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1.  Experimental Models of Duchenne Muscular Dystrophy: Relationship with Cardiovascular Disease 
Almost every boy that has Duchenne Muscular Dystrophy (DMD) will develop cardiac problems. Whereas, it used to be respiratory problems that was the main cause of death in these DMD boys; with the advent of better respiratory care it is now the cardiac involvement that is becoming the most common cause of their death. Once the heart is affected, there is progressive deterioration in the function of the heart over time. The main problem is the death of the cardiomyocytes. The cause of the cardiomyocyte death is due to the loss of dystrophin, this makes the sarcolemma more susceptible to damage, and leads to a cascade of calcium influx, calcium activated proteases and ultimately the death of the cardiomyocyte. The dead cardiomyocytes are replaced by fibrotic tissue, which results in a dilated cardiomyopathy (DCM) developing, which begins in the base of the left ventricle and progresses to involve the entire left ventricle. The treatments used for the DMD cardiomyopathy are based on ones designed for other forms of cardiac weakness and include ACE-inhibitors and β-blockers. New therapies based around the pathophysiology in DMD are now being introduced. This review will look at the pathophysiology of the cardiac problems in DMD and how the various animal models that are available can be used to design new treatment options for DMD boys.
PMCID: PMC3024556  PMID: 21258567
Cardiomyopathy; muscular dystrophy.
2.  AAV micro-dystrophin gene therapy alleviates stress-induced cardiac death but not myocardial fibrosis in >21-m-old mdx mice, an end-stage model of Duchenne muscular dystrophy cardiomyopathy 
Duchenne muscular dystrophy (DMD) is a fatal genetic disease caused by the absence of the sarcolemmal protein dystrophin. Dilated cardiomyopathy leading to heart failure is a significant source of morbidity and mortality in DMD. We recently demonstrated amelioration of DMD heart disease in 16 to 20-m-old dystrophin-null mdx mice using adeno-associated virus (AAV) mediated micro-dystrophin gene therapy. DMD patients show severe heart disease near the end of their life expectancy. Similarly, mdx mice exhibit profoundly worsening heart disease when they reach beyond 21 months of age. To more rigorously test micro-dystrophin therapy, we treated mdx mice that were between 21.2 to 22.7-m-old (average, 22.1 ± 0.2 months; N=8). The ΔR4-23/ΔC micro-dystrophin gene was packaged in the cardiotropic AAV-9 virus. 5 × 1012 viral genome particles/mouse were delivered to mdx mice via the tail vein. AAV transduction, myocardial fibrosis and heart function were examined 1.7 ± 0.2 months after gene therapy. Efficient micro-dystrophin expression was observed in the myocardium of treated mice. Despite the robust dystrophin expression, myocardial fibrosis was not mitigated. Most hemodynamic parameters were not improved either. However, ECG abnormalities were partially corrected. Importantly, treated mice became more resistant to dobutamine-induced cardiac death. In summary, we have revealed for the first time the potential benefits and limitations of AAV micro-dystrophin therapy in end-stage Duchenne dilated cardiomyopathy. Our findings have important implications for the use of AAV gene therapy in dilated cardiomyopathy and heart failure.
PMCID: PMC3389274  PMID: 22587991
Dilated cardiomyopathy; heart failure; gene therapy; Duchenne muscular dystrophy; dystrophin; AAV; Duchenne cardiomyopathy
3.  Injection of Vessel-Derived Stem Cells Prevents Dilated Cardiomyopathy and Promotes Angiogenesis and Endogenous Cardiac Stem Cell Proliferation in mdx/utrn−/− but Not Aged mdx Mouse Models for Duchenne Muscular Dystrophy 
It was hypothesized that mesoangioblast stem cells (aorta-derived mesoangioblasts [ADMs]) would restore dystrophin and alleviate or prevent dilated cardiomyopathy (DCM) in animal models of Duchenne muscular dystrophy (DMD). It was found that ADMs delay or prevent development of DCM in dystrophin-deficient heart, resulting in dystrophin expression, angiogenesis, stimulation of endogenous cardiac stem cell division, and the appearance of nestin+ cardiomyocytes of host origin. It was also found that timing of stem cell transplantation may be critical for achieving benefit with cell therapy in DMD cardiac muscle.
