Therapy Insight: cardiovascular complications associated with muscular dystrophies
Elizabeth M McNally* and Heather MacLeod About the authors
Correspondence *Department of Medicine, Section of Cardiology, University of Chicago, 5841 S Maryland, MC6088, Chicago, IL 60637, USA
Email emcnally@medicine.bsd.uchicago.edu
Summary
The muscular dystrophies are commonly associated with cardiovascular complications, including cardiomyopathy and cardiac arrhythmias. These complications are caused by intrinsic defects in cardiomyocyte and cardiac conduction system function, and by the presence of severe skeletal muscle disease, which also contributes to cardiac dysfunction. Unlike the skeletal muscle degenerative process, for which treatment options are currently limited, therapy is available for the cardiovascular complications that accompany muscular dystrophy. New therapies for skeletal muscle degeneration are moving into clinical trials and, ultimately, into clinical practice. These therapies are expected to also improve the cardiac function, longevity and wellbeing of muscular dystrophy patients.
Review criteria
Published articles for inclusion in this review were identified from the authors' extensive records of papers on skeletal muscle degeneration and regeneration, and the cardiovascular complications associated with muscular dystrophies.
Keywords:
cardiomyopathy, dystrophin, muscular dystrophy, myotonic dystrophy
Introduction
The muscular dystrophies are disorders of progressive skeletal muscle degeneration. Although often considered to be diseases of childhood, adult forms of muscular dystrophy occur and represent a spectrum of disease. Muscular dystrophies are a genetically heterogeneous group of disorders; there are at least 21 different monogenic causes of muscular dystrophy, and cardiovascular complications are commonly associated with some subtypes.1
In normal skeletal muscle, there is a robust regenerative response that leads to the formation of new myofibers, but in individuals with muscular dystrophy this regenerative response does not meet the demands created by the degenerative process. Muscular dystrophy is most commonly diagnosed by examining a muscle biopsy, although for some forms of muscular dystrophy, genetic testing is sufficient. Dystrophic muscle biopsy samples show the following features: an abnormally large distribution of myofiber size, indicative of an enhanced degeneration and regeneration; an increased number of myofibers with centrally placed nuclei, also thought to reflect increased regeneration; and replacement of myofibers by adipose and connective tissue. It is the replacement of myofibers by fibrofatty infiltration that effectively reduces myofiber mass and produces muscle weakness. The muscular dystrophies are a subclass of the myopathies, which are broadly defined by muscle weakness arising from a defect in the muscle itself. The processes that underlie muscular dystrophy and myopathy often adversely affect cardiac muscle. In this context, cardiomyocyte degeneration is a known complication of muscular dystrophy and might lead to both cardiomyopathy and disturbances of the cardiac conduction system.
At present, there is no cure for the skeletal muscle degeneration that occurs in muscular dystrophies and myopathies. There are, however, data to support various medical and device-based approaches to management of cardiomyopathy, and the cardiomyopathy associated with muscular dystrophy should not be an exception. Cardiomyopathy in the muscular dystrophies most typically takes on a dilated form with enlarged dimensions. Over time, reduced ventricular systolic function can develop. Global or regional impairment of ventricular function can occur in the presence or absence of symptoms of congestive heart failure. Cardiac rhythm disturbances can contribute significantly to the morbidity and mortality associated with muscular dystrophy, and should be paid special attention. In this review we describe briefly the mechanisms of the major forms of muscular dystrophy with cardiac involvement and discuss how to manage patients with these disorders.
Genetic causes of muscular dystrophy
There are several subtypes of muscular dystrophies, which are categorized based on genetics and molecular pathogenesis (Table 1). Here we discuss the relevant proteins and protein complexes.
Table 1 Genetic forms of muscular dystrophy grouped by molecular pathogenesis.
