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(Circulation. 1996;94:3168-3175.)
© 1996 American Heart Association, Inc.
Articles |
Myocardial Involvement Is Very Frequent Among Patients Affected With Subclinical Becker's Muscular Dystrophy
the Departments of Cardiology (P.M., C.V., M.M., G.F., S.D.V.), Neurology (M.F., F.M., M.P.F., C.A.), and Biology (G.A.D., M.M., M.L.M.), University of Padua, Padua, Italy.
Correspondence to Dr Paola Melacini, MD, Department of Cardiology, University of Padua, Via Giustiniani 2, 35128 Padua, Italy.
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Abstract |
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Background Several cases of Becker's muscular dystrophy (BMD) have been reported, which showed mild or subclinical skeletal muscle involvement with an overt dilated cardiomyopathy. Here, for the first time, a group of 28 patients with BMD who had a subclinical or benign myopathy have been studied through a thorough cardiological assessment.
Methods and Results Each patient underwent ECG and echocardiographic examinations. Molecular analyses of the dystrophin gene and protein were performed. An unexpectedly high incidence of myocardial involvement was observed among patients affected with subclinical (72%) or benign (60%) BMD. The cardiac involvement appears to develop early from the right ventricle. Both the increase in left ventricular end-diastolic volume and the reduction in the ejection fraction appeared to be age related. Severe left ventricular dilation with reduced ejection fraction, which could be complicated by life-threatening arrhythmias, may occur. Contrary to previous reports, which indicated the involvement of 5'-end mutations in cardiomyopathies as a result of dystrophin gene alterations, this study shows that despite the apparent concentration of deletions in two regions (5'-end and exons 47 through 49), no general conclusions can be drawn regarding the involvement of specific gene mutations in the development of cardiomyopathy.
Conclusions Cardiomyopathy is the main clinical feature and complication in patients affected by subclinical or mild BMD. The cardiac manifestation is characterized by early right ventricular involvement and is later associated with left ventricular impairment. In mild BMD, myocardial damage may develop because the patients, who are unaware of a possible cardiac involvement, are still able to perform strenuous muscle exercise and, through pressure or volume overload, may induce mechanical stress, which is harmful for dystrophin-deficient myocardial cells.
Key Words: cardiomyopathy • echocardiography • molecular biology • muscles
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Introduction |
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Duchenne's muscular dystrophy (DMD) and the milder variant, Becker's muscular dystrophy (BMD), are allelic X-linked recessive disorders that are characterized by progressive muscle wasting. The gene involved is extremely large and complex and encodes a 427-kD protein named dystrophin, which is mainly localized at the surface membrane of striated muscle fibers and probably links the cytoskeleton to the basal lamina via the dystrophin-associated glycoprotein complex.1
DMD is characterized by the absence of dystrophin, which is the result of stop codons originated by point mutations or out-of-frame intragenic deletions. On the contrary, in BMD, a dystrophin of abnormal molecular weight is often produced by in-frame deletions or duplications.2 Furthermore, a BMD phenotype is seldom produced by missense mutations.3 4
Because dystrophin analysis was first introduced as a diagnostic procedure, several cases of BMD have been reported that show mild or subclinical skeletal muscle involvement with overt dilated cardiomyopathy.2 5 6 7 8 9 10 11 12 13 14 15 16 17
Study goals were to evaluate cardiac involvement in a group of 28 patients with BMD who had mild skeletal muscle disease and to offer a genotype-phenotype correlation at the DNA level.
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Methods |
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Patients
Twenty-eight patients were selected from a group of 53 patients with BMD who were diagnosed through a complete neurological (clinical examination, muscle biopsy, dystrophin analysis) and a noninvasive cardiac evaluation (ECG and echocardiography). The 28 patients were selected on the basis of a subclinical or benign skeletal muscle involvement and were scored by the same physician as follows: group A, or subclinical, was characterized by elevated creatine kinase (CK) level, calf hypertrophy, cramps, myalgia, and myoglobinuria; group B, or benign, was characterized like subclinical but was also associated with muscle weakness in lower and/or upper girdles.18
Cardiological Evaluation
A complete cardiac evaluation was obtained from anamnesis, physical examination, chest radiography, ECG, and echocardiography.