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy. DMD patients lack dystrophin protein and develop skeletal muscle pathology and dilated cardiomyopathy (DCM). Approximately 20% succumb to cardiac involvement. We hypothesized that mesoangioblast stem cells (aorta-derived mesoangioblasts [ADMs]) would restore dystrophin and alleviate or prevent DCM in animal models of DMD. ADMs can be induced to express cardiac markers, including Nkx2.5, cardiac tropomyosin, cardiac troponin I, and α-actinin, and adopt cardiomyocyte morphology. Transplantation of ADMs into the heart of mdx/utrn−/− mice prior to development of DCM prevented onset of cardiomyopathy, as measured by echocardiography, and resulted in significantly higher CD31 expression, consistent with new vessel formation. Dystrophin-positive cardiomyocytes and increased proliferation of endogenous Nestin+ cardiac stem cells were detected in ADM-injected heart. Nestin+ striated cells were also detected in four of five mdx/utrn−/− hearts injected with ADMs. In contrast, when ADMs were injected into the heart of aged mdx mice with advanced fibrosis, no functional improvement was detected by echocardiography. Instead, ADMs exacerbated some features of DCM. No dystrophin protein, increase in CD31 expression, or increase in Nestin+ cell proliferation was detected following ADM injection in aged mdx heart. Dystrophin was observed following transplantation of ADMs into the hearts of young mdx mice, however, suggesting that pathology in aged mdx heart may alter the fate of donor stem cells. In summary, ADMs delay or prevent development of DCM in dystrophin-deficient heart, but timing of stem cell transplantation may be critical for achieving benefit with cell therapy in DMD cardiac muscle.
PMCID: PMC3659745  PMID: 23283493
Cellular therapy; Muscular dystrophy; Angiogenesis; Cardiac; Cellular proliferation; Neural stem cell; Cell transplantation
4.  Dilated cardiomyopathy and the dystrophin gene: an illustrated review. 
British Heart Journal  1994;72(4):344-348.
Cardiomyopathy is often found in patients with Duchenne and Becker muscular dystrophy, which are X linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects present in many different ways and cases of mild Becker muscular dystrophy have been described in which cardiomyopathy was severe. Female carriers of Duchenne muscular dystrophy can develop symptomatic skeletal myopathy alone or combined with dilated cardiomyopathy. They can also develop dilated cardiomyopathy alone. X linked dilated cardiomyopathy has been found in association with dystrophin defects. The relation between the molecular defects and the cardiac phenotypes has not yet been established. New mutations in the dystrophin gene are common and such mutations cause one third of the cases with Duchenne and Becker muscular dystrophy. This means that sporadic cases of cardiomyopathy caused by dystrophin defects are likely. This paper reports such a case in a boy of 14 who died of dilated cardiomyopathy. Before the cardiac investigation, which was performed one month before he died, he had not complained of muscular weakness. He had minor signs of limb girdle myopathy and slightly increased concentrations of serum creatine kinase. He was found to have an unusual deletion in the dystrophin gene.
PMCID: PMC1025544  PMID: 7833192
5.  Early manifestation of alteration in cardiac function in dystrophin deficient mdx mouse using 3D CMR tagging 
Duchenne muscular dystrophy (DMD) is caused by the absence of the cytoskeletal protein, dystrophin. In DMD patients, dilated cardiomyopathy leading to heart failure may occur during adolescence. However, early cardiac dysfunction is frequently undetected due to physical inactivity and generalized debilitation. The objective of this study is to determine the time course of cardiac functional alterations in mdx mouse, a mouse model of DMD, by evaluating regional ventricular function with CMR tagging.
In vivo myocardial function was evaluated by 3D CMR tagging in mdx mice at early (2 months), middle (7 months) and late (10 months) stages of disease development. Global cardiac function, regional myocardial wall strains, and ventricular torsion were quantified. Myocardial lesions were assessed with Masson's trichrome staining.
Global contractile indexes were similar between mdx and C57BL/6 mice in each age group. Histology analysis showed that young mdx mice were free of myocardial lesions. Interstitial fibrosis was present in 7 month mdx mice, with further development into patches or transmural lesions at 10 months of age. As a result, 10 month mdx mice showed significantly reduced regional strain and torsion. However, young mdx mice showed an unexpected increase in regional strain and torsion, while 7 month mdx mice displayed similar regional ventricular function as the controls.
