JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 67, NO.

21, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER http://dx.doi.org/10.1016/j.jacc.2016.02.081

REVIEW TOPIC OF THE WEEK

Dystrophin-Deficient Cardiomyopathy
Forum Kamdar, MD, Daniel J. Garry, MD, PHD

ABSTRACT

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: the development of diagnostic and genetic testing, as

Listen to this manuscript’s
audio summary by
JACC Editor-in-Chief
Dr. Valentin Fuster.
A HISTORICAL PERSPECTIVE
The earliest detailed descriptions of muscular dys-
trophies were by Meryon (1) in England in 1852 and by
Duchenne (2) in France in 1868, identifying a disease
that affected young boys with severe muscular
weakness and an abnormal increase in calf size.
Duchenne (2) observed fatty-fibrous replacement of
skeletal muscle in muscle biopsies obtained from
these boys; for this contribution, the disease was
named after him. In 1886, Gowers (3) described how a
child affected with muscular dystrophy used his arms
to rise from the ground. Although
muscular dystrophy (DMD) had been known as a
clinical entity since the 1860s, its cause was not
elucidated until over 100 years later. In a landmark
discovery, Louis Kunkel’s laboratory (1986) identified
the DMD gene responsible for causing DMD and, a
year later, demonstrated that mutations resulted
in the absence of the 427-kDa rod-like protein dys-
trophin (4,5). These major advancements allowed for
well as the establishment of disease models that have
enhanced our understanding of DMD. Although a
number of questions remain regarding the muscular
dystrophies, the rich history of discovery has signifi-
cantly accelerated our knowledge of DMD in the last
30-year period.
DYSTROPHINOPATHIES: INHERITANCE
DMD is the most common form of muscular dys-
trophy, affecting 1 in every 5,000 boys born in the
United States (Table 1) (6–8). DMD is a result of
Duchenne an inherited or spontaneous mutation of the DMD
gene. DMD is a 2.5-Mb gene located on chromosome
Xp21.1 (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 3
promoters: the M promoter produces the Dp427m
isoform, expressed in skeletal and cardiac muscle;
the B promoter produces Dp427c, expressed in
the brain; and the P promoter produces Dp427p,

From the Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota. Both authors have
reported that they have no relationships relevant to the contents of this paper to disclose.

Manuscript received December 14, 2015; revised manuscript received February 16, 2016, accepted February 23, 2016.
2534 Kamdar and Garry JACC VOL. 67, NO. 21, 2016

