Cardiac biomarkers – The Role of Cardiac biomarkers in myocardial injury, Creatine Kinase4 in treatment of in myocardial injury, CK-MB Isoenzyme in myocardial injury…See more below.
Cardiac biomarkers are released into the circulation when myocardial injury occurs. They play a pivotal role in the diagnosis, risk stratification and treatment of patients with chest pain and suspected acute coronary syndrome (ACS) as well as those with acute exacerbation of heart failure (Albert et al., 2000). Acute coronary syndromes (ACS) represent a range of ischemic heart disease from unstable angina to myocardial infarction (MI) and may include large areas of cardiac necrosis (Goldman and Ausiello, 2004).
The symptomatic manifestations of an acute myocardial infarction (AMI) may be varied, and ECG is also non-diagnostic in about 50% of cases, which poses a risk for potential misdiagnosis. Hence, biochemical markers and cardiac enzymes are considered not only important but essential for the diagnosis of myocardial infarction (Rajappa and Sharma, 2005).
Initially, the transaminases and creatine kinase (CK) were used as diagnostic markers, and gradually, improved markers like CK myocardial band (CK-MB) evolved and have been used to diagnose AMI and assess cardiac damage. Their non-specificity has been an issue which has led to the introduction of more specific and sensitive cardiac biomarkers, (for example, troponins). It is now generally accepted activity measurement of enzyme markers such as aspartate transaminase (AST), LDHN and CK-MB is of little value in the assessment of myocardial injury, because of the lack of tissue specificity (Alpert and Thygesen, 2000).
Troponins are more efficacious than earlier markers because they aid not only in diagnosis, but also in risk assessment and therapeutic decision making (Maynard, Adgey and Mentown, 2000). However, CK-MB is still used in the absence of troponins, but because of its limitations, research has paved the way for troponins to replace CK-MB as the ‘’gold-standard’’ diagnostic markers. The high sensitivity of cardiac troponin assays enables it to be useful in patient s with unstable angina, where the degree of cardiac injury is minor and considerably less than in AMI.
Myoglobin is also used as an early marker but lacks specificity and requires associated cardiac troponin measurements to confirm myocardial injury and eliminate myoglobin false positives (Mauro, 2004).
Creatine Kinase4 and CK-MB Isoenzyme
Chest pain can result from indigestion or from a serious heart problem. When the heart muscle dies during myocardial infarction (MI), it releases many molecules into the blood stream, one being creatine kinase (CK). Determination of serum levels of creatine kinase and its isoenzymes have long been used for the diagnosis of myocardial infarction (Keffer, 1996).
Creatine kinase (CK) is an enzyme present in many parts of the body whose physiological role is to maintain an adequate store of high energy phosphorylated creatine, which is used to restore ATP levels depleted v during muscle contraction. CK is composed of two subunits, each with a molecular weight of 43kDa. CK is shown to exist in three molecular forms viz MM, MB, and BB (B for brain and M for muscle).
CK-MM predominates in the skeletal muscle and CK-MB is most prevalent in the heart muscle where it comprises 15 – 40% of the total CK activity. Trace amounts of CK-MB are found in skeletal muscle injury will have increases in the absolutew concentrations of CK and CKMB. CK-BB is the predominant isoenzyme found in brain, colon, ileum, stomach and urinary bladder (Lott and Nemesanszky, 1996). Serum total CK activity and CK-MB concentration rise in parallel following myocardial injury, starting to increase 4-6hrs after injury, reaching peak serum concentrations after 12-24hrs and returning to baseline after 48-72hrs.
A significant elevation in the level of CK-MB has been observed in the heart effluent during myocardial ischemia band reperfusion in isolated rat hearts (Tiwari et al., 2008). Serum CK-MB is considerably more specific for myocardial damaged. Consequently, CK should not be used for the diagnosis of myocardial injury unless used in combination with other more specific cardiac markers (Jaffe et al., 2000).
Although, CK-MB has been the gold standard for detecting myocardial necrosis, it does have several limitations and is not an ideal marker. The limitations include – it is not an early marker, chances of false diagnosis of AMI and lack of cardiac specificity and levels may not be elevated even 6-8hrs after onset of symptoms, CK-MB isoforms have been used. CK-MB isoform have reduced this time to 2hrs.
The CK-MB isoform is twice as sensitive as conventional CK-MB. Its sensitivity in detecting AMI at 6hrs reportedly increased to 95.7% compared to 48% for conventional CK-MB (Patel and Jackson, 1999).
Creatine Kinase Isoforms
The M-subunit of creatine kinase was found to exist in plasma in multiple forms, despite the single form of MM and MB found in tissue. Three forms of the MM isoenzyme and two forms of the MB isoenzyme were subsequently identified and purified from plasma. In the case of CK-MM, the tissue isoform as designated CK-MM3. For CK-MB, the tissue form is designated CK-MB2; removal of the lysine residue from the carboxy terminus of the single M-subunit, catalysed by the action of carboxypeptidase-N, gives rise to the CK-MB1 isoform. Removal of the lysine residue which is positively charged leaves a more negatively charged isoform, providing a basis for separation of the isoforms by electrophoresis (Puleo et al., 19898). The B-subunit is not susceptible to enzymatic degradation, so only two isoforms of CK-MB exist.