Ambulatory ECGs were obtained using modified V1 and V5 leads and a portable ICR 24-hour tape recorder. Tapes were analyzed with a rapid scanner with a digital circuit for arrhythmia detection and data reduction (model 3, Pathfinder). During 24-hour Holter monitoring, the patients followed their normal daily routine and kept a diary of symptoms and activity levels. Ventricular arrhythmias were classified according to the Lown scale.
Echocardiographic examination included M-mode, two-dimensional, and Doppler echocardiography. A phased-array ultrasound system (model 77020 AC, Hewlett-Packard; model 1000 77030A, SONOS) with duplex 2.5- and 3.5-MHz transducers and a 2.0-MHz nonimaging transducer for imaging, spectral Doppler, and color flow mapping was used. Standard parasternal, apical, and subcostal views were stored on Panasonic AG 6200 videotapes that allowed frame-by-frame and real-time playback for detailed evaluation of structures and functions. Two-dimensional studies were evaluated by two independent observers for the presence of abnormal wall motion and regional structural abnormalities in the right19 and left ventricles. Segments were judged normal, hypokinetic (severe reduction in systolic inward and thickening), akinetic (no systolic endocardial excursion and thickening), or dyskinetic (paradoxical endocardial excursion and thickening). Agreement of interobserver analysis for segmental asynergy was seen in 98% of the segments visualized. Discrepancies were resolved by consensus. Left ventricular volumes were calculated using an ellipsoid biplane area-length model derived from left ventricular images in the apical four-chamber view.20 A discrepancy of >10 mL for left ventricular volume required the analysis of echocardiographic tracing by a third observer. Agreement was achieved by consensus. In our laboratory, the degree of interobserver and intraobserver correlation for left ventricular area (r=.94 and r=.98, respectively) and for left ventricular length (r=.95 and r=.96, respectively) was reasonable.
The ejection fraction was calculated as follows: ejection fraction=end-diastolic volume-end-systolic volume/end-diastolic volume.
End-diastolic and end-systolic right ventricular volumes were calculated using an area-length method derived from orthogonal planes (apical four-chamber and short-axis subcostal views).21 Levine's formula21 gives right ventricular volume as two thirds times the area in one view multiplied by the length in the other view.22 Interobserver and intraobserver variability for right ventricular area (r=.94 and r=.98, respectively) and for right ventricular length (r=.95 and r=.96, respectively) was acceptable.
In athletes, echocardiographic examination was repeated after 6 months of deconditioning.23 The right and left ventricular volumes calculated during the last examination were selected for this study.
Dystrophin Analysis
Open muscle biopsy specimens were obtained from quadriceps or biceps muscle from 26 patients after written informed consent was obtained. Dystrophin immunohistochemical analysis was performed on unfixed cryostat muscle sections using monoclonal antibodies against dystrophin carboxyl terminus (Dys-2, corresponding to the last 17 amino acids) and amino terminus domains (Dys-3, corresponding to exons 10 through 12). The reaction was developed with the immunofluorescence technique.24 To exclude that the absence of dystrophin labeling in muscle fibers was a result of active degeneration, ß-spectrin immunoreaction (NCL Spec-2) was used as a marker of membrane integrity. The pattern of dystrophin immunostaining was classified according to the following criteria: 1 indicates normal reaction; 2, reduced intensity in all fibers and nonnegative fibers; and 3, reduced intensity in all fibers associated with the presence of negative fibers (exceeding necrotic fibers).
Dystrophin Western blot was performed on SDS-PAGE using a monoclonal antibody against the carboxyl-terminal domain of the protein.18 Samples from both controls and patients were loaded into adjacent lanes to permit the determination of both dystrophin molecular mass and relative abundance.
The molecular mass of normal dystrophin was determined to be 
400 kD based on its relative mobility on SDS-PAGE.25 In this study, we used 400 kD as the "norm"; dystrophin that comigrated with adjacent normal dystrophin was assigned a molecular mass of 400 kD.
The quantity of dystrophin contained in each biopsy was determined through densitometric analysis as a percentage of the adjacent normal control samples. The amount of dystrophin was dependent on the amount of muscle tissue loaded into each lane, as determined by the posttransfer skeletal myosin Coomassie blue–stained gels that were adopted as a reference.
In 2 patients in whom a muscle biopsy was not available, the diagnosis was confirmed by the presence of an intragenic deletion in the dystrophin gene and by the family history, which showed X-linked inheritance of the disease.