DMD and BMD Cardiomyopathy MAY 31, 2016:2533–46

ABBREVIATIONS expressed in the Purkinje cells in the brain function or absence of 1 or several of these DGC pro-
AND ACRONYMS (Figure 1) (10). teins leads to plasma membrane fragility. DMD and
An out-of-frame mutation of 1 or several of Becker muscular dystrophy (BMD) arise from muta-
ACEI = angiotensin-converting
enzyme inhibitor
the 79 exons in the full-length Dystrophin tions in dystrophin, and other forms of muscular dys-
gene results in an absence of a functional trophies arise from mutations in DGC components. In
BMD = Becker muscular
dystrophy dystrophin protein, causing the DMD pheno- skeletal muscle, the DGC is located at regular intervals
CMR = cardiac magnetic type. DMD is inherited in an X-linked reces- in structures known as costameres, whereas in cardiac
resonance imaging sive manner, where a female carrier with 1 X muscle, the DGC is not located in discrete costameres
CRISPR = clustered regularly- chromosome carrying the DMD mutation has and may have a unique composition (15,16).
interspaced short palindromic a 50% chance of passing on the mutated X
repeat
chromosome to her son. Female carriers can
PATHOGENESIS AND PHYSICAL FINDINGS
DGC = dystroglycan complex
also have symptoms on the basis of their
DMD = Duchenne muscular Skeletal muscle and heart lacking functional dystro-
X-inactivation. Although the majority of DMD
dystrophy phin are mechanically weak, and contraction of the
mutations are inherited, spontaneous muta-
ECG = electrocardiogram cell (skeletal myocytes and cardiac myocytes) leads
tions account for 30% of DMD cases (11).
ICD = implantable to membrane damage (17–19) (Central Illustration).
cardioverter-defibrillator DYSTROPHIN AND DYSTROGLYCAN Loss of membrane integrity results in a cascade of
LVAD = left ventricular COMPLEX ORGANIZATION increased calcium influx into the cell and eventual
assist device
cell death. Clinically, dystrophin loss manifests as
LVEF = left ventricular ejection Dystrophin, a rod-shaped cytoplasmic pro- progressive muscle weakness (6). Symptoms are first
fraction
tein, connects the dystroglycan complex noted in early childhood and include calf pseudohy-
(DGC) to the intracellular contractile apparatus and pertrophy, an inability to stand without using the
extracellular matrix (ECM) of the cell (Figure 2) (12). arms for assistance (Gower maneuver), toe walking,
Dystrophin is similar to spectrin and consists of 2 and difficulty keeping up with peers. As the disease
ends separated by long, flexible, rod-like regions. The progresses, patients’ skeletal muscle becomes
N-terminus binds actin and the C-terminus binds to increasingly weak, causing atrophy and contractures,
glycoproteins in the sarcolemma. The role of dystro- which subsequently results in the loss of ambulation
phin is to stabilize the plasma membrane by trans- in their teens. Due to ongoing muscle damage, pa-
mitting forces generated by the sarcomeric tients with DMD have markedly elevated serum levels
contraction to the ECM (Figure 2). of the muscle protein creatine kinase (CK), which may
The DGC is a multimeric complex composed of be 10
to over 100
the normal limit, and an elevated
glycated integral membrane proteins and peripheral CK level is a diagnostic sign (20). The diagnosis of
proteins that form a structural link between the DMD can be confirmed by muscle biopsy demon-
filamentous (F)-actin cytoskeleton and the ECM in strating the absence of dystrophin (Figure 3) and
both cardiac and skeletal muscle (13). The DGC using genetic testing for dystrophin mutations.
is comprised of cytoskeletal proteins, dystrophin,
syntrophins, dystroglycans, sarcoglycans, DGC- SURVIVAL
associated proteins, neuronal nitric oxide synthase,
and dystrobrevin (14). The fully nucleated DGC pro- Historically, this progressive muscle weakness resul-
vides mechanical support to the skeletal or cardiac ted in loss of ambulation by 10 to 12 years of age and
plasma membrane during contraction, and loss of death during the second decade of life, primarily due
to respiratory failure. However, with the advent of
nocturnal ventilation, spinal stabilization surgery,
T A B L E 1 DMD Versus BMD
and steroid treatment, the life expectancy of boys
DMD BMD with DMD has increased to the late twenties to early
Dystrophin protein Absent Partially functional thirties (21) (Figure 4). Although respiratory failure
Incidence 1:5,000 male births 1:19,000 was previously the major cause of death, cardiomy-
Mean age at onset, yrs 3–5 12
opathy has now emerged as the leading cause of
Mean age of becoming w12 w27
nonambulatory, yrs death in patients with DMD (22).
Mean life expectancy, yrs Mid to late 20s 40s
Onset of cardiomyopathy, yrs 16–18 Variable; cardiomyopathy
NONCARDIAC TREATMENTS
may precede skeletal
symptoms
Advances in management, namely corticosteroid
BMD ¼ Becker muscular dystrophy; DMD ¼ Duchenne muscular dystrophy.
treatments, spinal stabilization, and improved pul-
monary support, have significantly improved the life
JACC VOL. 67, NO. 21, 2016 Kamdar and Garry 2535
MAY 31, 2016:2533–46 DMD and BMD Cardiomyopathy

F I G U R E 1 Dystrophin Gene and Protein

A B/Dp427

M/Dp427
R/Dp260 B,K/Dp140 S/Dp116 G/Dp71
Gene P/Dp427
500 kb 1000 kb 1500 kb 2500kb

Exons N terminus 1 2 1 2 3 4 4 5 5 6 6 7 7
0 0 0 0 5 0 6 0 3 0 9
Dystrobrevin binding site
Actin nNOS Dystroglycan Syntrophin binding site
binding binding Binding site
domain
B H H H 2 H
Structural NH2 1 COOH
1 2 3 4 4
Dy Sy
str n
og d tro
lyc ystro phin
Rod Domain an bre
vin

(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.

