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J Am Coll Cardiol Img, 2009; 2:139-142, doi:10.1016/j.jcmg.2008.10.009
© 2009 by the American College of Cardiology Foundation
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Editorial Comment

Noninvasive Differentiation Between Active and Healed Myocarditis by Cardiac Magnetic Resonance

Are We There Yet?*

Heiko Mahrholdt, MD*, Udo Sechtem, MD, FACC

Department of Cardiology, Robert-Bosch-Medical Center, Stuttgart, Germany

Key Words: myocarditis • endomyocardial biopsy • cardiac MR

Myocarditis is a common cardiac disease. It appears to be a major cause of sudden death, and may progress to chronic dilated cardiomyopathy. From the clinical point of view, there are several challenges unique to the management of patients with myocarditis. The first challenge is to establish the diagnosis of myocarditis, which is usually based on clinical, pathological, or a combination of diagnostic criteria. The second challenge is to follow the disease activity to identify patients who may be at risk of chronic dilated cardiomyopathy development, which seems to be associated with ongoing myocardial inflammation (1) and viral persistence (2).

Cardiac magnetic resonance (CMR) has recently emerged as a noninvasive tool to diagnose myocarditis (3–6), as well as to follow its course in living patients (3,7–9). Three features potentially associated with acute myocardial inflammation may be visualized by CMR: 1) tissue edema, which may result in an elevated T2 signal; 2) capillary leakage, which is speculated to be associated with an increased signal on T1-weighted spin-echo images after gadolinium administration (elevated global relative enhancement [gRE]); and 3) myocardial necrosis or scarring as indicated by the presence of late gadolinium enhancement (LGE).

Whereas no histological proof exists that the edema described pathologically in patients with myocarditis (10) correlates with the T2-signal elevation measurable in high-quality T2-weighted MR images, the association of T2 elevation and edema has been histologically proven in other conditions. Hence, the concept that T2-signal elevation indicates myocardial edema may make sense.

Hyperemia associated with capillary leakage or muscular inflammation was also never directly shown to be the cause of increased interstitial uptake of gadolinium in acute myocarditis. Theoretically, such studies could be performed in appropriate mouse models (11) using modern MR scanners (12). Unfortunately, there are no data yet from such animal studies, which would be crucial to prove the concepts of elevated T2 signal and gRE ratio to be good parameters to demonstrate myocardial inflammation.

In contrast to the 2 previous features, the presence of LGE has been repeatedly shown to be associated with histological proof of acute myocarditis (4,8). However, if scarring is the result of acute myocarditis it will—although often significantly smaller and sometimes beyond the resolution of CMR due to scar shrinking—remain when the acute inflammation has long subsided.

The concept of the Berlin group is that clinically acute inflammation is usually associated with T2-signal elevation, as well as an increase in gRE ratio. Consequently, they postulate that normalization of these 2 parameters will indicate the absence of acute inflammation. To prove their concept, in this issue of iJACC, Zagrosek et al. (13) serially assessed T2 signal, gRE ratio, and LGE at initial presentation, as well as after 18 months in 36 patients diagnosed with acute myocarditis by clinical criteria. The authors found an elevated T2-signal ratio during the clinically acute phase in 86% of patients, an abnormal gRE ratio was detected in 80%, and LGE was found in 63% of patients, respectively. During follow-up, the T2-signal ratio decreased from 2.4 to 1.9, the gRE-signal ratio decreased from 7.6 to 4.4, and the amount of LGE decreased from 38% to 22% of left ventricular mass. These findings are in line with pervious publications describing the individual time courses of each of those CMR parameters (4,7,14) in myocarditis patients. Based on these results Zagrosek et al. (13) conclude that the combined approach is capable of differentiating reversible and irreversible myocardial damage noninvasively. They also state that if none, or just 1 of T2-signal and gRE ratios is elevated, this has a negative predictive value of 100% to differentiate active from healed myocarditis in living patients.

