A new experimental study substantiates this idea, whereby hs-cTn assays were able to detect serum elevations of troponin from necrosis of a few milligrams of myocardium: an amount of irreversible injury beyond the resolution of any imaging technique. This was hypothesized by Jeremias and Gibson 53 to cause excessive wall tension and direct myofibrillar damage, resulting in cardiomyocyte death, and thus troponin release in the absence of ischaemia myocardial strain theory.
This is supported by both experimental studies and clinical observations. Cheng et al. Their data showed excessive stretch can result in apoptosis, which in the context of our discussion, may result in cTn release. Indeed, detection of cTn would be dependent on whether apoptotic cells lose membrane integrity. In a clinical study by Logeart et al. Patients with CAD and atherosclerotic abnormalities were excluded.
They made the following observations: i there is a positive correlation between cTnI concentration and both LV wall thickness and BNP levels; ii cTnI release occurs in patients without ischaemic disease. Combining these findings and those of previous studies where BNP levels and LV filling pressure were positively correlated, the authors postulated that the release of cTnI could be due to significantly high LV filling pressures, causing stretch-mediated cardiomyocyte death.
The authors also confirmed by imaging that these patients had increased wall thickness, which may have resulted in endocardial ischaemia and cardiomyocyte death. Increased preload diastolic wall stress is a key feature of the failing heart. Both clinical and experimental studies suggest it may initiate troponin release. In an elegant clinical study, Takashio et al. This approach was taken to exclude alternative clinical causes of troponin release e. The aetiology of HF in these patients was non-ischaemic e.
In Langendorff-perfused rat hearts, high preload resulted in greater degradation of cTnI: an effect attenuated by adding calpeptin a calpain inhibitor. As a result, Feng et al. As an aside, results from this study have been used to theorize the release of cTn during acute decompensated HF. Furthermore, it has been suggested that intact cTn may be released by live, viable myocytes, via stretch-mediated integrin stimulation.
This has been reported in cultured neonatal rat cardiomyocytes 93 where peptide-mediated integrin agonism was shown to result in increased cTnI release in the absence of necrosis [assessed by LDH assays and nuclear propidium iodide staining]. Jaffe and Wu 75 identify experimental issues with interpreting the findings from Hessel et al.
However, these issues aside, there is some simple physiology to consider when thinking about the idea of increased membrane permeability. It is clear that at present, as highlighted by Jaffe and Wu, 75 although necrosis is not a requisite for cTn release, cell death in any shape or form can result in its release e. Reaching a consensus on the mechanisms by which cTn is elevated in CKD and ESRD has been complicated by the multiple assay platforms available, but also by the fact that the stage of renal disease is not standardized across studies.
Most of the evidence available has been on ESRD patients undergoing regular haemodialysis. In such patients, cTnT is more frequently elevated than cTnI. Originally the rationale behind the cTn assay was relatively simple: myocardial necrosis leads to membrane disruption causing troponin release which is detected in serum.
The troponins have been used to diagnose acute myocardial injury and such use has become engrained in the Universal Definition of Acute Myocardial Infarction. Today however, with the evolving sensitivity of cTn assays, it is clear cTn is detectable in everyone and becomes elevated above the 99th percentile in stable chronic conditions. These features of the high-sensitivity assays have made the interpretation of cTn results more complex.
In recent years, the concept that troponin can be released with reversible cell injury, without necrosis, or even cell death, has been repeatedly suggested. In part, this is due to increased cTn being observed in several clinical situations whereby there are no obvious signs of overt cardiac disease, and in particular with the consistent finding of increased hs-cTn following extreme exercise. However, it is emphasized that current evidence reinforces the view that cTn is only released from cardiomyocytes upon irreversible cell death whether it be by necrosis or apoptosis etc.
Future research needs to embrace the high-sensitivity of the latest assays to expand their use in personalizing medical therapy. In particular, we believe that concentrations below and around the 99th percentile could be used to select higher risk patients for future randomized trials in HF and prevention of vascular events. Another under explored area is understanding if additional information, over and above concentration, is gained by measurement of post-translational modifications in circulating cTnI and cTnT.
Since varied forms of cTn can be detected in serum following AMI e. Conflict of interest : M. M is named as an inventor on a patent held by King's College London for the detection of cMyC as a biomarker of myocardial injury. The other authors have no declared conflicts of interest. Greaser ML , Gergely J. Purification and properties of the components from troponin.
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Brief myocardial ischemia produces cardiac troponin I release and focal myocyte apoptosis in the absence of pathological infarction in swine. As the authors of this review note, the utility of any test is only as good as the user.