expectancy of boys/men with DMD to the late
twenties and early thirties (21). Glucocorticoids are
one of the mainstays of treatment for DMD and have
been shown to improve muscle strength, function,
and pulmonary function (23). Glucocorticoids are
currently recommended in patients with DMD who
are 5 years of age or older who are not gaining or have
a decline in motor skills (24). Current glucocorticoid
protocols 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 on
and 10 days off; and daily deflazacort 0.9 mg/kg/day
(25). Deflazacort is another steroid that is used in the
DMD patient population and may have a more limited
side effect profile compared with prednisone (26).
Scoliosis and kyphosis, common,
sequelae of DMD, subsequently result in decreased
pulmonary function and discomfort in these patients;
however, implementing spinal stabilization surgery
using Harrington rods has improved survival, com-
fort, and pulmonary function (27). Respiratory com-
plications occur frequently in patients with DMD as
losing respiratory muscle strength
decreased ventilation, and they are at increased risk
for pneumonia, atelectasis, and respiratory failure
(28). The majority of deaths in end-stage DMD pre-
viously occurred as a result of respiratory failure and
infections; however, the introduction of noninvasive
nocturnal mechanical ventilation has improved sur-
vival in patients with DMD and may improve
cardiac function through afterload reduction (29,30).
Additionally, nutrition, exercise therapy, and psy-
chosocial support are critical in the interdisciplinary
care of patients with DMD (27).
CARDIAC INVOLVEMENT IN DMD
The reduction of respiratory-related deaths due to
nocturnal ventilation and spinal stabilization has
contributed to the increase of DMD cardiomyopathy
due to the increased survival and advanced age of
patients with DMD (21,31). The incidence of cardio-
myopathy in DMD increases with age. Although it is
estimated that 25% of boys have cardiomyopathy at
6 years of age and 59% by 10 years of age, cardiac
involvement is nearly ubiquitous in older patients
progressive with DMD, as more than 90% of young men over
18 years of age demonstrate evidence of cardiac
dysfunction (22). Dilated cardiomyopathy typically
has an onset in the midteen years and progressively
remodels and contributes to the demise of patients
with DMD (22,32) (Figure 5). Distinct dystrophin
mutations have been correlated to an increased
leading to incidence of cardiomyopathy and possible response
to treatment (33). Recognition of heart failure
symptoms in patients with DMD can be challenging
due to physical inactivity and other respiratory
complaints that can obscure the diagnosis (34).
Currently, clinical guidelines recommend the initial
cardiac screening at the time of diagnosis of DMD,
every 2 years until 10 years of age, and then yearly
thereafter (24).
2536 Kamdar and Garry
DMD and BMD Cardiomyopathy
F I G U R E 2 Schematic Diagram of the DGC
Extracellular
Sarcoglycans
Dystrophin
Intracellular
Actin cytoskeleton
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.
Most patients with DMD will have abnormal elec-
trocardiographic tracings. The classical pattern dem-
onstrates tall R waves and increased R/S amplitude in
lead V 1 , Q waves in the left precordial leads, right axis
deviation, or complete right bundle branch block
(Figure 6) (35–37). These electrocardiographic (ECG)
findings correlate with the pathological studies that
have demonstrated a predilection for fibrosis in the
basal posterior wall of the heart in patients with
muscular dystrophies and may reflect a reduction in
electrical activity in the inferobasal ventricular wall
(38). ECG findings are believed to precede echocar-
diographic findings of cardiomyopathy; however, no
correlation between ECG findings and the presence of
cardiomyopathy has yet been established (35,39). The
use of serum biomarkers, such as cardiac troponin or
B-type natriuretic peptides (BNPs), has not been well
established for DMD screening and will need further
examination in the future.
Arrhythmias are a common cardiac involvement in
patients with muscular dystrophies. Sinus tachy-
cardia is a common finding in patients with DMD
(40–42). Dystrophic patients have elevated heart
rates, even when compared with patients with other
muscular dystrophies or deconditioned patients (42).
Pathological examination of the heart in dystrophic
patients has demonstrated fibrosis of the conduction
system, in addition to the myocardium (43), which
may, in part, explain the autonomic dysfunction
in the DMD population (44,45). Additionally, sinus
tachycardia may correlate with cardiac dysfunction in
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
ECM
Laminin
α-dystroglycan
β-dystroglycan
Sarcolemma
