The 79 exons code for dystrophin, a 427-kDa protein that is expressed in the skeletal muscle, cardiomyocytes, and brain [7]. Dystrophin, a rod-shaped cytoplasmic protein, connects the dystroglycan complex (DGC) to the intracellular contractile apparatus and extracellular matrix (ECM) of the cell (◘ Fig. 12.2) [19]. Dystrophin is similar to spectrin and other structural proteins and consists of two ends separated by long, flexible rodlike regions. The N-terminus binds actin and the C-terminus binds to glycoproteins in the sarcolemma. The role of dystrophin is to stabilize the plasma membrane by transmitting forces generated by the sarcomeric contraction to the ECM.

The DGC is a multimeric complex composed of glycated integral membrane proteins and peripheral proteins that form a structural link between the f-actin cytoskeleton and the ECM in both the cardiac and skeletal muscle [20–23]. The DGC is comprised of cytoskeletal proteins, dystrophin, syntrophins, dystroglycans, sarcoglycans, DGC-associated proteins, neuronal nitric oxide synthetase, and dystrobrevin [24–26]. The fully nucleated DGC provides mechanical support to the skeletal or cardiac plasma membrane during contraction. Loss of function or absence of one or several of these DGC proteins leads to plasma membrane fragility.

DMD and Becker muscular dystrophy (BMD ) arise from mutations in dystrophin. Other forms of muscular dystrophies arise from mutations in the DGC components. In the skeletal muscle, the DGC is located at regular intervals in structures known as costameres, whereas in the cardiac muscle, the DGC is not located in discrete costameres [27]. The composition of the DGC in the skeletal muscle and cardiac myocytes may be different and differentially altered in dystrophin deficiency [28].

The skeletal muscle and hearts lacking functional dystrophin are mechanically weak, and contraction of the cell (skeletal myocytes and cardiac myocytes) leads to membrane damage [29, 30]. Loss of membrane integrity leads to a cascade of increased calcium influx into the cell and eventual cell death.

Clinically, the loss of dystrophin manifests as progressive muscle weakness [19, 31]. Symptoms are first noted in early childhood and include calf pseudohypertrophy, an inability to stand without using the arms for assistance (Gowers sign), toe walking, and difficulty keeping up with peers. As the disease progresses, the skeletal muscle becomes increasingly weak, causing atrophy and contractures that subsequently result in the loss of ambulation by the age of 10–12. Patients with DMD have markedly elevated serum levels of creatinine kinase (CK), a muscle protein, due to ongoing muscle damage. Creatinine kinase levels may be 10–100 times the normal limit in patients with DMD, and elevated CK levels are a diagnostic sign [32]. DMD diagnosis can be confirmed by muscle biopsy demonstrating the absence of dystrophin (◘ Fig. 12.3) and by genetic testing for dystrophin mutations.

Historically, this progressive muscle weakness resulted in the loss of ambulation by 10–12 years of age and death during the second decade of life mainly due to respiratory failure. However, with the advent of nocturnal ventilation, spinal surgery, and steroid treatment, the life expectancy of boys with DMD has increased to the late 20s to early 30s [33] (◘ Fig. 12.4). While respiratory problems used to be the major cause of death in DMD patients, cardiomyopathy now is the predominant cause of death in these patients [34].

Advances in management, namely, corticosteroid treatments, spinal stabilization, and improved pulmonary support, have significantly improved life expectancy of boys/men with DMD to the late 20s and early 30s [33]. Glucocorticoids are one of the mainstays of treatment for DMD and have been shown to improve muscle strength and function and pulmonary function in patients with DMD [35–39].

Nocturnal ventilation and spinal stabilization surgery have reduced respiratory-related deaths, but also increased DMD cardiomyopathy due to the advanced age of DMD patients [33, 57, 58]. Cardiac involvement is nearly ubiquitous in older DMD patients, as more than 90 % of young men over the age of 18 have evidence of cardiac dysfunction [34]. Dilated cardiomyopathy typically has an onset in the mid-teen years and progressively remodels and contributes to the demise of DMD patients [34, 59] (◘ Fig. 12.5). Distinct dystrophin mutations have been correlated to an increased incidence of cardiomyopathy and possible response to treatment [60].