Full tableFigures & Tables indexDownload Power Point slide (400K)
The dystrophin–glycoprotein complex
DYSTROPHIN–GLYCOPROTEIN COMPLEX plays a particularly important part in the muscular dystrophies, because mutations in the genes that encode its constituent proteins result in a distinct group of progressive degenerative muscle disorders that affect both adults and children (Figure 1).2, 3 Mutations in the genes encoding dystrophin or the SARCOGLYCAN proteins cause myofibers and cardiomyocytes to be abnormally susceptible to contraction-induced damage.4, 5, 6 An exception to this general observation is seen in muscle genetically engineered to lack 
-sarcoglycan, and this suggests that non-mechanical aspects of muscle membrane stability are adversely affected by blockade of this pathway.7 Despite isolated muscle studies that are consistent with contraction-induced muscle damage, it should not be concluded that exercise worsens the muscular dystrophies. The loss of the dystrophin protein, as occurs in most forms of Duchenne muscular dystrophy, is associated with destabilization of all the dystrophin-associated proteins, including the sarcoglycans. Loss of the sarcoglycan proteins is not associated with the concomitant loss of dystrophin, and yet it results in the same process of increased muscle degeneration. This suggests that the dissolution of the sarcoglycan complex, as a feature common to each of these genetically distinct disorders, is critical for the dystrophic process. Interestingly, dystrophin proteolysis appears to mediate noninherited, virally mediated forms of cardiomyopathy.8
Figure 1 Membrane-associated proteins in skeletal myofibers.
Mutations in the genes encoding the dystrophin–glycoprotein complex (sand colored) lead to membrane instability in cardiac and skeletal muscle producing cardiomyopathy and muscular dystrophy. Mutations in the gene encoding dysferlin (DYSF), which are a common cause of muscular dystrophy, lead to impaired skeletal muscle repair typically not associated with cardiomyopathy.
Full figure and legend (33K)Figures & Tables indexDownload Power Point slide (239K)When the sarcoglycan complex is destabilized, as it is in patients with dystrophin–glycoprotein complex gene mutations, both cardiac and skeletal myofibers become abnormally permeable to vital tracers.9 Membrane instability in cardiomyocyte and skeletal myofibers is associated with leakage of muscle-specific enzymes into the serum. Creatine kinase levels are substantially raised in these patients, and both the MM and MB isoforms are detected. Elevation of the MB isoform often indicates cardiomyocyte degeneration. The presence of the creatine kinase-MB isoform derives from regeneration of skeletal muscle, because regenerating muscle expresses variants not normally associated with mature skeletal muscle. In muscular dystrophies, where there is ongoing skeletal and cardiac muscle regeneration, skeletal muscle, as the greater contributor to body mass, contributes more to elevation of serum creatine kinase-MB.10 Similarly, troponin T and I isoforms, are unlikely to be reliable cardiac-specific markers in severe muscle degeneration.11
The degenerative process in skeletal muscle is often accompanied by a mononuclear-cell infiltrate, and inflammation might contribute to both cardiac muscle and skeletal muscle degeneration in these disorders.12, 13 Abnormal vascular reactivity occurs both in humans and in mouse models of muscular dystrophy, particularly if dystrophin–glycoprotein complex gene mutations are present.14, 15 Studies in mouse models of sarcoglycan mutations have indicated that this abnormal vascular reactivity develops as a consequence of cardiomyocyte degeneration in the heart.16 Restoration of the cardiomyocyte sarcoglycan complex in mice deficient for -sarcoglycan or 
-sarcoglycan corrected vascular spasm, but restoration of the vascular smooth sarcoglycan complex did not.17
Telethonin, titin and myotilin
Mutations in the genes encoding TELETHONIN (also known as T-cap), TITIN or MYOTILIN lead to rare forms of muscular dystrophy.18, 19, 20 Telethonin has an essential role in the passive stretch sensor in cardiomyocytes, and is known to form a complex with titin and muscle LIM protein that contributes to the elastic recoil properties of cardiomyocytes.21, 22 This recoil might be more essential for cardiac muscle than it is for skeletal muscle, because a null mutation in the gene encoding the muscle LIM protein results in an early-onset, lethal cardiomyopathy in mice.23 Myotilin also interacts with this complex and may similarly be involved in the stretch-sensing process.
