CVD-Cardiac Markers PDF

Cardiac Markers By Dr. Mohamed Attia Content Structure of the heart Blood circulation Myocardial Infarction Cardiac Markers Troponin CK and CK-MB LDH Heart and Cardiac tissues Heart: Human heart provides a continuous blood circulation...

Cardiac Markers By Dr. Mohamed Attia Content Structure of the heart Blood circulation Myocardial Infarction Cardiac Markers Troponin CK and CK-MB LDH Heart and Cardiac tissues Heart: Human heart provides a continuous blood circulation through the cardiac cycle and is one of the most vital organs in th human body. It is located between lungs in the middle of chest, behind and slightly to the left of the sternum Heart wall Innermost: The endocardium is formed by endothelial cells, and it lines the interior of the heart chambers and valves. Help in contraction Middle: The myocardium is the muscular middle layer of the heart that consists of heart muscle cells. Contains contractile heart muscle fibers. Outermost: The epicardium is formed by epithelial cells, and forms the outer cell layer of the heart. Cardiac tissues The pericardium is a membranous sac that surrounds the heart, holding heart to diaphragm and sternum. It consist of two layers fibrous pericardium and serous pericardium (which consists of the visceral pericardium (adheres to the epicardium) and parietal pericardium (the outer coat). The space between these two layers is called pericardial cavity and it contains pericardial fluid). Heart chambers The heart consists of four chambers in which blood flows. Blood enters the right atrium from the veins and passes through the right ventricle. The right ventricle pumps the blood to the lungs where it becomes oxygenated. The oxygenated blood from the lung is brought back to the heart by the pulmonary veins which enter the left atrium. From the left atrium blood flows into the left ventricle. The left ventricle (the largest and strongest chamber) pumps the blood to the aorta which will distribute the oxygenated blood to all parts of the body. Heart valves Blood is only pumped to one direction. Four heart valves ensure that blood does not flow backward within the heart. Atrioventricular (AV) valves: 1. Tricuspid valve: located between the right atrium and the right ventricle. 2. Mitral valve: located between the left atrium and the left ventricle. Semilunar valves: 3. Pulmonary valve: located between the right ventricle and the pulmonary artery. 4. Aortic valve: located between the left ventricle and the aorta. Blood vessels: comparison Arteries Arterioles Capillaries Venules Veins  The Circulatory System The heart works as a pump that pushes blood to the organs, tissues, and cells of body. Blood delivers oxygen and nutrients to every cell and removes the carbon dioxide and waste products made by those cells. Blood is carried from your heart to the rest of your body through a complex network of arteries, arterioles, and capillaries. Blood is returned to your heart through venules and veins. Pulmonary circulation Systemic circulation  Blood circulation Pulmonary circuit (step 1 to 4) Pulmonary circulation begins at the right ventricle, where the deoxygenated blood from the body tissues is pumped into the pulmonary arteries and to the lungs. In the lungs, the blood exchanges carbon dioxide (waste product of cellular respiration) to oxygen. The oxygenated blood them travels back to the heart and the left atrium, via the pulmonary vein.  Blood circulation Systemic circuit (step 5 to 11) The systemic circulation begins at the left ventricle that pumps oxygenated blood into the aorta. Aorta branches out into smaller arteries, which carry the oxygenated blood to the rest of the body (with the exception of lungs). Oxygen is delivered to the body tissues and exchanged to carbon dioxide. The now deoxygenated blood is carried back to the heart and the right atrium via veins. Note: Atrial blood carries O2, and venous blood carries CO2. However, one exception includes pulmonary arteries, which contain the most deoxygenated blood in the body, while the pulmonary veins contain oxygenated blood. Coronary circulation The heart muscle, like every other organ or tissue in your body, needs oxygen and nutrients-rich blood to survive. Coronary circulation is the circulation of blood in the blood vessels that supply the heart muscle (myocardium). Coronary arteries supply oxygenated