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.
Muscular dystrophy; neuromuscular disease; cardiomyopathy; heart failure; pediatric; Duchenne; Becker
Posterior instrumented spinal fusion is indicated for progressive scoliosis that develops in Duchenne muscular dystrophy (DMD) patients. Whilst spinal fusion is known to improve quality of life, there is inconsistency amongst the literature regarding its specific effect on respiratory function. Our objective was to determine the effect of scoliosis correction by posterior spinal fusion on respiratory function in a large cohort of patients with DMD. Patients with DMD undergoing posterior spinal fusion were compared to patients with DMD not undergoing surgical intervention.
An observational study of 65 patients with DMD associated scoliosis, born between 1961 and 2001: 28 of which underwent correction of scoliosis via posterior spinal fusion (Surgical Group) and 37 of which did not undergo surgical intervention (Non-Surgical Group). Pulmonary function was assessed using traditional spirometry. Comparisons were made between groups at set times, and by way of rates of change over time.
There was no correlation between the level of respiratory dysfunction and the severity of scoliosis (as measured by Cobb angle) for the whole cohort. The Surgical Group had significantly worse respiratory function at a comparable age pre-operatively compared to the Non-Surgical Group, as measured by per cent predicted forced vital capacity (p = 0.02) on spirometry. The rate of decline of forced vital capacity and per cent predicted forced vital capacity was not slowed following surgery compared to the non-operated cases. There was no significant difference in survival between the two groups.
Severity of scoliosis was not a key determinant of respiratory dysfunction. Posterior spinal fusion did not reduce the rate of respiratory function decline. These two points suggest that intrinsic respiratory muscle weakness is the main determinant of decline in respiratory function in DMD.
Duchenne muscular dystrophy; Dystrophin; Respiratory function; Spirometry; Scoliosis; Surgical intervention
To determine the survival in a population of German patients with Duchenne muscular dystrophy.
Patients and methods:
Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected.
67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years.
Conclusion and clinical relevance:
our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.
duchenne muscular dystrophy; survival; ventilation
BACKGROUND—Respiratory failure is the commonest
cause of death in patients with Duchenne muscular dystrophy (DMD). Life
expectancy is less than one year once diurnal hypercapnia develops.
This study examines the effects of nasal intermittent positive pressure
ventilation (NIPPV) on survival in symptomatic Duchenne patients with
established ventilatory failure.
METHODS—Nocturnal NIPPV was applied in 23 consecutive patients with DMD of mean (SD) age 20.3 (3.4) years who
presented with diurnal and nocturnal hypercapnia.
RESULTS—One year and five year survival rates were
85% (95% CI 69 to 100) and 73% (95% CI 53 to 94), respectively.
Early changes in arterial blood gas tensions following NIPPV occurred
with mean (SD) PO2 increasing from 7.6 (2.1) kPa to 10.8 (1.3) kPa and mean (SD)
PCO2 falling from 10.3 (4.5) kPa to 6.1 (1.0) kPa. Improvements in arterial blood gas tensions were maintained
over five years. Health perception and social aspects of SF-36 health
related quality of life index were reported as equivalent to other
groups with non-progressive disorders using NIPPV.
CONCLUSION—Nasal ventilation is likely to increase
survival in hypercapnic patients with Duchenne muscular dystrophy and
should be considered as a treatment option when ventilatory failure develops.
Almost all patients with Duchenne muscular dystrophy (DMD) eventually develop respiratory failure. Once 24 h ventilation is required, either due to incomplete effectiveness of nocturnal noninvasive ventilation (NIV) or bulbar weakness, it is common practice to recommend invasive tracheostomy ventilation; however, noninvasive daytime mouthpiece ventilation (MPV) as an addition to nocturnal mask ventilation is also an alternative.
The authors’ experience with 12 DMD patients who used 24 h NIV with mask NIV at night and MPV during daytime hours is reported.