Despite normal global ventricular function, CMR tagging detected a biphasic change in myocardial wall strain and torsion, with an initial increase at young age followed by progressive decrease at older ages. These results suggest that CMR tagging can provide more sensitive measures of functional alterations than global functional indexes in dystrophin-related cardiomyopathies.
PMCID: PMC2774673  PMID: 19849858
6.  Ex Vivo Stretch Reveals Altered Mechanical Properties of Isolated Dystrophin-Deficient Hearts 
PLoS ONE  2012;7(3):e32880.
Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan-null and laminin-α2 mutant mice, but not in dysferlin-null mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.
PMCID: PMC3298453  PMID: 22427904
7.  Dystrophin analysis in idiopathic dilated cardiomyopathy. 
Journal of Medical Genetics  1993;30(11):955-957.
Idiopathic dilated cardiomyopathy (DCM) is characterised by ventricular dilatation and impaired systolic function resulting in congestive heart failure and frequently death. A dilated cardiomyopathy is common in patients with symptomatic Duchenne/Becker muscular dystrophy, a disease caused by dystrophin gene defects. However, cardiomyopathy is rarely the predominant clinical feature of this form of muscular dystrophy. To determine whether dystrophin gene defects might account for a significant number of patients with apparently isolated idiopathic DCM, we performed dystrophin gene analysis in 27 DCM patients, who were ascertained as part of a prospective study on idiopathic DCM. No dystrophin gene defects were found in our patients, whose average age was 50 years. These data suggest that dystrophin defects are not a common cause of idiopathic DCM in this age group in the absence of skeletal muscle cramps or weakness.
PMCID: PMC1016607  PMID: 8301653
8.  Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers† 
Cardiovascular Research  2009;85(3):444-453.
The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in ∼30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proved promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment.
Methods and results
Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5–6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (<1% present after 12 weeks by immunodetection), PPMO therapy also provided a durable cardiac improvement in cardiac hypertrophy and diastolic dysfunction for up to 7 months after the initiation of treatment.
These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.
PMCID: PMC2802205  PMID: 19815563
Duchenne muscular dystrophy; Morpholino; Oligomers; Cardiomyopathy; Therapy; Exon skipping; Alternative RNA splicing
9.  Characteristics and Outcomes of Cardiomyopathy in Children with Duchenne or Becker Muscular Dystrophy: A Comparative Study from The Pediatric Cardiomyopathy Registry 
American heart journal  2008;155(6):998-1005.
To determine in pediatric Duchenne (DMD) and Becker (BMD) muscular dystrophy or other dilated cardiomyopathies (ODCM) whether outcomes differ by diagnosis.
Children with dilated cardiomyopathy are treated as a single undifferentiated group.
This cohort study of 128 children with DMD, 15 with BMD, and 312 with ODCM uses outcome measures of LV size and function, death, heart transplant, and death or transplant.
At cardiomyopathy diagnosis, the DMD and BMD groups had similar mean ages (14.4 and 14.6 years), prevalence of CHF (30% and 33%), and LV fractional shortening (FS) z-scores (median, −5.2 for DMD and −6.7 for BMD). The BMD group had more severe mitral regurgitation (P=.05) and a higher mean LV end-diastolic dimension Z-score than the DMD group (2.9±1.5 vs. 1.2±1.9, P=.002). DMD group survival was lower than in BMD or ODCM groups (P=.06) at 5-years (57%, 100%, and 71% respectively). In BMD, 25% received cardiac transplants within 0.4 years of cardiomyopathy diagnosis. The combined DMD and BMD group had less LV dilation and a closer-to-normal LVFS at cardiomyopathy diagnosis than the ODCM group. After 2 years, LV dilation increased and LVFS did not change in the combined DMD and BMD group; for OCDM patients, LV dilation did not progress and LVFS improved.
Children with DMD and cardiomyopathy have a higher mortality. BMD has a high heart transplantation rate in the 5 years after diagnosis of cardiomyopathy. Serial echocardiography demonstrates a different disease course for DMD and BMD patients compared with ODCM patients.