Transmembrane and extracellular matrix proteins
The congenital muscular dystrophies are clinically evident at birth and arise from gene defects that affect transmembrane and extracellular matrix proteins, as well as proteins that are thought to glycosylate extracellular matrix proteins.24 Mutations in the gene encoding FUKUTIN RELATED PROTEIN lead to congenital muscular dystrophy and limb-girdle muscular dystrophy. Some mutations in this gene produce cardiomyopthy with less skeletal muscle weakness.25 Overexpression of a related enzyme is sufficient to alleviate features of these disorders and this approach might have therapeutic applications.26
Nuclear membrane proteins
An emerging category of genetic diseases that lead to both heart and muscle dysfunction arises from mutations in the LMNA gene. The LMNA gene encodes the inner nuclear membrane proteins lamin A and lamin C. These proteins are alternately spliced at the 3' end leading to proteins with different carboxyl-termini. The lamins are intermediate filament proteins that form a scaffold at the nuclear membrane, where they regulate a number of nuclear processes, including DNA replication, transcription, chromatin attachments and nuclear transport.27 Lamin A and lamin C are expressed in terminally differentiated cells, including heart and skeletal muscle cells. Autosomal dominant mutations in LMNA lead to cardiomyopathy and muscular dystrophy, and one of the earliest features of some LMNA mutations is atrioventricular heart block and sudden death. With LMNA mutations arrythmias can occur before skeletal muscle disease or even before cardiomyopathy is clearly present.28
Additional membrane-associated proteins
Studies investigating the effect of mutations in the gene encoding dysferlin (DYSF) have provided an alterative mechanism for the pathogenesis of muscular dystrophy. Dysferlin is a transmembrane protein that binds phospholipids in a calcium-dependent manner and is highly expressed in skeletal and cardiac muscle.29, 30, 31, 32 Mice engineered to lack dysferlin protein exhibit delayed muscle membrane repair of laser-induced lesions in skeletal myofibers;33 therefore, as opposed to dystrophin–glycoprotein complex mutations that mediate muscular dystrophy by promoting muscle degeneration, mutations in DYSF result in abnormal muscle membrane repair. In DYSF mutant muscle there is a secondary reduction of calpain 3, a calcium-activated protease that is highly expressed in skeletal muscle. Mutations in the gene encoding calpain 3 (CAPN3) are a relatively common genetic finding in patients with limb-girdle muscular dystrophy.34 Caveolin-3, a protein thought to be important for membrane recycling and, potentially, membrane repair, binds directly to dysferlin,35 and mutations in the gene encoding caveolin-3 (CAV3) cause a rare, dominantly inherited form of muscular dystrophy and muscle disease.36 Thus, it is an attractive hypothesis that these three different forms of muscular dystrophy share a defect in skeletal muscle repair mechanisms. Interestingly, unlike dystrophin–glycoprotein complex mutations, mutations in the DYSF, CAPN3 or CAV3 genes are not typically associated with cardiomyopathy.37, 38 The repair mechanisms responsible for resealing tears in large skeletal myofibers might differ substantially for the much smaller cardiomyocytes; hence, the defects that lead to skeletal muscle loss in these disorders are likely to be less relevant for cardiomyocytes, possibly explaining the reduced incidence of cardiomyopathy in these disorders.
Regeneration
Muscle-derived stem cells, known as satellite cells, are responsible for skeletal muscle regeneration. Like other stem cells, satellite cells divide asymmetrically to self-renew and to generate myoblasts committed to the skeletal muscle lineage (Figure 2). Labeling of myoblasts with tritiated thymidine has shown that after fusion, nuclei reside in a central position within the myofiber.39 Over time, these nuclei move to their mature position in the myofiber periphery. Regeneration in cardiac muscle is much less clear. In utero, cardiomyocytes divide readily in the growing heart.40 In the perinatal period, cell division slows markedly and most cardiomyocytes become suspended in the cell cycle and are binucleate. DNA labeling of mature hearts reveals small numbers of dividing cells or mitotic figures. It has been suggested that small, immature myocytes reside in the heart, and these cells might be capable of regeneration.41 At present, cardiac regeneration remains controversial, unlike skeletal muscle where the regenerative pathway and cell responsible for regeneration have been defined.
Figure 2 Muscle regeneration.
Skeletal muscle regeneration involves satellite cells that reside under the basement membrane. After skeletal muscle injury, satellite cells become activated and undergo differentiation into myoblasts. Myoblasts differentiate down the skeletal muscle lineage and fuse to existing myotubes to regenerate muscle. Muscle regeneration is activated in response to muscular dystrophy although the regenerative capacity might be insufficient to meet the demands of ongoing degeneration. Evidence for ongoing regeneration in the cardiomyopathy associated with muscular dystrophy is lacking.