DNA Analysis
DNA was extracted using a salting-out procedure from peripheral blood samples. Genomic DNA was amplified by multiplex polymerase chain reactions (PCR) for deletion screening (involving exons 1 through 13, 16, 17, 19, 21, 25, 26, 30, 32, 34, 41 through 55, 60, and the muscle promoter) and by semiquantitative multiplex PCRs (involving exons 3, 4, 7, 8, 12, 13, 16, 19, 21, 32, 41 through 43, 50, 53, 57, and 60) for duplication screening.26
Statistical Analysis
Values of the different parameters used in cardiological assessment were expressed as mean±SD. The upper and lower 95% confidence limits of normal right or left ventricular volume and the ejection fraction were given as the group mean value±1.645 SD. ANOVA was performed to evaluate the groups of patients and control subjects. Where significance was found, the Student-Newman-Keuls post hoc procedure was applied to determine differences between specific mean values. A value of P<.05 was considered significant. Linear regression analysis was used to assess the correlation between the age of patients and either ventricular volumes or ejection fractions.
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Results |
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In a group of 53 patients who had been diagnosed with BMD, on the basis of dystrophin analysis and/or DNA analysis, 28 patients (53%) showed subclinical or benign skeletal muscle involvement. Eighteen (34%) were classified as subclinical (group A) and 10 (19%) as benign (group B) (Table 1
).
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Skeletal Muscle Involvement
In groups A and B, patient ages ranged from 6 to 48 years (mean, 17.8±9.6 years) (Table 1
). Seventeen patients (61%) had a previous family history of the disease. CK levels were always high in these patients, ranging from 316 to 32 700 IU/L (n.v. 0 to 190 IU/L). Exertional myoglobinuria was observed in 39% of patients; calf hypertrophy, 75%; and cramps or myalgia, 75%. It is interesting to note that myoglobinuria was observed in 50% of the patients in group A but by only 20% of the patients in group B. Muscle cramps and myalgia were reported by 60% of patients in group B and by 83% in group A.
Dystrophin Analysis
In both A and B groups, dystrophin molecular mass was normal (400 kD) in 7 patients (27%), reduced in 17 patients (65%), and increased in 2 patients (8%) (Table 1). Relative abundance of dystrophin was normal in 6 patients (23%) and reduced in 20 patients (77%) (Fig 1). Dystrophin immunostaining showed a normal pattern in 3 patients (15%), a decreased intensity of reaction in 11 patients (42%), and complex abnormalities (ie, reduced intensity of labeling and presence of dystrophin-negative fibers) in 12 patients (46%) (Fig 2).
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DNA Analysis
Among the patients in groups A and B, 16 patients (57%) showed intragenic in-frame deletions. Very large intragenic duplications (involving exons 13 through 42 and 19 through 41) were observed in 2 patients (7%) in group B (Table 1). No deletions or duplications could be detected in 10 patients (36%). The location and extent of the intragenic deletions observed in groups A and B are reported in Fig 3.
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Cardiac Involvement
Of the patients in groups A and B, 19 (68%) showed myocardial involvement; however, all except 2 were asymptomatic. Of the 2 patients showing cardiac symptoms, 1 experienced lipothymia and the other reported dyspnea (NYHA class II). The former patient died suddenly despite having a pacemaker implanted; the latter patient's dyspnea worsened (NYHA class III) despite administration of appropriate drug therapy. No patients had symptoms of right-side heart failure.
Eleven patients (39%) had a normal ECG tracing. Eight patients showed minor ECG abnormalities, such as incomplete right bundle-branch block (3 patients) or R/S>1 in V1 (5 patients), that could be considered normal in this age group. Left bundle-branch block was observed in 3 patients, and left anterior fascicular block and first-degree atrioventricular block occurred in 1 patient. Two patients had aspecific ST-segment changes in the precordial leads, and 2 had negative T waves in right precordial leads (Table 2). Life-threatening ventricular arrhythmias (Lown 4b) were documented in only 1 patient, who died suddenly. Benign, isolated, monomorphic ventricular premature beats were recorded in 4 patients (Lown 1), and polymorphic beats were recorded in 1 patient (Lown 3).