PMCID: PMC2729548  PMID: 18513510
Muscular dystrophy; neuromuscular disease; cardiomyopathy; heart failure; pediatric; Duchenne; Becker
10.  Cardiac involvement in Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ): electrocardiographic, echocardiographic, and morphologic studies 
Cardiac mortality in Duchenne muscular dystrophy (DMD) has recently become important, because risk of respiratory failure has been reduced due to widespread use of the respirator. The cardiac involvement is characterized by distinctive electrocardiographic abnormalities or dilated cardiomyopathy, but the pathogenesis has remained obscure. In research on DMD, Golden retriever-based muscular dystrophy (GRMD) has attracted much attention as an animal model because it resembles DMD, but GRMD is very difficult to maintain because of their severe phenotypes. We therefore established a line of dogs with Beagle-based canine X-linked muscular dystrophy in Japan (CXMDJ) and examined the cardiac involvement.
The cardiac phenotypes of eight CXMDJ and four normal male dogs 2 to 21 months of age were evaluated using electrocardiography, echocardiography, and histopathological examinations.
Increases in the heart rate and decreases in PQ interval compared to a normal littermate were detected in two littermate CXMDJ dogs at 15 months of age or older. Distinct deep Q-waves and increase in Q/R ratios in leads II, III, and aVF were detected by 6–7 months of age in all CXMDJ dogs. In the echocardiogram, one of eight of CXMDJ dogs showed a hyperechoic lesion in the left ventricular posterior wall at 5 months of age, but the rest had not by 6–7 months of age. The left ventricular function in the echocardiogram indicated no abnormality in all CXMDJ dogs by 6–7 months of age. Histopathology revealed myocardial fibrosis, especially in the left ventricular posterobasal wall, in three of eight CXMDJ dogs by 21 months of age.
Cardiac involvement in CXMDJ dogs is milder and has slower progression than that described in GRMD dogs. The distinct deep Q-waves have been ascribed to myocardial fibrosis in the posterobasal region of the left ventricle, but our data showed that they precede the lesion on echocardiogram and histopathology. These findings imply that studies of CXMDJ may reveal not only another causative mechanism of the deep Q-waves but also more information on the pathogenesis in the dystrophin-deficient heart.
PMCID: PMC1698931  PMID: 17140458
11.  Chronic administration of membrane sealant prevents severe cardiac injury and ventricular dilatation in dystrophic dogs 
The Journal of Clinical Investigation  2010;120(4):1140-1150.
Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration caused by lack of the cytoskeletal protein dystrophin. Dystrophin deficiency causes muscle membrane instability, skeletal muscle wasting, cardiomyopathy, and heart failure. Advances in palliative respiratory care have increased the incidence of heart disease in DMD patients, for which there is no cure or effective therapy. Here we have shown that chronic infusion of membrane-sealing poloxamer to severely affected dystrophic dogs reduced myocardial fibrosis, blocked increased serum cardiac troponin I (cTnI) and brain type natriuretic peptide (BNP), and fully prevented left-ventricular remodeling. Mechanistically, we observed a markedly greater primary defect of reduced cell compliance in dystrophic canine myocytes than in the mildly affected mdx mouse myocytes, and this was associated with a lack of utrophin upregulation in the dystrophic canine cardiac myocytes. Interestingly, after chronic poloxamer treatment, the poor compliance of isolated canine myocytes remained evident, but this could be restored to normal upon direct application of poloxamer. Collectively, these findings indicate that dystrophin and utrophin are critical to membrane stability–dependent cardiac myocyte mechanical compliance and that poloxamer confers a highly effective membrane-stabilizing chemical surrogate in dystrophin/utrophin deficiency. We propose that membrane sealant therapy is a potential treatment modality for DMD heart disease and possibly other disorders with membrane defect etiologies.
PMCID: PMC2846060  PMID: 20234088
12.  Full-length dystrophin expression in half of the heart cells ameliorates β-isoproterenol-induced cardiomyopathy in mdx mice 
Human molecular genetics  2004;13(15):1669-1675.