Recognition of cardiomyopathy in DMD patients can be challenging due to physical inactivity and other respiratory complaints that can obscure the diagnosis [61]. Currently, clinical guidelines recommend initial cardiac screening at the time of diagnosis of DMD, and every 2 years until age 10, and then yearly thereafter [40].

Most DMD patients will have abnormal electrocardiographic tracings. The classical pattern demonstrates tall R waves and increased R/S amplitude in lead V1, Q waves in the left precordial leads, right axis deviation, or complete right bundle branch block [62–64] (◘ Fig. 12.6). These ECG findings correlate to the pathological studies that have shown a tendency to develop fibrosis in the heart’s basal posterior wall in patients with muscular dystrophies and may reflect reduced electrical activity in the inferobasal wall [65]. ECG findings are believed to precede echocardiographic findings of cardiomyopathy, but no correlation between ECG findings, and the presence of cardiomyopathy has yet been established [62, 66].

Arrhythmias are a common cardiac involvement in patients with muscular dystrophies. Sinus tachycardia is a common finding in patients with DMD [67–69]. Dystrophic patients experience elevated heart rates even when compared to patients with other muscular dystrophies or deconditioned patients [69]. Pathological examination of the heart in dystrophic patients has shown fibrosis of the conduction system in addition to the myocardium [70], which may explain autonomic cardiac dysfunction in the DMD population [71, 72].

Additionally, sinus tachycardia may correlate with cardiac dysfunction in patients with DMD [73]. Dalmaz et al. reported that urinary catecholamines increased in DMD patients around the age of 10 years, which corresponded to the time of heart rate elevation and cardiac involvement [74]. In patients with DMD cardiomyopathy, atrial arrhythmias including atrial fibrillation, atrial flutter, and atrial tachycardias can occur. Ventricular tachycardia, premature ventricular contractions (PVCs), and other conduction abnormalities have been noted and are correlated with progressive ventricular dilation and dysfunction [75].

Cardiac imaging can be challenging in patients with end-stage DMD due to scoliosis, ventilation, and contractures. Imaging modalities commonly used include echocardiography and cardiac magnetic resonance imaging (MRI).

Echocardiography in DMD cardiomyopathy shows regional wall motion abnormalities in the posterior basal wall, left ventricular dilation, and overall reduced systolic function [76]. Current guidelines recommend obtaining an echocardiogram at the time of diagnosis or by age 6, with repeat echocardiograms every 1–2 years until age 10. After age 10, it is recommended that patients have an annual echocardiogram to assess left ventricular function [51]. While echocardiography is easily accessible, relatively quick, and a cost-effective imaging modality, it can be technically challenging in patients with DMD due to chest wall deformities, scoliosis, and respiratory dysfunction, thus limiting the diagnostic yield [77].

CMR imaging has been used with DMD patients and can provide one of the most accurate assessments of left ventricular size and function [78–80]. Silva et al. performed gadolinium contrast-enhanced CMR on ten patients with dystrophinopathies (eight DMD and two BMD patients) and were the first to demonstrate late gadolinium enhancement (LGE) by CMR in a dystrophic heart. They further reported that, using echocardiography, LGE was present even with normal left ventricular function [71].

Pulchalski et al. subsequently performed a study of 74 patients with DMD; the majority had LGE in the posterobasal region of the left ventricle in a subepicardial distribution [81]. This pattern of LGE in the basal inferior and inferolateral walls is consistent with the pathological findings of fibrosis in the inferior basal wall (◘ Fig. 12.7) [65, 82]. A large single-center study by Hor et al. retrospectively evaluated LGE in 314 DMD patients and demonstrated that LGE increased with age and with decreasing left ventricular ejection fraction [LVEF] [83]. Thus, CMR imaging may provide an earlier detection of cardiovascular involvement in DMD and enable accurate and reproducible quantification of left ventricular function and size and promote initiation of earlier cardioprotective treatment. While CMR has many imaging benefits for patients with DMD, it can also be challenging, especially in the pediatric population, due to the need for sedation, higher costs, and limited access to this type of specialized imaging .

Studies have shown the benefits of corticosteroid therapy and, as shown by echocardiography and cardiac MRI, support the notion that steroid treatment delays left ventricular dysfunction in DMD patients [59].