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Echocardiographic findings showed structural, dimensional, and/or dynamic right ventricular abnormalities in 18 patients (64%) (Table 2 and Fig 4). Left ventricular impairment, with or without right ventricular dysfunction (Fig 4), was observed in 8 patients (28%). Ejection fraction was reduced in 6 patients (21%) (Fig 4). Left ventricular wall motion abnormalities were present in 6 patients (21%). Echocardiographic data appeared to be age related. Linear regression analysis (Fig 5) showed a significant correlation between the age of patients and left ventricular end-diastolic volume (r=.70, P<.001) or ejection fraction (r=-.59, P<.01).
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In group A, 13 patients (72%) showed myocardial involvement. Right ventricular end-diastolic volume was significantly increased in comparison with control values (P<.05) (Table 3). Right ventricular impairment was associated with left ventricular dysfunction in only 4 patients (31%).
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In group B, 6 patients (60%) showed myocardial involvement. A significant increase in right ventricular end-diastolic volume (P<.05) was observed (Table 3). Right ventricular impairment was observed in all except 1 patient, in whom evaluation of the right ventricle was impossible because of a marked enlargement of the left ventricle. In group B, left ventricular involvement was present in 4 patients (66%) and was characterized by a significant increase in left ventricular end-diastolic volume (P<.05) and a reduction in left ventricular ejection fraction (P<.05) compared with values in both control and group A patients (Table 3).
Development of Myocardial Involvement
The study of the development of myocardial disease was made possible by follow-up of 1 patient from a family with a recurrence of dilated cardiomyopathy associated with mild dystrophinopathy. At the age of 8 years, the proband (Fig 6) complained of cramps and myoglobinuria after exercise and showed elevated serum CK levels; after muscle biopsy and dystrophin analysis, the patient was diagnosed with BMD. DNA analysis showed an in-frame intragenic deletion involving exons 48 and 49. Two maternal uncles had had dilated cardiomyopathy and had died suddenly at age 35. Both uncles had calf hypertrophy and elevated CK levels; no dystrophin analysis at the protein and DNA level was available for them. However, it is suspected that they were affected by the same disease as the proband because calf hypertrophy, elevated CK, and X-linked inheritance would indicate this. The proband's mother, an obligate carrier, had both a normal CK level and normal echocardiographic findings. The proband underwent the first echocardiographic examination at age 14: severe dilation of the right ventricle associated with a mild left ventricular enlargement was found. A second evaluation, performed 4 years later, confirmed the right ventricular dilation and revealed further enlargement of left ventricle. No life-threatening arrhythmias were recorded with 24-hour Holter monitoring.
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Discussion |
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Patients with BMD often show cardiac involvement.9 27 28 Myocardial disease in patients with mild dystrophinopathies is occasionally reported.5 10 11 13 15 17 29 30
Unexpectedly, data from this study have shown that the incidence of cardiac abnormalities is particularly high (72%) among patients affected by a subclinical dystrophinopathy. It is worth noting that despite very mild muscle disease, some of these patients had severe left ventricular involvement. One of them, who was affected by dilated cardiomyopathy, died suddenly in the presence of life-threatening ventricular arrhythmias, and another is presently considered for inclusion in the list to undergo heart transplantation.
A familial case with sudden death and dilated cardiomyopathy in two maternal uncles was analyzed. Although in both uncles a left ventricular dilation was clearly present, in the proband, cardiac impairment was characterized by early right ventricular involvement and, subsequently, left ventricular impairment. His left ventricle underwent progressive enlargement over a 4-year period. This finding confirms the hypothesis, which was elaborated from a previous cross-sectional study,9 of early right ventricular involvement.
Of the patients in groups A and B with cardiac involvement, 10 (52.6%) showed intragenic deletions in the dystrophin gene and 2 (10.5%) showed intragenic duplications. Therefore, 63.1% showed major alterations in dystrophin size. This percentage is similar (66.6%) to that observed among patients in the same groups showing no cardiac involvement; thus, variations in dystrophin size are apparently unrelated to the development of myocardial disease.
