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REVIEW TOPIC OF THE WEEK

Dystrophin-Deficient Cardiomyopathy

Forum Kamdar, MD, Daniel J. Garry, MD, PHD

ABSTRACT

Fro

rep

Ma

Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural

cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular

dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting

symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated

muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophin-

opathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to

their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular

therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients

with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review

focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient.

(J Am Coll Cardiol 2016;67:2533–46) © 2016 by the American College of Cardiology Foundation.

DYSTROPHINOPATHIES:

A HISTORICAL PERSPECTIVE

The earliest detailed descriptions of muscular dys-trophies were by Meryon (1) in England in 1852 and byDuchenne (2) in France in 1868, identifying a diseasethat affected young boys with severe muscularweakness and an abnormal increase in calf size.Duchenne (2) observed fatty-fibrous replacement ofskeletal muscle in muscle biopsies obtained fromthese boys; for this contribution, the disease wasnamed after him. In 1886, Gowers (3) described how achild affected with muscular dystrophy used his armsto rise from the ground. Although Duchennemuscular dystrophy (DMD) had been known as aclinical entity since the 1860s, its cause was notelucidated until over 100 years later. In a landmarkdiscovery, Louis Kunkel’s laboratory (1986) identifiedthe DMD gene responsible for causing DMD and, ayear later, demonstrated that mutations resultedin the absence of the 427-kDa rod-like protein dys-trophin (4,5). These major advancements allowed for

m the Cardiovascular Division, Lillehei Heart Institute, University of Min

orted that they have no relationships relevant to the contents of this pap

nuscript received December 14, 2015; revised manuscript received Febru

the development of diagnostic and genetic testing, aswell as the establishment of disease models that haveenhanced our understanding of DMD. Although anumber of questions remain regarding the musculardystrophies, the rich history of discovery has signifi-cantly accelerated our knowledge of DMD in the last30-year period.

DYSTROPHINOPATHIES: INHERITANCE

DMD is the most common form of muscular dys-trophy, affecting 1 in every 5,000 boys born in theUnited States (Table 1) (6–8). DMD is a result ofan inherited or spontaneous mutation of the DMDgene. DMD is a 2.5-Mb gene located on chromosomeXp21.1 (5,9), and is the largest known gene,harboring 79 exons and encoding a 14-kb transcript(Figure 1). The full-length dystrophin gene has 3promoters: the M promoter produces the Dp427misoform, expressed in skeletal and cardiac muscle;the B promoter produces Dp427c, expressed inthe brain; and the P promoter produces Dp427p,

nesota, Minneapolis, Minnesota. Both authors have

er to disclose.

ary 16, 2016, accepted February 23, 2016.

TABLE 1 DMD Vers

Dystrophin protein

Incidence

Mean age at onset, y

Mean age of becominnonambulatory, y

Mean life expectancy

Onset of cardiomyopa

BMD ¼ Becker muscular

ABBR EV I A T I ON S

AND ACRONYMS

ACEI = angiotensin-converting

enzyme inhibitor

BMD = Becker muscular

dystrophy

CMR = cardiac magnetic

resonance imaging

CRISPR = clustered regularly-

interspaced short palindromic

repeat

DGC = dystroglycan complex

DMD = Duchenne muscular

dystrophy

ECG = electrocardiogram

ICD = implantable

cardioverter-defibrillator

LVAD = left ventricular

assist device

LVEF = left ventricular ejection

fraction

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2534

expressed in the Purkinje cells in the brain(Figure 1) (10).

An out-of-frame mutation of 1 or several ofthe 79 exons in the full-length Dystrophingene results in an absence of a functionaldystrophin protein, causing the DMD pheno-type. DMD is inherited in an X-linked reces-sive manner, where a female carrier with 1 Xchromosome carrying the DMD mutation hasa 50% chance of passing on the mutated Xchromosome to her son. Female carriers canalso have symptoms on the basis of theirX-inactivation. Although the majority of DMDmutations are inherited, spontaneous muta-tions account for 30% of DMD cases (11).

DYSTROPHIN AND DYSTROGLYCAN

COMPLEX ORGANIZATION

Dystrophin, a rod-shaped cytoplasmic pro-tein, connects the dystroglycan complex

(DGC) to the intracellular contractile apparatus andextracellular matrix (ECM) of the cell (Figure 2) (12).Dystrophin is similar to spectrin and consists of 2ends separated by long, flexible, rod-like regions. TheN-terminus binds actin and the C-terminus binds toglycoproteins in the sarcolemma. The role of dystro-phin is to stabilize the plasma membrane by trans-mitting forces generated by the sarcomericcontraction to the ECM (Figure 2).

