Cardiac biomarkers, particularly of the older variety, have rarely assisted in the diagnosis of myocarditis1 except for patients who present acutely.2 In that setting, increased concentrations of creatine kinase MB (CK-MB) have been observed. Myocarditis may be confused with acute myocardial infarction because the constellation of symptoms, abnormal electrocardiograms, and increased marker protein concentrations is similar to what is seen with acute infarction. The correct diagnosis often is delineated only by demonstration of normal coronary arteries and subsequent biopsy findings.
In the more chronic setting, increased concentrations of CK-MB are unusual. In the Myocarditis Treatment Trial, mean CK-MB values were not significantly greater in patients with myocarditis than in control patients and only 5% of patients had increases.1 The reasons for this are unclear but likely relate to 1 or several of the following.
1) The lack of sensitivity of CK-MB
Only 15% of the CK-MB that is depleted from the heart finds its way into the blood when ischemic heart disease is the cause of the release. Thus, the so-called release ratio for CK-MB is low. In experimental models of 2 hours of occlusion and reperfusion, this ratio doubles to 30% because release is flow limited.3 This may be the case with myocarditis in which coronary perfusion may be normal or at least reduced to a lesser extent than with coronary occlusion. Troponin measurements are more sensitive.4
2) The time window during which increased concentrations of CK-MB occur after cardiac injury is constrained5
Increases usually occur early after the onset of cardiac injury (4-6 hours) and are gone within 48 to 72 hours. Thus, transitory severe injury can be missed by late presentation and the more subtle changes, because of the lack of sensitivity.
3) Lack of specificity
It may well be that some increases of CK-MB do occur but are ignored because of a lack of specificity of CK-MB for the heart, especially in complex medical situations.6
4) Degradation in lymph
Much of the CK and CK-MB that is released when myocytes are injured is degraded in lymph.7 This is one of the reasons why the so-called release ratio (see above) is so low.
Accordingly, a lymphocytic infiltrate associated with myocarditis might still further degrade CK-MB, further reducing its sensitivity.
The situation with troponin markers is substantially different for multiple reasons. 1) Troponin markers are more sensitive than CK-MB4
In comparative studies with troponin measurements, it is clear that the sensitivity for detection of an abnormality and the increment of change in response to a given injury are far less for CK-MB than for the troponin markers.4'8 Some of this may be because there are constitutive levels of CK-MB in blood that are presumably from skeletal muscle that must be overcome before an abnormality can be detected. However, the cytosolic pool of CK-MB and the early releasable pool (mostly localized to the cytosol) of troponin are roughly comparable in magnitude.8'9 The remainder of the troponin is complexed to the contractile apparatus. Overall, there is 13-fold more cardiac troponin I (cTnl)8 and 15-fold more cardiac troponin T (cTnT) than CK-MB per gram of myocardium.9 Furthermore, the release ratio appears to be high, appro aching 100%.10 Thus, not only are more instances of cardiac injury detected with troponin measurements but the increment of change in them is substantially greater.
2) The time during which troponin values are increased is substantially greater
Troponin markers frequently are increased for 10 to 14 days, depending on the specific circumstance of the cardiac injury and the assay used.5 This is because in addition to having an early releasable pool comparable in size to the pool for CK-MB, these markers are complexed in large abundance to the contractile apparatus.8,9 Thus, they are released early (4-6 hours) in a time course similar to that of CK-MB but also continue to be released over time from this huge complexed pool of protein as the damaged area is remodeled. Thus, the time during which cardiac injury can be detected is substantially prolonged. This allows the troponin measurements to be used similarly to lactate dehydrogenase isoenzymes for the retrospective diagnosis of acute myocardial infarction and prolongs the time during which increases can be detected.5
3) Increased specificity
Troponin markers have nearly perfect specificity for the heart. Thus, even minor increases indicate cardiac involvement.11,12
4) Degradation in myocardium
Finally, although degradation of troponin does occur, it may be (author's speculation) less extensive than with CK-MB. Such degradation also occurs at the carboxy and amino terminal ends of the molecules,13 so that assays that use monoclonal antibodies to the central portion of the molecule are likely to be unaffected.