Syntrophin
nNOS Dystrobrevin
COOH
patients with DMD (46). Dalmaz et al. (47) demon-
strated that urinary catecholamines increased in
patients with DMD around 10 years of age, which
corresponded temporally to heart rate elevation and
cardiac involvement. In patients with DMD cardio-
myopathy, atrial arrhythmias, including atrial fibril-
lation, atrial flutter, and atrial tachycardias, can also
occur. Ventricular tachycardia, premature ventricular
complexes, and other conduction abnormalities have
been 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 QT
dispersion has been identified as a risk factor for
ventricular arrhythmias in DMD; however, there was
no prognostic value of signal-averaged ECG (49,50).
The role of implantable cardioverter-defibrillators
(ICDs) is well-established for primary prevention of
sudden 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). The
guidelines discourage the use of ICDs for a patient
with a life expectancy <1 year, and ICDs may not have
been utilized in the past due to the previous high
mortality in patients with DMD. The recent use of
neurohormonal therapy may also improve LVEF to
reduce the risk of sudden cardiac death. We would
recommend ICD implantation candidacy for patients
with DMD with LVEF <35%; however, an individual-
ized discussion with patients and families is neces-
sary, given the course of disease progression.
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
CENTRAL ILLUSTRATION Duchenne Muscular Dystrophy: Pathogenesis and Therapies
DUCHENNE MUSCULAR DYSTROPHY
Disease typically affects boys
(1 in every 5,000 boys born in the U.S.)
Possible learning
difficulties
Scoliosis
Cardiomyopathy
Weak
respiratory
muscles
Muscle loss
and weakness
leading to
loss of
ambulation
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.
CARDIAC IMAGING IN DMD
Cardiac imaging can be challenging in patients with
end-stage DMD due to scoliosis, ventilation abnor-
malities, and contractures. Current, commonly used
imaging modalities include echocardiography and
cardiac magnetic resonance (CMR). Echocardiography
in DMD cardiomyopathy has demonstrated regional
wall motion abnormalities in the posterior basal wall,
left ventricular dilation, and overall reduced systolic
function (52). Current guidelines recommend an
echocardiogram at the time of diagnosis or by 6 years
of age, with repeat echocardiograms every 1 to 2 years
until 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 modality
to utilize, it can be technically challenging in
patients with DMD due to chest wall deformities,
scoliosis, and respiratory dysfunction, thus limiting
the diagnostic yield (53). CMR has been used to image
patients with DMD and can provide one of the most
accurate assessments of left ventricular size and
Kamdar and Garry 2537
DMD and BMD Cardiomyopathy
PATHOGENESIS THERAPIES
Inherited or Current cardiac treatments
spontaneous mutation
in the DMD gene • Steroid treatment (glucocorticoids)
• Neurohormonal therapy: Angiotensin
converting enzyme inhibitors (ACEIs) and
angiotensin receptor blockers (ARBs)
Absence of dystrophin—
the anchor that connects
Dystrophin the extracellular matrix Current non-cardiac treatments
and membrane proteins • Noninvasive nocturnal ventilation
to the cell cytoskeleton
• Nutrition, exercise therapy,
and psychological support
• Spinal stabilization
Contraction of muscle
cell leads to cell
membrane damage Emerging treatments
• Implantable cardioverter defibrillation
• Beta-blockers
Increased calcium
influx into damaged • Aldosterone inhibitors
cell leads to cell death • Exon skipping
• Dystrophin gene replacement
Progressive • Gene editing mediated with CRISPR/Cas9
muscle weakness • Advanced heart failure therapies
function (54–56). Silva et al. (54) performed gadolin-
ium contrast-enhanced CMR on 10 patients with
dystrophinopathies (8 patients with DMD and 2 with
BMD) and were the first to demonstrate late gado-
linium enhancement (LGE) by CMR in the dystrophic
heart. They further demonstrated that LGE was pre-
sent by echocardiography, even with normal left
ventricular 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 subepicardial
distribution (Figure 7). This pattern of LGE in the
basal inferior and inferolateral walls is consistent
with 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 to
increase with age and correlates with a decline in
LVEF (59,60). Thus, CMR may provide earlier detec-
tion of cardiovascular involvement in DMD, allow for
accurate and reproducible quantification of left ven-
tricular function and size, and promote initiation of
earlier cardioprotective treatment. CMR has many
imaging benefits for patients with DMD; however, it
can also be challenging in the pediatric population
2538 Kamdar and Garry JACC VOL. 67, NO. 21, 2016

