Advantages and Disadvantages of Biochemical Markers in Cardiovascular Disease - Literature review Example

Advantages and Disadvantages of Biochemical Markers in Cardiovascular Disease Introduction Cardiovascular disease is the most common cause of morbidity in the world and the most common presentation is myocardial infarction (McPherson, 2010). It affects one in three Americans (Howie-Esquivel and White, 2008). While atherosclerosis is the most common and haunted cardiovascular disease, the most important manifestation is myocardial infarction. Prediction and determination of established cardiovascular disease has been a challenge to health professionals aiming for preventive strategies. While routine tests like lipid profile, blood pressure, blood sugar, ECG and ECHO provide a gross information of the cardiovascular status, estimation of risk and presence of cardiovascular disease is possible only through definite markers of the disease. The ultimate aim of prevention of cardiovascular disease is to prevent end-organ injury like myocardial infarction. Myocardial infarction mainly presents as chest pain. Infact, chest pain is a common cause for attendance to emergency departments. While millions of people present with chest pain every year, only about 10- 15 percent are actually diagnosed with myocardial infarction (Pasupathi et al, 2009). Lack of appropriate diagnostic and clinical tools to ascertain the presence of myocardial infarction has contributed to unnecessary hospitalization, investigations and expenses (Pasupathi et al, 2009). It is often is difficult to rule out acute myocardial infarction from several other causes of chest pain. But, in view of the high rate of morbidity and mortality associated with the condition, it becomes imperative on the part of clinician to diagnose it and treat in promptly (McPherson, 2010). While ECG is useful in diagnosing acute myocardial infarction, it is not a very sensitive and specific test for diagnosing the condition (Statland, 1996). Infact, in more than 50 percent cases, ECG is non-diagnostic with atypical features (Statland, 1996). Over several years CK-MB was the gold standard for diagnosing acute myocardial infarction. However, recent research has tarnished the image of even that test and troponin testing has replaced that (Statland, 1996). As of now, the search for ideal cardiac marker continues and currently, a combination of more than one marker is used to establish correct diagnosis and prognosis. Ideal marker for use in clinical cardiology would be that which is cardiac specific, that which rises immediately after infarct begins, that which after elevation, remains in the blood for some time, that which is easy to measure, that whose measurements have a broad rage that is dynamic, that whose results turn around quickly without any waste of time and that whose diagnostic application has been verified by appropriate clinical studies (Statland, 1996 and Khana and Wattanasuwanb, 2004). While currently several biochemical markers are used rampantly to establish diagnosis of myocardial infarction in an acute setting, lack of specificity and sensitivity of the markers questions justification of their use (Pasupathi et al, 2009). In this essay, the role of biochemical markers in predicting, diagnosis and prognosticating cardiovascular disease will be discussed with reference to their advantages and disadvantages through review of appropriate literature. Common biochemical markers in clinical cardiology Common biochemical markers which are employed in clinical cardiology are cardiac enzymes like creatine phosphokinase-MB or CPK-MB and other isoforms, lactate dehydrogenase-1 or LDH-1 or hydroxybutyrate dehydrogenase, lipoprotein-associated phospholipase A or LAP-A and aspartate aminotransferase or AAT; myoglobin, cardiac troponins T and I, cardiac natriuretic pepprotein and inflammatory marker C-reacive protein or CRP (Pasupathi et al, 2009). Cardiac enzymes The first cardiac enzyme that was studied and reported to be useful in detecting acute myocardial infection is serum glutamate oxaloacetate transaminase by Karmen and colleagues, in the early 1950s. After that, in the next decade, creatinine kinase and lactate dehydrogenase were widely used as cardiac markers (Pasupathi, 2009). Of these, creatinine kinase was used as a marker of choice because of its early rise during cardiac injury. The isozymes, CPK-MB which is detectable using antibodies against B-subunit was found to be more specific for this purpose. Hydroxybutyrate dehydrogenase, an isozyme of LDH, known as LDH-1, was also used because of its specificity in the detection of myocardial damage in early