Duboc et al. evaluated the impact of angiotensin-converting enzyme (ACE) inhibitors , which have proven effective in asymptomatic adults with left ventricular dysfunction, and in patients with DMD with preserved left ventricular function [84]. The investigators randomized 57 children with DMD (mean age of 10.7 years) to the ACE inhibitor perindopril (2–4 mg/day) or placebo. At 3 years of follow-up, there was no significant difference in LV function between the children treated with perindopril or placebo. However, at the 3-year mark, all patients were switched to perindopril treatment and followed for an additional 2 years. After crossing over to perindopril at 2 years, there was no difference in mean LV function between those patients treated with perindopril initially versus those initially treated with placebo.

However, the initial placebo group had 8 of 29 patients with LVEF < 45 % and only 1 of 27 patients in the perindopril group (p = 0.02), which suggests that early treatment with perindopril was effective in preventing progression to left ventricular dysfunction in DMD. Subsequently, these patients were followed for 10 years, and in the initial placebo group, only 65 % of patients were alive versus 92.9 % in the initial perindopril group (p = 0.013), which emphasized that early use of an ACE inhibitor reduced mortality in patients with DMD [85].

Treatment guidelines recommend initiation of ACE inhibitors in patients with DMD only once LV dysfunction has developed [51], but based on the studies by Duboc et al., we recommend initiation of an ACE inhibitor before the development of left ventricular dysfunction in patients with DMD, as they are at high risk for developing left ventricular dysfunction (American College of Cardiology heart failure stages A and B) [84, 85]. Additionally, for those patients who are intolerant to ACE inhibitors, angiotensin receptor blockers (ARBs) can also be used. ARBs have been shown as effective as ACE inhibitors in DMD [86].

While the benefit of ACE inhibitors in DMD cardiomyopathy has been definitive, the efficacy of beta-blockers in DMD cardiomyopathy has been less clear. The use of carvedilol has been assessed in pediatric DMD patients with elevated atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP), and a low ejection fraction (EF < 40 %), as measured by echocardiography. No significant difference in carvedilol-treated patients was seen regarding symptoms of left ventricular dysfunction [87]. However, in a study by Rhodes et al., carvedilol was shown efficacious in patients with DMD cardiomyopathy [88].

When superimposed on background therapy of ACE inhibitors, the use of carvedilol in this patient population remains unclear. An analysis of 13 patients with DMD who were treated with ACE-I versus ACE-I and carvedilol revealed a beneficial effect of beta-blocker therapy in increasing left ventricular shortening and decreasing left ventricular end-diastolic dimensions, as shown by echocardiography [89]. In contrast, a recent study by Viollet et al. tested ACE inhibitor alone versus ACE inhibitor and metoprolol, but in this study, low-dose beta-blocker was added only for heart rates above 100 bpm or if arrhythmias occurred [90]. The results of this study showed an improvement from pretreatment LVEF in both groups, but no difference between the treatment groups. Further research with larger groups of patients and more robust trial designs are needed to definitively address the use of beta-blockers in DMD. Based on current ACC/American Heart Association/Heart Failure Society of America guidelines, we recommend that beta-blockers be initiated in DMD patients with left ventricular dysfunction [91].

Spironolactone , an aldosterone inhibitor, is a standard heart failure therapy and has also been demonstrated in the mouse model to improve cardiomyopathy [92]. In a recently completed randomized double-blinded clinic trial, eplerenone, an aldosterone receptor antagonist versus placebo, was added to the background therapy of ACE inhibitors or ARBs in DMD patients with normal LV function to assess the efficacy of eplerenone in preventing cardiomyopathy in DMD.

Twenty patients were randomized to eplerenone and 20 to placebo. They were followed for 6 and 12 months using cardiac MRI. The primary endpoint at 12 months was change in left ventricular circumferential strain, which is a marker of contractility. At 12 months, the decline in LV circumferential strain was lower in the group treated with eplerenone than the placebo group, although there was no overall change in left ventricular function in either group [93]. This study, while small, demonstrated attenuation of progressive left ventricular dysfunction that occurs in DMD. And while this study is positive, further studies to assess the impact of eplerenone in DMD survival are warranted.