Full figure and legend (20K)Figures & Tables indexDownload Power Point slide (225K)Therapy
Established management
Practice guidelines for the management of heart failure have been derived based on data from clinical trials.42 Most of these trials were conducted in adult patients with reduced systolic function and the symptoms of heart failure. Similar studies to address mortality benefit in the muscular dystrophy population are difficult because of the small number of patients. Nonetheless, in the absence of studies that demonstrate specific mortality benefits for muscular dystrophy patients, it seems reasonable to adopt these practices. The benefit of afterload reduction achieved by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers plus 
-receptor blockade is clear for cardiomyopathy patients without muscular dystrophy, and there is no reason to avoid this standard regimen in muscular dystrophy patients. The use of the aldosterone agonist spironolactone and the cardiac glycoside digoxin should also be considered because these agents might also be of benefit. Diuretics should be pursued as needed for the management of fluid overload.
A central question that dominates the cardiomyopathy care of muscular dystrophy patients is when to initiate medical therapy. Recently, a prospective study demonstrated beneficial effects of angiotensin-converting-enzyme inhibitors in young Duchenne patients, suggesting that early intervention can actually prevent the development of dilated cardiomyopathy and reduced systolic function.43 The muscular dystrophy population, particularly patients with Duchenne muscular dystrophy or limb-girdle muscular dystrophy caused by sarcoglycan gene mutations, is at high risk of developing cardiomyopathy; therefore, additional studies investigating the effectiveness of early afterload reduction, -receptor blockade and the effect of steroids should be performed to determine whether onset of cardiomyopathy can be slowed or eliminated with pharmacologic therapy. Cardiac transplantation has been effective in patients with the milder variant Becker muscular dystrophy and in the maternal carriers of dystrophin gene mutations.44, 45
Arrhythmia management is an equally important aspect of managing cardiomyopathy patients, and the cardiomyopathy that accompanies muscular dystrophy is no exception. Careful surveillance through history taking, as well as Holter and event monitoring, should be routinely performed. Both bradycardic and tachycardic rhythm disturbances occur and can be treated with device implantation. Because this clinical need frequently arises late in the life of many muscular dystrophy patients, device implantation might be limited by KYPHOSCOLIOSIS and muscle wasting. For some patients, the use of external home defibrillators is an alternative approach. In Duchenne and the limb-girdle muscular dystrophies caused by sarcoglycan gene mutations, irregular heart rhythms tend to parallel the onset and course of progressive ventricular dilation and dysfunction.46
In two forms of muscle disease, irregular heart rhythms arise at an early stage in the disease, or even at presentation. The first of these diseases is myotonic dystrophy, a myopathic process commonly associated with first-degree atrioventricular heart block, bundle-branch block or both, reflecting involvement of the cardiac conduction system.47 Myotonic dystrophy type I, more common than myotonic dystrophy type II, arises from a trinucleotide expansion on chromosome 19 that alters gene function and produces messenger RNA-mediated cytotoxic effects.48 More recently, the cardiac involvement in myotonic dystrophy type II has been described.49 Myotonic dystrophy is a class II indication for pacemaker implantation, and patients should be monitored regularly for lengthening PR intervals.50 Individuals with muscular dystrophy associated with mutations in the LMNA gene are also at risk of cardiac arrhythmia events, and close monitoring and prophylactic device implantation should be considered for these patients.28
Compromise of respiratory musculature leads to hypoventilation and is a contributor to right heart dysfunction, particularly in Duchenne muscular dystrophy. Guidelines for the management of pulmonary complications in Duchenne muscular dystrophy have been outlined and should be adopted to diminish cardiac complications that arise from respiratory dysfunction.51
Experimental therapy
New experimental therapies for muscular dystrophies are now emerging (Box 1). Gene replacement therapy relies on a range of viral vectors for delivery. For example, broad transduction of skeletal and cardiac muscle in mouse models has been achieved by use of adeno-associated virus serotypes.52 Cell-based therapies are also being explored for the regeneration of skeletal and cardiac muscle;53, 54 skeletal muscle stem cells, when delivered systemically, might also home to cardiac muscle and result in muscle regeneration. Caution is advised, however, because skeletal muscle-like differentiation could occur within the heart, which would alter electrical properties and cardiac function. Finally, growth-factor-based gene therapy is emerging as a successful approach for stimulating muscle growth. Growth factors that are currently being studied for effects on skeletal muscle regeneration include insulin-like growth factor 1, and factors that inhibit myostatin.55, 56 Data generated thus far indicate that insulin-like growth factor 1-based therapies might have direct effects on the stimulation of cardiac growth. The effect of myostatin on cardiac growth is not known. Further work is required, and these therapies should be evaluated for their beneficial and adverse effects on the heart.