stages. However, currently, research has shown that these enzymes lack in tissue specificity, and hence measurement of the activity of these enzymes does not have much value in the assessment and evaluation of myocardial injury (Pasupathi, 2009). Even phospholipase and AAT do not have much implications in clinical cardiology as of now. 1. Creatine Kinase or CK and CK-MB CK is a dimer in cytoplasm. It has 2 subunits, M and B and the various isoforms are CK-MB, CK-BB and CK-MM isoenzymes. While CK-MM is mainly present in striated muscles, CK-MB is present in cardiac muscle and comprises of 15-40 percent of over all CK activity in the heart muscle (Pasupathi et al, 2009). CK-BB is mainly found in brain, gastrointestinal tract and urinary bladder. CK is an important enzyme involved in the regulation of the utilization and production of high energy phosphate in tissues with contractile properties like muscles. The enzyme is also involved in transferring high-energy phosphate bonds from the site of production of ATP, i.e., the mitochondria, to the cytoplasm, which is the site of utilization, via creatine phosphate (Pasupathi, 2009). CK in mitochondria is in an unstable form and hence cannot be measured. The total activity of CK and CK-MB in serum rise after myocardial injury. The enzymes are detectable after 4-6 hours after injury and peak concentrations are seen after 12- 24 hours. They return to baseline after 48- 72 hours (Pasupathi et al, 2009). CK-MB is mainly raised in myocardial damage. Rapid return of the enzymes to normal levels makes them the most useful laboratory investigation to confirm myocardial infarction. However, the use of laboratory equipment requires expertise and the enzyme rises even in skeletal muscle damage. Hence, its use is impractical and it can be used as a cardiac marker only in combination with another cardiac marker (Pasupathi et al, 2009). According to Karras and Kane (2001), "a prudent strategy when assessing ED patients with chest pain and nondiagnostic ECGs is to order CK-MB and troponin values on presentation in the hope of making an early diagnosis of AMI or unstable coronary syndrome." Myoglobin Myoglobin is a very small molecule and is the first non-enzyme protein used for diagnosis of acute myocardial infarction. It is released within one hour into circulation and has high negative predictive value and high sensitivity. However, since it is present even in skeletal muscles, it is not clinically specific for myocardial injury (Pasupathi et al, 2009). Cardiac troponin Currently, this is the biomarker of choice for detecting myocardial injury. Its use as cardiac maker began in 1990s. It is highly specific and sensitive for myocardial injury (Apple et al, 2004). However, it is not useful as early marker because of release after 4-6 hours like CK-MB. As of now, it is the most specific cardiac marker (Babuin and Jaffe , 2005). It remains elevated for 4- 10 days after onset of acute myocardial injury and the peak concentration levels correlate well with the size of infarct (newby et al, 2003). The role of various noxious factors like hypertension, cigarrette smoking, hyperglycemia and atherogenic lipoproteins is well established. These factors elicit the secretion of leukocyte stable adhesion molecules which ultimately cause migration of monocytes into subintimal space, thus initiating fatty streak. Through this process of atherogenesis, cytokines are beleived to be involved, along with other bioactive molecules and also cell, characteristic of inflmmatory proceess. Thus, inflammatory markers like CRP can be considered as important markers of cardiovascular disease and help in the prediction of cardiovascular disease (Pearson et al, 2003). Other than CRP, other biochemical markers of cardiovascular disease are soluble adhesin molecules, cytokines like interleukins and tunor necrosis factor and acute phase reactants like fibrinogen. Soluble adhesin molecules, fibrinogen and some cytokines and unstable and difficult to assay (Pearson et al, 2003). Thus CRP remains an important biochemical predictor for cardiovascular disease. however, there is not juch evidence to support the role of CRP and other markers in the prediction of cardiovascular disease. So, these biochemical markers cannot be used for primary Some research has pointed to correlation between markers like CRP and fibrinogen, and recurrent cardiovascular events and death in established cardiovascular disease. Research has shown that rised serum CRP in unstable angina and acute myocadial infarction is a good predictor of new coronary events (Pearson et al, 2003). Cardiac troponin has several advantages like "cardiospecific