DMD and BMD Cardiomyopathy MAY 31, 2016:2533–46

F I G U R E 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) DMD muscle 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.

due to the need for sedation, cost, and lack of acces-

sibility. Thus, we propose that CMR be obtained at the
time of diagnosis and annually after 10 years of age,
F I G U R E 4 Interventions Prolong Survival in DMD unless contraindicated.

30 PHARMACOLOGICAL TREATMENT OF
CARDIOMYOPATHY

CORTICOSTEROIDS. There is evidence that cortico-

20 steroids can improve not only muscular function, but
Age At Death

also cardiac function in dystrophinopathies (61–63).

One of the earliest studies was an evaluation of 21
patients with DMD treated with deflazacort for more
10 than 3 years who had a significantly lower incidence of
cardiomyopathy at 3 years than DMD control subjects
(5% vs. 58%) (62). Similarly, in a study of 48 patients
with DMD who had received either deflazacort or
0
prednisone, the steroid-treated DMD group had
SS

s
0

90

80

70

60

higher fractional shortening than patients with un-

99
t+

19
19

19
19
1
n

ed
nt

ed

d
ed
Ve

treated DMD (32). Another small study of children

e
Ve

Di
Di

Di
Di

with DMD demonstrated that the 14 patients treated

A marked increase in survival of patients with DMD has been achieved with the addition
with steroids through the 4.5-year follow-up had less
of ventilation strategies (vent) and spinal stabilization surgeries (SS). Adapted with ventricular dilation and systolic dysfunction than
permission from Eagle et al. (21). DMD ¼ Duchenne muscular dystrophy. those who had not received steroids (53). In one of
the largest retrospective studies that included 462
JACC VOL. 67, NO. 21, 2016 Kamdar and Garry 2539
MAY 31, 2016:2533–46 DMD and BMD Cardiomyopathy

F I G U R E 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.

patients with DMD, those treated with steroids had a who received steroids had significantly lower cardio-
delay in the onset of cardiomyopathy (64). Addition- vascular mortality and incidence of new cardiomy-
ally, another retrospective study that included 86 opathy than control subjects, which was largely
patients with DMD concluded that patients with DMD driven by a reduction in heart failure–related

F I G U R E 6 ECG Changes in DMD

Electrocardiogram (ECG) from a patient with DMD. The ECG demonstrates sinus tachycardia, Q waves in leads I, aVL, and V4 to V6, and large R waves in
V1 and V2. DMD ¼ Duchenne muscular dystrophy.
2540 Kamdar and Garry
DMD and BMD Cardiomyopathy
F I G U R E 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 ¼
cardiac magnetic resonance; DMD ¼ Duchenne muscular dystrophy;
MRI ¼ magnetic resonance imaging; RV ¼ right ventricle.
deaths (65). However, a confounding variable in this
study is that the patients with DMD treated with ste-
roids also began taking angiotensin-converting
enzyme inhibitors (ACEIs) approximately 3 years
earlier than the control subjects, which may have also
been cardioprotective and had an effect on the results.
Although several studies have demonstrated a
delay in onset of cardiomyopathy in patients with
DMD, these have all been retrospective, observational
studies with inherent limitations. Additionally, the
variability of steroid dosing and duration poses a
challenge to interpretation of the data and broad
application of the results. To rigorously assess the
effect of corticosteroid use on ventricular function in
patients with DMD, a prospective randomized
controlled trial will be necessary.
ACEIs AND ANGIOTENSIN RECEPTOR BLOCKERS.
ACEIs and angiotensin receptor blockers (ARBs) are a
cornerstone of neurohormonal modulation in heart
failure and were shown to be effective in the reduc-
tion of cardiovascular mortality in patients with heart
failure (51). Duboc et al. (66) assessed the effect of
ACEIs in patients with DMD with preserved left
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
ventricular function. They randomized 57 children
with DMD (mean age 10.7 years) to perindopril (2 to 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. How-
ever, 3 years following enrollment, 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 func-
tion between those patients treated with perindopril
initially versus those initially treated with placebo.
However, in the initial placebo group, 8 of 29 patients
had LVEF <45%, whereas only 1 of 27 patients had LV
dysfunction in the perindopril group (p ¼ 0.02),
supporting the notion that early treatment with per-
indopril was effective in preventing progression to
left ventricular dysfunction in DMD. After a 10-year
follow-up period, only 65% of patients in the initial
placebo group were alive versus 92.9% in the initial
perindopril group (p ¼ 0.013), which emphasized that
early initiation of an ACEI reduced mortality in pa-
tients with DMD (67). Current guidelines for DMD
recommend initiation of ACEI in patients with DMD
only 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 10
years of age) before the development of left ventric-
ular dysfunction in patients with DMD, as they are at
high risk for developing left ventricular dysfunction
(ACC heart failure stages A and B). Additionally, for
those patients who are intolerant to ACEIs, ARBs can
also be used, as they were demonstrated to be as
effective as ACEIs in DMD (68).
BETA-ADRENERGIC RECEPTOR BLOCKERS. Although
the benefit of ACEIs in DMD cardiomyopathy has been
definitively established, the efficacy of beta-blockers
in DMD cardiomyopathy has been less clear. The use
of carvedilol has been assessed in pediatric patients
with DMD who have elevated atrial natriuretic peptide
(ANP) or BNP and a low ejection fraction (EF <40%) by
echocardiography with no significant difference in
carvedilol-treated patients with respect to symptoms
or left ventricular dysfunction (69). However, in a
study by Rhodes et al. (70), carvedilol was shown to be
efficacious 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 DMD
who were treated with ACEI versus ACEI and carve-
dilol, echocardiography revealed a beneficial effect of
beta-blocker therapy in increasing left ventricular
shortening and decreasing left ventricular
end-diastolic dimensions (71). In contrast, a recent
study by Viollet et al. (72) tested ACEI alone versus
JACC VOL. 67, NO. 21, 2016 Kamdar and Garry 2541
MAY 31, 2016:2533–46 DMD and BMD Cardiomyopathy