BOX 1: Emerging experimental therapies for muscular dystrophy.
Cell-based
Myoblast transplant
Muscle-derived stem cells
Nonmuscle-derived stem cells
Gene-based
Viral replacement—adenovirus, adeno-associated virus
Heregulin-mediated utrophin upregulation
Gene repair
Induced exon skipping
Stop codon read through
Growth-factor-modulated
Insulin-like growth factor 1
Myostatin inhibition
Growth-factor-based and cell-based therapies might be broadly applicable to all muscle degenerative disorders. Certain gene-based therapies, however, will require a precise genetic diagnosis before the designing of gene-specific therapy. For example, it was recently shown that HEREGULIN can upregulate utrophin in mice carrying a mutation in dystrophin.57 In this model, heregulin treatment was effective in improving muscle mass. Because some therapies are directed at certain genetic forms of muscular dystrophy but not others, the molecular mutations responsible for each case of muscular dystrophy will need to be defined prior to initiating these therapies. Muscular dystrophy patients frequently present to the cardiologist without a clear molecular diagnosis. Genetic tests for many muscular dystrophies are commercially available, and most require only a simple blood draw. Muscle biopsy is used regularly to augment genetic diagnosis, and should be performed, if needed, for molecular diagnosis. A correct molecular diagnosis is highly useful to predict which muscular dystrophy patients are at risk of cardiac complications. Molecular diagnoses are also of great benefit for potentially at-risk relatives, who might not be obviously affected by muscle weakness but could still be at risk of cardiac complications (e.g. carrier mothers of Duchenne muscular dystrophy patients). Careful family history should be taken paying strict attention to history of sudden cardiac death.
Conclusion
Many forms of muscular dystrophy affect the heart in the form of cardiomyopathy and/or cardiac arrhythmias. Those muscular dystrophies that arise from mutations in dystrophin–glycoprotein complex and those that arise from LMNA gene mutations are at high risk for cardiovascular complication. Muscular dystrophy associated with DYSF or CAPN3 gene mutations appear to have a lower incidence of concomitant cardiac disease. Specific prospective trials are needed for cardiomyopathy with muscular dystrophy; therefore, in the absence of strong evidence, at this time, it is reasonable to adopt standard pharmacologic approaches for cardiomyopathy management. The timing for beginning this treatment is unclear, but might be earlier than for other forms of cardiomyopathy given the known progressive nature of cardiomyopathy with muscular dystrophy. Cardiac arrhythmias can be life threatening, and muscular dystrophy patients should be monitored closely for signs and symptoms of cardiac arrhythmia events. As with all cardiomyopathy patients, treatment aimed at arrhythmia prevention should be sought. Early identification of cardiac complications is possible through imaging and monitoring and can reduce morbidity and mortality in the muscular dystrophies.
Acknowledgments
EMM is supported by the Muscular Dystrophy Association, the NIH and the Burroughs Wellcome Fund.
References
- Laval SH and Bushby KM (2004) Limb-girdle muscular dystrophies—from genetics to molecular pathology. Neuropathol Appl Neurobiol 30: 91–105 | Article | PubMed | ISI | ChemPort |
- Lapidos KA et al. (2004) The dystrophin glycoprotein complex: signaling strength and integrity for the sarcolemma. Circ Res 94: 1023–1031 | Article | PubMed | ISI | ChemPort |
- Blake DJ and Martin-Rendon E (2002) Intermediate filaments and the function of the dystrophin-protein complex. Trends Cardiovasc Med 12: 224–228 | Article | PubMed | ISI | ChemPort |
- Petrof BJ et al. (1993) Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A 90: 3710–3714 | PubMed | ChemPort |
- Danialou G et al. (2001) Dystrophin-deficient cardiomyocytes are abnormally vulnerable to mechanical stress-induced contractile failure and injury. Faseb J 15: 1655–1657 | PubMed | ISI | ChemPort |
- Dellorusso C et al. (2001) Tibialis anterior muscles in mdx mice are highly susceptible to contraction-induced injury. J Muscle Res Cell Motil 22: 467–475 | Article | PubMed | ChemPort |