Gene therapy holds great promise for curing Duchenne muscular dystrophy (DMD), the most common fatal inherited childhood muscle disease. Success of DMD gene therapy depends upon functional improvement in both skeletal and cardiac muscle. Numerous gene transfer studies have been performed to correct skeletal muscle pathology, yet little is known about cardiomyopathy gene therapy. Since complete transduction of the entire heart is an impractical goal, it becomes critical to determine the minimal level of correction needed for successful DMD cardiomyopathy gene therapy. To address this question, we generated heterozygous mice that persistently expressed the full-length dystrophin gene in 50% of the cardiomyocytes of mdx mice, a model for DMD. We questioned whether dystrophin expression in half of the heart cells was sufficient to prevent stress-induced cardiomyopathy. Heart function of mdx mouse is normal in the absence of external stress. To determine the therapeutic effect, we challenged 3-month-old mice with β-isoproterenol. Cardiomyocyte sarcolemma integrity was significantly impaired in mdx but not in heterozygous and C57Bl/10 mice. Importantly, in vivo closed-chest hemodynamic assays revealed normal left ventricular function in β-isoproterenol-stimulated heterozygous mice. Since the expression profile in the heterozygous mice mimicked viral transduction, we conclude that gene therapy correction in 50% of the heart cells may be sufficient to treat cardiomyopathy in mdx mice. This finding may also apply to the gene therapy of other inherited cardiomyopathies.
PMCID: PMC2431460  PMID: 15190010
13.  Emergent Dilated Cardiomyopathy Caused by Targeted Repair of Dystrophic Skeletal Muscle 
Duchenne muscular dystrophy (DMD) is a fatal disease characterized by deterioration of striated muscle, affecting skeletal and cardiac muscles. Recently, several therapeutic approaches have shown promise for repairing dystrophic skeletal muscles. However, these methods often leave the dystrophic heart untreated. Here we show that, in comparison to fully dystrophin-deficient animals, targeted transgenic repair of skeletal muscle, but not cardiac muscle, in otherwise dystrophin-deficient (mdx) mice paradoxically elicited a fivefold increase in cardiac injury and dilated cardiomyopathy in these animals in vivo. Skeletal muscle repair was shown to increase the voluntary activity of the mdx mice as quantified by voluntary running on the exercise wheel. Because the dystrophin-deficient heart is highly sensitive to increased stress, we hypothesize that increased activity (enabled by the repaired skeletal muscle) provided the stimulus for heightened cardiac injury and heart remodeling. In support of this hypothesis, the primary cellular compliance defect in dystrophin-deficient cardiac myocytes was found to be unchanged by skeletal muscle repair in the mdx mice. These findings provide new information on the evolution of cardiac disease in dystrophin-deficient animals and underscore the importance of implementing global striated muscle therapies for muscular dystrophy.
PMCID: PMC2592846  PMID: 18414480
14.  An unusual case of left ventricular aneurysm in duchenne muscular dystrophy 
Duchenne muscular dystrophy (DMD) leads to structural heart disease, including dilated cardiomyopathy, in 90% of patients >18 years of age. Despite the ubiquity of cardiomyopathy associated with DMD, ventricular aneurysms in these patients have rarely been reported. We present a case of a basal inferoposterior aneurysm of the left ventricle in a 23-year-old male patient with DMD.
PMCID: PMC3000834  PMID: 21073752
15.  Dystrophin deficient cardiomyopathy in mouse: Expression of Nox4 and Lox are associated with fibrosis and altered functional parameters in the heart 
Neuromuscular disorders : NMD  2008;18(5):371-381.
Duchenne muscular dystrophy (DMD; dystrophin-deficiency) causes dilated cardiomyopathy in the second decade of life in affected males. We studied the dystrophin-deficient mouse heart (mdx) using high frequency echocardiography, histomorphometry, and gene expression profiling. Heart dysfunction was prominent at 9-10 months of age and showed significantly increased LV internal diameter (end systole) and decreased posterior wall thickness. This cardiomyopathy was associated with a 30% decrease in shortening fraction. Histologically, there was a 10-fold increase in connective tissue volume (fibrosis). mRNA profiling with RT-PCR validation showed activation of key pro-fibrotic genes, including Nox4 and Lox. The Nox gene family expression differed in mdx heart and skeletal muscle, where Nox2 was specifically induced in skeletal muscle while Nox4 was specifically induced in heart. This is the first report of an altered profibrotic gene expression profile in cardiac tissue of dystrophic mice showing echocardiographic evidence of cardiomyopathy.
PMCID: PMC2430663  PMID: 18440230
Duchenne muscular dystrophy; cardiomyopathy; echocardiography; mouse; Nox4; Lox
16.  Progress in gene therapy of dystrophic heart disease 
Gene therapy  2012;19(6):678-685.
