Cardiac Involvement in Patients with Muscular Dystrophies: Magnetic Resonance Imaging Phenotype and Genotypic Considerations

I.1 Molecular and Genetic Features

Duchenne and Becker muscular dystrophy (DMD and BMD, respectively) are X-linked disorders affecting the synthesis of dystrophin, a large sarcolemmal protein that is absent in DMD¹¹ and reduced in amount or abnormal in size in BMD patients¹². Dystrophin provides the connection between a large multimeric complex of glycoproteins in the muscle cell membrane (termed the dystrophin-glycoprotein complex, DGC) and intracellular actin filaments (Fig. 1), thereby transmitting forces generated by sarcomere contraction to the extracellular matrix^{13, 14}. Correlations between dystrophin mutations and onset of cardiomyopathy have been noted¹⁵; some mutations result in only cardiomyopathy without skeletal myopathy¹⁶. Other proteins not shown in Fig. 1 that are particularly involved in both inside-out and outside-in transmission between the myocyte and the extracellular matrix include vinculin and talin; ongoing investigations are further defining their role in cardiomyopathies, particularly those associated with muscular dystrophies.

Dystrophin has an important role in stabilizing the cell membrane of both skeletal and cardiac myocytes^{17, 18}, and its absence produces sarcolemmal fragility and muscle cell degeneration. Dystrophin deficiency may also lead to conformational changes in stretch-activated calcium channels, resulting in pathologic leakage of calcium in the muscle cytosol¹⁹. Intracellular calcium accumulation then leads to protease activation, increased reactive oxygen species production and cell death^{20, 21}. Finally, impaired vasoregulation occurs via marked reduction in membrane-associated neuronal nitric oxide synthase (nNOS, Fig. 1) in both cardiac and skeletal muscle²². Without dystrophin, nNOS mislocalizes to the cytosol; this greater distance between nNOS and the sarcolemma may impair NO diffusion through the myocyte membrane to the microvasculature. As a consequence, insufficient NO release follows muscle contraction resulting in muscle ischemia²³. Unopposed vasoconstriction may, therefore, explain the necrosis observed in skeletal and cardiac muscle of dystrophinopathy patients. Microvasculature abnormalities have also been shown to result primarily from absence of dystrophin or sarcoglycan components of the DGC in cardiomyocytes^{24, 25}.

X inactivation, the random process by which one of the two X chromosomes in female cells becomes transcriptionally inactive, may result in cardiomyocytes with an active X-chromosome with the abnormal dystrophin gene. The X-chromosome containing the normal dystrophin gene may become inactivated in cardiac muscle to a greater degree than in skeletal muscle, causing female carriers to develop dystrophinopathic cardiomyopathy. The exact prevalence and severity of such in the carrier population is uncertain^26–29.

I.2 Cardiac Disease and Imaging Phenotype

Almost all DMD patients who survive to the third decade of life display cardiomyopathy³⁰. Recognition may be delayed by relative physical inactivity obscuring symptomatology. This most common and severe form of childhood muscular dystrophies is associated with increased R/S ratio in the right precordial ECG leads, deep Q waves in the lateral leads, conduction abnormalities and arrhythmias (mainly supraventricular but also ventricular).

BMD patients, whose skeletal myopathy occurs later and progresses more slowly, experience worse cardiomyopathy than DMD patients: up to 70% have LV dysfunction by echocardiography. Perhaps because of less skeletal muscle weakness, these patients can perform more strenuous exercise with dystrophin-deficient myocardial muscle fibers and have earlier manifestations of myocardial disease³¹.

Most CMR data in muscular dystrophies currently exists for patients with DMD and BMD. The pathology of cardiomyopathy in patients with dystrophinopathy classically produces subepicardial fibrosis of the inferolateral wall³², remarkably similar to the pattern observed in some patients with viral myocarditis (Figs. 2–3, Movie Files 1–2). Myocardial damage in DMD/BMD has been postulated to result from mechanical stress imposed on a metabolically and structurally abnormal myocardium, although it remains unclear how a genetic abnormality presumably affecting the heart in a diffuse manner may result in a segmental distribution. Whether the inferolateral wall is more vulnerable due to regional molecular changes caused by the mutation or if this regional susceptibility results from exposure to higher mechanical stress remains to be elucidated¹⁰. Of note, enterovirus infection has been shown to produce myocardial damage via cleavage of dystrophin³³; this mechanism may help explain the similarity in LGE pattern between myocarditis and dystrophin-associated cardiomyopathy.

