and troponin forms released following myofibril necrosis. (From Gaze DC, Collinson PO. Multiple molecular forms of circulating cardiac troponin: analytical and clinical significance. Ann Clin Biochem 2008;45:349-59. Figure courtesy of Paul Collinson.) Troponin T (TnT) Tropomyosin-binding subunit Valuable tool in the diagnosis of AMI Useful for assessment of early and late AMI; elevated also in renal diseases and muscular dystrophy Sensitive marker for the diagnosis of unstable angina (angina at rest) Useful in monitoring the effectiveness of thrombolytic therapy in AMI patients In AMI, it rises within 3-4 hours after onset of myocardial damage, peak level is at 10-24 hours, return to normal in 7 days (but may remain elevated for 10-14 days Serum levels > 1.5 ng/mL à considered to be suggestive of AMI Troponin I (TnI) Inhibitory subunit or actin-binding unit Highly specific for AMI à not elevated in renal failure patients and no detectable amount in the skeletal muscles Gold standard test for AMI 13x more abundant in the myocardium than CK-MB on weight basis Very sensitive indicator of even minor amount of cardiac necrosis In AMI, levels begin to rise 3-6 hours, peak in 12-18 hours, return to normal in 5-10 days Troponins Methods: measured in serum by immunoassay Reference values of TnT and TnI as cardiac markers depend on the antibodies and calibrators used in the immunoassay  Other Markers of Cardiac Damage Small heme protein found in skeletal and cardiac muscle Myoglobin Transports and stores oxygen from hemoglobin to Heart-type fatty intracellular respiratory enzymes of contractile cells acid-binding protein (H-FABP) Has higher affinity of oxygen than oxygen has Ischemia-modified Approx. 2% of the total muscle protein albumin (IMA) Having a molecular weight of only 18 kDA, myoglobin apparently leaks from damage cells rapidly than other proteins Potential nephrotoxin à has to be excreted when plasma concentration exceeds reference ranges  Other Markers of Cardiac Damage Diagnostic Significance: One of the protein markers to diffuse out of Myoglobin ischemic myocardium Heart-type fatty Marker for chest pain (angina) and early detection acid-binding of AMI protein (H-FABP) In AMI (screening test), the onset is 1-3 hours, peak Ischemia-modified level 5-12 hours, normalize in 18-30 hours albumin (IMA) Useful marker for monitoring the success or failure of reperfusion ↑: AMI, angina, rhabdomyolysis, muscle trauma, extrenuous exercise, IM injection, acute renal failure  Other Markers of Cardiac Damage Methods: Measured in serum by immunoassay Myoglobin Heart-type fatty At high levels in urine, it produces a positive acid-binding dipstick reaction for occult blood due to protein (H-FABP) pseudoperoxidase activity Ischemia-modified albumin (IMA) AMI value: >100 µg/L  Other Markers of Cardiac Damage Small protein, which behaves much like myoglobin (kinetics and release) Myoglobin Found in all muscles, but more abundant in Heart-type fatty heart (vs myoglobin) acid-binding protein (H-FABP) Sensitivity: H-FABP> cTnT or myoglobin Ischemia-modified Specificity: cTnT > H-FABP albumin (IMA) H-FABP and cTnI: can be used for early diagnosis of MI/ACS Using both: rule out patients bet 3 and 6 hours after chest pain  Other Markers of Cardiac Damage Measures changes that occur in albumin in the presence of ischemia à can detect ischemia before damage has occurred to the heart Myoglobin Free radical formation occurs during tissue ischemia is believed Heart-type fatty to modify albumin within minutes of ischemia and lasts for about acid-binding 6 hours protein (H-FABP) These modification alter its ability to bind to transition metal by its N-terminal domain Ischemia-modified albumin (IMA) Method: Spectrophotometric determination of albumin’s binding to cobalt IMA is not specific for cardiac damage but it has a clinical sensitivity for ACS of 50-90% Its use will complement troponin and CK-MB detection  upcph Marker for CHF: BNP  https://www.researchgate.net/publication/332797145/figure/fig1/AS:779410676412426@15 62837394720/Pathways-of-NT-proBNP-and-BNP-synthesis-from-proBNP-The-proBNP- was-cleaved-by-CORIN.png B-type natriuretic peptide (BNP) A hormone that is mainly released from the myocardial ventricles à in response to increased pressure and volume load proBNP à cleaved by protease N-terminal pro-B-type natriuretic peptide (NT-proBNP) B-type natriuretic peptide (BNP) : active Method: Measured by immunoassay Specimen: For BNP: EDTA whole blood/plasma using plastic blood collection tube For NT-proBNP: serum, heparin plasma, EDTA plasma Reference values: laboratory must determine their own; depends on age, sex BNP: 100 pg/mL (aged