The DGC is a multimeric complex composed ofglycated integral membrane proteins and peripheralproteins that form a structural link between thefilamentous (F)-actin cytoskeleton and the ECM inboth cardiac and skeletal muscle (13). The DGCis comprised of cytoskeletal proteins, dystrophin,syntrophins, dystroglycans, sarcoglycans, DGC-associated proteins, neuronal nitric oxide synthase,and dystrobrevin (14). The fully nucleated DGC pro-vides mechanical support to the skeletal or cardiacplasma membrane during contraction, and loss of

us BMD

DMD BMD

Absent Partially functional

1:5,000 male births 1:19,000

rs 3–5 12

grs

w12 w27

, yrs Mid to late 20s 40s

thy, yrs 16–18 Variable; cardiomyopathymay precede skeletalsymptoms

dystrophy; DMD ¼ Duchenne muscular dystrophy.

function or absence of 1 or several of these DGC pro-teins leads to plasma membrane fragility. DMD andBecker muscular dystrophy (BMD) arise from muta-tions in dystrophin, and other forms of muscular dys-trophies arise from mutations in DGC components. Inskeletal muscle, the DGC is located at regular intervalsin structures known as costameres, whereas in cardiacmuscle, the DGC is not located in discrete costameresand may have a unique composition (15,16).

PATHOGENESIS AND PHYSICAL FINDINGS

Skeletal muscle and heart lacking functional dystro-phin are mechanically weak, and contraction of thecell (skeletal myocytes and cardiac myocytes) leadsto membrane damage (17–19) (Central Illustration).Loss of membrane integrity results in a cascade ofincreased calcium influx into the cell and eventualcell death. Clinically, dystrophin loss manifests asprogressive muscle weakness (6). Symptoms are firstnoted in early childhood and include calf pseudohy-pertrophy, an inability to stand without using thearms for assistance (Gower maneuver), toe walking,and difficulty keeping up with peers. As the diseaseprogresses, patients’ skeletal muscle becomesincreasingly weak, causing atrophy and contractures,which subsequently results in the loss of ambulationin their teens. Due to ongoing muscle damage, pa-tients with DMD have markedly elevated serum levelsof the muscle protein creatine kinase (CK), which maybe 10� to over 100� the normal limit, and an elevatedCK level is a diagnostic sign (20). The diagnosis ofDMD can be confirmed by muscle biopsy demon-strating the absence of dystrophin (Figure 3) andusing genetic testing for dystrophin mutations.

SURVIVAL

Historically, this progressive muscle weakness resul-ted in loss of ambulation by 10 to 12 years of age anddeath during the second decade of life, primarily dueto respiratory failure. However, with the advent ofnocturnal ventilation, spinal stabilization surgery,and steroid treatment, the life expectancy of boyswith DMD has increased to the late twenties to earlythirties (21) (Figure 4). Although respiratory failurewas previously the major cause of death, cardiomy-opathy has now emerged as the leading cause ofdeath in patients with DMD (22).

NONCARDIAC TREATMENTS

Advances in management, namely corticosteroidtreatments, spinal stabilization, and improved pul-monary support, have significantly improved the life

FIGURE 1 Dystrophin Gene and Protein

A

B

B/Dp427

M/Dp427

P/Dp427500 kb 1000 kb

R/Dp260 B,K/Dp140 S/Dp116 G/Dp71

1500 kb 2500kb

COOH

Dystrobrevin binding siteSyntrophin binding site

Dystroglycan

Syntrophindystrobrevin

DystroglycanBinding site

nNOSbinding

Rod Domain

Actinbindingdomain

1 2 10

H1

H2

H3

H4

241

20

30

40

45

50

56

60

63

70

79

Gene

Exons

Structural NH2

N terminus

(A) The 79 exons of the full-length dystrophin gene with promoters for the alternatively spliced isoforms indicated by red arrows and boxes

specific for each promoter. Full-length dystrophin promoters include: M, muscle promoter; B, brain promoter; and P, Purkinje promoter. Other,

shorter dystrophin isoforms include: Dp260, expressed in the retina (R); Dp140, expressed in kidney (K) and brain (B); Dp116, expressed in

Schwann cells (S); and Dp71, which is ubiquitously expressed. (B) Schematic of the protein structure of dystrophin, including the actin-binding

site at the N-terminus and the DGC protein-binding site at the C-terminus. The rod domain contains 24 spectrin-like repeats with 4 hinge

regions. DGC ¼ dystroglycan complex.

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expectancy of boys/men with DMD to the latetwenties and early thirties (21). Glucocorticoids areone of the mainstays of treatment for DMD and havebeen shown to improve muscle strength, function,and pulmonary function (23). Glucocorticoids arecurrently recommended in patients with DMD whoare 5 years of age or older who are not gaining or havea decline in motor skills (24). Current glucocorticoidprotocols that have been tested in randomized clin-ical trials include: daily prednisone 0.75 mg/kg/day;intermittent prednisone 0.75 mg/kg/day, 10 days onand 10 days off; and daily deflazacort 0.9 mg/kg/day(25). Deflazacort is another steroid that is used in theDMD patient population and may have a more limitedside effect profile compared with prednisone (26).

Scoliosis and kyphosis, common, progressivesequelae of DMD, subsequently result in decreasedpulmonary function and discomfort in these patients;however, implementing spinal stabilization surgeryusing Harrington rods has improved survival, com-fort, and pulmonary function (27). Respiratory com-plications occur frequently in patients with DMD aslosing respiratory muscle strength leading todecreased ventilation, and they are at increased riskfor pneumonia, atelectasis, and respiratory failure(28). The majority of deaths in end-stage DMD pre-viously occurred as a result of respiratory failure andinfections; however, the introduction of noninvasivenocturnal mechanical ventilation has improved sur-vival in patients with DMD and may improvecardiac function through afterload reduction (29,30).