The mean (± SD) age and vital capacity (VC) at initiation of nocturnal (only) NIV subjects were 17.8±3.5 years and 0.90±0.40 L (21% predicted), respectively; and, at the time of MPV, 19.8±3.4 years and 0.57 L (13.2% predicted), respectively. In clinical practice, carbon dioxide (CO2) levels were measured using different methods: arterial blood gas analysis, transcutaneous partial pressure of CO2 and, predominantly, by end-tidal CO2. While the results suggested improved CO2 levels, these were not frequently confirmed by arterial blood gas measurement. The mean survival on 24 h NIV has been 5.7 years (range 0.17 to 12 years). Of the 12 patients, two deaths occurred after 3.75 and four years, respectively, on MPV; the remaining patients continue on 24 h NIV (range two months to 12 years; mean 5.3 years; median 3.5 years).
Twenty-four hour NIV should be considered a safe alternative for patients with DMD because its use may obviate the need for tracheostomy in patients with chronic respiratory failure requiring more than nocturnal ventilation alone.
Duchenne; Lung volume recruitment; Neuromuscular; Noninvasive ventilation; Ventilation
The various measures used to treat the symptoms of Duchenne muscular dystrophy (DMD), i.e. medication with steroids, early operation on contractures and spine deformities as well as cardiac diagnostics and therapy, should always be accompanied by careful monitoring of the patient's respiratory status. Therapy for respiratory failure, in particular long-term ventilation, is now generally accepted as essential for DMD patients. The provision of assisted ventilation has made a decisive contribution to the quality of life for older patients and the stigma hitherto attached to it as being merely a means of keeping a patient comfortable towards the end of life has now been dispelled. Even outside the hospital, assisted ventilation has become routine. These days it is not uncommon for patients on assisted ventilation to have their life extended by 10 years or more.
Non-invasive ventilation is sufficient if used concomitantly with coughing aids. Before undergoing orthopaedic surgery the patient' s respiratory status has to be carefully assessed in order to minimize the risk of perioperative complications. Feeding and swallowing problems may develop if the patient has a scoliosis of the cervical spine region, even if he has had thoraco-lumbar spine surgery. There is still insufficient awareness of this potential problem in relation to respiratory care.
Interdisciplinary collaboration between hospitals, general practitioners, muscle and respiratory centres, as well as advocacies and self-help groups is vital. The administration of aids to support DMD patients is now facilitated by guidelines drawn up by several centres of excellence. Here we mainly describe the historic development of respiratory care at the Ulm Neuromuscular Centre.
Duchenne muscular dystrophy; respiratory failure; non-invasive ventilation; increased survival
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)
natriuretic peptides; echocardiography; multigated radionuclide ventriculography; cardiomyopathy; home mechanical ventilation; Duchenne muscular dystrophy
To explore clinical heterogeneity of Duchenne muscular dystrophy (DMD), viewed as a major obstacle to the interpretation of therapeutic trials
A retrospective single institution long-term follow-up study was carried out in DMD patients with both complete lack of muscle dystrophin and genotyping. An exploratory series (series 1) was used to assess phenotypic heterogeneity and to identify early criteria predicting future outcome; it included 75 consecutive steroid-free patients, longitudinally evaluated for motor, respiratory, cardiac and cognitive functions (median follow-up: 10.5 yrs). A validation series (series 2) was used to test robustness of the selected predictive criteria; it included 34 more routinely evaluated patients (age>12 yrs). Multivariate analysis of series 1 classified 70/75 patients into 4 clusters with distinctive intellectual and motor outcomes: A (early infantile DMD, 20%): severe intellectual and motor outcomes; B (classical DMD, 28%): intermediate intellectual and poor motor outcome; C (moderate pure motor DMD, 22%): normal intelligence and delayed motor impairment; and D (severe pure motor DMD, 30%): normal intelligence and poor motor outcome. Group A patients had the most severe respiratory and cardiac involvement. Frequency of mutations upstream to exon 30 increased from group A to D, but genotype/phenotype correlations were restricted to cognition (IQ>71: OR 7.7, 95%CI 1.6–20.4, p<0.003). Diagnostic accuracy tests showed that combination of “clinical onset <2 yrs” with “mental retardation” reliably assigned patients to group A (sensitivity 0.93, specificity 0.98). Combination of “lower limb MMT score>6 at 8 yrs” with “normal or borderline mental status” reliably assigned patients to group C (sensitivity: 1, specificity: 0.94). These criteria were also predictive of “early infantile DMD” and “moderate pure motor DMD” in series 2.