In the literature, several patients with dilated cardiomyopathy associated with mild skeletal involvement have been reported as a result of deletions or point mutations of the 5'-end region of the dystrophin gene.10 17 Consequently, the hypothesis was put forward that the absence of the muscle-type dystrophin isoform could create a compensatory overproduction of other dystrophin isoforms transcribed in skeletal muscle but not in the heart. However, a deletion in the muscle promoter region without selective cardiac disease has also been reported.2 31
More recently, the finding of a point mutation at the 5' splicing site of the first intron in 1 patient prompted speculation about the possible involvement of this region in the origins of dystrophin-related cardiomyopathy.29 However, several patients with dilated cardiomyopathy associated with mild myopathy have been described, in whom such deletion affected the proximal or the middle portion of the dystrophin rod domain.2 13 14 27 28 30 32 In this study, all of the intragenic deletions associated with myocardial disease and mild skeletal involvement were in the region encompassing exons 47 through 49.
Despite the apparent concentration of deletions associated with cardiomyopathy in two different regions of the dystrophin gene (5'-end and 47 through 49), it would be incautious to draw general conclusions regarding the location of the specific gene mutations that cause cardiomyopathy. On the other hand, it is worth noting that the distribution of the above-mentioned deletions is different from what one could expect in that the two major deletional hot spots are centered, respectively, in introns 7 and 44.33
One relevant finding of this study was the unexpectedly high incidence of myocardial involvement among patients with mild or subclinical dystrophinopathy. The natural history of myocardial and skeletal muscle impairment in dystrophinopathies has yet to be defined. It is true that some patients with subclinical or benign myopathy are in the early stages of their disease and would be expected to have a clinical progression of muscular dystrophy with a subclinical myocardial involvement, but in other patients, severe and symptomatic cardiomyopathy has been observed in the adult stage in the absence of further muscle disease progression.10 15 29 Furthermore, patients with BMD who had severe dilated cardiomyopathy underwent successful cardiac transplantation30 34 35 because of their favorable skeletal muscle condition. Because of the paucity of skeletal muscle symptoms, it is possible that in some patients with idiopathic dilated cardiomyopathy, the role of dystrophin mutations has been, mistakenly, ignored.
The reason why some dystrophinopathic patients develop cardiomyopathy is still obscure, and the current hypotheses appear to be somewhat simplistic. On the other hand, it is possible that because they are unaware of possible cardiac involvement, patients with subclinical or mild myopathy may perform intensive or excessive muscle exercise. Such pressure and/or volume overload on the left and right ventricles could induce mechanical stress, which might be harmful for dystrophin-deficient myocardial cells.36 Although there are no clinical data to support the idea that increased use of dystrophin-deficient muscle speeds the clinical progression of skeletal and cardiac muscle weakness, some experimental results have shed new light on exercise-induced muscle damage and progression in dystrophinopathies.37 38 Consequently, progressive dilation of both ventricles may ensue and produce a dilated cardiomyopathy that could mimic a different, genetically determined39 cardiac disease. In this light, patients affected with mild dystrophinopathy should be discouraged from performing intense physical exercise. Furthermore, athletes with calf hypertrophy and elevated CK should undergo careful cardiological evaluation to prevent unsuspected cardiac injuries, which in some patients may lead to sudden death.
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Acknowledgments |
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This work was supported by the Italian Muscular Dystrophy Association (UILDM). Financial support from the Veneto Region, the Ministry of University (MURST), and Telethon-Italy (grant 552) is gratefully acknowledged.
Received March 25, 1996; revision received July 17, 1996; accepted July 31, 1996.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Ervasti JM, Campbell KP. Membrane organization of the dystrophin-glycoprotein complex. Cell. 1991;66:1121-1131.[Medline] [Order article via Infotrieve]
2. Beggs AH, Hoffman EP, Snyder JR, Arahata K, Specht L, Shapiro F, Angelini C, Sugita H, Kunkel LM. Exploring the molecular basis for variability among patients with Becker muscular dystrophy: dystrophin gene and protein studies. Am J Hum Genet. 1991;49:54-67.[Medline] [Order article via Infotrieve]
3.
Lenk U, Hanke R, Thiele H, Speer A. Point mutations at the carboxy terminus of the dystrophin gene: implications for an association with mental retardation in DMD patients. Hum Mol Genet. 1993;2:1877-1881.