Additionally, nutrition, exercise therapy, and psy-chosocial support are critical in the interdisciplinarycare of patients with DMD (27).

CARDIAC INVOLVEMENT IN DMD

The reduction of respiratory-related deaths due tonocturnal ventilation and spinal stabilization hascontributed to the increase of DMD cardiomyopathydue to the increased survival and advanced age ofpatients with DMD (21,31). The incidence of cardio-myopathy in DMD increases with age. Although it isestimated that 25% of boys have cardiomyopathy at6 years of age and 59% by 10 years of age, cardiacinvolvement is nearly ubiquitous in older patientswith DMD, as more than 90% of young men over18 years of age demonstrate evidence of cardiacdysfunction (22). Dilated cardiomyopathy typicallyhas an onset in the midteen years and progressivelyremodels and contributes to the demise of patientswith DMD (22,32) (Figure 5). Distinct dystrophinmutations have been correlated to an increasedincidence of cardiomyopathy and possible responseto treatment (33). Recognition of heart failuresymptoms in patients with DMD can be challengingdue to physical inactivity and other respiratorycomplaints that can obscure the diagnosis (34).Currently, clinical guidelines recommend the initialcardiac screening at the time of diagnosis of DMD,every 2 years until 10 years of age, and then yearlythereafter (24).

FIGURE 2 Schematic Diagram of the DGC

ECMLaminin

Sarcoglycans

Dystrophin

Actin cytoskeleton

Extracellular

Intracellular

Syntrophin

nNOS

Sarcolemma

αα-dystroglycan

β-dystroglycan

Dystrobrevin

COOH

NH3

The DGC spans the sarcolemma and links the cytoplasmic actin cytoskeleton to the ECM via dystrophin. Transmembrane components of the DGC

include sarcoglycans, beta-dystroglycan, and extracellular alpha-dystroglycan, which binds laminin. Cytoplasmic components include dystrophin

(or utrophin), which binds dystrobrevin, syntrophin, and nitric oxide synthase. DGC ¼ dystroglycan complex; ECM ¼ extracellular matrix.

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DMD and BMD Cardiomyopathy M A Y 3 1 , 2 0 1 6 : 2 5 3 3 – 4 6

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Most patients with DMD will have abnormal elec-trocardiographic tracings. The classical pattern dem-onstrates tall R waves and increased R/S amplitude inlead V1, Q waves in the left precordial leads, right axisdeviation, or complete right bundle branch block(Figure 6) (35–37). These electrocardiographic (ECG)findings correlate with the pathological studies thathave demonstrated a predilection for fibrosis in thebasal posterior wall of the heart in patients withmuscular dystrophies and may reflect a reduction inelectrical activity in the inferobasal ventricular wall(38). ECG findings are believed to precede echocar-diographic findings of cardiomyopathy; however, nocorrelation between ECG findings and the presence ofcardiomyopathy has yet been established (35,39). Theuse of serum biomarkers, such as cardiac troponin orB-type natriuretic peptides (BNPs), has not been wellestablished for DMD screening and will need furtherexamination in the future.

Arrhythmias are a common cardiac involvement inpatients with muscular dystrophies. Sinus tachy-cardia is a common finding in patients with DMD(40–42). Dystrophic patients have elevated heartrates, even when compared with patients with othermuscular dystrophies or deconditioned patients (42).Pathological examination of the heart in dystrophicpatients has demonstrated fibrosis of the conductionsystem, in addition to the myocardium (43), whichmay, in part, explain the autonomic dysfunctionin the DMD population (44,45). Additionally, sinustachycardia may correlate with cardiac dysfunction in

patients with DMD (46). Dalmaz et al. (47) demon-strated that urinary catecholamines increased inpatients with DMD around 10 years of age, whichcorresponded temporally to heart rate elevation andcardiac involvement. In patients with DMD cardio-myopathy, atrial arrhythmias, including atrial fibril-lation, atrial flutter, and atrial tachycardias, can alsooccur. Ventricular tachycardia, premature ventricularcomplexes, and other conduction abnormalities havebeen noted, and patients with DMD with left ven-tricular ejection fraction (LVEF) <35% have a signifi-cantly higher burden of ventricular tachycardia(48,49). In addition to low LVEF, increased QTdispersion has been identified as a risk factor forventricular arrhythmias in DMD; however, there wasno prognostic value of signal-averaged ECG (49,50).

The role of implantable cardioverter-defibrillators(ICDs) is well-established for primary prevention ofsudden cardiac death in patients with an LVEF <35%;however, the use of ICDs has not been well estab-lished in patients with DMD cardiomyopathy (51). Theguidelines discourage the use of ICDs for a patientwith a life expectancy <1 year, and ICDs may not havebeen utilized in the past due to the previous highmortality in patients with DMD. The recent use ofneurohormonal therapy may also improve LVEF toreduce the risk of sudden cardiac death. We wouldrecommend ICD implantation candidacy for patientswith DMD with LVEF <35%; however, an individual-ized discussion with patients and families is neces-sary, given the course of disease progression.

CENTRAL ILLUSTRATION Duchenne Muscular Dystrophy: Pathogenesis and Therapies

DUCHENNE MUSCULAR DYSTROPHY PATHOGENESIS THERAPIES

Disease typically affects boys(1 in every 5,000 boys born in the U.S.)