In , more than 1. Only one-fifth of these patients were admitted for further observation and treatment. For the remainder of these patients, the chief complaint of chest pain was attributed to diagnoses other than an acute myocardial infarction.
As overall visits to EDs continue to increase, the accuracy of assessment of patients presenting with chest pain becomes even more important.
In the initial triage process, the first electrocardiogram ECG can be nondiagnostic for acute coronary syndrome ACS ; patient symptoms may be atypical for the classic presentation of acute myocardial infarction AMI , or the patient may be an unreliable historian. Thus, timely and accurate diagnosis of patients presenting with chest pain cannot be understated; yet, the timely and efficient diagnosis of acute coronary syndromes can still pose a significant challenge for the emergency physician.
The adage, "A tool is only as useful as its user," holds somewhat true when describing the use of biochemical markers in evaluating chest pain. In selecting a cardiac biomarker, it is important to assess its clinical utility and role in the etiologic diagnosis of chest pain. An ideal biomarker may have the following qualities: a profile that quickly and accurately identifies patients with acute myocardial infarction AMI or myocardial ischemia; be present in high concentrations in cardiac tissue; be absent from other tissues; and be undetectable in the blood stream of healthy patients.
This ideal biomarker also should be rapidly released from injured tissues and should maintain elevated serum levels, with elevated levels corresponding to the degree of myocardial injury. Furthermore, a perfect biomarker should also be inexpensive, rapidly available, and biochemically simple enough to be run by any laboratory at any time of day. To date, no such biomarker exists. The utility of a biomarker can be objectively evaluated by its sensitivity, specificity, and the calculation of the likelihood ratios.
In brief, the more sensitive a marker, the higher the chance that it will correctly detect patients with myocardial injury. However, a marker with a higher specificity will more correctly aid in identifying those patients who truly do not have myocardial injury.
This added specificity may allow for improved throughput flow and disposition of these patients, limiting unnecessary or otherwise inconclusive workups of cardiac chest pain.
The process of myocardial ischemia results in multiple pathophysiologic events. In the earliest phase, myocardial ischemia leads to cellular acidosis. This, in turn, creates increased permeability of the cell wall with resultant leakage or spilling of intracellularly contained chemical molecules.
As ischemia evolves into infarction, the cell wall becomes more unstable, with eventual breakdown and further release of cytoplasmic structures into the circulatory system. Markers that are smaller are released first and are detected sooner in serum analyses.
Markers that do not bind to other structures in the circulatory system also have a higher chance of being detected in the serum. Rate of clearance by kidney and liver, as well as kinetic properties of regional blood flow and lymphatic systemics will affect the presence of markers in the serum. However, these two markers are found in a variety of body tissues and are elevated in many different disease processes, making them less sensitive or specific, and they have long been abandoned as useful markers of cardiac disease in the acute setting.
Myoglobin is a small protein found in the cytoplasm of both skeletal and cardiac muscle tissue. This oxygen-carrying molecule tends to be released early during infarction because of its small size, and thus serum levels of myoglobin tend to be elevated far earlier than other cardiac markers. The early increase in myoglobin levels would suggest a significant advantage for the early detection of myocardial infarction.
However, there are two notable disadvantages to myoglobin as a biomarker. It is relatively nonspecific to myocardium, and clearance depends heavily upon renal function. Serial myoglobin determinations have demonstrated many times to be the most useful diagnostic strategy in detecting the presence of myocardial injury.
Tucker et al. The disadvantages of myoglobin as a single biomarker should be emphasized. The rapidity of the rise and fall in serum allows for a limited diagnostic window. Several other reasons exist for elevated levels of myoglobin, including but not limited to renal failure, muscle injury or inflammation, and many other chronic disease states, all of which substantially increases false-positive opportunities.
In general, myoglobin may have little utility as a single biomarker for acute coronary syndrome or myocardial disease more than six hours after onset of symptoms. Multi-marker approaches utilizing myoglobin have shown superior sensitivities to biomarkers used alone, especially when deployed very early in the diagnostic period. Kontos et al. Creatine Kinase. Creatine kinase CK is an enzyme expressed by various body tissues but found in highest quantities in cardiac and skeletal muscle tissues.
It is a large molecule that is released by injured cardiac muscle, travels in the lymphatic system, and is not detectable in serum until three to eight hours after myocardial injury. The serum levels of enzyme are highest at hours after cardiac injury and subsequently return to baseline levels in three to four days. Because of the ubiquitous nature of CK, the isoenzyme CK-MB traditionally is measured when discussing cardiac evaluation. There are two subunits of CK: M, found predominantly in muscle tissue, and B, found predominantly in the brain.
