Magnetic resonance imaging findings in acute myocarditis and correlation with immunohistological parameters

The relative enhancement was calculated quantitatively from T1-weighted spin echo images obtained before and after intravenous administration of 0.1 mmol of gadolinium-based contrast agent per kg body weight (Magnevist^® Schering, Germany) with the injection-speed of 2 ml/s. The time interval between injection and imaging was 15 s. Here, myocardial signal intensities were calculated from five unenhanced axial slices and the corresponding five postcontrast slices. Two regions of interest (ROIs) were defined on unenhanced images: one ROI encompassing the left ventricular myocardium and another ROI in the musculus erector spinae

Since the body coil has a rather homogeneous signal reception profile, this coil was used for measuring the relative signal intensities of myocardium and skeleton muscle. Thus, the inhomogeneous signal profile of the cardiac surface coil was avoided.

In our study, relative enhancement has a sensitivity of only 48.8% for detecting immunohistologically proven acute myocarditis, which is low compared with data reported in the literature These results suggest that relative enhancement alone is not a reliable diagnostic criterion or screening test for acute myocarditis [1, 2]. The negative predictive value and accuracy are also low at 42.5% and 42.5%, respectively. On the other hand, specificity and positive predictive value are relatively high (73.8% and 78.4%, respectively) and similar to the values reported from comparable studies. Higher values were found by Gutberlet et al. [2]. One can only speculate why our results are poorer. One possible explanation is the difference in the number of patients examined: 131 in our study versus 83 in the study by Gutberlet et al. and 47 in the study by Abdel-Aty et al. [1]. These differences might lead to greater variance in the data and hence affect the results. The discrepancy may also be due to the fact that Gutberlet et al. only investigated patients with chronic myocarditis. It is conceivable that myocardial inflammation starting out as a focal lesion may extend throughout the myocardium as the condition becomes chronic. This assumption is confirmed by the results reported by Laissy et al. showing focal enhancement within the first 7 days after the onset of symptoms and diffuse relative enhancement further along the course [7]. As our patients were examined at the acute stage within 2 weeks of the onset of clinical symptoms, it is conceivable that the signal enhancement in an early focus of myocardial inflammation is compensated for by the normal signal intensity of surrounding healthy myocardial tissue. This is because we calculated a mean value of relative enhancement from the signal intensities measured throughout the myocardium visible on the respective images. This method may lead to a normal MRI result in patients with immunohistologically proven myocarditis. A third possible explanation is that different patient selection criteria were used, which might in particular explain the difference in results between our study and that of Abdel-Aty et al., who examined patients who potentially had myocarditis and completely healthy volunteers without symptoms. On the other hand, our entire study population consisted of individuals with a high clinical suspicion of acute myocarditis. As a result, our controls were patients who were immunohistologically negative for acute myocarditis. This means that we had no definitive evidence for the absence of myocarditis in the control patients as immunohistology has low sensitivity because of a relatively high sampling error of endomyocardial biopsy, which may explain the relatively moderate sensitivity of relative enhancement in our study. It is of note that in the study of Abdel-Aty et al. myocardial biopsies were obtained in only two patients, which might also have distorted the results because no gold standard diagnosis was available for most of the patients and definitive proof of myocarditis was not available for the patients with relative enhancement at MR [1].

In our study, the group of patients with immunohistologically proven myocarditis had a mean relative enhancement of 4.4 with a standard deviation of ±2.17 versus 3.78 ± 2.68 in the patients with negative immunohistology; the difference between the two groups is not significant. These values are comparable to those found by Gutberlet et al., whereas Abdel-Aty et al. reported a mean relative enhancement in diseased patients of 6.8 with a standard deviation of ±4.0. The difference may be due to the small number of cases examined by Abdel-Aty et al. or the fact that they examined asymptomatic healthy individuals as controls. The latter point alone does not explain the higher mean value of relative enhancement as such but the examination of asymptomatic patients as controls might explain the clearer separation of the two groups in the study of Abdel-Aty et al. compared with a control group consisting of symptomatic patients with suspected myocarditis in our study.

Logistic regression taking into account age and sex revealed no significant correlation between relative enhancement and myocarditis with p = 0.188. The odds ratio is 2.4; in other words, there is a 2.4-fold higher chance of relative enhancement being positive in patients with myocarditis versus patients without myocarditis. This is not a hard indicator but is meaningful as a clue in conjunction with other findings. In conclusion, relative enhancement alone is not a sufficient diagnostic parameter for myocarditis, and our results in acute myocarditis are even poorer than published data on chronic myocarditis [7]. Nevertheless, relative enhancement is useful as one of several criteria in diagnosing myocarditis.

The relative water content we found in our patients with proven myocarditis is below that reported by other authors [1, 2]. Again, the discrepancies may be due to the problems outlined above (different numbers of patients, selection criteria, lack of proof of disease by endomyocardial biopsy); in addition, general problems associated with the measurement of water content may play a role. When there is oedema, the fluid content of tissue is increased. Most of the fluid comes from the blood vessels. Extravasation may be caused by inflammatory processes in the setting of myocarditis or might be due to inflammatory or destructive vasculopathies. Examples of vessel diseases include vasculitis or microangiopathy in diabetes mellitus. The results are also influenced by the fact that relative water content is calculated in relation to that of skeletal muscle. If there is additional oedema of the skeletal muscle of whatever aetiology, the MRI result for relative water content will be pseudonormal. Investigating the distribution of relative enhancement in myocardium and skeletal muscle in patients with myocarditis, Laissy et al. found increased enhancement of both the myocardium and peripheral skeletal muscle within the first 7 days after onset of symptoms, suggesting that there is either systemic inflammation or involvement of skeletal muscle [7]. This might also hold true for relative oedema.

In summary, relative water content alone is even less suitable for diagnosing myocarditis compared with relative enhancement. Relative water content may be interpreted as a clue pointing to the disease but, based on our results, this parameter does not allow more concrete diagnostic conclusions to be drawn.

Late enhancement is the only one of the three MRI parameters for which we found a comparable or even higher statistical significance compared with the study of chronic myocarditis by Gutberlet et al. However, our results are again poorer than those reported by Abdel-Aty et al. Late enhancement has a high specificity compared with relative enhancement and relative water content, while sensitivity is low, rendering this parameter superior to the other two MRI criteria for confirming suspected disease with the low sensitivity precluding the use of this parameter for detecting myocarditis, e.g. in a screening test.

There are several possible explanations for the low sensitivity of late enhancement. Late enhancement, or the persistence of contrast agent in the interstitial space, occurs not only during acute inflammation but also when there is remodelling during healing or may reflect scar tissue or fibrosis as late sequelae of acute myocarditis [11]. It is conceivable that, despite symptomatic disease, the immunohistological examination may be positive before an organised focus of inflammation becomes morphologically apparent or before there is myocyte loss with subsequent scar formation or fibrosis, conditions that are associated with contrast medium extravasation into the interstitial space seen as late enhancement on MR images. Hence, it can be assumed that cell loss has not yet occurred in acute myocarditis and there is no necrosis or scar tissue to produce late enhancement. Late enhancement significantly correlates with immunohistologically proven myocarditis in our study (p = 0.021 or p = 0.027). The odds ratio of approx. 2.8 suggests that the probability of seeing late enhancement in patients with myocarditis has the highest probability of all three MRI criteria investigated. Nevertheless, late enhancement alone does not provide a reliable diagnostic criterion for myocarditis.

Combining all three MRI parameters, a positive result for one of the three was found to have a sensitivity of 39,3% with the highest specificity of 91.3% being observed when all three criteria were positive.

Our results suggest that all MRI criteria should be used in combination to arrive at a well-founded conclusion regarding the presence of myocarditis, which is notoriously difficult to diagnose. A positive MRI result may thus serve as a basis for ordering further diagnostic tests. If all three MRI parameters are positive in a patient with the classical clinical symptoms, a diagnosis of myocarditis can be made with a high degree of specificity.

In our study, endomyocardial biopsy specimens were sampled from different septal regions although some earlier publications already recommended targeted biopsy from potential sites of inflammation suggested by late enhancement on MR images [5, 12]. Non-targeted biopsy increases the sampling error, resulting in lower sensitivity [13]. Our biopsy technique may have distorted the MRI results as the immunohistological examination defined the group of patients with myocarditis in our study. The second problem directly following from this procedure is that we classified borderline myocarditis as positive for myocarditis. This milder form of disease may lead to less pronounced changes in the MRI parameters investigated, which also affects our results.

Although we investigated a larger number of patients than both Gutberlet et al. and Abdel-Aty et al., the study is still too small to obtain truly representative statistical data. This is suggested by the measure of quality of logistic regression, the Nagelkerke’s R-square, which is 0.127 and thus well below the maximum possible value of nearly 1.

While MRI is quite accurate, shown both in our study and the most important studies [14] reported in the literature, it should not be used alone to diagnose myocarditis. The final conclusion to be drawn from the results presented here is that all parameters that can be derived from cardiovascular magnetic resonance imaging taken together allow good non-invasive diagnosis of myocarditis with high specificity but have to be supplemented by additional tests for adequate diagnostic management of myocarditis.