- Hack AA et al. (1999) Muscle degeneration without mechanical injury in sarcoglycan deficiency. Proc Natl Acad Sci U S A 96: 10723–10728 | Article | PubMed | ChemPort |
- Badorff C et al. (2000) Enteroviral protease 2A directly cleaves dystrophin and is inhibited by a dystrophin-based substrate analogue. J Biol Chem 275: 11191–11197 | Article | PubMed | ChemPort |
- Matsuda R et al. (1995) Visualization of dystrophic muscle fibers in mdx mouse by vital staining with Evans blue: evidence of apoptosis in dystrophin-deficient muscle. J Biochem (Tokyo) 118: 959–964 | PubMed | ChemPort |
- McLaurin MD et al. (1997) Cardiac troponin I, cardiac troponin T, and creatine kinase MB in dialysis patients without ischemic heart disease: evidence of cardiac troponin T expression in skeletal muscle. Clin Chem 43: 976–982 | PubMed | ISI | ChemPort |
- Saggin L et al. (1990) Cardiac troponin T in developing, regenerating and denervated rat skeletal muscle. Development 110: 547–554 | PubMed | ChemPort |
- Porter JD et al. (2002) A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice. Hum Mol Genet 11: 263–272 | Article | PubMed | ChemPort |
- Wehling-Henricks M et al. (2004) Prednisolone decreases cellular adhesion molecules required for inflammatory cell infiltration in dystrophin-deficient skeletal muscle. Neuromuscul Disord 14: 483–490 | PubMed |
- Thomas GD et al. (1998) Impaired metabolic modulation of alpha-adrenergic vasoconstriction in dystrophin-deficient skeletal muscle. Proc Natl Acad Sci U S A 95: 15090–15095 | Article | PubMed | ChemPort |
- Sander M et al. (2000) Functional muscle ischemia in neuronal nitric oxide synthase-deficient skeletal muscle of children with Duchenne muscular dystrophy. Proc Natl Acad Sci U S A 97: 13818–13823 | Article | PubMed | ChemPort |
- Coral-Vazquez R et al. (1999) Disruption of the sarcoglycan-sarcospan complex in vascular smooth muscle: a novel mechanism for cardiomyopathy and muscular dystrophy. Cell 98: 465–474 | Article | PubMed | ISI | ChemPort |
- Wheeler MT et al. (2004) Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy. J Clin Invest 113: 668–675 | Article | PubMed | ChemPort |
- Moreira ES et al. (2000) Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet 24: 163–166 | Article | PubMed | ISI | ChemPort |
- Hauser MA et al. (2000) Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum Mol Genet 9: 2141–2147 | Article | PubMed | ChemPort |
- Hackman P et al. (2002) Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet 71: 492–500 | Article | PubMed | ISI | ChemPort |
- Knoll R et al. (2002) The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell 111: 943–955 | Article | PubMed | ISI | ChemPort |
- Omens JH et al. (2002) Muscle LIM protein deficiency leads to alterations in passive ventricular mechanics. Am J Physiol Heart Circ Physiol 282: H680–H687 | PubMed | ChemPort |
- Arber S et al. (1997) MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88: 393–403 | Article | PubMed | ISI | ChemPort |
- Muntoni F et al. (2004) Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol 17: 205–209 | Article | PubMed | ISI | ChemPort |
- Brockington M et al. (2001) Mutations in the fukutin-related protein gene (FKRP) identify limb girdle muscular dystrophy 2I as a milder allelic variant of congenital muscular dystrophy MDC1C. Hum Mol Genet 10: 2851–2859 | Article | PubMed | ISI | ChemPort |
- Barresi R et al. (2004) LARGE can functionally bypass alpha-dystroglycan glycosylation defects in distinct congenital muscular dystrophies. Nat Med 10: 696–703 | Article | PubMed | ISI | ChemPort |
- Ostlund C and Worman HJ (2003) Nuclear envelope proteins and neuromuscular diseases. Muscle Nerve 27: 393–406 | Article | PubMed | ISI | ChemPort |
- van Berlo JH et al. (2005) Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations portend a high risk of sudden death? J Mol Med 83: 79–83 | PubMed |
- Bashir R et al. (1998) A gene related to Caenorhabditis elegans spermatogenesis factor fer-1 is mutated in limb-girdle muscular dystrophy type 2B. Nat Genet 20: 37–42 | Article | PubMed | ISI | ChemPort |
- Anderson LV et al. (1999) Dysferlin is a plasma membrane protein and is expressed early in human development. Hum Mol Genet 8: 855–861 | Article | PubMed | ISI | ChemPort |
