Author + information
- Vincenzo Giglio, MD⁎ (, )
- Vincenzo Pasceri, MD, PhD, FACC,
- Loredana Messano, MD,
- Quintino Parisi, MD,
- Gabriele Rinelli, MD,
- Luciano Pasquini, MD,
- Antonio Dello Russo, MD,
- Aldo Broccolini, MD, PhD,
- Giuliana Galluzzi, MD, PhD,
- Mario Pescatori, MD, PhD,
- Massimiliano Mirabella, MD,
- Teresa Gidaro, MD,
- Fortunato Mangiola, MD and
- Enzo Ricci, MD
- ↵⁎Centre for Neuromuscular Diseases, Uildm, Prospero Santacroce St., 5, 00167 Rome, Italy
To the Editor:Becker muscular dystrophy (BMD) is an allelic X-linked recessive disorder characterized by an in frame deletion encompassing one or more exons of the dystrophin gene, with a large phenotypic spectrum, ranging between severe childhood-onset muscular disease to asymptomatic cases. Cardiac involvement (leading to cardiomyopathy and heart failure) is frequent, age-dependent, and unpredictable (1). Since there is no direct relationship between severity of skeletal and cardiac involvement, cardiomyopathy frequently develops in patients with normal skeletal muscle function (2).
Recently, we showed that ultrasound tissue characterization (UTC) of myocardium is able to detect widespread signs of cardiac involvement even in Duchenne muscular dystrophy (DMD) children with normal electrocardiographs (ECGs) and left ventricular systolic function (3). This surprising observation lead to the hypothesis that UTC may be a useful tool in assessing early myocardial involvement in patients with other genetic diseases causing structural changes of myocardium (4). To further explore this hypothesis, we performed UTC analysis in a group of 34 BMD patients with no cardiac symptoms (ages 4 to 33 years, mean 17 ± 10 years), all with normal ECGs, left ventricular diastolic and systolic function, and segmental wall motion at baseline two-dimensional echocardiography, and in 34 healthy age-matched control subjects. The diagnosis of BMD was confirmed by muscular biopsy in all cases. None of the patients was under pharmacological treatment.
Ultrasound tissue characterization analysis of the myocardium was performed in the parasternal short-axis view as previously reported (3). In order to obtain a detailed regional analysis of the myocardium, UTC parameters were measured at basal, mid- (papillary muscles), and apical level, in all 16 myocardial segments of the left ventricle, a technique never performed before. All UTC parameters were compared using non-parametric statistics (Mann-Whitney Utest and Kruskal-Wallis analysis of variance). Bonferroni correction was applied for multiple comparisons of the same variable (i.e., comparison of UTC parameters in multiple myocardial segments). Correlations were assessed by Spearman’s rank correlation test. A value of p < 0.05 was considered significant. All values are shown as mean ± SD.
No significant differences were found in the mean values of ejection fraction and in the mean values of Doppler mitral inflow and annular tissue Doppler imaging velocity between BMD patients and healthy control subjects. Analysis of both cyclic variation of integrated backscatter (cvIBS) and calibrated integrated backscatter (cIBS) was performed on 539 segments in control subjects and on 534 segments in patients, as quality of imaging was inadequate in 5 segments of the control group and in 10 segments of BMD patients.
Overall, BMD patients and control subjects displayed different curves of distribution of cvIBS (mean value of 5.3 ± 2.0 dB vs. 8.4 ± 0.9 dB, p < 10−6) (Fig. 1A)and cIBS (mean value of 27.0 ± 6.5 dB vs. 24.7 ± 2.6 dB, p < 10−6) (Fig. 1B).
Figure 2shows a UTC analysis for a patient and a control subject in an inferior base segment.
A comparison of UTC values in each segment showed that BMD patients had significantly lower cvIBS values in all 16 myocardial segments: median 5.2 dB, range 4.4 to 7.0 dB in BMD patients; median 8.3 dB, range 7.9 to 8.7 dB in control subjects (p < 0.0002 for all segments); moreover, in all segments SD was larger in BMD patients than in the control group. Conversely, cIBS was significantly different between BMD patients and control subjects only in the inferior, posterolateral base and inferolateral mid-segments from basal through apical levels. In anterior, lateral, and septal segments, cIBS was not significantly different in the two groups, although SD was constantly larger in the BMD group as compared to the control group.
Patients with a deletion of exons 48, 49, or both (n = 15) had lower values of cvIBS as compared to patients with deletions of different exons (n = 19) (4.8 ± 0.6 dB vs. 5.6 ± 0.9 dB, respectively, p = 0.009). These two groups had similar cIBS values (27.3 ± 3.2 dB vs. 26.5 ± 4.1 dB, p = 0.33). Neither age nor severity of muscular involvement (patients divided into four grades of muscular involvement) were significantly correlated to cvIBS (r = −0.10, p = 0.56 for age; r = −0.23, p = 0.18 for severity) or cIBS (r = 0.08, p = 0.64 for age; r = 0.22, p = 0.22 for severity) values.
The present study shows that UTC can identify early changes of myocardial physical properties in patients with BMD, even in the absence of left ventricular diastolic and systolic dysfunction.
In BMD patients, differences in the amount of myocardial dystrophin and in the site of the deletion, as well as other still-unidentified factors, are probably the molecular basis of the cardiac involvement that is common in BMD patients, with ECG changes in about 70% of cases (2) and reduced systolic function in up to 60% (1). Since the muscle involvement is often mild and heart disease is a frequent cause of death in BMD (in up to 50% of patients) (5), cardiac transplantation has been successfully performed in these patients. This wide spectrum of genetic background and phenotypic expression is confirmed by the wide range of variation of cvIBS and cIBS in BMD patients, whereas in normal control subjects, both parameters are always within a very narrow range in all myocardial segments. Yet, despite this variation, UTC analysis could easily identify widespread changes of myocardial features in BMD patients compared with control subjects. In particular, cvIBS values in BMD patients were markedly different from the control group; no overlap was observed between cvIBS mean values in any of the sampled myocardial segments. Conversely, significant changes in cIBS were detected only in the inferior, posterolateral base and inferolateral mid-segments. These UTC findings in BMD patients as previously described in DMD patients (3) support the hypothesis that myocardial UTC analysis could reveal the early signs of a future evolution toward a segmental myocardial dysfunction.
Furthermore, we found that patients with a deletion encompassing exons 48 and/or 49 had lower values of cvIBS than patients with different or other deletions, possibly suggesting more subtle changes of myocardial physical properties in these patients, in agreement with a previous study suggesting a more frequent cardiac involvement in BMD patients carrying deletions involving exons 48 or 49 (2).
Probably, cvIBS is able to detect a different “cellular milieu” and, finally, early changes of myocardial properties in BMD patients, even in the absence of functional myocardial dysfunction.
Our results show that a myocardial involvement is always present in BMD patients, independent of age, type of deletion, amount of dystrophin in muscle, and severity of skeletal muscle involvement, despite a normal left ventricular diastolic and systolic function.
This paper provides UTC values, in the widest number of myocardial segments ever sampled, in BMD patients with a functionally normal heart.
Please note: This study was supported by Telethon Italy grant number GUP030559.
- American College of Cardiology Foundation
- Steare S.E.,
- Dubowitz V.,
- Benatar A.
- Melacini P.,
- Fanin M.,
- Danieli G.A.,
- et al.
- Giglio V.,
- Pasceri V.,
- Messano L.,
- et al.
- Towbin J.