Normally, the tissue isoform variant (CK-MB2) is in equilibrium with the plasma isoform (CK-MB1), with the ratio being close to 1:1. During acute myocardial infarction (AMI), large amounts of CK-MB2 are released which are not completely converted to CK-MB1 B in plasma, leading to a higher ratio of CK-MB2 : CK-MB1(>1.5). A change in the ratio of CK-MB2 : CK-MB1 can be detected using high voltage gel electrophoresis, even though there is no significant change in the plasma concentration of CK-MB. Presence of an increased ratio has high diagnostic sensitivity for necrosis of myocardial tissues, especially 0 – 6 hours after onset (Puleo et al., 1994).
Systematic prospective studies have confirmed CK-MB isoforms as an early marker of myocardial injury and estrablished a CK-MB2 : CK-MB1 ratio above 1.5 : 1 as a diagnostic criterion (Puleo et al., 1989; Wu et al., 1999). The isoform ratio returns to normal within 18 – 30 hours after injury. It has been suggested that a normal 1 : 1 isoform ratio in a sample collected at least 6 hrs after an event effectively excludes a diagnosis of myocardial infarction (MI). The rapid return to normal values makes the CK-MB isoforms the best available laboratory investigation for the confirmation of reinfarction (Wu et al., 1999). However, because of less cardiospecificity and levels not being easily obtained, it introduces subjectivity into the interpretation of results. These disadvantages have led to an increased use of troponins than CK-MB or its isoforms in diagnosing ASMI. And as stated earlier, troponins have now replaced CK-MB as the ‘’gold standard’’ for diagnosis of myocardial injury (Mercer, 1997).
Cardiac troponins (cTn) have a high sensitivity and specificity for myocardial damage and are considered the biomarker of choice for detection of cardiac injury (Adams et al., 1993). Cardiac troponin (cTn) is an inhibitory protein complex located on the actin filament in all striated muscles, and consists of three (3) interacting and functionally distinct subunits (troponin I, T and C) (Trevisanuto et al., 2006).
Since the first report on the measurement of the cardiac troponin T (cTnT) in 1989 (Katua et al., 1989) followed by the subsequent description of the measurement of the cardiac troponin I (cTnI) in 1993 (Adams et al., 1993) there has been a revolution in the cardiac marker measurements. Although the half-life of cTnI is relatively short (90minutes), its diagnostic time range is unusually wide (ranging from a few hours to 10 – 14 days after the episode of myocardial injury) as a consequence of intracellular compartmentatrion (Adamcova, 2003).
Troponins do not exist in the blood of health persons or are suggested to exist in very small amounts (Archer, 2005). Due t6o their great sensitivity and specificit fos myocardial cell damage, cardiac troponins (cTn and cTnT) have been considered as the ‘’gold standard’’ for myocardial injury and have shown better efficacy than earlier markers (Babuin and Jaffe, 2005). In recent years, it has been suggested as an important marker of cardiac diseases in veterinary medicine (O’Brien et al., 2006). Elevated serum levels of troponin are detectable within 4 to 8 hours after the onset of chest pain, reaching peak concentration inn approximately 12 to 24 hours and remaining elevated for 3 – 10 days following AMI, giving them a wide diagnostic window of other cardiacmarkers giving them an advantage (Kumar and Cannon, 2009). Cardiac troponin elevations at lower concentrations than the 99th percentile value used for MI diagnosis may identify patients who have not had an MI but still have a risk of having an adverse cardiac event (Vasudevan et al., 2013).
Elevated cTn levels indicate cardiac injury, including acute perimyocarditis, acute coronary syndrome (ACS), stroke, pulmonary embolism, sepsis, acute heart failure and tachycardia. Therefore, more precise tests are needed. To satisfy this necessity, high sensitivity TnT (hsTnT) has been developed. It enables determination of very low cTn concentrations. The higher sensitivity of this assay has allowed for improved identification of patients with AMI presenting in the first three(3) hours following symptom onset. Even small increases are associated with a higher risk of death and other adverse outcomes (Vasdudevan et al., 2013).
The advantages of cardiac troponins have been highlighted by their roles in cardiospecific diagnosis, risk stratification, prognostic risk assessment, estimation of infarct size, detecting myocardial reinfarction, detection of coronary reperfusion, renal failure and chemotherapy (Jagannadha et al., 2010; and Scott and Meg, 2008).