- Davis DB et al. (2002) Calcium-sensitive phospholipid binding properties of normal and mutant ferlin C2 domains. J Biol Chem 277: 22883–22888 | Article | PubMed | ISI | ChemPort |
- Liu J et al. (1998) Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 20: 31–36 | Article | PubMed | ISI | ChemPort |
- Bansal D et al. (2003) Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature 423: 168–172 | Article | PubMed | ISI | ChemPort |
- Fanin M et al. (2001) Calpain-3 and dysferlin protein screening in patients with limb-girdle dystrophy and myopathy. Neurology 56: 660–665 | PubMed | ChemPort |
- Matsuda C et al. (2001) The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle. Hum Mol Genet 10: 1761–1766 | Article | PubMed | ISI | ChemPort |
- Woodman SE et al. (2004) Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases. Neurology 62: 538–543 | PubMed | ChemPort |
- Bushby K et al. (2003) 107th ENMC international workshop: the management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th–9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 13: 166–172 | PubMed | ChemPort |
- Muntoni F (2003) Cardiomyopathy in muscular dystrophies. Curr Opin Neurol 16: 577–583 | PubMed |
- McGeachie JK and Grounds MD (1999) The timing between skeletal muscle myoblast replication and fusion into myotubes, and the stability of regenerated dystrophic myofibres: an autoradiographic study in mdx mice. J Anat 194: 287–295 | Article | PubMed |
- Manasek FJ (1968) Mitosis in developing cardiac muscle. J Cell Biol 37: 191–196 | Article | PubMed | ChemPort |
- Beltrami AP et al. (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763–776 | Article | PubMed | ISI | ChemPort |
- Hunt SA et al. (2001) ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation 104: 2996–3007 | PubMed | ChemPort |
- Duboc D et al. (2005) Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 45: 855–857 | Article | PubMed | ChemPort |
- Melacini P et al. (1998) Cardiac transplantation in a Duchenne muscular dystrophy carrier. Neuromuscul Disord 8: 585–590 | PubMed | ChemPort |
- Rees W et al. (1993) Heart transplantation in patients with muscular dystrophy associated with end-stage cardiomyopathy. J Heart Lung Transplant 12: 804–807 | PubMed | ChemPort |
- Corrado G et al. (2002) Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am J Cardiol 89: 838–841 | Article | PubMed |
- Groh WJ et al. (2002) Severity of cardiac conduction involvement and arrhythmias in myotonic dystrophy type 1 correlates with age and CTG repeat length. J Cardiovasc Electrophysiol 13: 444–448 | Article | PubMed |
- Ranum LP and Day JW (2002) Myotonic dystrophy: clinical and molecular parallels between myotonic dystrophy type 1 and type 2. Curr Neurol Neurosci Rep 2: 465–470 | PubMed |
- Schoser BG et al. (2004) Sudden cardiac death in myotonic dystrophy type 2. Neurology 63: 2402–2404 | PubMed | ChemPort |
- Gregoratos G et al. (2002) ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Cardiovasc Electrophysiol 13: 1183–1199 | PubMed | ISI |
- Finder JD et al. (2004) Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 170: 456–465 | PubMed |
- Gregorevic P et al. (2004) Systemic delivery of genes to striated muscles using adeno-associated viral vectors. Nat Med 10: 828–834 | Article | PubMed | ISI | ChemPort |
- Gussoni E et al. (1999) Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401: 390–394 | Article | PubMed | ISI | ChemPort |
- LaBarge MA and Blau HM (2002) Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 111: 589–601 | Article | PubMed | ISI | ChemPort |
- Barton ER et al. (2002) Muscle-specific expression of insulin-like growth factor I counters muscle decline in mdx mice. J Cell Biol 157: 137–148 | Article | PubMed | ISI | ChemPort |
- Bogdanovich S et al. (2002) Functional improvement of dystrophic muscle by myostatin blockade. Nature 420: 418–421 | Article | PubMed | ISI | ChemPort |
- Krag TO et al. (2004) Heregulin ameliorates the dystrophic phenotype in mdx mice. Proc Natl Acad Sci U S A 101: 13856–13860 | Article | PubMed | ChemPort |
Competing interests
The authors declared no competing interests.
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Subject areas under which this article appears: Cardiomyopathy and heart failure | Concomitant disease