ACEI and metoprolol; in this study, a low-dose

F I G U R E 8 Cardiac Fibrosis in DMD
beta-blocker was added only for heart rates above
100 beats/min or if arrhythmias occurred. The results
showed an improvement from pre-treatment LVEF
in both groups, but no difference between them.
Further research with larger groups of patients and
more robust trial designs are needed to definitively
address the use of beta-blockers in DMD; however, on
the basis of current guidelines, we would recommend
that beta-blockers be initiated in patients with DMD
who have left ventricular dysfunction (51).
MINERALOCORTICOID RECEPTOR ANTAGONISTS.
Aldosterone inhibitors, such as spironolactone or
eplerenone, are standard heart failure therapy for
patients with LVEF <35% and New York Heart Asso-
ciation functional class II to VI symptoms (51). In a
recently completed randomized double-blinded clin-
ical trial, eplerenone, an aldosterone antagonist, or
placebo was added to background therapy of ACEIs or
ARBs in patients with DMD who had normal LV Photomicrograph of the basal posterior wall of the left ventricle in a patient with DMD
function to assess the efficacy of eplerenone in pre- demonstrating subepicardial fibrotic replacement (blue) of the myocardium using Masson
venting cardiomyopathy in DMD. Twenty patients trichrome stain. DMD ¼ Duchenne muscular dystrophy.
were randomized to eplerenone and 20 to placebo,
and they were followed for 6 and 12 months with
CMR. The primary endpoint was change in left ven- immunosuppression, had no difference in post-
tricular circumferential strain, which is a marker operative intubation, and were able to be rehabili-
of contractility, at 12 months. The investigators tated (74). Ruiz-Cano et al. (75) described a Spanish
observed that the decline in LV circumferential strain single-center experience with heart transplantation in
was lower in the group treated with eplerenone than 3 patients with BMD who underwent cardiac trans-
in the placebo group, although there was no overall plantation with a mean follow-up duration of 57
change in left ventricular function in either group months; this study also demonstrated that patients
(73). This small study demonstrated attenuation of with BMD had an intraoperative and post-operative
progressive left ventricular dysfunction that occurs in course comparable to nonmuscular dystrophy
DMD; although this study is positive, further studies patients undergoing heart transplantation. Patanè
to assess the effect of eplerenone on DMD survival are et al. (76) also described a single case of successful
warranted. Table 2 summarizes cardiac pharmaco- transplantation in a patient with cardiomyopathy
logical treatments for DMD cardiomyopathy. secondary to BMD. We performed a more recent
multicenter registry analysis of cardiac trans-
CARDIAC TRANSPLANTATION AND plantation using the Cardiac Transplant Research
LEFT VENTRICULAR ASSIST DEVICES Database and identified 29 patients with muscular
dystrophies, of whom 15 had BMD and 3 had DMD, who
The only curative therapy for end-stage heart failure underwent cardiac transplantation between 1995 and
remains cardiac transplantation. Heart failure with 2005 and compared them with 275 nonmuscular dys-
multisystem organ involvement and inability to trophy, nonischemic patients matched for age, body
rehabilitate after cardiac transplantation has been a
relative contraindication for orthotopic heart trans-
T A B L E 2 DMD Cardiomyopathy Treatment
plantation, and thus has limited the broad use of this
therapy in the DMD/BMD population. Rees et al. (74) Level of Evidence