The heart is frequently afflicted in muscular dystrophy. In severe cases, cardiac lesion may directly result in death. Over the years, pharmacological and/or surgical interventions have been the mainstay to alleviate cardiac symptoms in muscular dystrophy patients. Although these traditional modalities remain useful, the emerging field of gene therapy has now provided an unprecedented opportunity to transform our thinking/approach in the treatment of dystrophic heart disease. In fact, the premise is already in place for genetic correction. Gene mutations have been identified and animal models are available for several types of muscular dystrophy. Most importantly, innovative strategies have been developed to effectively deliver therapeutic genes to the heart. Dystrophin-deficient Duchenne cardiomyopathy is associated with Duchenne muscular dystrophy (DMD), the most common lethal muscular dystrophy. Considering its high incidence, there has been a considerable interest and significant input in the development of Duchenne cardiomyopathy gene therapy. Using Duchenne cardiomyopathy as an example, here we illustrate the struggles and successes experienced in the burgeoning field of dystrophic heart disease gene therapy. In light of abundant and highly promising data with the adeno-associated virus (AAV) vector, we have specially emphasized on AAV-mediated gene therapy. Besides DMD, we have also discussed gene therapy for treating cardiac diseases in other muscular dystrophies such as limb-girdle muscular dystrophy.
PMCID: PMC3628728  PMID: 22318092
muscular dystrophy; heart; cardiomyopathy; Duchenne muscular dystrophy; dystrophin; sarcoglycan
17.  Cardiomyopathy in the dystrophin/utrophin-deficient mouse model of severe muscular dystrophy is characterized by dysregulation of matrix metalloproteinases 
Neuromuscular disorders : NMD  2012;22(11):1006-1014.
Cardiomyopathy is a significant component in Duchenne muscular dystrophy. Although mdx mice are deficient in dystrophin, they only develop mild indicators of cardiomyopathy before 1 year-of-age, making therapeutic investigations using this model lengthy. In contrast, mdx mice also lacking utrophin (utrn−/−;mdx) show severely reduced cardiac contractile function and histological indicators of cardiomyopathy by 8–10 weeks-of-age. Here we demonstrate that utrn−/−;mdx mice show a similar pattern of cardiac damage to that in dystrophic patients. Matrix metalloproteinases required for ventricular remodeling during the evolution of heart failure are upregulated in utrn−/−;mdx mice concurrent with the onset of cardiac pathology by 10 weeks-of-age. Matrix metalloproteinase activity is further dysregulated due to reduced levels of endogenous tissue inhibitors and co-localizes with fibroblasts and collagen I-containing scars. utrn−/−;mdx mice are therefore a very useful model for investigating potential cardiac therapies.
PMCID: PMC3484217  PMID: 22749475
cardiomyopathy; heart failure; Duchenne muscular dystrophy; mdx; utrophin; matrix metalloproteinases; MMPs; tissue inhibitors of matrix metalloproteinases; TIMP; remodeling; MMP-9; TIMP-2
18.  AAV-9 micro-dystrophin gene therapy ameliorates electrocardiographic abnormalities in mdx mice 
Human gene therapy  2008;19(8):851-856.
Adeno-associated virus (AAV) mediated micro-dystrophin gene therapy holds great promise for treating Duchenne muscular dystrophy (DMD). Previous studies have revealed excellent skeletal muscle protection. Cardiac muscle is also compromised in DMD patients. Here we show that a single intravenous injection of AAV serotype-9 (AAV-9) micro-dystrophin vector efficiently transduced the entire heart in neonatal mdx mice, a dystrophin-deficient mouse DMD model. Furthermore, micro-dystrophin therapy normalized the heart rate, PR interval and QT interval. Cardiomyopathy index was also significantly improved in treated mdx mice. Our study demonstrates for the first time that AAV micro-dystrophin gene therapy can ameliorate the electrocardiographic abnormalities in a mouse model for DMD.
PMCID: PMC2888653  PMID: 18666839
19.  Cardiac assessment of patients with late stage Duchenne muscular dystrophy 
Netherlands Heart Journal  2009;17(6):232-237.
Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.
Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.
Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.
Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.19789685)
PMCID: PMC2711248  PMID: 19789685
natriuretic peptides; echocardiography; multigated radionuclide ventriculography; cardiomyopathy; home mechanical ventilation; Duchenne muscular dystrophy
20.  Challenges and opportunities in dystrophin-deficient cardiomyopathy gene therapy 
Human molecular genetics  2006;15(SPEC):R253-R261.
The last decade has evidenced unprecedented progress in gene therapy of Duchenne and Becker muscular dystrophy (DMD and BMD) skeletal muscle disease. Cardiomyopathy is a leading cause of morbidity and mortality in both patients and carriers of DMD, BMD and X-linked dilated cardiomyopathy. However, there is little advance in heart gene therapy. The gene, the vector, vector delivery, the target tissue and animal models are five fundamental components in developing an effective gene therapy. Intensive effort has been made in optimizing gene transfer vectors and methods. Systemic and/or local delivery of recombinant adeno-associated viral vector have resulted in widespread transduction in the rodent heart. The current challenge is to define other parameters that are essential for a successful gene therapy such as the best candidate gene(s), the optimal expression level and the target tissue. This review focuses on these long-ignored aspects and points out future research directions. In particular, we need to address whether all or only some of the recently developed mini- and microgenes are protective in the heart, whether partial correction can lead to whole heart function improvement, whether over-expression is hazardous and whether correcting skeletal muscle disease can slow down or stop the progression of cardiomyopathy. Discussion is also made on whether the current mouse models can meet these research needs.
PMCID: PMC2581718  PMID: 16987891
21.  Mutational Spectrum of DMD Mutations in Dystrophinopathy Patients: Application of Modern Diagnostic Techniques to a Large Cohort 
Human Mutation  2009;30(12):1657-1666.
Mutations in the DMD gene, encoding the dystrophin protein, are responsible for the dystrophinopathies Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and X-linked Dilated Cardiomyopathy (XLDC). Mutation analysis has traditionally been challenging, due to the large gene size (79 exons over 2.2 Mb of genomic DNA). We report a very large aggregate data set comprised of DMD mutations detected in samples from patients enrolled in the United Dystrophinopathy Project, a multicenter research consortium, and in referral samples submitted for mutation analysis with a diagnosis of dystrophinopathy. We report 1111 mutations in the DMD gene, including 891 mutations with associated phenotypes. These results encompass 506 point mutations (including 294 nonsense mutations) and significantly expand the number of mutations associated with the dystrophinopathies, highlighting the utility of modern diagnostic techniques. Our data supports the uniform hypermutability of CGA>TGA mutations, establishes the frequency of polymorphic muscle (Dp427m) protein isoforms and reveals unique genomic haplotypes associated with `private' mutations. We note that 60% of these patients would be predicted to benefit from skipping of a single DMD exon using antisense oligonucleotide therapy, and 62% would be predicted to benefit from an inclusive multi-exon skipping approach directed toward exons 45 through 55.
PMCID: PMC3404892  PMID: 19937601
dystrophinopathy; Duchenne Muscular Dystrophy; DMD; Becker Muscular Dystrophy; BMD; mutation detection
22.  Adeno-Associated Virus Serotype-9 Microdystrophin Gene Therapy Ameliorates Electrocardiographic Abnormalities in mdx Mice 
Human Gene Therapy  2008;19(8):851-856.
Adeno-associated virus (AAV)-mediated microdystrophin gene therapy holds great promise for treating Duchenne muscular dystrophy (DMD). Previous studies have revealed excellent skeletal muscle protection. Cardiac muscle is also compromised in DMD patients. Here we show that a single intravenous injection of AAV serotype-9 (AAV-9) microdystrophin vector efficiently transduced the entire heart in neonatal mdx mice, a dystrophin-deficient mouse DMD model. Furthermore, microdystrophin therapy normalized the heart rate, PR interval, and QT interval. The cardiomyopathy index was also significantly improved in treated mdx mice. Our study demonstrates for the first time that AAV microdystrophin gene therapy can ameliorate the electrocardiographic abnormalities in a mouse model for DMD.