Inherited or spontaneous mutation in the DMD gene

Possible learning difficulties

Scoliosis

Weak respiratory

muscles

Muscle loss and weakness

leading toloss of

ambulation

Absence of dystrophin—the anchor that connects the extracellular matrixand membrane proteinsto the cell cytoskeleton

Contraction of muscle cell leads to cell membrane damage

Increased calcium influx into damaged cell leads to cell death

Progressive muscle weakness

Cardiomyopathy

Current cardiac treatments

• Steroid treatment (glucocorticoids)• Neurohormonal therapy: Angiotensin

converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs)

Current non-cardiac treatments

• Noninvasive nocturnal ventilation• Nutrition, exercise therapy,

and psychological support• Spinal stabilization

Emerging treatments

• Implantable cardioverter defibrillation • Beta-blockers• Aldosterone inhibitors• Exon skipping• Dystrophin gene replacement• Gene editing mediated with CRISPR/Cas9• Advanced heart failure therapies

Dystrophin

Kamdar, F. et al. J Am Coll Cardiol. 2016;67(21):2533–46.

ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; CRISPR/Cas9 ¼ clustered regularly interspaced short palindromic

repeats/CRISPR-associated systems; DMD ¼ Duchenne muscular dystrophy.

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CARDIAC IMAGING IN DMD

Cardiac imaging can be challenging in patients withend-stage DMD due to scoliosis, ventilation abnor-malities, and contractures. Current, commonly usedimaging modalities include echocardiography andcardiac magnetic resonance (CMR). Echocardiographyin DMD cardiomyopathy has demonstrated regionalwall motion abnormalities in the posterior basal wall,left ventricular dilation, and overall reduced systolicfunction (52). Current guidelines recommend anechocardiogram at the time of diagnosis or by 6 yearsof age, with repeat echocardiograms every 1 to 2 yearsuntil 10 years of age. After 10 years of age, it is rec-ommended that patients have an annual echocar-diogram to assess left ventricular function (27).Although echocardiography is easily accessible, rela-tively quick, and a cost-effective imaging modalityto utilize, it can be technically challenging inpatients with DMD due to chest wall deformities,scoliosis, and respiratory dysfunction, thus limitingthe diagnostic yield (53). CMR has been used to imagepatients with DMD and can provide one of the mostaccurate assessments of left ventricular size and

function (54–56). Silva et al. (54) performed gadolin-ium contrast-enhanced CMR on 10 patients withdystrophinopathies (8 patients with DMD and 2 withBMD) and were the first to demonstrate late gado-linium enhancement (LGE) by CMR in the dystrophicheart. They further demonstrated that LGE was pre-sent by echocardiography, even with normal leftventricular function (54). Puchalski et al. (57) subse-quently performed a study of 74 patients with DMD,where the majority of patients had LGE in the post-erobasal region of the left ventricle in a subepicardialdistribution (Figure 7). This pattern of LGE in thebasal inferior and inferolateral walls is consistentwith the pathological findings of fibrosis in the infe-rior basal wall (38,58) (Figure 8). Myocardial fibrosis,as assessed by LGE in DMD, has been demonstrated toincrease with age and correlates with a decline inLVEF (59,60). Thus, CMR may provide earlier detec-tion of cardiovascular involvement in DMD, allow foraccurate and reproducible quantification of left ven-tricular function and size, and promote initiation ofearlier cardioprotective treatment. CMR has manyimaging benefits for patients with DMD; however, itcan also be challenging in the pediatric population

FIGURE 4 Interventions Prolong Survival in DMD

30

20

10

Age

At D

eath

0

Vent +

SS

Vent 1

990s

Died 19

90sDied

1980s

Died 19

70s

Died 19

60s

A marked increase in survival of patients with DMD has been achieved with the addition

of ventilation strategies (vent) and spinal stabilization surgeries (SS). Adapted with

permission from Eagle et al. (21). DMD ¼ Duchenne muscular dystrophy.

FIGURE 3 Absence of Dystrophin in DMD Skeletal Muscle

Photomicrographs of cross sections of normal and DMD human skeletal muscle. (A) Normal muscle biopsy shows relatively uniform fiber

diameter and peripherally located nuclei, with no fiber degeneration, inflammation, or endomysial fibrosis. (B) DMDmuscle biopsy shows varied

fiber diameter, inflammation, necrotic changes with fat, and fibrous replacement of normal muscle tissue. (C) Normal muscle biopsy stained for

dystrophin, which is located at the plasmalemma (brown). (D) DMD muscle biopsy stained for dystrophin, demonstrating the absence of

dystrophin expression. DMD ¼ Duchenne muscular dystrophy.

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due to the need for sedation, cost, and lack of acces-sibility. Thus, we propose that CMR be obtained at thetime of diagnosis and annually after 10 years of age,unless contraindicated.