The gold standard for treating end-stage or advanced heart failure remains cardiac transplantation. When a patient has heart failure with multisystem organ involvement and is not expected to be able to rehabilitate after cardiac transplantation, a heart transplant is not advised. These contraindications have limited the applicability of heart transplants for patients with muscular dystrophy .

Rees et al. were the first to describe heart transplantation in patients with muscular dystrophies in a single German center [94]. Of the 582 transplants performed, three patients with DMD and one patient with BMD underwent cardiac transplantation, with a mean duration of follow-up of 40 months. They described that these patients tolerated immunosuppression, had no difference in postoperative intubation, and were able to be rehabilitated [94].

Ruiz-Cano et al. described a Spanish single-center experience with heart transplantation in three patients with BMD who underwent cardiac transplantation with a mean follow-up duration of 57 months. These investigators also demonstrated that BMD patients had an intraoperative and postoperative course comparable to nonmuscular dystrophy patients undergoing heart transplantation [95].

Patane et al. described a single case of successful transplantation in a patient with cardiomyopathy secondary to BMD [96]. We performed a more recent multicenter registry analysis of cardiac transplantation from the Cardiac Transplant Research Database and identified 29 patients with muscular dystrophies. Of those, 15 had BMD and three had DMD and underwent cardiac transplantation between 1995 and 2005. We compared them to 275 nonmuscular dystrophy, non-ischemic patients who were matched for age, body mass index, gender, and race [97] and found no significant difference in survival at 1 or 5 years, transplant rejection, infection, or allograft vasculopathy between the muscular dystrophy and nonmuscular dystrophy patients.

These studies described comparable outcomes of cardiac transplantation in a small and select group of patients with DMD and BMD with end-stage cardiomyopathy. However, the functional status of these patients prior to transplantation was not known, and these studies may have a selection bias. Further research regarding cardiac transplantation in patients with DMD and BMD with end-stage cardiomyopathy is needed.

Given the scarcity of organs for heart transplantation, left ventricular assist devices (LVADs) have been proven effective in treating patients with end-stage or advanced heart failure as well. These devices are also applicable to a larger population, including those with muscular dystrophies, as they can be used as destination therapy without the need for transplantation [98, 99].

Two groups recently reported cases of successful implantation of LVADs as destination therapy in DMD patients [100, 101]. Amedeo et al. were the first to describe LVAD implantation in two pediatric DMD patients [100]. These investigators implanted the Jarvik 2000 LVAD in a 15-year-old boy with DMD who had inotrope refractory heart failure and in a 14-year-old boy with DMD who was bridged from extracorporeal membrane oxygenation to a Jarvik 2000 LVAD. The first patient was discharged 3 months after LVAD implantation and the second patient 6 months after LVAD implantation.

Ryan et al. subsequently described the HeartMate II LVAD implantation in a 29-year-old male patient with DMD and end-stage heart failure and a HeartWare LVAD implantation in a 23-year-old female symptomatic DMD carrier with end-stage heart failure [101].

LVAD as destination therapy is a potentially promising therapy to address end-stage heart failure in patients with dystrophin-deficient heart failure. However, postoperative complications including respiratory failure, rehabilitation, bleeding, stroke, and arrhythmias need to be evaluated further in this population. Extensive preoperative and postoperative management in an experienced center would be necessary for LVAD implantation in the DMD population. Larger studies are needed to evaluate the efficacy and outcomes in this population.

In 1955, German physicians Becker and Kiener described an X-linked muscular dystrophy with a much milder clinical course than DMD, which is now known as Becker muscular dystrophy [102, 103]. In 1984, the gene responsible for BMD was located on the X chromosome [104] and, subsequently, that mutations in the DMD gene resulted in BMD [105]. BMD has an incidence of 1:19,000 and is an X-linked recessive disorder resulting from a mutation of the dystrophin gene [106]. Compared to patients with DMD, who have a complete absence of dystrophin, dystrophin mutations in BMD tend to be in-frame and result in misfolded or abnormal and less-functional protein [107].

Patients with BMD have an age of onset that is typically later than those with DMD [108] (◘ Table 12.1). While the muscular symptoms may be less severe, over 70 % of patients with BMD also develop cardiomyopathy [109, 110], and it is the leading cause of death in BMD patients [51].