DMD can be divided into 4 sub-phenotypes differing by severity of muscle and brain dysfunction. Simple early criteria can be used to include patients with similar outcomes in future therapeutic trials.
Cloned cDNA sequences representing exons from the Duchenne/Becker muscular dystrophy (DMD/BMD) gene were used for deletion screening in a population of 287 males males affected with DMD or BMD. The clinical phenotypes of affected boys were classified into three clinical severity groups based on the age at which ambulation was lost. Boys in group 1 had DMD, losing ambulation before their 13th birthday; those in group 2 had disease of intermediate severity, losing ambulation between the ages of 13 and 16 years; and boys in group 3 had BMD, being ambulant beyond 16 years. A fourth group consisted of patients too young to be classified. Clinical group allocation was made without previous knowledge of the DNA results. A gene deletion was found in 124 cases where the clinical severity group of the affected boy was known. The extent of the deletions was delineated using cDNA probes. There were 74 different deletions. Fifty-five of these were unique to individual patients, but the other 19 were found in at least two unrelated patients. The different clinical groups showed generally similar distributions of deletions, and the number of exon bands deleted (that is, deletion size) was independent of phenotype. Some specific deletion types, however, correlated with the clinical severity of the disease. Deletion of exons containing HindIII fragments 33 and 34 and 33 to 35 were associated with BMD and were not found in patients with DMD. Deletions 3 to 7 occurred in four patients with the intermediate phenotype and one patient with BMD. Other shared deletions were associated with DMD, although in four cases patients with disease of intermediate severity apparently shared the same deletion with boys with DMD. The range of phenotypes observed, and the overlap at the genetic level between severe and intermediate and mild and intermediate forms of dystrophy, emphasizes the essential continuity of the clinical spectrum of DMD/BMD. There were no characteristic deletions found in boys with mental retardation or short stature which differed from deletions in affected boys without these features.
Duchenne muscular dystrophy (DMD), caused by mutations in the dystrophin gene, is a common and lethal form of muscular dystrophy. With progressive disease, most patients succumb to death from respiratory and/or heart failure. However, the mechanisms, especially those governing cardiac inflammation and fibrosis in DMD, remain less well understood. Matrix metalloproteinase (MMPs) are a group of extracellular matrix proteases involved in tissue remodelling in both physiological and pathophysiological conditions. Previous studies have shown that MMP-9 exacerbates myopathy in dystrophin-deficient mdx mice. However, the role and the mechanisms of action of MMP-9 in cardiac tissue and the biochemical mechanisms leading to increased levels of MMP-9 in mdx mice remain unknown. Our results demonstrate that the levels of MMP-9 are increased in heart of mdx mice. Genetic ablation of MMP-9 attenuated cardiac injury, left ventricle dilation, and fibrosis in one-year old mdx mice. Echocardiography measurements showed improved heart function in Mmp9-deficient mdx mice. Deletion of Mmp9 gene diminished the activation of extracellular-regulated kinase ½ and Akt kinase in heart of mdx mice. Ablation of MMP-9 also suppressed the expression of MMP-3 and MMP-12 in heart of mdx mice. Finally, our experiments have revealed that osteopontin, an important immunomodulator, contributes to the increased amounts of MMP-9 in cardiac and skeletal muscle of mdx mice. This study provides a novel mechanism for development of cardiac dysfunction and suggests that MMP-9 and OPN are important therapeutic targets to mitigating cardiac abnormalities in DMD patients.
Currently, there is no cure for Duchenne and Becker muscular dystrophies (DMD/BMD). However, clinical trials with new therapeutic strategies are being conducted or considered. A comprehensive database is critical for patient recruitment and efficacy evaluation. China has the largest population, yet, no comprehensive database for DMD/BMD is available. Our study registered the data of the DMD/BMD patients in East China.
A modified registry form of Remudy (http://www.remudy.jp/) was applied to Chinese DMD/BMD patients through the outpatient clinic at Children’s Hospital of Fudan University, Shanghai during the period of August 2011 to December 2013. The data included geographic distribution of patients, age at diagnosis, clinical manifestation, genetic analysis and treatment status.
194 DMD and 35 BMD patients were registered. Most patients lived in East China, namely Jiangsu province, Anhui province, Zhejiang province, Jiangxi province, Shanghai, Fujian province and Shandong province. All individuals aged less than 18 years (age limit to a children’s hospital). Diagnosis was made for a majority of patients during the age of 3–4 (16.6%) and 7–8 (14.8%) years old. Exon deletion was the most frequent genetic mutations (65.5% and 74.3%) followed by point mutations (14.4% and 11.4%), duplications (9.8% and 8.6%) and small insertion/deletion (9.3% and 2.9%) for DMD and BMD, respectively. 82.5% of DMD registrants were ambulatory, and all the BMD registrants were able to walk. 26.3% of DMD registrants have been treated with steroids. Cardiac functions were examined for 46.4% DMD boys and 45.7% BMD boys and respiratory functions were examined for 18.6% DMD boys and 14.3% BMD boys. Four boys with abnormal cardiac function were prescribed for treatment with cardiac medicine. 33.2% of DMD patients are eligible for exon skipping therapy, and among them 9.2% and 4.3% patients are eligible for skipping exon 51 and 53, respectively.
The database is the first linking accurate genetic diagnosis with clinical manifestation and treatment status of dystrophinopathy patients in East China. It provides comprehensive information essential for further patient management, especially for promotion of international cooperation in developing experimental therapies such as exon skipping and read-through of nonsense mutations targeting a subgroup of DMD patient population.
Duchenne and Becker muscular dystrophy; The CHFU database; Patient management
Prenatal diagnosis for Duchenne muscular dystrophy (DMD) was introduced in the Netherlands in 1984. We have investigated the impact of 26 years (1984–2009) of prenatal testing. Of the 635 prenatal diagnoses, 51% were males; nearly half (46%) of these were affected or had an increased risk of DMD. As a result 145 male fetuses were aborted and 174 unaffected boys were born. The vast majority (78%) of females, now 16 years or older, who were identified prenatally have not been tested for carrier status. Their average risk of being a carrier is 28%. We compared the incidences of DMD in the periods 1961–1974 and 1993–2002. The incidence of DMD did not decline but the percentage of first affected boys increased from 62 to 88%. We conclude that a high proportion of families with de novo mutations in the DMD gene cannot make use of prenatal diagnosis, partly because the older affected boys are not diagnosed before the age of five. Current policy, widely accepted in the genetic community, dictates that female fetuses are not tested for carrier status. These females remain untested as adults and risk having affected offspring as well as progressive cardiac disease. We see an urgent need for a change in policy to improve the chances of prevention of DMD. The first step would be to introduce neonatal screening of males. The next is to test females for carrier status if requested, prenatally if fetal DNA is available or postnatally even before adulthood.
carrier testing; Duchenne muscular dystrophy; neonatal screening; preimplantation genetic diagnosis; prenatal diagnosis
Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease affecting 1 in 3,500 live male births. It is an X-linked recessive disease caused by a defective dystrophin gene. The disease is characterized by progressive limb weakness, respiratory and cardiac failure and premature death. Fibrosis is a prominent pathological feature of muscle biopsies from patients with DMD. It directly causes muscle dysfunction and contributes to the lethal DMD phenotype. Although gene therapy and cell therapy may ultimately provide a cure for DMD, currently the disease is devastating, with no effective therapies. Recent studies have demonstrated that ameliorating muscle fibrosis may represent a viable therapeutic approach for DMD. By reducing scar formation, antifibrotic therapies may not only improve muscle function but also enhance muscle regeneration and promote gene and stem cell engraftment. Antifibrotic therapy may serve as a necessary addition to gene and cell therapies to treat DMD in the future. Therefore, understanding cellular and molecular mechanisms underlying muscle fibrogenesis associated with dystrophin deficiency is key to the development of effective antifibrotic therapies for DMD.
Antifibrotic therapy; Duchenne muscular dystrophy; Muscle fibrosis
Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (εcc).
We used CMR to assess effects of corticosteroids alone (Group A) or in combination with ACEI or ARB (Group B) on heart rate (HR), left ventricular ejection fraction (LVEF), mass (LVM), end diastolic volume (LVEDV) and circumferential strain (εcc) in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results.
Patients in Group A (114 studies) were younger than those in Group B (92 studies)(10 ± 2.4 vs. 12.4 ± 3.2 years, p < 0.0001), but HR, LVEF, LVEDV and LVM were not different. Although εcc magnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004), age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, εcc worsened regardless of treatment group.
These results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.
Cardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients.
Eighty-eight male DMD/BMD patients (age 29 ± 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT).
During a mean follow-up time of 47 ± 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF (HR, 95% CI: 0.94, 0.89-0.97, p = 0.001) and the presence of “transmural” LGE (HR, 95% CI: 2.89, 1.09-7.68, p = 0.033) were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio (HR, 95% CI: 11.50, 4.49-29.43, p < 0.0001) in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing “transmural” LGE had a significantly lower event-free-survival (HR, 95% CI: 13.48, 1.89-96.12, p = 0.009) compared to those without.
An impaired LV systolic function (LV-EF ≤45%) and a “transmural” pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter “transmural LGE” is of additive prognostic value.
Muscular dystrophy; Cardiomyopathy; CMR; Cardiac events; Prognosis; LGE
Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.
skeletal muscle; Duchenne muscular dystrophy; muscle wasting; autophagy; Akt–mTOR axis; mdx mice; therapeutic target
Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy and an X-linked recessive, progressive muscle wasting disease caused by the absence of a functional dystrophin protein. Dystrophin has a structural role as a cytoskeletal stabilization protein and protects cells against contraction-induced damage. Dystrophin also serves a signaling role through mechanotransduction of forces and localization of neuronal nitric oxide synthase (nNOS), which produces nitric oxide (NO) to facilitate vasorelaxation. In DMD, the signaling defects produce inadequate tissue perfusion caused by functional ischemia due to a diminished ability to respond to shear stress induced endothelium-dependent dilation. Additionally, the structural defects seen in DMD render myocytes with an increased susceptibility to mechanical stress. The combination of both defects is necessary to generate myocyte damage, which induces successive rounds of myofiber degeneration and regeneration, loss of calcium homeostasis, chronic inflammatory response, fibrosis, and myonecrosis. In individuals with DMD, these processes inevitably cause loss of ambulation shortly after the first decade and an abbreviated life with death in the third or fourth decade due to cardio-respiratory anomalies. There is no known cure for DMD, and although the culpable gene has been identified for more than twenty years, research on treatments has produced few clinically relevant results. Several recent studies on novel DMD therapeutics are vascular targeted and focused on attenuating the inherent functional ischemia. One approach improves vasorelaxation capacity through pharmaceutical inhibition of either phosphodiesterase 5 (PDE5) or angiotensin-converting enzyme (ACE). Another approach increases the density of the underlying vascular network by inducing angiogenesis, and this has been accomplished through either direct delivery of vascular endothelial growth factor (VEGF) or by downregulating the VEGF decoy-receptor type 1 (VEGFR-1 or Flt-1). The pro-angiogenic approaches also seem to be pro-myogenic and could resolve the age-related decline in satellite cell (SC) quantity seen in mdx models through expansion of the SC juxtavascular niche. Here we review these four vascular targeted treatment strategies for DMD and discuss mechanisms, proof of concept, and the potential for clinical relevance associated with each therapy.
Duchenne muscular dystrophy; VEGF; Flt-1; Flk-1; Nitric oxide; PDE5 inhibitor; ACE inhibitor; Satellite cell; Muscle regeneration; Myofiber damage
To review current approaches for obtaining patient data in Duchenne muscular dystrophy (DMD) and consider how monitoring and comparing outcome measures across DMD clinics could facilitate standardized and improved patient care.
We reviewed annual standardized data from cystic fibrosis (CF) clinics and DMD care guidelines and consensus statements; compared current approaches to obtain DMD patient data and outcome measures; and considered the best method for implementing public reporting of outcomes, to drive improvements in health care delivery.
Current methods to monitor DMD patient information (MD STARnet, DuchenneConnect, and TREAT-NMD) do not yet provide patients with comparative outcome data. The CF patient registry allows for reporting of standard outcomes across clinics and is associated with improved CF outcomes. A similar patient registry is under development for the Muscular Dystrophy Association (MDA) clinic network. Suggested metrics for quality care include molecular diagnosis, ambulatory status and age at loss of ambulation, age requiring ventilator support, and survival.
CF longevity has increased by almost 33% from 1986 to 2010, in part due to a CF patient registry that has been stratified by individual care centers since 1999, and publically available since 2006. Implementation of outcome reporting for MDA clinics might promote a similar benefit to patients with DMD.
This study sought to evaluate the natural history of occult cardiac dysfunction in Duchenne Muscular Dystrophy (DMD).
DMD is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (εcc) would decrease in DMD prior to global systolic functional abnormalities regardless of age or ventricular ejection fraction (EF).
We evaluated cardiac magnetic resonance image (CMR) data from 70 DMD patients and 16 aged-matched control subjects. Standard imaging data included steady-state free precession (SSFP) short-axis cine stack images, cine myocardial tagged images and myocardial delayed enhancement (MDE, an indicator of myocardial fibrosis) sequences. Analysis was performed using QMASS® and HARP® softwares. DMD patient data was subdivided by age (< 10 years or > 10 years), EF (> 55% or <55%) and the presence or absence of MDE.
DMD patients with normal EF had reduced εcc at an early age (<10 years) compared to control subjects (p< 0.01). DMD patients >10 years with normal EF had further decline in εcc compared to younger DMD patients (p<0.01). There was further decline in εcc with age in patients with reduced EF (p<0.01) without MDE. The oldest patients, with both reduced EF and positive MDE, exhibited the lowest εcc. None of the patients had ventricular hypertrophy.
Myocardial strain abnormalities are prevalent in young DMD patients despite normal EF, and these strain values continue to decline with advancing age. Strain analysis in combination with standard CMR and MDE imaging provides a means to stratify DMD cardiomyopathy.
Duchenne Muscular Dystrophy; Cardiac Magnetic Resonances Imaging; Circumferential Strain
The age when boys lose the ability to walk independently is one of the milestones in the progression of Duchenne muscular dystrophy (DMD). We have used this as a measure of disease severity in a group of 30 patients with DMD and six patients with intermediate Duchenne/Becker dystrophy (D/BMD). Dystrophin analysis was performed on tissue sections and western blots of muscle biopsy specimens from these patients and the relationships that were found between clinical severity and abundance of dystrophin labelling are reported. All patients with intermediate D/BMD had dystrophin labelling that was detected on sections and blots. Weak dystrophin labelling was found in sections from 21/30 DMD cases and on blots in 18/30 cases. Two non-exclusive patterns of dystrophin labelling were observed on sections: very clear labelling on a small percentage of fibres (usually < 1%) or very weak labelling on a much higher proportion (about 25%). The mean age at loss of mobility among the DMD patients with no dystrophin labelling on tissue sections was 7.9 years (range 6.3-9.5) while the mean age among those with some labelling was 9.9 years (range 8.0-11.9); this is a significant difference. Quantitative estimates of dystrophin abundance were obtained from densitometric analysis of dystrophin bands on blots. In the whole group of 36 patients, a significant positive relationship was found between the abundance of dystrophin and the age at loss of independent mobility. It is concluded that even the very low concentrations of dystrophin found in DMD patients may have some functional significance.
Nearly-universal cardiomyopathy in Duchenne muscular dystrophy (DMD) contributes to heart failure and death. As DMD patients show myocardial fibrosis well before functional impairment, we postulated that earlier treatment using drugs with anti-fibrotic effect may be beneficial.
Methods and Results
Three groups of 10 utrn+/−;mdx or “het” mice with skeletal myopathy and cardiomyopathy that closely mimics clinical DMD were studied. One het group received spironolactone and lisinopril starting at 8 weeks-of-life (het-treated-8), a second received the same starting at 4 weeks-of-life (het-treated-4), and the third het group was untreated. At 20 weeks, all mice had normal EFs though circumferential strain rate was abnormal (−0.21±0.08) in untreated hets. This improved to −0.40±0.07 in het-treated-8 mice (p=0.003), and further improved to −0.56±0.10 in het-treated-4 mice (p=0.014 for het-treated-4 vs. het-treated-8). Treated mice showed less cardiomyocyte damage, with a 44% reduction in intra-cardiomyocyte serum IgG localization in het-treated-8 mice (p<0.0001), and further 53% reduction in het-treated-4 mice (p=0.0003 vs. het-treated-8); matrix metalloproteinases were similarly reduced. Cardiac, limb and diaphragm function by ex vivo muscle testing remained at 80% of normal with early treatment compared to a decline to 40% of normal skeletal muscle function without treatment.
These findings offer clinically-available medications with proven anti-fibrotic effect as a new therapeutic strategy in DMD. Early initiation greatly attenuated myocardial disease and, for the first time with these drugs, improved skeletal myopathy. Thus, early initiation of such agents warrants further clinical evaluation to maintain ambulatory, respiratory and cardiac function for DMD and related myopathies.
cardiomyopathy; muscles; aldosterone antagonist
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.
Cardiac dysfunction in boys with Duchenne muscular dystrophy (DMD) is a leading cause of death. Cardiac resynchronization therapy (CRT) has been shown to dramatically decrease mortality in eligible adult population with congestive heart failure. We hypothesized that mechanical dyssynchrony is present in DMD patients and that cardiovascular magnetic resonance (CMR) may predict CRT efficacy.
DMD patients (n = 236) were stratified into 4 groups based on age, diagnosis of DMD, left ventricular (LV) ejection fraction (EF), and presence of myocardial fibrosis defined as positive late gadolinum enhancement (LGE) compared to normal controls (n = 77). Dyssynchrony indices were calculated based on timing of CMR derived circumferential strain (ecc). The calculated indices included cross-correlation delay (XCD), uniformity of strain (US), regional vector of variance (RVV), time to maximum strain (TTMS) and standard deviation (SD) of TTMS. Abnormal XCD value was defined as > normal + 2SD. US, RVV, TTMS and SD were calculated for patients with abnormal XCD.
There was overall low prevalence of circumferential dyssynchrony in the entire DMD population; it increased to 17.1% for patients with abnormal EF and to 31.2% in the most advanced stage (abnormal EF with fibrosis). All but one DMD patient with mechanical dyssynchrony exhibited normal QRS duration suggesting absence of electrical dyssynchrony. The calculated US and RVV values (0.91 ± 0.09, 1.34 ± 0.48) indicate disperse rather than clustered dyssynchrony.
Mechanical dyssynchrony is frequent in boys with end stage DMD-associated cardiac dysfunction. It is associated with normal QRS complex as well as extensive lateral fibrosis. Based on these findings, it is unlikely that this patient population will benefit from CRT.
Duchenne muscular dystrophy (DMD) is a common X-linked recessive disease of muscle degeneration and death. In order to provide accurate and reliable genetic counseling and prenatal diagnosis, we screened DMD mutations in a cohort of 119 Chinese patients using multiplex ligation-dependent probe amplification (MLPA) and denaturing high performance liquid chromatography (DHPLC) followed by Sanger sequencing. In these unrelated DMD patients, we identified 11 patients with DMD small mutations (9.2%) and 81 patients with DMD deletions/duplications (del/dup) (68.1%), of which 64 (79.0%) were deletions, 16 (19.8%) were duplications, and one (1.2%) was both deletion and duplication. Furthermore, we analyzed the frequency of DMD breakpoint in the 64 deletion cases by calculating exon-deletion events of certain exon interval that revealed a novel mutation hotspot boundary. To explore why DMD rearrangement breakpoints were predisposed to specific regions (hotspot), we precisely characterized junction sequences of breakpoints at the nucleotide level in 21 patients with exon deleted/duplicated in DMD with a high-resolution SNP microarray assay. There were no exactly recurrent breakpoints and there was also no significant difference between single-exon del/dup and multiple-exon del/dup cases. The data from the current study provided a comprehensive strategy to detect DMD mutations for clinical practice, and identified two deletion hotspots at exon 43–55 and exon 10–23 by calculating exon-deletion events of certain exon interval. Furthermore, this is the first study to characterize DMD breakpoint at the nucleotide level in a Chinese population. Our observations provide better understanding of the mechanism for DMD gene rearrangements.
Duchenne muscular dystrophy (DMD), an X-linked disorder affects approximately 1 in 5000 males, is universally associated with heart disease. We previously identified myocardial disease by late gadolinium enhancement (LGE) in DMD subjects at various stages of disease, but the true prevalence is unclear. Cardiovascular magnetic resonance (CMR) is well established for both assessment of ventricular function and myocardial fibrosis by LGE. We sought to establish i) prevalence and distribution of LGE in a large DMD population and ii) relationship among LGE, age, LVEF by CMR and current living status.
Current living status, demographic and CMR data including ventricular volumes, LVEF and LGE from 314 DMD patients undergoing evaluation at a single large tertiary referral center were analyzed.
113 of 314 (36%) of DMD subjects showed LGE positivity with prevalence increasing from 17% of patients <10 years to 34% of those aged 10–15 years and 59% of those >15 years-old. Patients with LVEF ≥55% were LGE positive in 30% of cases; this increased to 84% for LVEF <55%. LGE was more prevalent in the free wall (531/1243, 42.7%) vs. septal segments (30/565, 5.3%). Patients with septal involvement were significantly older and had lower LVEF than those with isolated free wall LGE. Ten percent (11/113) patients who had LGE died 10.8 months after CMR. Only one patient from the LGE negative group died. Patients who died had higher heart rate, larger left ventricular volume and mass, greater number of positive LGE segment and increase incident of septal LGE compared to those who remained alive.
In DMD patients, LGE occurs early, is progressive and increases with both age and decreasing LVEF. Segmentally, the incidence of the number of positive LGE segments increase with age and lower LVEF. Older patients and those who died during the study period had more septal LGE involvement. The current studies suggest that the time course and distribution of LGE-positivity may be an important clinical biomarker to aid in the management of DMD-associated cardiac disease.
Cardiovascular magnetic resonance; Duchenne muscular dystrophy; Late gadolinium enhancement; Ejection fraction; Myocardial fibrosis