Myoglobin was the first non-enzymatic protein used for diagnosis of acute myocardial infarction (AMI), dating back to the 1970s. As a small molecule (17.8kDa), it has the advantage of responding very rapidly (as early as 1 hour upon symptom onset), rising and falling earlier than CK-MB or troponin. A negative value will exclude infarction, and is useful in the early hours of chest pain (Vasudevan et al., 2013). However, the clinical specificity of myoglobin is poor due to its abundant presence not only in myocardial but also in skeletal muscle cells. Therefore, injury in nskel;etal muscle may also trigger an elevation in the plasma concentration of myoglobin (Storrow and Gibler, 1999).
Lactate dehydrogenase is an enzyme found in nearly all living cells (animals, plants and prokaryotes). The enzyme is present in all cells of the body with highest concentrations in the heart, liver cells, muscle, kidney, lungs and erythrocytes. As with other proteins used as tissue-function markers, the appearance of lactate dehydrogenase (LDH) in the serum occurs only after prolonged hypoxia and is elevated in a number of clinical conditions including cardiorespiratory diseases, malignancy, haemolysis and disorders of the liver, kidneys, lungs and muscles (Tietz, 2006).
LDH exists in four (tetrameric) isoforms, composed of H and M subunits. These two subunits can form five possible tetramers : 4M, 4H, and three mixed tetramers (3H1M, 2H2M, and 1H3M). These five isoforms are enzymatically similar but show different tissue distribution.
LDH1 (4H) – in the heart, RBC, as well as the brain
LDH2 (3H1M) – in the reticuloendothelial system
LDH3 (2H2M) – in the lungs
LDH4 (1H3M) – in the kidneys
LDSH5 (4M) – in the liver and striated muscle (Van Eerd and Kreutzer, 1996).
Tissue specificity is derived from the fact that there is tissue-specific synthesis of subunits in well-defined ratios. Most notably, heart muscle cells preferentially synthesize H-subunits, while liver cells synthesize M-subunits nearly exclusively. Skeletal muscle also synthesizes largely M-subunits so that LDH-5(4M) is both liver and skeletal muscle form of LDH. The LDH-1(4H) and LDH-5(4M) FORMS are most often used to indicate heart or liver pathology respectively (Tietz, 2006).
Lactate dehydrogenase (LDH) is used as a marker of myocardial infarction (MI). LDH-1 (4H) appears elevated in the serum about 24 – 48 hours after a myocardial infarction, but is generally not as useful as troponin or CK-MB for detection of myocardial infarction, unless the MI occurred at least 24 hours prior to testing (Tietz, 2006). Normally, LDH-2 is greater than LDH-1, however, when a MI has occurred, there is a “flip” in the usual ratio of LDH-1/LDH-2 from <1 to >1 (or at least >0.9). use of the ratio for evaluation of patients with possible cardiovascular injury has largely been replaced by TPNT/Troponin T, serum (Tietz, 2006).
Cardiac Biomarkers and Myocardial Infarction
Cardiovascular disease is the leading cause of morbidity and mortality in humans in the United States (American Heart Association, 2005). The primary role of cardiac troponin testing in human medicine is for diagnosis of ischemic heart disease such as myocardial infarction. In humans MI occurs after the rupture of an atherosclerotic plaque in the coronary arteries resulting in platelet aggregation, clotting, and either large vessel occlusion or distal embolization (Collinson and Stubbs, 2003).
For years, according to the World Health Organization (WHO), MI has been defined casa syndrome requiring at least 2 or 3 diagnostic criteria (Tunstall-Pedoe et al., 1994). These criteria included an appropriate clinical history and presentation, electrocardiogram (ECG) changes typical for MI, and elevated cardiac enzymes, such as total creatine kinase (CK) and its myocardial form (CK-MB), lactate dehydrogenase and aspartate aminotransferase.
Total CK, Lactate dehydrogenase and aspartate aminotransferase have poor specificity for cardiac damage (Tsung and Tsung, 2005). While CK-MB is more specific than total CK for injury to the heart, it is not as cardiac-specific as the troponins (Adams et al., 1993). CK-MB levels also return to baseline within 48 hours so late diagnosis of MI is not possible with this marker, whereas troponin levels remain elevated for approximately 10days (Rajappa and Sharma, 2005).
Because humans may not have typical clinical signs and ECG changes may be non-diagnostic, a joint committee of the European Society of Cardiology and the American College of Cardiology (ESC/ACC) developed a new definition for the diagnosis of MI in 2000 (Antman et al., 2000). This new definition was based predominantly on the use of biomarkers such as the troponins in the diagnosis of MI.
Any elevation of troponin above the reference range is considered abnormal. In humans, the reference ranges for troponins are set at the 99th percentile of the control group (3SD from the mean). Owing to the release kinetics of troponins, it is possible that patients presenting within hours of an acute ischemic event may not have elevated cTn levels. It is therefore recommended that samples be taken at the time of admission, at 6 – 9 ours and again 12 – 24 hours after presentation (Antman et al., 2000). In situations where an early diagnosis is needed, a biomarker that rises rapidly, such as myoglobin or CK-MB in addition to the later-rising troponin may be used (Antman, 2000).
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