blood to the heart muscle, and cardiac veins drain away the blood once it has been deoxygenated. There are two primary coronary arteries, the right coronary artery and left main coronary artery. Both of these originate from the root of the aorta. Interruptions of coronary circulation quickly cause heart attacks (myocardial infarctions), in which the heart muscle is damaged by oxygen starvation. Types of heart disease  Heart Attack With acute coronary obstruction (Myocardial Infarction, MI) Without acute coronary obstruction MI is extremely dangerous condition caused by a lack of blood flow to your heart muscle. Ischemia is a condition in which the blood flow (and thus oxygen) is restricted or reduced in a part of the body. Symptoms of MI MARKERS OF CARDIAC DAMAGE Cardiac markers are biomarkers measured to evaluate heart function. Most of the early markers identified were enzymes, and as a result, the term "cardiac enzymes" is sometimes used. However, not all of the markers currently used are enzymes. Cardiac markers or cardiac enzymes are proteins that leak out of injured myocardial cells through their damaged cell membranes into the bloodstream. CARDIAC MARKERS Until the 1980s, the enzymes SGOT and LDH were used to assess cardiac injury. Now, the markers most widely used in detection of MI are MB subtype of the enzyme creatine kinase (CK-MB) and cardiac troponins T and I as they are more specific for myocardial injury. Note: An ECG remains the most specific diagnostic tool in evaluating the patient with chest pain however, the initial ECG may be negative/non-diagnostic in > 40% of AMI cases. CARDIAC MARKERS Note: the perfect cardiac marker test, with a 100% early sensitivity + 100% specificity in diagnosing an AMI, does not exist different cardiac marker tests are used in varying combinations. Why it is done? Cardiac enzymes levels help diagnose chest pain or other signs and symptoms of a heart attack. CARDIAC MARKERS Limitations: Depending on the marker, it can take between 2 to 24 hours for the level to increase in the blood. Additionally, determining the levels of cardiac markers in the laboratory takes time. Cardiac markers are therefore not useful alone in diagnosing a myocardial infarction in the acute phase. The clinical presentation and results from an ECG are more appropriate in the acute situation. Cardiac Markers 1. Troponin  Cardiac Troponin Troponin is a complex of three regulatory proteins 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 to the tropomyosin to form Actin troponin- tropomyosin complex ✓ Troponin-I: binds to the actin filament to hold the troponin- tropomyosin complex in place and inhibits ATPase activity of actomyosin. Tropomyosin T > I on PAGE (False)  Cardiac Troponin Cardiac Troponin I (cTnI) is a cardiac muscle protein with a molecular weight of 23.9 kilodaltons. Together with troponin T (TnT) and troponin C (TnC), TnI forms a troponin complex in heart to play a fundamental role in the transmission of intracellular calcium signal, actin-myosin interaction. Although troponin I is also found in skeletal muscle, cardiac troponin I (cTnI) has additional amino acid residues on its N-terminal which distinguishes it from its skeletal muscle form making cTnI a specific marker for indicating cardiac infarction. cTnI is released rapidly into blood stream soon after the onset of acute myocardial infarction (AMI). Its release pattern is similar to CK-MB (4-6 hours after the onset of AMI). CK-MB level returns to normal after 36-48 hours, while levels of cTnI remains elevated for up to 6-10 days. The level of cTnI is below 0.06 ng/mL in average in healthy people, and also not detected in the patients with skeletal muscle injury. Therefore, cTnI is a specific marker for diagnosis of AMI patients. The level of cTnI may reach 100-1300 ng/mL in some AMI patients.  