diagnosis, risk stratification, prognostic risk assessment, and therapeutic choices" (Pasupathi et al, 2009 and (Apple et al, 2004)). In a study by Apple et al (2004), patients with elevated levels of cardiac troponins were at increased risk of death than those with normal levels. Another advantage with cardiac troponin assay is that, it is very easy to perform the test and the results can be made available within few minutes. According to Hamm and colleagues (cited in Pasupathi et al, 2009), troponin levels can be used as tools for rapid triage in patients presenting with chest pain. The study reported that those with normal troponin levels did not have significant events in a 30 day follow up. In yet another study (cited in Pasupathi et al, 2009), coronary artery disease was detected in more than 90 percent patients presenting with normal ECG, but elevated troponin levels. Some recent studies have demonstrated rise of troponin in other conditions like renal failure, sepsis and hypovolemia, questioning their specificity with respect to myocardial infarction (Pasupathi et al, 2009). According to a study conducted by Wu (2009), serial testing for tropinin is useful to differentiate between ischemic and no-ischemic causes of troponin ise and hence must be used along with other laboratory tests in patients who present with features of myocardial infarction. Cardiac Inflammatory Markers The role of various noxious factors like hypertension, cigarette smoking, hyperglycemia and atherogenic lipoproteins is well established. These factors elicit the secretion of leukocyte stable adhesion molecules which ultimately cause migration of monocytes into subintimal space, thus initiating fatty streak. Through this process of atherogenesis, cytokines are believed to be involved, along with other bioactive molecules and also cell, characteristic of inflmmatory process. Thus, inflammatory markers like C-reactive protein or CRP can be considered as important markers of cardiovascular disease and help in the prediction of cardiovascular disease (Pearson et al, 2003). Other than CRP, other biochemical markers of cardiovascular disease are soluble adhesin molecules, cytokines like interleukins and tunor necrosis factor and acute phase reactants like fibrinogen. Soluble adhesin molecules, fibrinogen and some cytokines and unstable and difficult to assay (Pearson et al, 2003). Thus CRP remains an important biochemical predictor for cardiovascular disease. however, there is not much evidence to support the role of CRP and other markers in the prediction of cardiovascular disease. So, these biochemical markers cannot be used for primary Some research has pointed to correlation between markers like CRP and fibrinogen, and recurrent cardiovascular events and death in established cardiovascular disease. Research has shown that raised serum CRP in unstable angina and acute myocardial infarction is a good predictor of new coronary events (Pearson et al, 2003). Experts have proved the association between rise in CRP and risk of myocardial infarction. This is because, atherosclerosis is an inflammatory process and hence associated with rise in inflammatory markers like CRP. CRP as such is not a specific tool for this purpose because of "large intra-individual variation in plasma concentration" (Pasupathi et al, 2009). Hence, using CRP may misclassify the risk status. Another inflammatory marker studied in this regard is interleukin-8 or IL-8. Rise in this marker points to risk of progression and rupture of atherosclerotic plaque (Blankenberg et al, 2003). Serum myeloperoxide or MPO is "an independent cardiovascular risk factor in patients with chest pain but with a negative serum TnT (i.e. patients with no evidence of myocardial necrosis on presentation)of this marker is useful" (cited in Pasupathi et al, 2009). MPO is a haem-containing enzyme that is present abundantly in polymorph nuclear neutrophils or PMN, which occur in "the damaged atherosclerotic plaques associated with acute coronary syndromes" (Pasupathi et al, 2009). Further studies are warranted to prove the benefits of this assay in evaluating and assessing myocardial infarction. There is some evidence about the role of cardiotrophin-1 and metalloproteinase-1 in detecting myocardial remodelling in patients with chronic hypertension to ascertain the risk of hypertensive heart disease (Gonzalez et al, 2009). Analyte Stability Assay Availability World Health Organization Standards Available? Interassay Precision Soluble adhesion molecules (eg, E-selectin, P-selectin, intracellular adhesion molecule-1, vascular cell adhesion molecule-1) Unstable (unless frozen) Limited No CV Read More