PHARMACOLOGICAL TREATMENT OF

CARDIOMYOPATHY

CORTICOSTEROIDS. There is evidence that cortico-steroids can improve not only muscular function, butalso cardiac function in dystrophinopathies (61–63).One of the earliest studies was an evaluation of 21patients with DMD treated with deflazacort for morethan 3 years who had a significantly lower incidence ofcardiomyopathy at 3 years than DMD control subjects(5% vs. 58%) (62). Similarly, in a study of 48 patientswith DMD who had received either deflazacort orprednisone, the steroid-treated DMD group hadhigher fractional shortening than patients with un-treated DMD (32). Another small study of childrenwith DMD demonstrated that the 14 patients treatedwith steroids through the 4.5-year follow-up had lessventricular dilation and systolic dysfunction thanthose who had not received steroids (53). In one ofthe largest retrospective studies that included 462

FIGURE 5 DMD Cardiac Disease Progression

Schematic outlining DMD cardiomyopathy disease progression. Initially, patients with DMD have structurally normal hearts. Subsequently, patients with

DMD develop fibrosis of the inferobasal wall as the earliest sign of myocardial involvement. Over time, this leads to progressive fibrosis, left ventricular (LV)

dysfunction, and dilation leading to end-stage heart failure. DMD ¼ Duchenne muscular dystrophy.

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patients with DMD, those treated with steroids had adelay in the onset of cardiomyopathy (64). Addition-ally, another retrospective study that included 86patients with DMD concluded that patients with DMD

FIGURE 6 ECG Changes in DMD

Electrocardiogram (ECG) from a patient with DMD. The ECG demonstrat

V1 and V2. DMD ¼ Duchenne muscular dystrophy.

who received steroids had significantly lower cardio-vascular mortality and incidence of new cardiomy-opathy than control subjects, which was largelydriven by a reduction in heart failure–related

es sinus tachycardia, Q waves in leads I, aVL, and V4 to V6, and large R waves in

FIGURE 7 CMR Demonstrating Dilated Cardiomyopathy and

Fibrosis in a Patient With DMD

CMR delayed enhancement image in the basal short-axis view,

performed on a 1.5-T MRI. This image demonstrates near trans-

mural enhancement (gray) in the left ventricular (LV) basal-

midanterolateral, inferolateral, and lateral wall (area denoted by

dashed white line) consistent with myocardial scar or fibrosis. This

is in an 18-year-old male patient with DMD and exon 24 deletion

with associated cardiomyopathy (LV ejection fraction 33%). CMR ¼cardiac magnetic resonance; DMD¼ Duchennemuscular dystrophy;

MRI ¼ magnetic resonance imaging; RV ¼ right ventricle.

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deaths (65). However, a confounding variable in thisstudy is that the patients with DMD treated with ste-roids also began taking angiotensin-convertingenzyme inhibitors (ACEIs) approximately 3 yearsearlier than the control subjects, which may have alsobeen cardioprotective and had an effect on the results.

Although several studies have demonstrated adelay in onset of cardiomyopathy in patients withDMD, these have all been retrospective, observationalstudies with inherent limitations. Additionally, thevariability of steroid dosing and duration poses achallenge to interpretation of the data and broadapplication of the results. To rigorously assess theeffect of corticosteroid use on ventricular function inpatients with DMD, a prospective randomizedcontrolled trial will be necessary.

ACEIs AND ANGIOTENSIN RECEPTOR BLOCKERS.

ACEIs and angiotensin receptor blockers (ARBs) are acornerstone of neurohormonal modulation in heartfailure and were shown to be effective in the reduc-tion of cardiovascular mortality in patients with heartfailure (51). Duboc et al. (66) assessed the effect ofACEIs in patients with DMD with preserved left

ventricular function. They randomized 57 childrenwith DMD (mean age 10.7 years) to perindopril (2 to 4mg/day) or placebo. At 3 years of follow-up, there wasno significant difference in LV function between thechildren treated with perindopril or placebo. How-ever, 3 years following enrollment, all patients wereswitched to perindopril treatment and followed for anadditional 2 years. After crossing over to perindoprilat 2 years, there was no difference in mean LV func-tion between those patients treated with perindoprilinitially versus those initially treated with placebo.However, in the initial placebo group, 8 of 29 patientshad LVEF <45%, whereas only 1 of 27 patients had LVdysfunction in the perindopril group (p ¼ 0.02),supporting the notion that early treatment with per-indopril was effective in preventing progression toleft ventricular dysfunction in DMD. After a 10-yearfollow-up period, only 65% of patients in the initialplacebo group were alive versus 92.9% in the initialperindopril group (p ¼ 0.013), which emphasized thatearly initiation of an ACEI reduced mortality in pa-tients with DMD (67). Current guidelines for DMDrecommend initiation of ACEI in patients with DMDonly after LV dysfunction has developed (27); how-ever, on the basis of studies by Duboc et al. (66,67),we would recommend initiation of an ACEI (by 10years of age) before the development of left ventric-ular dysfunction in patients with DMD, as they are athigh risk for developing left ventricular dysfunction(ACC heart failure stages A and B). Additionally, forthose patients who are intolerant to ACEIs, ARBs canalso be used, as they were demonstrated to be aseffective as ACEIs in DMD (68).BETA-ADRENERGIC RECEPTOR BLOCKERS. Althoughthe benefit of ACEIs in DMD cardiomyopathy has beendefinitively established, the efficacy of beta-blockersin DMD cardiomyopathy has been less clear. The useof carvedilol has been assessed in pediatric patientswith DMDwho have elevated atrial natriuretic peptide(ANP) or BNP and a low ejection fraction (EF <40%) byechocardiography with no significant difference incarvedilol-treated patients with respect to symptomsor left ventricular dysfunction (69). However, in astudy by Rhodes et al. (70), carvedilol was shown to beefficacious in patients with DMD cardiomyopathy.When superimposed on background therapy of ACEIs,the use of carvedilol in this patient population re-mains unclear. In an analysis of 13 patients with DMDwho were treated with ACEI versus ACEI and carve-dilol, echocardiography revealed a beneficial effect ofbeta-blocker therapy in increasing left ventricularshortening and decreasing left ventricularend-diastolic dimensions (71). In contrast, a recentstudy by Viollet et al. (72) tested ACEI alone versus