were the first to describe heart transplantation Corticosteroids þþ

in patients with muscular dystrophies in a single ACE inhibitors þþþ

German center. Of 582 transplants performed, 3 Beta-blockers þ

Mineralocorticoid receptor antagonists þ
patients with DMD and 1 patient with BMD underwent
cardiac transplantation with a mean duration of ACE ¼ angiotensin-converting enzyme; DMD ¼ Duchenne muscular dystrophy.
follow-up of 40 months. These patients tolerated
2542 Kamdar and Garry
DMD and BMD Cardiomyopathy
mass index, sex, and race (77). We demonstrated that
there was no significant difference in 1- or 5-year sur-
vival, transplant rejection, infection, or allograft vas-
culopathy between the patients with and without
muscular dystrophy. These studies described compa-
rable 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 documented, and these studies may have a
selection bias. We propose that orthotopic heart
transplantation should be considered for the patient
with DMD or BMD who has end-stage heart failure,
provided that other comorbidities do not limit survival
(i.e., respiratory failure). Further research regarding
cardiac transplantation in patients with DMD and BMD
who 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 those
with muscular dystrophies, as LVADs can be used as
destination therapy without the need for trans-
plantation (78,79). Two groups recently reported
cases of successful implantation of LVADs as desti-
nation therapy in patients with DMD (80,81). Amodeo
et al. (80) were the first to describe LVAD implanta-
tion in 2 pediatric patients with DMD. These in-
vestigators implanted the Jarvik 2000 LVAD (Jarvik
Heart Inc., New York, New York) 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 Jar-
vik 2000 LVAD. These patients were discharged 3 and
6 months after LVAD implantation, respectively.
Ryan et al. (81) subsequently described implantation
of the HeartMate II LVAD (Thoratec, Pleasanton,
California) in a 29-year-old male patient with DMD
and end-stage heart failure and of the HeartWare
LVAD (HeartWare, Framingham, Massachusetts) in a
23-year-old female symptomatic DMD carrier with
end-stage heart failure.
The LVAD as destination therapy is a potentially
promising therapy to address end-stage heart failure
in patients with dystrophin-deficient heart failure;
however, post-operative complications, including
respiratory failure, rehabilitation, bleeding, stroke,
and arrhythmias, will need to be evaluated further in
this population. Extensive pre- and post-operative
management in an experienced center would be
necessary for LVAD implantation in the DMD popu-
lation, and larger studies will be needed to evaluate
the efficacy and outcomes in this population.
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
BMD AND CARDIOMYOPATHY
In 1955, German physicians Becker and Kiener (82)
described an X-linked muscular dystrophy with a
milder clinical course than DMD, now known as
Becker muscular dystrophy (83). In 1984, it was
demonstrated that the gene responsible for BMD is
located 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-linked
recessive disorder resulting from a mutation of the
dystrophin gene (86). However, in comparison with
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 (87). Patients with BMD have a
typically later age of onset and less severe clinical
involvement compared with patients with DMD
(Table 1) (88). Although the muscular symptoms may
be less severe, over 70% of patients with BMD also
develop cardiomyopathy (89), and it is the leading
cause of death in patients with BMD (27). Cardiomy-
opathy may be more severe in patients with BMD than
in patients with DMD (90,91). The onset of cardio-
myopathy is variable in BMD and is not correlated to
skeletal muscle involvement (89,92). CMR studies
have demonstrated an inferobasal fibrotic pattern in
patients with BMD similar to that seen in DMD (93).
Patients with BMD cardiomyopathy should receive
standard medical heart failure therapy (51). As pa-
tients with BMD have a relatively milder skeletal
muscle phenotype, selected patients with BMD have
received LVADs and heart transplantation for severe
cardiomyopathy with good outcomes (74–77).
CARRIER STATUS AND CARDIOMYOPATHY
As DMD and BMD affect males, given that it is
inherited in an X-linked recessive manner, females
can be carriers of DMD and BMD. The majority of DMD
and BMD is inherited, and thus there are a significant
number of female carriers of DMD and BMD. The
majority of female carriers of DMD and BMD are
asymptomatic; however, female carriers can become
symptomatic or become manifesting carriers. Mani-
festing carriers can have symptoms, such as mild
muscle weakness, elevated serum creatinine kinase,
and cardiomyopathy (94,95). Hoogerwaard et al.
(96,97) evaluated 90 women who were carriers of
dystrophin mutations and identified 22% with symp-
toms, including muscle weakness, and 18% with evi-
dence of dilated left ventricles. The age of onset of
carriers is variable, and the proportion of symptomatic
carriers has ranged from 2.5% of 22% in prior studies
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
(96,97). X-inactivation is the mechanism where 1 of the
2 X chromosomes in female cells randomly becomes
transcriptionally inactive. It is postulated that carriers
can become symptomatic on the basis of the extent of
random X-inactivation of the normal X chromosome
versus the dystrophic X chromosome. Although DMD
and BMD carriers have been identified as having car-
diomyopathy, the prevalence and severity of disease