The rationale to perform CMR in BMD/DMD patients in addition to the current standard of care (monitoring by echocardiography and ECG) is based on 2 sets of observations. First, studies have shown that early initiation of standard heart failure therapy can delay the onset and progression of left ventricular systolic dysfunction and potentially even lead to reverse remodeling in patients with X-linked dystrophinopathy^2–6. Second, it has been shown that myocardial fibrosis detected by late gadolinium-enhancement imaging may be observed even when findings by echocardiography are still normal^{9, 10} (Fig. 2). CMR can therefore serve as a more sensitive means to detect early cardiac involvement and help to decide when cardioprotective treatment should be instituted. In addition to late gadolinium-enhancement, CMR also provides accurate and reproducible quantification of LV volumes, making this modality well suited for monitoring response to both standard therapy and novel treatment strategies.

Cardiac screening has been recommended for female DMD/BMD mutation carriers, particularly beginning after the teenage years as they are known to be at risk for developing cardiomyopathy²⁸. Interestingly, CMR has revealed a similar pattern of myocardial fibrosis in mutation carriers as that seen in DMD patients (Fig. 4)³⁴. Since myocardial damage in carriers has been observed even in absence of clinically-apparent muscular weakness, cardiac screening should be considered in female relatives of DMD/BMD patients.

II.1 Clinical and Genetic Features

The nuclear envelope is composed of a double lipid bilayer that separates the contents of the nucleus from the cytoplasm. Within the inner nuclear membrane are a variety of integral proteins. Emery-Dreifuss muscular dystrophy (EDMD) is a form of muscular dystrophy caused by mutations in these nuclear membrane proteins. One of these proteins, emerin, (Fig. 1) is almost completely absent in the X-linked form of EDMD due to a mutation in the EMD gene³⁵. The exact function of emerin is not clear; it binds to a variety of other nuclear factors involved in gene regulation, mRNA splicing, ordering of chromatin structure and nuclear assembly³⁶. EDMD can also occur as an autosomal dominant (AD) or recessive (AR) disorder resulting from mutations in the LMNA gene that encodes lamins A and C³⁷. Lamins A and C are nuclear intermediate-filament proteins which closely interact with emerin and other nuclear membrane proteins, thereby forming aproteinaceous meshwork (the nuclear lamina) that underlies the inner nuclear membrane (Fig. 1). This meshwork has an important role inmaintaining the architecture and mechanical strengthof the nucleus; it also serves as a scaffold for various other nuclear factors involved in DNA replication, chromatin organization and transcription^38–41. Deficiency in either emerin or lamin A/C typically results in the triad of contractures, muscle weakening and cardiac conduction defects by mechanisms that remain elusive.

Cardiac involvement in EDMD patients is common and usually becomes evident in the third decade as muscle weakness progresses⁸, though cardiac manifestations have also been reported in young adults without muscle weakness. Since cardiac dysfunction portends a high risk of sudden death⁴², careful follow-up of these patients is mandatory. In EDMD, normal myocardium is gradually replaced by fibrous and adipose tissue, a process that usually starts in the atria (leading to atrial arrhythmias), often involves the atrioventricular node (leading to conduction abnormalities sometimes requiring pacemaker implantation) and eventually affects the ventricles (causing progressive dilatation and systolic failure)^{43, 44}. Because sudden death may be the presenting symptom in this disease, cardiac screening of relatives (including female carriers with X-linked EDMD) has been recommended^{7, 44}.

II.2 Cardiac Magnetic Resonance Imaging Phenotype

In EDMD, CMR data are limited due to the rarity of the disease but also because of the frequent need for pacemaker implantation in this population (particularly in the more advanced stages of the disease). A study by Smith et al.⁴⁵ in 8 patients with the AD subtype of EDMD (EDMD2; LMNA gene mutation at 1q21) showed that early stage disease does not display apparent fibrosis, despite the presence of more subtle myocardial abnormalities including a decrease in systolic circumferential strain in the inferior segment. This suggests a different pathogenesis of cardiac involvement in EDMD compared to DMD/BMD, where fibrosis typically precedes systolic dysfunction.