4. Saad FA, Vita G, Toffolatti L, Danieli GA. A possible missense mutation detected in the dystrophin gene by double strand conformation analysis. Neuromuscul Disord. 1994;4:335-341.[Medline] [Order article via Infotrieve]
5. Gold R, Kress W, Meurers B, Meng G, Reichmann H, Muller CR. Becker muscular dystrophy: detection of unusual disease courses by combined approach to dystrophin analysis. Muscle Nerve. 1992;15:214-218.[Medline] [Order article via Infotrieve]
6. Hayashi Y, Ikeda U, Ogawa T, Miyashita H, Sekiguchi H, Arahata K, Shimada K. Becker-type muscular dystrophy associated with hypertrophic cardiomyopathy. Am Heart J. 1994;128:1265-1266.
7.
Katiyar BC, Misra S, Somani PN, Chatejri AM. Congestive cardiomyopathy in a family of Becker's X-linked muscular dystrophy. Postgrad Med J. 1977;53:12-15.
8.
Kuhn E, Fiehn W, Schroder JM, Assmus H, Wagner A. Early myocardial disease and cramping myalgia in Becker-type muscular dystrophy: a kindred. Neurology. 1979;29:1144-1149.
9. Melacini P, Fanin M, Danieli GA, Fasoli G, Villanova C, Angelini C, Vitiello L, Miorelli M, Buja GF, Mostacciuolo ML, Pegoraro E, Dalla Volta S. Cardiac involvement in Becker muscular dystrophy. J Am Coll Cardiol. 1993;22:1927-1934.[Abstract]
10.
Muntoni F, Cau M, Ganau A, Congiu R, Arvedi G, Mateddu A, Marrosu MG, Cianchetti C, Realdi G, Cao A, Melis MA. Deletion of the dystrophin muscle-promoter region associated with X-linked dilated cardiomyopathy. N Engl J Med. 1993;329:921-925.
11. Muntoni F, Wilson L, Marrosu G, Marrosu MG, Cianchetti C, Mestroni L, Ganau A, Dubowitz V, Sewry C. A mutation in the dystrophin gene selectively affecting dystrophin expression in the heart. J Clin Invest. 1995;96:693-699.
12. Nigro G, Comi LI, Politano L, Limongelli FM, Nigro V, De Rimini ML, Giugliano MAM, Petretta VR, Passamano L, Restucci B, Fattore L, Tebloev K, De Luca F, Raia P, Esposito MG. Evaluation of the cardiomyopathy in Becker muscular dystrophy. Muscle Nerve. 1995;18:283-291.[Medline] [Order article via Infotrieve]
13. Palmucci L, Doriguzzi C, Mongini T, Chiado'-Piat L, Restagno G, Carbonara A, Paolillo V. Dilating cardiomyopathy as the expression of Xp21 Becker type muscular dystrophy. J Neurol Sci. 1992;111:218-221.[Medline] [Order article via Infotrieve]
14. Siciliano G, Fanin M, Angelini C, Pollina LE, Miorin M, Saad FA, Freda MP, Muratorio A. Prevalent cardiac involvement in dystrophin Becker type mutation. Neuromuscul Disord. 1994;4:381-386.[Medline] [Order article via Infotrieve]
15.
Towbin JA, Hejtmancik JF, Brink P, Gelb B, Zhu XM, Chamberlain JS, McCabe ERB, Swift M. X-linked dilated cardiomyopathy: molecular evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus. Circulation. 1993;87:1854-1865.
16. Yazawa M, Ikeda S, Owa M, Haruta S, Yanagisawa N, Tanaka E, Watanabe M. A family of Becker's progressive muscular dystrophy with severe cardiomyopathy. Eur Neurol. 1987;27:13-19.[Medline] [Order article via Infotrieve]
17. Yoshida K, Ikeda S, Nakamura A, Kagoshima M, Takeda S, Shoji S, Yanagisawa N. Molecular analysis of the Duchenne muscular dystrophy gene in patients with Becker muscular dystrophy presenting with dilated cardiomyopathy. Muscle Nerve. 1993;16:1161-1166.[Medline] [Order article via Infotrieve]
18. Angelini C, Fanin M, Pegoraro E, Freda MP, Cadaldini M, Martinello F. Clinical-molecular correlation in 104 mild X-linked muscular dystrophy patients: characterization of subclinical phenotypes. Neuromuscul Disord. 1994;4:349-358.[Medline] [Order article via Infotrieve]
19. Daliento L, Turrini P, Nava A, Rizzoli G, Angelini A, Buja G, Scognamiglio R, Thiene G. Arrhythmogenic right ventricular cardiomyopathy in young versus adult patients: similarities and differences. J Am Coll Cardiol. 1995;25:655-664.[Abstract]
20. Schiller NB. Two-dimensional echocardiographic determination of left ventricular volume, systolic function, and mass: summary and discussion of the 1989 recommendations of the American Society of Echocardiography. Circulation. 1991;84:280-287.