PMCID: PMC2888653  PMID: 18666839
23.  Cardiac Expression of a Mini-dystrophin That Normalizes Skeletal Muscle Force Only Partially Restores Heart Function in Aged Mdx Mice 
Duchenne muscular dystrophy (DMD) affects both skeletal and cardiac muscle. It is currently unclear whether the strategies developed for skeletal muscle can ameliorate cardiomyopathy. Synthetic mini-/micro-dystrophin genes have yielded impressive skeletal muscle protection in animal models. The 6-kb ΔH2-R19 minigene is particularly promising because it completely restores skeletal muscle force to wild-type levels. Here, we examined whether expressing this minigene in the heart, but not skeletal muscle, could normalize cardiac function in the mdx model of DMD cardiomyopathy. Transgenic mdx mice were generated to express the ΔH2-R19 minigene under the control of the α-myosin heavy-chain promoter. Heart structure and function were examined in adult and very old mice. The ΔH2-R19 minigene enhanced cardiomyocyte sarcolemmal strength and prevented myocardial fibrosis. It also restored the dobutamine response and enhanced treadmill performance. Surprisingly, heart-restricted ΔH2-R19 minigene expression did not completely normalize electrocardiogram and hemodynamic abnormalities. Overall, systolic function and ejection fraction were restored to normal levels but stroke volume and cardiac output remained suboptimal. Our results demonstrate that the skeletal muscle–proven ΔH2-R19 minigene can correct cardiac histopathology but cannot fully normalize heart function. Novel strategies must be developed to completely restore heart function in DMD.
PMCID: PMC2714701  PMID: 19066599
24.  Left ventricular T2 distribution in Duchenne Muscular Dystrophy 
Although previous studies have helped define the natural history of Duchenne Muscular Dystrophy (DMD)-associated cardiomyopathy, the myocardial pathobiology associated with functional impairment in DMD is not yet known.
The objective of this study was to assess the distribution of transverse relaxation time (T2) in the left ventricle (LV) of DMD patients, and to determine the association of myocardial T2 heterogeneity to the severity of cardiac dysfunction. DMD patients (n = 26) and normal control subjects (n = 13) were studied by Cardiovascular Magnetic Resonance (CMR). DMD subject data was stratified based on subject age and LV Ejection Fraction (EF) into the following groups: A (<12 years old, n = 12); B (≥12 years old, EF ≤ 55%, n = 8) and C (≥12 years old, EF = 55%, n = 6). Controls were also stratified by age into Groups N1 (<12 years, n = 6) and N2 (>12 years, n = 5). LV mid-slice circumferential myocardial strain (εcc) was calculated using tagged CMR imaging. T2 maps of the LV were generated for all subjects using a black blood dual spin echo method at two echo times. The Full Width at Half Maximum (FWHM) was calculated from a histogram of LV T2 distribution constructed for each subject.
In DMD subject groups, FWHM of the T2 histogram rose progressively with age and decreasing EF (Group A FWHM= 25.3 ± 3.8 ms; Group B FWHM= 30.9 ± 5.3 ms; Group C FWHM= 33.0 ± 6.4 ms). Further, FWHM was significantly higher in those with reduced circumferential strain (|εcc| ≤ 12%) (Group B, and C) than those with |εcc| > 12% (Group A). Group A FWHM was not different from the two normal groups (N1 FWHM = 25.3 ± 3.5 ms; N2 FWHM= 24.0 ± 7.3 ms).
Reduced EF and εcc correlates well with increased T2 heterogeneity quantified by FWHM, indicating that subclinical functional impairments could be associated with pre-existing abnormalities in tissue structure in young DMD patients.
PMCID: PMC2846924  PMID: 20298602
25.  Multiple pathogenetic mechanisms in X linked dilated cardiomyopathy 
Heart  2004;90(8):835-841.
X linked dilated cardiomyopathy is a familial disease that is allelic to Duchenne and Becker muscular dystrophies and caused by mutations in the dystrophin gene. In several families with X linked dilated cardiomyopathy, the pattern of expression of dystrophin mutations in cardiac muscle differs from that in skeletal muscle. A number of these mutations affect transcription and splicing of the dystrophin gene in a tissue specific manner; others may affect regions of dystrophin that are presumed to have a more important role in cardiac than in skeletal muscle. These mutations are important because they highlight the fundamental differences in processing of the dystrophin gene between skeletal and cardiac tissues, as well as differences in the functional domains more relevant for one tissue or the other. This review focuses on the major mechanisms that have been proposed to explain this disorder.
PMCID: PMC1768363  PMID: 15253946
dystrophin; X linked dilated cardiomyopathy; splicing; protein domains

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