III.1 Clinical and Genetic Features

Limb-girdle muscular dystrophy (LGMD) refers to a group of disorders with great clinical and genetic heterogeneity, all characterized by weakness affecting the proximal musculature. AD and AR inheritance patterns have been identified. The more common AR subtypes usually have an earlier age of onset, and show more rapid disease progression compared to AD variants. The subtypes mostly associated with cardiac involvement (manifest as conduction disorders and/or myocardial disease) are those associated with a defect in the genes encoding for the α-(LGMD2D), β-(LGMD2E), γ-(LGMD2C) or δ-(LGMD2F) subunits of the dystrophin-associated sarcoglycan complex in heart and skeletal muscle (Fig. 1)⁴⁶. Cardiomyopathy is also very common in LGMD2I, caused by a mutation in fukutin-related protein (FKRP). FKRP is an enzyme involved in the glycosylation of α-dystroglycan, a peripheral membrane component of the dystrophin-associated glycoprotein complex. Post-translational glycosylation by FRKP allows α-dystroglycan to bind with the extracellular matrix, making it an important component in the link among cytoskeleton, sarcolemmal dystrophin-associated glycoprotein complex and extracellular matrix.

The AD subtype LGMD1B is also caused by a defect in the LMNA gene encoding for lamin A/C, resulting in a phenotype similar to autosomal dominant EDMD but with a different distribution of muscle involvement. The pelvic girdle weakness in LGMD1B is slowly progressive, sparing the lower muscles. Additionally, contractures and cardiac disease manifestations (atrioventricular block, sudden death, atrial paralysis, atrial fibrillation/flutter and dilated cardiomyopathy) tend to occur later compared to autosomal dominant EDMD^{47, 48}.

Different mutations involving the LMNA gene have been described, resulting in a clinically heterogeneous group of disorders (laminopathies) spanning muscular dystrophy, progeria, familial partial lipodystrophy and Charcot-Marie-Tooth disease. The muscular dystrophies associated with LMNA gene mutation that cause cardiac disease include the autosomal variants of EDMD, LGMD1B, and a third disorder commonly referred to as dilated cardiomyopathy with conductive system disease. The last, although initially linked to chromosome 1p1-1q1⁴⁹ was later associated with mutations in the lamin A/C gene (1p1-q21 locus)⁵⁰. Patients with this defect develop sinus node dysfunction, atrioventricular node dysfunction, ventricular arrhythmias and adult-onset cardiomyopathy with little clinical evidence of skeletal myopathy. The inheritance pattern is autosomal dominant with high penetrance, and patients have a high risk of sudden death⁵⁰.

III.2 Cardiac Imaging Phenotype

In lamin A/C cardiomyopathy, we have demonstrated midmyocardial scarring of the basal interventricular septum by LGE that occurs well before the onset of ventricular dilatation and systolic dysfunction (Fig. 4), and which may herald conduction system disease⁵¹. This midwall fibrosis is similar in distribution to that observed at autopsy, and in our experience is often associated with diastolic dysfunction. Further studies are needed to define the prognostic significance of midwall fibrosis in this population, as it may represent substrate for potentially fatal ventricular arrhythmias seen in these patients as reported in other cardiomyopathies^52–54. While skeletal muscle disease may not be readily apparent clinically, we have detected clear alterations involving the medial head of the gastronemius muscles by magnetic resonance imaging (Fig. 5), similar to that described in patients with EDMD2⁵⁵. This suggests the presence of a continuum between phenotypes with predominant cardiac involvement and phenotypes with cardiac and skeletal muscle compromise⁵⁶.