TABLE 2 DMD Cardiomyopathy Treatment

Level of Evidence

Corticosteroids þþACE inhibitors þþþBeta-blockers þMineralocorticoid receptor antagonists þ

ACE ¼ angiotensin-converting enzyme; DMD ¼ Duchenne muscular dystrophy.

FIGURE 8 Cardiac Fibrosis in DMD

Photomicrograph of the basal posterior wall of the left ventricle in a patient with DMD

demonstrating subepicardial fibrotic replacement (blue) of the myocardium using Masson

trichrome stain. DMD ¼ Duchenne muscular dystrophy.

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ACEI and metoprolol; in this study, a low-dosebeta-blocker was added only for heart rates above100 beats/min or if arrhythmias occurred. The resultsshowed an improvement from pre-treatment LVEFin both groups, but no difference between them.Further research with larger groups of patients andmore robust trial designs are needed to definitivelyaddress the use of beta-blockers in DMD; however, onthe basis of current guidelines, we would recommendthat beta-blockers be initiated in patients with DMDwho have left ventricular dysfunction (51).

MINERALOCORTICOID RECEPTOR ANTAGONISTS.

Aldosterone inhibitors, such as spironolactone oreplerenone, are standard heart failure therapy forpatients with LVEF <35% and New York Heart Asso-ciation functional class II to VI symptoms (51). In arecently completed randomized double-blinded clin-ical trial, eplerenone, an aldosterone antagonist, orplacebo was added to background therapy of ACEIs orARBs in patients with DMD who had normal LVfunction to assess the efficacy of eplerenone in pre-venting cardiomyopathy in DMD. Twenty patientswere randomized to eplerenone and 20 to placebo,and they were followed for 6 and 12 months withCMR. The primary endpoint was change in left ven-tricular circumferential strain, which is a markerof contractility, at 12 months. The investigatorsobserved that the decline in LV circumferential strainwas lower in the group treated with eplerenone thanin the placebo group, although there was no overallchange in left ventricular function in either group(73). This small study demonstrated attenuation ofprogressive left ventricular dysfunction that occurs inDMD; although this study is positive, further studiesto assess the effect of eplerenone on DMD survival arewarranted. Table 2 summarizes cardiac pharmaco-logical treatments for DMD cardiomyopathy.

CARDIAC TRANSPLANTATION AND

LEFT VENTRICULAR ASSIST DEVICES

The only curative therapy for end-stage heart failureremains cardiac transplantation. Heart failure withmultisystem organ involvement and inability torehabilitate after cardiac transplantation has been arelative contraindication for orthotopic heart trans-plantation, and thus has limited the broad use of thistherapy in the DMD/BMD population. Rees et al. (74)were the first to describe heart transplantationin patients with muscular dystrophies in a singleGerman center. Of 582 transplants performed, 3patients with DMD and 1 patient with BMD underwentcardiac transplantation with a mean duration offollow-up of 40 months. These patients tolerated

immunosuppression, had no difference in post-operative intubation, and were able to be rehabili-tated (74). Ruiz-Cano et al. (75) described a Spanishsingle-center experience with heart transplantation in3 patients with BMD who underwent cardiac trans-plantation with a mean follow-up duration of 57months; this study also demonstrated that patientswith BMD had an intraoperative and post-operativecourse comparable to nonmuscular dystrophypatients undergoing heart transplantation. Patanèet al. (76) also described a single case of successfultransplantation in a patient with cardiomyopathysecondary to BMD. We performed a more recentmulticenter registry analysis of cardiac trans-plantation using the Cardiac Transplant ResearchDatabase and identified 29 patients with musculardystrophies, of whom 15 had BMD and 3 had DMD, whounderwent cardiac transplantation between 1995 and2005 and compared them with 275 nonmuscular dys-trophy, nonischemic patients matched for age, body

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mass index, sex, and race (77). We demonstrated thatthere was no significant difference in 1- or 5-year sur-vival, transplant rejection, infection, or allograft vas-culopathy between the patients with and withoutmuscular dystrophy. These studies described compa-rable outcomes of cardiac transplantation in a smalland select group of patients with DMD and BMD withend-stage cardiomyopathy; however, the functionalstatus of these patients prior to transplantation wasnot documented, and these studies may have aselection bias. We propose that orthotopic hearttransplantation should be considered for the patientwith DMD or BMD who has end-stage heart failure,provided that other comorbidities do not limit survival(i.e., respiratory failure). Further research regardingcardiac transplantation in patients with DMD and BMDwho have end-stage cardiomyopathy is warranted.