Troponin I Cardiac troponin I (cTnI) is a cardiac muscle protein with a molecular weight of 24 kilo-Daltons. The cTnI has an additional amino acid residues on its N-terminal that are not exist on the skeletal form. Serum increase (4 - 6) hours Troponin T is a tropomyosin-binding subunit of troponin. This peptide is the largest of the three troponin subunits and interacts with both troponin I and troponin C. Troponin T is not directly involved in the Ca2+-regulatory interactions in the troponin complex, but the presence of troponin T, in addition to troponins C and I, is required for the Ca2+-regulated contractile interaction to take place. The regulatory role of troponin T is to confer the Ca2+ sensitivity to the neutralizing effect of troponin C. TROPONIN LEVELS Less than 5% in cytosol Troponin levels begin to rise 4-6 hours after onset of myocardial injury. Elevations in Troponin-I and Troponin-T can persist for up to 10 days after MI Thus, further studies have failed to find a source of Troponin-I outside the heart, but have found some Troponin-T in skeletal muscle Troponin T and I are not detected in healthy individuals Significant increase in Troponins reflects myocardial necrosis  Both cTnT and cTnI have been shown to be highly specific for cardiac injury, but the fourth generation cTnT assay was shown to have cross-reactivity with a protein found in skeletal muscle of patients with primary Limitations skeletal muscle disease. There are increases in both cTnT and cTnI in a minority of patients with chronic renal failure, with a higher percentage of abnormal results occurring for cTnT. TROPONIN ASSAY Troponin-T (TnT): (Roche Diagnostics, Germany) Troponin-I (Inl): (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)  2. Total Creatine Kinase (CK) & CK- MB TOTAL CREATINE KINASE (CK) Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phospho-creatine kinase, is an enzyme expressed by various tissues and cell types. Creatine is produced by the body at rate of 1-2 g/ day from the amino acids, glycine, arginine and methionine. The liver is the major site of creatine production, but some is also produced in the kidney and pancreas. It exists as free creatine and creatine phosphate (CP). TOTAL CREATINE KINASE (CK) Function CK catalyzes the conversion of creatine and consumes adenosine triphosphate (ATP) to create phosphocreatine and adenosine diphosphate (ADP). CK TOTAL CREATINE KINASE (CK) Role of phosphocreatine (PC) In tissues and cells that consume ATP rapidly, especially skeletal muscle, phosphocreatine serves as an energy reservoir (buffer) for the rapid buffering and regeneration of ATP in situ. Thus, when muscle contracts, ATP is consumed to form ADP, in this case CK catalyze the re-phosphorylation of ADP to form ATP using Crp as the phosphorylation reservoir.  TOTAL CREATINE KINASE (CK) creatine phosphate shuttle The creatine-P formed in the mitochondria travels to the contractile proteins in the cytoplasm of the muscle fiber. The polymer, or complex, of contractile proteins is called a myofibril. Contraction of a myofibril is coupled to the hydrolysis of ATP to ADP. The immediate replenishment of ATP is catalyzed by a second creatine kinase, residing on the myofibril, that catalyzes the conversion of creatine-P to creatine. This reversal of the reaction takes place in the mitochondrion. This reaction, as well as the product formed by gradual spontaneous degradation of creatine-P. The scenario depicted in opposite figure, conversion of the creatine-P energy buffer, bound to myofibrils, to creatine and regeneration of creatine-P in the mitochondrion, is called the creatine phosphate shuttle.  CK-ISOENZYMES In the cells, the CK enzyme is a dimeric protein that consists of two subunits, which can be either B (brain-type) or M (muscle-type). There are, therefore, three different cytosolic isoenzymes: CK-BB (CK1), CK-MB (CK2) and CK-MM (CK3). 1. CK-BB (CK1) occurs mainly in brain tissues and others (lungs, prostate, bladder, uterus), and its levels do rarely have any significance in bloodstream. 2. Skeletal muscle expresses CK-MM (98%) and low levels of CK-MB (1%). 3. The myocardium (heart muscle), in contrast, expresses CK-MM about 70% and CK-MB up to 30%. CK-MB Serum CK-MB mainly comes from myocardial tissue, so it is the first cardiac enzyme to be elevated after MI In the first 4 to 6 hours after a heart attack, the concentration of CK-MB in blood begins to rise. It reaches its highest level in 12 to 24 hours and returns to normal within 2 to 3 days. The sensitivity at 4 hours is < 50%, but the sensitivity should reach - 100% for AMI 10 - 12 hours after the onset of the chest pain An AMI cannot be ruled-out before - 9 - 10 hours after the onset of symptoms; longer if the patient has ongoing chest pain  CK-MEASUREMENT Sample: Non hemolyzed serum or plasma sample is used Result: Total CK: males 0–200 U/L, females 0–160 U/L, CK-MB: