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* Axial Centro de Imagem, Belo Horizonte
Federal University of Minas Gerais Medical School, Minas Gerais, Brazil
Human Genome Research Center, Biosciences Institute, University of São Paulo
Heart Institute (InCor) University of São Paulo Medical School, São Paulo, Brazil
Manuscript received May 22, 2006; revised manuscript received September 21, 2006, accepted October 16, 2006.
* Reprint requests and correspondence: Dr. Carlos E. Rochitte, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Setor de Ressonância Magnética e Tomografia Cardiovascular, Avenida Dr. Enéas de Carvalho Aguiar, 44, Andar AB, Cerqueira César, São Paulo, SP, Brazil 05403-000. (Email: rochitte{at}incor.usp).
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Background: Muscular dystrophy is a genetic disease that involves skeletal and cardiac tissues of humans. Cardiomyopathy is common, and death secondary to cardiac or respiratory diseases occurs early in life. Cardiovascular magnetic resonance is a reliable method for assessing global and regional cardiac function, allowing also for the detection of myocardial fibrosis (MF).
Methods: Ten patients with Duchenne or Becker dystrophies were studied by CMR. Physical examination, Chagas disease serological tests, electrocardiogram, chest radiograph, total creatine kinase, and Doppler echocardiogram were also obtained in all patients.
Results: Patients with MF had a lower ejection fraction than those without. Myocardial fibrosis (midwall and/or subepicardial) was observed in 7 of the 10 patients, and the lateral wall was the most commonly involved segment. There was moderate correlation between segmental MF and dysfunction.
Conclusions: Cardiovascular magnetic resonance can identify MF and may be useful for detecting the early stages of cardiomyopathy in MD. Future work will be needed to evaluate whether CMR can influence cardiomyopathy and outcomes.
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Death secondary to cardiac or respiratory causes typically occurs in the second to third decade in Duchenne and in the fourth to fifth decade in Becker MD (3,4). In MD autopsy, end-stage cardiac disease is characterized by alternating areas of myocyte hypertrophy, atrophy, and fibrosis (5,6). Clinical studies of cardiomyopathy show that the heart disease process is underway long before symptoms appear (7,8).
Cardiovascular magnetic resonance (CMR) is a precise and reliable method for assessing global and regional cardiac function (9,10). Myocardial delayed enhancement (MDE) is the best noninvasive method for evaluating myocardial fibrosis (MF) caused by ischemic (10,11) or nonischemic disease (12,13). We hypothesized that MDE can detect and quantify myocardial damage caused by MD at early stages of disease.
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Informed consent from patients or their legal representatives preceded CMR evaluation and Chagas disease serological test. Clinical characteristics are shown in Table 2.
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Data analysis.
End-systolic LV volume, end-diastolic LV volume, and LV ejection fraction (LVEF) were measured using ReportCard 2.0 software (GE Medical Systems), applying the Simpson method. On the MDE short-axis images, we evaluated the number of LV segments with MF using a standard LV 17-segment model. Two independent observers scored segmental MDE transmurality as the visual percent area enhanced (nontransmural 
50%, or transmural >51%), and 2 other observers evaluated myocardial function as normal, mild hypokinesia, severe hypokinesia, and akinesia or dyskinesia. Patterns of MDE were classified as subendocardial, midwall, subepicardial, and transmural.
Statistical analysis. Data are presented as mean ± standard deviation. Chi-square analysis was used for comparison between proportions. Student t test was used for comparison between groups with and without MF. Simple linear regression was used to compare total CK levels with LVEF. The kappa test was used for agreement between observers and MF versus segmental dysfunction. The Kruskal-Wallis test was used to compare mean scores among different segments. A limitation of the statistical analysis was the small sample size.
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Segmental LV function and MF. For 2 independent observers, segmental MF was present in 33 (19.4%) and 25 (14.7%) segments. Regional dysfunction was present in 25 (14.7%) and in 23 (13.5%) segments. There was good interobserver agreement when analyzing LV function (kappa 0.76, p < 0.001) and segmental MF (kappa 0.75, p < 0.001). Comparing 340 observations (2 observers combined), we noted moderate agreement between segmental MF and dysfunction, kappa 0.41, p < 0.001. Only 10.6% of segments with normal function showed MF, and 43.8% of the dysfunctional segments had no MF. Among 58 MF observations, 27 (56.2%) had abnormal contractility. The agreement between the segmental MF extent and the degree of segmental dysfunction was fair (kappa 0.31, p < 0.001). Additionally, there was no segmental dysfunction in 31 (53.5%) of 58 MF observations, particularly with nontransmural MF (26 of 42, 61.9%).
Atypical patterns of MDE occurred in 89% of segments with MF; MF was midwall in 57.8% and subepicardial in 31.1%. Segmental MF was unequally distributed, with lateral segments being most commonly involved for both observers (Table 4), and with the highest score (more MF) for the combined observers (p = 0.003 by Kruskal-Wallis test).
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We used the ability of CMR to delineate RV and LV morphology, function, and myocardial tissue characteristics in patients with Duchenne and Becker MD. The presence of MF was consistently shown by the MDE technique in our patients with MD.
The frequent finding of MF, even in patients with preserved global LV and RV function, supports the current belief that heart disease begins much earlier than the onset of symptoms (7). Moreover, this observation suggests that CMR can be useful for the early detection of heart disease over and above the sole information on ventricular function provided by the conventional Doppler echocardiogram. We also observed that even among patients with MF, the chest radiograph and electrocardiogram were completely normal. Another interesting observation is the detection of myocardial injury at a very young age. We detected MF in 2 of 4 patients 10 years old with normal echocardiogram, a time when drug treatment is still not usually indicated (14).
Global LV dysfunction was associated with the presence of MF, indicating an MF role in the development of cardiomyopathy and heart failure in MD. Myocardial delayed enhancement pattern preserving subendocardium and more frequently located in the LV lateral wall has been observed in other cardiomyopathies (12,13). The correlation between segments with MF and dysfunction reinforces the pathophysiological link. In this regard, the dystrophin gene mutation has been associated not only with X-linked dilated cardiomyopathy, but also with sporadic dilated cardiomyopathy (15,16). Previous work has suggested that dystrophin gene exon 51 to 52 mutations protect against the development of dilated cardiomyopathy (17). We had 1 case with this specific mutation and 2 cases with the exon 48, 49, and 50 mutations (Table 1). All 3 of these patients had MF on CMR studies. Moreover, of 7 patients with MF, only 2 had abnormal echocardiography. In light of our data, it is possible that patients with normal echocardiography might already have myocardial injury shown by CMR studies. Therefore, the use of CMR, leading to a more detailed evaluation of these patients, particularly the MF detection, can be useful.
Standard heart failure management, although supported by few data, has been used in this group of patients with suboptimal results (18). Systemic glucocorticoid administration is becoming the standard treatment for skeletal muscle disease, and it may be beneficial to cardiac function. Therefore, further studies are needed to investigate the use of MF by CMR as a surrogate for the beginning of medical therapy for heart failure, with potentially better results. Moreover, the early use of drugs, known to act on the development of MF, such as aldosterone and angiotensin-converting enzyme inhibitors, also needs to be investigated.
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