Given the scarcity of organs for heart trans-plantation, the use of left ventricular assist devices(LVADs), demonstrated to be to be effective in treat-ing patients with end-stage or advanced heart failure,is applicable to a larger population, including thosewith muscular dystrophies, as LVADs can be used asdestination therapy without the need for trans-plantation (78,79). Two groups recently reportedcases of successful implantation of LVADs as desti-nation therapy in patients with DMD (80,81). Amodeoet al. (80) were the first to describe LVAD implanta-tion in 2 pediatric patients with DMD. These in-vestigators implanted the Jarvik 2000 LVAD (JarvikHeart Inc., New York, New York) in a 15-year-old boywith DMD who had inotrope-refractory heart failureand in a 14-year-old boy with DMD who was bridgedfrom extracorporeal membrane oxygenation to a Jar-vik 2000 LVAD. These patients were discharged 3 and6 months after LVAD implantation, respectively.Ryan et al. (81) subsequently described implantationof the HeartMate II LVAD (Thoratec, Pleasanton,California) in a 29-year-old male patient with DMDand end-stage heart failure and of the HeartWareLVAD (HeartWare, Framingham, Massachusetts) in a23-year-old female symptomatic DMD carrier withend-stage heart failure.

The LVAD as destination therapy is a potentiallypromising therapy to address end-stage heart failurein patients with dystrophin-deficient heart failure;however, post-operative complications, includingrespiratory failure, rehabilitation, bleeding, stroke,and arrhythmias, will need to be evaluated further inthis population. Extensive pre- and post-operativemanagement in an experienced center would benecessary for LVAD implantation in the DMD popu-lation, and larger studies will be needed to evaluatethe efficacy and outcomes in this population.

BMD AND CARDIOMYOPATHY

In 1955, German physicians Becker and Kiener (82)described an X-linked muscular dystrophy with amilder clinical course than DMD, now known asBecker muscular dystrophy (83). In 1984, it wasdemonstrated that the gene responsible for BMD islocated on the X chromosome (84) and, subsequently,that mutations in the DMD gene resulted in BMD (85).BMD has an incidence of 1:19,000 and is an X-linkedrecessive disorder resulting from a mutation of thedystrophin gene (86). However, in comparison withpatients with DMD who have a complete absence ofdystrophin, dystrophin mutations in BMD tend to bein-frame and result in misfolded or abnormal and lessfunctional protein (87). Patients with BMD have atypically later age of onset and less severe clinicalinvolvement compared with patients with DMD(Table 1) (88). Although the muscular symptoms maybe less severe, over 70% of patients with BMD alsodevelop cardiomyopathy (89), and it is the leadingcause of death in patients with BMD (27). Cardiomy-opathy may be more severe in patients with BMD thanin patients with DMD (90,91). The onset of cardio-myopathy is variable in BMD and is not correlated toskeletal muscle involvement (89,92). CMR studieshave demonstrated an inferobasal fibrotic pattern inpatients with BMD similar to that seen in DMD (93).Patients with BMD cardiomyopathy should receivestandard medical heart failure therapy (51). As pa-tients with BMD have a relatively milder skeletalmuscle phenotype, selected patients with BMD havereceived LVADs and heart transplantation for severecardiomyopathy with good outcomes (74–77).

CARRIER STATUS AND CARDIOMYOPATHY

As DMD and BMD affect males, given that it isinherited in an X-linked recessive manner, femalescan be carriers of DMD and BMD. The majority of DMDand BMD is inherited, and thus there are a significantnumber of female carriers of DMD and BMD. Themajority of female carriers of DMD and BMD areasymptomatic; however, female carriers can becomesymptomatic or become manifesting carriers. Mani-festing carriers can have symptoms, such as mildmuscle weakness, elevated serum creatinine kinase,and cardiomyopathy (94,95). Hoogerwaard et al.(96,97) evaluated 90 women who were carriers ofdystrophin mutations and identified 22% with symp-toms, including muscle weakness, and 18% with evi-dence of dilated left ventricles. The age of onset ofcarriers is variable, and the proportion of symptomaticcarriers has ranged from 2.5% of 22% in prior studies

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(96,97). X-inactivation is themechanismwhere 1 of the2 X chromosomes in female cells randomly becomestranscriptionally inactive. It is postulated that carrierscan become symptomatic on the basis of the extent ofrandom X-inactivation of the normal X chromosomeversus the dystrophic X chromosome. Although DMDand BMD carriers have been identified as having car-diomyopathy, the prevalence and severity of diseaseare incompletely defined (96,98). We recommend thatall female dystrophinopathy carriers be screened forcardiomyopathy, including CMR, at the time of diag-nosis of their children (99,100).

X-LINKED DILATED CARDIOMYOPATHY

X-linked dilated cardiomyopathy (XLDCM) was firstdescribed in 1987 and is an extremely rare cardiomy-opathy resulting from mutations in the DMD gene thataffects teenage males and their mothers (101,102).Patients with XLDCMhave normal dystrophin levels inskeletal muscle, but a complete loss of dystrophin incardiac muscle, thus making it a distinct phenotype(i.e., cardiomyopathy without overt skeletal muscledisease) from DMD or BMD (103). The rapidly pro-gressive cardiomyopathy associated with XLDCMresults in death between 10 and 20 years of age.