21.
Levine RA, Gibson TC, Aretz T, Gillam LD, Guyer DE, King ME, Weyman AE. Echocardiographic measurements of right ventricular volume. Circulation. 1984;69:497-505.
22.
Scognamiglio R, Fasoli G, Nava A, Miraglia G, Thiene G, Dalla Volta S. Contribution of cross-sectional echocardiography to the diagnosis of right ventricular dysplasia at the asymptomatic stage. Eur Heart J. 1989;10:538-542.
23.
Maron BJ, Pelliccia A, Spirito P. Cardiac disease in young trained athletes: insight into methods for distinguishing athlete's heart from structural heart disease, with particular emphasis on hypertrophic cardiomyopathy. Circulation. 1995;91:1596-1601.
24. Fanin M, Pegoraro E, Angelini C. Absence of dystrophin and spectrin in regenerating muscle fibers from Becker muscular dystrophy patients. J Neurol Sci. 1994;123:88-94.[Medline] [Order article via Infotrieve]
25. Hoffman EP, Brown RH, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51:919-928.[Medline] [Order article via Infotrieve]
26. Saad FA, Galvagni F, Danieli GA. Rapid detection of human dystrophin gene mutations by multiplex semi-quantitative PCR (MSQ PCR). Basic Appl Myol. 1993;3:229-231.
27. Nigro G, Politano L, Nigro V, Petretta VR, Comi LI. Mutation of dystrophin gene and cardiomyopathy. Neuromuscul Disord. 1994;4:371-379.[Medline] [Order article via Infotrieve]
28.
Steare SE, Dubowitz V, Benatar A. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J. 1992;68:304-308.
29.
Milasin J, Muntoni F, Severini GM, Bartoloni L, Vatta M, Krajinovic M, Mateddu A, Angelini C, Camerini F, Falaschi A, Mestroni L, Giacca M. A point mutation in the 5' splice site of the dystrophin gene first intron responsible for the X-linked dilated cardiomyopathy. Hum Mol Genet. 1996;5:73-79.
30. Piccolo G, Azan G, Tonin P, Arbustini E, Gavazzi A, Banfi P, Mora M, Morandi L, Tedeschi S. Dilated cardiomyopathy requiring cardiac transplantation as initial manifestation of Xp21 Becker type muscular dystrophy. Neuromuscul Disord. 1994;4:143-146.[Medline] [Order article via Infotrieve]
31.
Boyce FM, Beggs AH, Feener C, Kunkel LM. Dystrophin is transcribed in brain from a distant upstream promoter. Proc Natl Acad Sci U S A. 1991;88:1276-1280.
32.
Olfors A, Eriksson BO, Kyllerman M, Martinsson T, Wahlstrom J. Dilated cardiomyopathy and the dystrophin gene: an illustrated review. Br Heart J. 1994;72:344-348.
33. Van Ommen GJB, Den Dunnen JT, Casula L, Blondel LAJ, Grootscholten PM, Ginjaar HB, Van Paassen HMB, Bakker E, Moorman AFM. Duchenne and Becker muscular dystrophy mutations, studied at the gene and protein level. In: Angelini C, Danieli GA, Fontanari D, eds. Muscular Dystrophy Research: From Molecular Diagnosis Toward Therapy. Amsterdam, Netherlands: Excerpta Medica; 1991:13-22.
34.
Donofrio PD, Challa VR, Hackshaw BT, Mills SA, Cordell R. Cardiac transplant in a patient with muscular dystrophy and cardiomyopathy. Arch Neurol. 1989;46:705-707.
35. Casazza F, Brambilla G, Salvato A, Morandi L, Grande E, Bonacina E. Dilated cardiomyopathy and successful cardiac transplantation in Becker's muscular dystrophy: follow-up after two years. G Ital Cardiol. 1988;18:753-757.[Medline] [Order article via Infotrieve]
36. Maeda M, Nakao S, Miyazato H, Setoguchi M, Arima S, Higuchi I, Osame M, Taira A, Nomoto K, Toda H, Tahata M, Atsuchi Y, Tanaka H. Cardiac dystrophin abnormalities in Becker muscular dystrophy assessed by endomyocardial biopsy. Am Heart J. 1995;129:702-707.[Medline] [Order article via Infotrieve]
37.
Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993;90:3710-3714.
38. Sandri M, Podhorska-Okolow M, Geromel V, Rizzi C, Arslan P, Franceschi C, Carraro U. Sudden spontaneous exercise increases myonuclear ubiquitination and apoptosis of dystrophin deficient muscle. Basic Appl Myol. 1996;6:285-289.
39. Krajinovic M, Pinamonti B, Sinagra G, Vatta M, Severini GM, Milasin J, Falaschi A, Camerini F, Giacca M, Mestroni L, Dilenarda A, Lardieri G, Morgera T, Silvestri F, Bussani R, Davanzo M, Meringolo G. Linkage of familial dilated cardiomyopathy to chromosome 9. Am J Hum Genet. 1995;57:846-852.[Medline] [Order article via Infotrieve]
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 B. Gavillet, J.-S. Rougier, A. A. Domenighetti, R. Behar, C. Boixel, P. Ruchat, H.-A. Lehr, T. Pedrazzini, and H. Abriel Cardiac Sodium Channel Nav1.5 Is Regulated by a Multiprotein Complex Composed of Syntrophins and Dystrophin Circ. Res., August 18, 2006; 99(4): 407 - 414. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Jefferies, B. W. Eidem, J. W. Belmont, W. J. Craigen, S. M. Ware, S. D. Fernbach, S. R. Neish, E. O. Smith, and J. A. Towbin Genetic Predictors and Remodeling of Dilated Cardiomyopathy in Muscular Dystrophy Circulation, November 1, 2005; 112(18): 2799 - 2804. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Y. Park, Y. Ahn, W. S. Park, J. H. Lim, H. W. Park, J. H. Kim, Y. J. Hong, W. Kim, M. H. Jeong, J. G. Cho, et al. Rapid progression from hypertrophic cardiomyopathy to heart failure in a patient with Becker's muscular dystrophy Eur J Heart Fail, June 1, 2005; 7(4): 684 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Varghese and D J Pennell Late gadolinium enhanced cardiovascular magnetic resonance in Becker muscular dystrophy Heart, September 1, 2004; 90(9): e59 - e59. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N Cohen and F Muntoni Multiple pathogenetic mechanisms in X linked dilated cardiomyopathy Heart, August 1, 2004; 90(8): 835 - 841. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yue, J. W. Skimming, M. Liu, T. Strawn, and D. Duan Full-length dystrophin expression in half of the heart cells ameliorates {beta}-isoproterenol-induced cardiomyopathy in mdx mice Hum. Mol. Genet., August 1, 2004; 13(15): 1669 - 1675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yue, Z. Li, S. Q. Harper, R. L. Davisson, J. S. Chamberlain, and D. Duan Microdystrophin Gene Therapy of Cardiomyopathy Restores Dystrophin-Glycoprotein Complex and Improves Sarcolemma Integrity in the Mdx Mouse Heart Circulation, September 30, 2003; 108(13): 1626 - 1632. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saotome, Y. Yoshitomi, S. Kojima, and M. Kuramochi Dilated Cardiomyopathy of Becker-Type Muscular Dystrophy with Exon 4 Deletion: A Case Report Angiology, May 1, 2001; 52(5): 343 - 347. [Abstract] [PDF]
|
|
|
|
 |
|
 E. Arbustini, M. Diegoli, P. Morbini, B. Dal Bello, N. Banchieri, A. Pilotto, F. Magani, M. Grasso, J. Narula, A. Gavazzi, et al. Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1760 - 1768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Badorff, N. Berkely, S. Mehrotra, J. W. Talhouk, R. E. Rhoads, and K. U. Knowlton Enteroviral Protease 2A Directly Cleaves Dystrophin and Is Inhibited by a Dystrophin-based Substrate Analogue J. Biol. Chem., April 6, 2000; 275(15): 11191 - 11197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Beggs Dystrophinopathy, The Expanding Phenotype: Dystrophin Abnormalities in X-Linked Dilated Cardiomyopathy Circulation, May 20, 1997; 95(10): 2344 - 2347. [Full Text]
|
|
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