However, because of the large amount of skeletal muscle within the human body, relatively small amounts of muscle injury can release enough CK-MB to result in elevated levels. Therefore, abnormal CK-MB elevations can occur with vigorous exercise, rhabdomyolysis, trauma, myositis, and muscular dystrophy.
It is initially detected in serum at four to six hours after injury, peaking at hours, with normalization at two to three days. How useful is the CK-MB serum measurement? The sensitivity in diagnosis of AMI relies heavily on elapsed time since symptom chest pain onset. Therefore, significant variability in utility exists in part due to different types of assays, differences in diagnostic thresholds, and the heterogeneous enrollment criteria in the literature.
This range tends to decrease as time from symptom onset extends beyond 12 hours. In conditions that increase total CK values, concomitant elevations in CK-MB values also can increase false-positive rates. In the ED setting, a single CK-MB measurement cannot provide confirmation of an acute coronary syndrome or other myocardial event. There is general consensus that CK-MB measurements made within hours of symptom onset provide greater sensitivity and specificity in diagnosis of AMI.
The American College of Cardiology, the American Heart Association, and the European Society of Cardiology have jointly agreed that serum troponin measurement is the accepted standard biomarker for diagnosis of acute myocardial infarction and for the diagnosis of acute coronary syndrome.
Testing of monoclonal antibodies is the technique used to detect cardiac troponins in serum. These assays are composed of different antibody configurations that recognize different isotopes, thereby providing differences in coefficients of variability as well as differences with calibration materials.
The 99th percentile reference limits provide a basis for establishing appropriate cutoff concentrations. What this means is that cTnI values indicative of myocardial damage range from 0. A review of stored plasma samples from participants in the population-based Dallas Heart Study evaluated the prevalence of cTnT elevations in the general population using contemporary assays.
This study found that In the ongoing search for the rapid and reliable diagnosis of AMI, there have been several investigations of newer, more sensitive troponin assays. Reichlin et al. Their multicenter analysis showed that the diagnostic accuracy at patient ED presentation was significantly higher with each of the ultra-sensitive troponin assays as compared to the standard assay.
However, as with any potential change in evidence, it is important to consider all aspects of that evidence. In one case report series, the use of highly sensitive cardiac troponin cTnI increased both the true-positive and the false-negative rates of patients suspected to have AMI at presentation.
In another patient with blunt cardiac trauma, the initial cTnI was positive but later showed that this finding was not related to changes of myocardial ischemia. Most importantly, it stresses that we have yet to find a single biomarker that can be used unilaterally or in one isolated testing to conclusively detect AMI or ACS.
Elevated troponin values have important diagnostic and prognostic implications for patients. Therefore, it is important to recognize that a wide variety of conditions are associated with elevated serum troponin, so that diagnostic confusion and treatment dilemmas are reduced. Patients with renal disease may have elevated cardiac troponin cTn measurements in the absence of clinically suspected myocardial ischemia or infarction. There are several theories behind this finding.
One hypothesis suggests that uremia-induced skeletal myopathy leads to increased troponin in renal failure. What is least likely is that elevated serum troponin is due to decreased clearance of this molecule by a diseased kidney. Regardless of the underlying mechanism of elevated serum troponin, it is important for the clinical practitioner to understand the significance of these values.
In suspected ACS with underlying renal failure, assessment of elevated cardiac troponins can be problematic. Sequential serum troponins should be obtained in this situation delta troponin. An elevated but nonvarying troponin level indicates no new myocardial injury or infarction. With the use of the most current assays, cTnT is elevated more frequently that cTnI in patients with renal disease or failure.
Apple et al. During the past several years, B-type natriuretic peptide has been recognized as a useful marker in detecting the presence of left ventricular dysfunction. This is more evident in the presence of systolic dysfunction. BNP has both vasodilative and diuretic as well as natriuretic properties and is released by the ventricles as a neurohormonal response to ventricular wall stress.
NT-pro BNP has a longer half-life one to two hours vs. There is recent evidence that BNP measurements may be useful in providing prognostic information in patients with ACS. The expression of BNP is independent of myocardial injury and cell death, and this alternative mechanism has the potential of identifying patients who are at risk but may not have necessarily crossed the threshold of cell necrosis. Given that BNP is clearly associated with ventricular dysfunction, the logical hypothesis is that the setting of acute coronary occlusion and prolonged ischemia will lead to ventricular dysfunction and the expression of BNP.