Cardiomyopathy may be more severe in BMD patients than in DMD patients. This could be due to BMD patients being ambulatory much longer, placing greater stress on the heart [111–113]. The onset of cardiomyopathy is variable in BMD and is not correlated to skeletal muscle involvement [109, 114].

Cardiac magnetic resonance studies have shown a similar inferobasal fibrotic pattern in BMD and DMD patients [115]. Patients with BMD cardiomyopathy should receive standard medical heart failure therapy [91]. Given that BMD patients have a relatively milder skeletal muscle phenotype, several of these patients have received heart transplantation for severe cardiomyopathy with good outcomes (see Transplant/LVAD section) [94–97].

While DMD and BMD affect males—given that they are inherited in an X-linked recessive manner—females can be carriers. The majority of DMD and BMD are inherited; thus, a significant number of females are carriers of DMD and BMD. Most female carriers of DMD and BMD are asymptomatic; however, female carriers can become symptomatic or become manifesting carriers. Manifesting carriers can have symptoms such as mild muscle weakness, elevated serum creatinine kinase, and, also, cardiomyopathy [116, 117]. Hoogerwaard et al. evaluated 90 women who were carriers of dystrophin mutations and identified 22 % with symptoms including muscle weakness and 18 % with evidence of a dilated left ventricle [118]. The age of onset for carriers is variable and the percent of symptomatic carriers has ranged from 2.5 to 22 % in prior studies [120].

X inactivation is the process by which one of the two X chromosomes in female cells randomly becomes transcriptionally inactive. It is postulated that carriers can become symptomatic based on the extent of random X inactivation of the normal X chromosome versus the dystrophic X chromosome. While DMD and BMD carriers have been identified to have cardiomyopathy, the prevalence and severity of disease are incompletely defined [118, 121–123]. We recommend that all female dystrophinopathy carriers be screened for cardiomyopathy .

Animal models of DMD have played an important role in elucidating mechanisms of dystrophin deficiency. The dystrophin-deficient mdx mouse, dystrophin/utrophin double knockout mouse (U-dko), and the golden retriever muscular dystrophy (GRMD) models are the most studied models regarding cardiac phenotype (◘ Fig. 12.8).

The mdx mice arise from a naturally occurring nonsense point mutation in exon 23 of the DMD gene. This mutation results in the formation of a stop codon and the absence of full-length dystrophin [126, 127]. The skeletal muscle phenotype in these animals has been well characterized and is relatively mild. Young mice do not typically have any cardiac involvement, but after 10 months of age, they begin to develop signs of cardiomyopathy, including poor contractility, myocardial necrosis, and fibrosis, as well as echocardiographic and electrocardiographic changes [128, 129].

While a significant cardiomyopathy is not seen in younger mdx mice under normal conditions, various forms of stress, such as beta-adrenergic stress or pressure overload, demonstrate a cardiomyopathic phenotype [130–132]. Thus, the mdx mouse shares a similar genotype and some features of cardiomyopathy that are seen in patients with DMD. The mdx mice, however, do not develop cardiomyopathy until relatively late in comparison to patients, although the mdx mice have a mildly reduced lifespan compared to normal control mice [133].

In a recent study, Long et al. used the emerging technology of genome editing to genetically correct the dystrophin mutation in the mdx mouse [134]. The genome-edited mdx mice had between 2 and 100 % correction of the gene with this strategy. Mosaic mdx mice, with only 17 % correction of dystrophin by gene editing, had a nearly normal muscle phenotype [134].

Mdx/utrophin double knockout mouse model : Utrophin is an autosomal paralogue of dystrophin, which is upregulated in the mdx mouse [135]. The upregulation of utrophin in the mdx mouse likely compensates for the loss of dystrophin, thus producing a less severe phenotype. The utrophin and dystrophin double knockout mouse was generated to evaluate the impact of utrophin upregulation. Compared to the mdx mouse, the double knockout mouse model has a much more severe phenotype [136, 137]. Double knockout mice are smaller, with progressive muscle atrophy, and die prematurely at about 10 weeks of age. The double knockout mouse also develops a severe cardiomyopathy by 8 weeks, which is comparable to that of an aged mdx mouse [136]. The double knockout mouse may more closely represent human DMD.