Nonetheless, in the Myocarditis Treatment Trial, 34% of patients had increased values of cTnl.1 The majority of these increases were in patients whose samples were obtained within 1 month of the onset of symptoms. In the 20 early patients (within 1 month), 11 had increases compared with only 1 of 12 patients who presented later. It may well be that other increases would have been detected had the other patients been available for testing earlier or if newer more sensitive assays capable of detecting still lower values had been used. Both of these suggestions are speculative but have important potential patho-physiologic correlates.
The fact that patients who presented earlier were more likely to have increased cTnI values might be taken to suggest that the majority of damage associated with myocarditis is acute, and then subsequent damage may be due to a more indolent and thus more difficult to detect process or even "remodeling" that occurs as an acute and chronic compensation to acute cardiac injury. This speculation has potentially important therapeutic implications as well as diagnostic ones. Such an observation might fit with the impression of an improved prognosis when there is an exuberant immune response.14 This response might lead to a greater degree of necrosis. If so, an increased troponin value could be a positive prognostic factor. Conversely, it may be that a diminished or absent immune response with less associated acute cardiac injury might mark the group most at risk for the progression of the disease. This hypothesis needs to be tested. It could be that treating patients who have troponin increases to reduce the extent of cardiac injury may require a different approach than the treatment of those with less exuberant immune responses. It may be that protocols designed to inhibit remodeling might be efficacious. In contrast, patients with a more indolent pattern in which concentrations of troponin may be low may require a totally different approach. Such a pattern might also explain why such patients are hard to diagnose biochemically because the amount of ongoing necrosis is so modest. Such a finding would also exacerbate the known difficulty with the Dallas biopsy criteria in which sampling selection can make the finding of necrosis difficult.
This synthesis suggests that troponin increases indicate irreversible injury, but this is far from proven. Experimental studies suggest that there are protein interactions that occur that could lead to the release of troponin fragments in response to reversible injury.13 Whether this phenomenon is important pathophysiologically is unclear.
The second implication is that low levels, but ones that are above the range for normals, might be useful in this disease. The cut points used to diagnose ischemic heart disease are substantially above what we know normal values are. Thus, what has been termed this "gray area" might permit more subtle diagnoses to be made. This might be of substantial importance in those with the indolent form of myocarditis.
These speculations also have significant implications for the use of the biopsy as a diagnostic tool. It is likely that low levels of myocardial injury are difficult to detect by biopsy because of selection bias. Two experimental animal studies have documented that there is a good relationship between the histologic evidence of myocardial damage and the extent of troponin increase.1'15 Thus, in the absence of a high-sensitivity approach (the use of abnormal values in the gray area) during a relatively indolent phase, detection of necrosis may be impossible, not only by biopsy but also by troponin measurement.
The data from Lauer and associates16 suggest that increased troponin values should be considered a surrogate for cardiac injury. This would avoid the difficulty of selection bias as part of the cardiac biopsy. These investigators augmented the credibility of their diagnosis by looking for specific lymphocyte pools by using immunohistochemistry. They found that the cTnT value was increased in 28 of the 80 patients they found with possible myocarditis. Only 5 met biopsy criteria. However, histologic criteria using specific lymphocyte labeling revealed myocarditis in 26 of the 28 patients with increased cTnT values. They also found that 23 of the 52 patients (44%) without cTnT increases met immuno-histochemical criteria. It is unclear whether including those with cTnT values in the gray area would have substantially improved sensitivity and what the cost might have been to specificity. However, at present, the use of troponin values and abnormal lymphocytes is likely adequate for the diagnosis of myocarditis. This approach will augment the diagnostic frequency of myocarditis.
The synthesis suggested is that the biopsy diagnosis of myocarditis in 6% to 10% of patients suspected of having it is a reflection of the lack of sensitivity of the Dallas criteria and specifically the criteria for necrosis.14'16 The lymphocyte pools one might look for could vary depending on whether one is dealing with an autoimmune myocarditis, a viral etiology, a combination of both, or a better-defined entity such as giant cell myocarditis. Nonetheless, it appears likely that the difficulty with the diagnosis of myocarditis can be overcome to some extent by the use of troponin values and immunohistochemistry. With these new criteria, the diagnosis of myocarditis types is likely to increase substantially.
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