How should one put these results into perspective with the existing body of literature? The largest study examining patients with clinically suspected chronic myocarditis by CMR and histopathology (9) found absence of T2 elevation in 33%, and no elevated gRE ratio in 37% of those shown to have inflammation by histology. Hence, one-third of patients with persisting inflammation would have elevation of 1 of these 2 CMR parameters.

Unfortunately, the study of Gutberlet et al. (9) does not tell us how often both parameters were below the pre-defined cutoff values even though histology indicated the persistence of inflammation. De Cobelli et al. (6) found absence of T2-ratio elevation in 78% of patients with chronic inflammation by histopathological criteria. However, these investigators did not perform gRE imaging, perhaps because the image quality is frequently suboptimal for this pulse sequence. Taken together, these 2 studies cast serious doubt on whether the finding by Zagrosek et al. (13) that ongoing inflammation is 100% excluded in patients in whom 1 or both of the 2 parameters, T2 signal and gRE ratio, are normal can be applied to larger patient groups in whom biopsy is available.

A basic meta-analysis of most data available on CMR in human myocarditis (Table 1) (3–6,8,15–22) does not show an advantage of the combined approach compared with each individual technique, contradicting the report of Abdel Aty et al. (5), who first described a substantial benefit of adding T2 signal and gRE ratio to LGE imaging for myocarditis workup. This discrepancy most likely can also be explained by the fact that CMR findings for T2 signal and gRE ratio have never been systematically confirmed by histopathology. Following Bayes' principle of boolean information processing, combining tests with suboptimal sensitivities and specificities does not necessarily improve the performance of the combined approach. Thus, multicenter data using histopathological evaluation as the gold standard are needed.


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  		Table 1 Basic Meta-Analysis of Most Data Available on CMR in Human Myocarditis
 
When managing patients with inflammatory heart disease today, it should be kept in mind that despite the merits of CMR, which is capable of giving clues on the presence and distribution of inflammatory damage in the myocardium, as well as helping to guide endomyocardial biopsy to minimize sampling error (4), endomyocardial biopsy is the only technique that can directly assess the presence and intensity of myocardial inflammation in vivo. Therefore, it is the technique of choice if clinically indicated to differentiate between active and healed myocarditis. Biopsy samples can be safely obtained from the right as well as from the left ventricle, yielding a rate of severe complications that is not significantly different from the complication rate of standard coronary angiography ({approx}0.1% in experienced centers) (23–25). Endomyocardial biopsy also provides information on the underlying cause of inflammation, such as viral or bacterial infection of the myocardium, or myocardial autoimmune processes, such as giant cells, or Churg-Strauss syndrome. This information, however, which CMR imaging will not be able to obtain in the near future, is essential for patient management decisions. The importance of endomyocardial biopsy is reflected in the current guidelines recommending it for basically all patients with developing nonischemic heart failure, as well as for several other nonischemic conditions (26).

Nevertheless, Zagrosek et al. (13) are to be congratulated on systematically collecting 18 months of follow-up data on patients with myocarditis who all underwent a combined CMR triple protocol including T2, gRE, and LGE. Their results underscore that the time is now ready for evaluating this combined CMR approach in a larger multicenter study (ideally with endomyocardial biopsy of many patients as the standard of reference). More data are needed before we can be reasonably sure that the combined CMR approach holds promise to reshape myocarditis patient management in the future.


   Footnotes
 
* Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. Back

* Reprint requests and correspondence: Dr. Heiko Mahrholdt, Robert-Bosch-Medical Center, Auerbachstrasse 110, Stuttgart 70376, Germany (Email: heiko.mahrholdt{at}rbk.de).


   REFERENCES
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Related Article

Cardiac Magnetic Resonance Monitors Reversible and Irreversible Myocardial Injury in Myocarditis
Anja Zagrosek, Hassan Abdel-Aty, Philipp Boyé, Ralf Wassmuth, Daniel Messroghli, Wolfgang Utz, Andre Rudolph, Steffen Bohl, Rainer Dietz, and Jeanette Schulz-Menger
J. Am. Coll. Cardiol. Img. 2009 2: 131-138. [Abstract] [Full Text] [PDF]




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