Canine models: The canine model of dystrophin deficiency is a large animal model of DMD that more closely resembles human disease. The golden retriever muscular dystrophy (GRMD) dog model is one of the best-characterized dog models of DMD [138]. In 1988, Valentine et al. described a family of golden retrievers with male members affected by a severe neurodegenerative disorder with muscle weakness and gait abnormalities, and absence of dystrophin on muscle biopsy, which paralleled human DMD [138]. Subsequently, the mutation was identified to be a single mutation in the consensus splice site of intron 6, which leads to an out-of-frame mutation and absence of dystrophin during RNA processing [139].

GRMD dogs develop significant muscle weakness by 2 months of age with progressive weakness and also have a reduced lifespan [140]. GRMD dogs also develop a severe cardiomyopathy [141]. GRMD is a useful model to better understand DMD cardiomyopathy and test new therapies; however, the larger size of the GRMD dogs can increase maintenance costs and restrict their use [142]. GRMD colonies operate in the United States at the University of North Carolina at Chapel Hill and the Fred Hutchinson Cancer Center in Seattle. Other colonies exist in Brazil, France, Japan, and the Netherlands.

Human cell–based models : Animal models have been useful to evaluate the pathophysiology of DMD; however, they have limitations and do not fully recapitulate the disease phenotype observed in human patients. Obtaining human tissues, especially cardiomyocytes, is challenging and poses a risk to the patient. The advent of human inducible pluripotent stem cells (hiPSCs) in 2007 has been a major scientific development [143, 144].

hiPSCs represent a novel tool to study human genetic diseases though cellular reprogramming of patient-specific cells that retain the genetic composition and are pluripotent. hiPSCs have been used to study various cardiac diseases including hypertrophic cardiomyopathy and long QT syndrome [145, 146]. hiPSC disease modeling is a promising method to study DMD cardiomyopathy. Several hiPSC lines from patients with various mutations have been derived [147, 148]. We and other groups have successfully differentiated the DMD patient-specific hiPSC to cardiomyocytes. Modeling DMD cardiomyopathy using hiPSC is a promising method to elucidate the pathophysiology of DMD cardiomyopathy and test novel therapies [149].

A major challenge for treating DMD is finding therapies that address dystrophin deficiency and that target both the cardiac and skeletal muscle. A number of promising emerging therapies include exon skipping, dystrophin mini-gene replacement, sealants, and gene-editing strategies.

Myotonic dystrophies are among the most common inherited, adult-onset, muscular dystrophies that have multisystem impact. Myotonic dystrophies are characterized by myotonia or a delay in relaxation of muscle contraction. Myotonic dystrophy leads to skeletal muscle weakness and muscle wasting and, in end-stage disease, respiratory muscle weakness. Patients also have endocrine abnormalities that commonly include hypogonadism and insulin resistance. The gastrointestinal system is also impacted and dysphagia, reflux, and hypermotility are often noted. Central nervous system and ocular manifestations include cataracts, cognitive impairment, and hypersomnolence. Cardiac consequences of myotonic dystrophy are also prominent, and predominantly involve conduction abnormalities and arrhythmias, although cardiomyopathy is being increasingly identified [193].

In 1909, German physician Hans Steinert and English physicians Frederick Batten and H. P. Gibb described for the first time a muscular dystrophy that was characterized by myotonia, or involuntary muscle contraction and delayed relaxation, and muscle weakness [194, 195]. This disorder was initially called Steinert disease and, later, myotonic dystrophy.

In 1911, Griffith described a patient with myotonic dystrophy who had bradycardia with a heart rate of 30 bpm, and subsequently, other early clinical reports of cardiovascular abnormalities in muscular dystrophy were reported [196, 197]. Nearly 80 years later, the gene responsible for myotonic dystrophy was identified [198]. However, in 1994, a group of patients who had clinical features similar to what is now classified as myotonic dystrophy type 1, but without the gene mutation, were described [199, 200]. This was later classified as myotonic dystrophy type 2. The gene responsible for the pathogenesis was identified in 2001 [201]. The two genetically defined subtypes of myotonic dystrophies are myotonic dystrophy type 1 and myotonic dystrophy type 2 (◘ Table 12.2).