IV.1 Clinical and Genetic Features

Myotonic dystrophy (DM) is an autosomal dominant muscular dystrophy that produces progressive skeletal muscle wasting and cardiac conduction abnormalities; multisystem manifestations include cataracts, testicular failure, hypogammaglobulinemia and insulin resistance. As shown in the Table, two types of DM have been identified. DM1 is the most common form and is associated with an abnormal expansion of a CTG-trinucleotide repeat sequence in the DMPK gene that codes for myotonic dystrophy protein kinase, a protein mainly expressed in smooth, cardiac and skeletal muscle cells. Disease severity and age of onset in DM1 correlates with CTG expansion length, and the number of repeats can increase from one generation to the next (anticipation). DM2 on the other hand is associated with an expanded CCTG-tetranucleotide repeat in a totally unrelated gene, coding for zinc finger protein. In both cases, the gene including the abnormal repeat sequences is transcribed into RNA but not translated. The mutant RNA accumulates in the nucleus⁵⁷ and disturbs the function of RNA-binding proteins that normally participate in splicing of pre-messenger RNA into mature mRNA. This eventually results in abnormal function of different genes, including those encoding for the muscle-specific chloride channel ClC-1 and insulin receptor, at least partially explaining the features of myotonia and insulin resistance in patients with DM⁵⁸.

Atrioventricular and intraventricular conduction defects are common in both DM1 and DM2. Infra-hisian block is likely an important cause of sudden death in these patients^{59, 60}. As in many other types of muscular dystrophy, cardiac arrhythmias may occur early in the disease course i.e. in the absence of severe neuromuscular impairment. Structural heart disease is also frequently observed in DM, with LV dilatation or hypertrophy observed in approximately 20% of patients, and LV systolic dysfunction in 14%⁶¹. Clinical heart failure, however, is less common—2% according to that same report.

IV.2 Cardiac Imaging Phenotype

Gaul et al. recently described the CMR findings in 9 patients with LGMD2I (due to a mutation in the FKRP gene)⁶². They found CMR to be more sensitive than conventional diagnostic investigations (ECG and echocardiography) for detecting cardiac involvement, which was manifest as a decrease in ejection fraction and/or an increase in LV volumes and mass. Unfortunately, no results from late gadolinium-enhancement imaging were reported in that study. Our own experience with CMR in patients with LGMD2I suggests that at an early stage, when LV size and function are still normal, midmyocardial scarring may be observed. As cardiomyopathy advances, extensive myocardial fibrosis is apparent (Fig. 6).

A similar pattern of fibrosis was recently reported by Yilmaz et al. in a patient with LGMD2C⁶³. Taken together, these findings suggest that different abnormalities within the dystrophin-sarcoglycan-dystroglycan complex may all lead to cardiomyocyte instability and damage, eventually resulting in a characteristic (but non-specific) pattern of fibrosis.

Patients with DM may present with cardiomyopathy, which usually is more benign in DM2 compared to DM1. CMR may help define the LV abnormalities of the disease: dilatation, systolic dysfunction, hypertrophy, and occasionally non-compaction^{64, 65}. Typical LGE patterns have not been reported in DM. In our experience, mild midwall fibrosis involving the septum is occasionally present; the clinical significance of this finding in DM remains uncertain.

V.1 Myocardial Strain Analysis

The assumption that cardiac dysfunction can be prevented (or at least be attenuated) in patients with MD has led to the belief that therapy should be initiated at an early stage of the disease, rather than delayed until ventricular dilatation or systolic dysfunction become apparent. CMR has been proposed as a sensitive screening tool for that purpose by its ability to show myocardial fibrosis, even when the LV is otherwise structurally normal. Another means of revealing occult cardiac dysfunction in patients with MD may be provided by strain analysis. Ashford et al. used CMR tagging to show that boys with DMD exhibit abnormal global and segmental circumferential strain compared to age- and gender-matched controls, despite similar LV volumes and ejection fraction⁶⁶. Similar findings were recently reported by Hor et al., who showed abnormalities in myocardial strain preceded both the age-dependent decline in ejection fraction and the appearance of myocardial fibrosis in DMD patients⁶⁷. This group recently showed that strain analysis better captures serial decline in LV function compared to EF⁶⁸. The sensitivity of strain imaging analysis by CMR could potentially be used not only to reveal occult cardiac dysfunction, but also to assess the efficacy of existing or novel therapeutic agents. Some questions remain, however, regarding these tools, particularly in terms of their accuracy for measuring strain on a segmental (rather than global) level, but also with respect to the reproducibility of strain measurements among centers. Prospective and multicenter studies that randomize patients to therapeutic decision making with or without strain imaging analysis are therefore critically needed before these new techniques can become adopted into the clinical management of patients with muscular dystrophy⁶⁹.