Studies have illustrated that elevations in plasma BNP levels in patients with AMI may be biphasic in those with large infarctions with systolic dysfunction. Other studies seem to demonstrate that BNP is a predictor of early and late cardiac events in patients who present with ST-segment elevation as well as non ST-segment elevation acute coronary syndrome. BNP also has been shown to increase acutely after ischemia and to normalize after reversible ischemia.
In patients undergoing stress testing, BNP seems to rise proportional to the size of the ischemic territory after exercise. See Table 2. In a prospective study of patients, Bassan et al. The authors concluded that the sensitivity of BNP was superior to the other cardiac markers in detecting emergency department chest pain patients presenting with non-ST-segment elevation myocardial infarctions without clinical left ventricular dysfunction.
The weight of evidence suggests that increased BNP levels cannot be used as a proxy for the degree of myocardial necrosis, but rather, can be used to assess the impact of the ischemic event on ventricular dysfunction and thus may be used as an additional predictive tool in the setting of chest pain with nondiagnostic ECGs and other biomarkers.
There is no evidence to show that BNP or NT-Pro BNP is useful as a single biomarker in the identification of patients with acute coronary artery disease, but there is clear evidence for its use in a multivariate model as a screen for rapidly identifying patients who may be at risk for coronary artery disease. Furthermore, the use of BNP for risk stratification in patients who present with chest pain and its prognostic value in the short term for patients with acute coronary syndrome, holds significant promise.
As newer studies emerge, the evidence seems to suggest that other biomarkers may be more useful in the risk assessment of patients with chest pain. Collinson et al. The emergency physician often is challenged by patients who present with chest pain but who have an atypical story, unreliable history, or clinically uncertain diagnosis. This population was closely studied by McErlean and colleagues.
Their study showed that cTnT and CK-MB were comparable in identifying patients at high risk for in-hospital adverse events. However, they also showed that patients with intermediate cTnT values had a higher risk of suffering an early adverse event. Thus, in patients deemed as having ACS by other criteria, a negative cTnT did not reduce the risk to enable discharge from the emergency department. Although the evidence can be contradictory, there is general consensus that an initial cTnT has higher specificity and positive predictive value for underlying cardiac ischemia or infarction than traditional serial CK-MB measurements.
James et al. Cameron et al. Morita el al. Brown et al. The overall sensitivities and negative predictive values did decrease slightly for all comers with chest pain and the potential for acute coronary syndrome, but remained higher when the combination of myoglobin, CK-MB, and cTnI were used alone even though the authors could not effectively conclude that the incremental value of adding BNP differed significantly with biomarker panels that included myoglobin.
The authors also suggest that measuring BNP identified an additional patient with acute myocardial infarction for every 14 false positives. The Academy supports an accelerated protocol for cardiac marker use that includes: an early marker that is reliably increased in the blood within six hours of symptoms and a definitive marker that is increased in the blood after six to nine hours. The two markers best fitting these criteria are CK-MB recommended as the early detection marker and cardiac troponin recommended as the definitive marker.
See Table 3. The natural process of myocardial ischemia, injury, or necrosis is a dynamic cellular event. This pathophysiology strongly supports the diagnostic strategy of obtaining serial biomarker measurements, ideally over a six- to nine-hour period. Whereas a single cardiac marker determined at time of ED presentation has low sensitivity for detection of AMI, serial biomarker evaluation has high sensitivity for diagnosing AMI.
The ED physician evaluating a patient with chest pain faces the challenges of inaccurate historical time of symptom onset and nondiagnostic ECGs. The utility of serial biomarker measurements is extremely beneficial in these situations. Hamm et al. This group also looked at individual marker sensitivities and concluded that even in patients presenting with less than four hours of chest pain, cTnI demonstrated the highest early sensitivities for detecting AMI.
Although not routinely used in the ED setting, there are a host of other cardiac biomarkers that have been studied in the setting of acute coronary syndromes. Heart-type fatty acid binding protein and ischemia modified albumin are two of the more prominent markers for potential development in ED use. Fatty acid-binding protein is ubiquitous in the cytoplasm of fatty acid-utilizing cells and functions as a cellular transporter of fatty acids. In the setting of myocardial ischemia or infarction, the loss of sarcolemmal integrity in injured myocytes leads to rapid release of H-FABP into the circulation.
This immediate release significantly precedes the release of CK-MB and cardiac troponins, and so H-FABP has been suggested as the ideal marker for the early detection of ischemic myocardial necrosis.
The study by Nakata et al. However, the authors noted that an important limitation in their study was the prolonged time up to 24 hours to obtain a quantitative result of H-FABP. Further validation and comparison of qualitative versus quantitative results are required.
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