EMERGING THERAPIES

A major challenge for treatment of DMD is therapiesthat address dystrophin deficiency and target bothcardiac and skeletal muscle (Central Illustration). Anumber of promising therapies are emerging,including exon skipping, dystrophin gene replace-ment, and gene-editing strategies.EXON SKIPPING. DMD mutations are heterogeneous,but the majority of mutations arise from anout-of-frame deletion or duplication within the DMDgene’s 79 exons. These mutations affect the normaltranscription of dystrophin messenger ribonucleicacid open reading frame and subsequently preventthe full-length dystrophin protein from being tran-scribed. A novel therapy for the treatment of DMDinvolves exon skipping within the central roddomain, which can restore the normal messengerribonucleic acid reading frame and convert anout-of-frame mutation to a less severe in-framemutation, comparable to those seen in BMD. Thiscan be achieved through the use of antisense oligo-nucleotides (AONs), which are short, syntheticnucleic acid fragments that regulate ribonucleic acidsplicing (104). Antisense oligonucleotides for exonskipping that target exon 51 of the DMD gene, whichaccounts for w13% of DMD mutations, including dri-sapersen (GSK-2402698, GlaxoSmithKline, Brentford,

United Kingdom; Prosensa, Leiden, the Netherlands)and eteplirsen (AVI 4658, Sarepta Therapeutics,Cambridge, Massachusetts), are currently beingexamined in clinical trials. Initial phase I and II trialsfor both eteplirsen and drisapersen were promisingin restoring dystrophin expression, but did notdemonstrate a significant change in the primaryendpoint, the 6-min walk test. Major side effectsincluded renal toxicity and thrombocytopenia(105,106). These drugs are being further evaluated inphase III clinical trials.

DYSTROPHIN GENE AND CELL THERAPY. As dystro-phin mutations lead to complete absence of thefunctional dystrophin protein in DMD, 1 of the stra-tegies to mitigate the disease sequelae is genereplacement therapy using recombinant adenoviralvirus vectors (rAAV). In comparison to the exonskipping strategy, which currently is available onlyfor exon 51 skipping, gene replacement strategies canbe beneficial for all patients with DMD, regardless oftheir specific DMD mutation. A limitation of rAAVtechnology is the inability to deliver the large,full-length dystrophin gene due to packaging limita-tions (107). However, the observation of mildlyaffected patients with BMD who had very large dys-trophin gene deletions led to the understanding thattruncated dystrophins could be functional (85,108).This led to the development of micro- or mini-dystrophins, which contain only the essential, func-tional regions of the gene and can be packagedwithin the rAAV (109). Dystrophin gene replacementtherapy has been effective in mouse models; howev-er, in large animal models, efficacy has been limiteddue to the host immune response (110,111). In a hu-man pre-clinical trial of mini-dystrophin gene trans-fer, 6 patients with DMD received injections ofmini-dystrophin, but none demonstrated significantincreases in dystrophin levels and 1 patient had animmune response (112,113). In addition, cell therapyinitiatives for DMD cardiomyopathy usingcardiosphere-derived cells and/or induced pluripo-tent stem cell derivatives have shown improvementin both cardiac function and exercise capacity of themdx (dystrophin knockout) mouse model. Genereplacement and cell therapies, although limited byimmune side effects, may be overcome by immuno-suppressant regimens and may represent promisingtherapies for DMD cardiomyopathy.

DYSTROPHIN GENE EDITING. Gene editing is anemerging technology for DMD. Gene editing can bemediated by clustered regularly interspaced shortpalindromic repeats (CRISPR)/CRISPR-associatedsystems (Cas) to alter or edit the genome (114,115).

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The CRISPR/Cas9 system binds to the target gene andgenerates a double-stranded deoxyribonucleic acidbreak, which then can be replaced by the correctedgene sequence. This system precisely removes themutated gene of interest and replaces it with a func-tional copy of the gene. Gene editing using aCRISPR/Cas9 strategy was utilized in vivo to correctthe DMD gene mutation in the germline of mdx mice(116). In mosaic mdx mice with only 17% correction ofdystrophin by gene editing, a normal muscle pheno-type was observed. This nascent technology haspossible therapeutic benefits in patients with DMD,and further animal studies evaluating cardiac func-tion are needed. Recently, adult mdx mice were alsosuccessfully treated using a gene-editing strategy(117,118).

CONCLUSIONS

Cardiomyopathy is a leading cause of death in theDMD population. Early detection and intervention

with medical and device therapies are warranted.Given the significant cardiomyopathic phenotype inthe dystrophinopathy population, we have estab-lished a neurocardiomyopathy clinic where thesepatients have a comprehensive evaluation with heartfailure cardiologists and neuromuscular neurologists.We believe that increasing attention by heart failure–trained subspecialists and the establishment ofdedicated neurocardiomyopathy clinics will enhanceour understanding of the mechanisms of DMD car-diomyopathy and ultimately have an effect on themorbidity and mortality of this disease.

ACKNOWLEDGMENT The authors are grateful forartwork assistance by Ms. Cynthia DeKay.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Daniel J. Garry, Cardiovascular Division, LilleheiHeart Institute, University of Minnesota, 2231 6thStreet Southeast, 4-146 CCRB, Minneapolis, Minne-sota 55455. E-mail: garry@umn.edu.

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KEY WORDS Becker muscular dystrophycardiomyopathy, Duchenne musculardystrophy cardiomyopathy, musculardystrophy cardiomyopathy