V.2 Fat vs. Water Imaging

Histological studies of autopsy hearts from DMD patients suggest a component of fat infiltration, described as “predominantly epimyocardial” in a small case series³². CMR may distinguish fat using either cine or LGE imaging techniques that take advantage of the consistent difference in resonant frequency of water vs. fat protons⁷⁰. Studying 3 DMD dogs with these techniques, Kellman et al. demonstrated that extensive epicardial hyperenhacement on LGE imaging that at least in part was attributable to fat⁷¹. Our experience in one patient with early myocardial disease using the same technique suggests that LGE in patients with dystrophin-associated cardiomyopathy may also demonstrate a component of fatty infiltration (Fig. 7, Movie File 3). T2-weighted CMR, which depicts myocardial water’s distribution, may provide additional insights into the myocardial disease of DMD⁷².

VI.1 Suggested CMR Protocol

When designing a CMR examination for the patient with muscular dystrophy, the key clinical questions should be addressed: What is the degree of LV dysfunction? What evidence is there for myocardial disease? What pattern of disease is present? What is the likelihood of functional recovery? Acquisitions should include cine imaging in all standard long axis and contiguous short axis planes; real-time cine techniques may be necessary in patients who have difficulty breathholding. Fat-suppressed or fat-only cine imaging if available may help delineate the extent of myocardial fat infiltration. Finally, LGE acquisition forms the cornerstone of any CMR protocol in patients with cardiomyopathy, and the same is true in evaluating the MD patient. While the optimal contrast dose and acquisition timing have not been specifically interrogated in MD cardiomyopathy LGE imaging, our experience suggests that values similar to those used for other nonischemic cardiomyopathies (save amyloidosis) perform well. If fat and water can be distinctly imaged with specialized LGE sequences, these may shed further insight into the extent of fibrosis vs. fatty infiltration of the myocardium. While absence of hyperenhancement has established value in predicting response to, for instance, medical and resynchronization therapies in other cardiomyopathy populations, the predictive value in MD-associated myocardial disease remains to be established. Given evidence that subclinical abnormalities in regional strain may precede overt contractile dysfunction, strain analysis may be included at centers where robust postprocessing affords reproducible results.

VI.2 Clinical Implications of Findings

Increased recognition of subclinical myocardial changes with advanced imaging raises challenging management questions. Evidence-based guidelines for patients with cardiomyopathy advocate initiation of drugs like angiotensin converting enzyme inhibitors (ACEI) and beta-blockers in stage B cardiomyopathy, defined in the adult guidelines as “impaired left ventricular (LV) function, hypertrophy, or geometric chamber distortion”⁷³. Pediatric guidelines also advocate ACEI therapy for subclinical LV dysfunction⁷⁴; notably, neither document addresses management of myocardial fibrosis that may be present in the absence of structural and functional changes. Our approach is to initiate ACEI and occasionally aldosterone antagonist therapy, given the proven antifibrotic effect of both in other cardiomyopathy populations⁷⁵, if CMR demonstrates myocardial fibrosis in the muscular dystrophy patient and particularly in the lamin A/C mutation-positive patient. While one prospective, randomized trial in children with DMD supports a possible long-term benefit with ACEI even if the initial LV ejection fraction by echocardiography is normal⁷⁶, it is unknown if any of these patients had subclinical fibrosis in the absence of CMR data. A strategy of fibrosis-guided initiation of cardioprotective drug therapy requires prospective, randomized trial data before it can be widely advocated.

Electrophysiological testing should be considered in muscular dystrophy-associated cardiomyopathies known to affect conduction system such as DM and lamin A/C. Timing of such may be informed by symptoms suspicious for conduction system disease or conduction abnormalities by electrocardiography⁷⁷. We have observed longer PR intervals in lamin A/C patients with septal fibrosis by CMR relative to those of mutation-positive patients without evident fibrosis⁵¹; longitudinal studies are suggested to test the predictive value of hyperenhancement for pacemaker requirement in appropriate DM and lamin A/C patients.