are incompletely defined (96,98). We recommend that
all female dystrophinopathy carriers be screened for
cardiomyopathy, including CMR, at the time of diag-
nosis of their children (99,100).
X-LINKED DILATED CARDIOMYOPATHY
X-linked dilated cardiomyopathy (XLDCM) was first
described in 1987 and is an extremely rare cardiomy-
opathy resulting from mutations in the DMD gene that
affects teenage males and their mothers (101,102).
Patients with XLDCM have normal dystrophin levels in
skeletal muscle, but a complete loss of dystrophin in
cardiac muscle, thus making it a distinct phenotype
(i.e., cardiomyopathy without overt skeletal muscle
disease) from DMD or BMD (103). The rapidly pro-
gressive cardiomyopathy associated with XLDCM
results in death between 10 and 20 years of age.
EMERGING THERAPIES
A major challenge for treatment of DMD is therapies
that address dystrophin deficiency and target both
cardiac and skeletal muscle (Central Illustration). A
number 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
out-of-frame deletion or duplication within the DMD
gene’s 79 exons. These mutations affect the normal
transcription of dystrophin messenger ribonucleic
acid open reading frame and subsequently prevent
the full-length dystrophin protein from being tran-
scribed. A novel therapy for the treatment of DMD
involves exon skipping within the central rod
domain, which can restore the normal messenger
ribonucleic acid reading frame and convert an
out-of-frame mutation to a less severe in-frame
mutation, comparable to those seen in BMD. This
can be achieved through the use of antisense oligo-
nucleotides (AONs), which are short, synthetic
nucleic acid fragments that regulate ribonucleic acid
splicing (104). Antisense oligonucleotides for exon
skipping that target exon 51 of the DMD gene, which
accounts for w13% of DMD mutations, including dri-
sapersen (GSK-2402698, GlaxoSmithKline, Brentford,
Kamdar and Garry 2543
DMD and BMD Cardiomyopathy
United Kingdom; Prosensa, Leiden, the Netherlands)
and eteplirsen (AVI 4658, Sarepta Therapeutics,
Cambridge, Massachusetts), are currently being
examined in clinical trials. Initial phase I and II trials
for both eteplirsen and drisapersen were promising
in restoring dystrophin expression, but did not
demonstrate a significant change in the primary
endpoint, the 6-min walk test. Major side effects
included renal toxicity and thrombocytopenia
(105,106). These drugs are being further evaluated in
phase III clinical trials.
DYSTROPHIN GENE AND CELL THERAPY. As dystro-
phin mutations lead to complete absence of the
functional dystrophin protein in DMD, 1 of the stra-
tegies to mitigate the disease sequelae is gene
replacement therapy using recombinant adenoviral
virus vectors (rAAV). In comparison to the exon
skipping strategy, which currently is available only
for exon 51 skipping, gene replacement strategies can
be beneficial for all patients with DMD, regardless of
their specific DMD mutation. A limitation of rAAV
technology is the inability to deliver the large,
full-length dystrophin gene due to packaging limita-
tions (107). However, the observation of mildly
affected patients with BMD who had very large dys-
trophin gene deletions led to the understanding that
truncated 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 packaged
within the rAAV (109). Dystrophin gene replacement
therapy has been effective in mouse models; howev-
er, in large animal models, efficacy has been limited
due to the host immune response (110,111). In a hu-
man pre-clinical trial of mini-dystrophin gene trans-
an
fer, 6 patients with DMD received injections of
mini-dystrophin, but none demonstrated significant
increases in dystrophin levels and 1 patient had an
immune response (112,113). In addition, cell therapy
initiatives for DMD cardiomyopathy using
cardiosphere-derived cells and/or induced pluripo-
tent stem cell derivatives have shown improvement
in both cardiac function and exercise capacity of the
mdx (dystrophin knockout) mouse model. Gene
replacement and cell therapies, although limited by
immune side effects, may be overcome by immuno-
suppressant regimens and may represent promising
therapies for DMD cardiomyopathy.
DYSTROPHIN GENE EDITING. Gene editing is an
emerging technology for DMD. Gene editing can be
mediated by clustered regularly interspaced short
palindromic repeats (CRISPR)/CRISPR-associated
systems (Cas) to alter or edit the genome (114,115).
2544 Kamdar and Garry JACC VOL. 67, NO. 21, 2016

DMD and BMD Cardiomyopathy MAY 31, 2016:2533–46

The CRISPR/Cas9 system binds to the target gene and
generates a double-stranded deoxyribonucleic acid
break, which then can be replaced by the corrected
gene sequence. This system precisely removes the
mutated gene of interest and replaces it with a func-
tional copy of the gene. Gene editing using a
CRISPR/Cas9 strategy was utilized in vivo to correct
the DMD gene mutation in the germline of mdx mice
(116). In mosaic mdx mice with only 17% correction of
dystrophin by gene editing, a normal muscle pheno-
type was observed. This nascent technology has
possible therapeutic benefits in patients with DMD,
and further animal studies evaluating cardiac func-
tion are needed. Recently, adult mdx mice were also
successfully treated using a gene-editing strategy
(117,118).
CONCLUSIONS
Cardiomyopathy is a leading cause of death in the
DMD population. Early detection and intervention
with medical and device therapies are warranted.
Given the significant cardiomyopathic phenotype in
the dystrophinopathy population, we have estab-
lished a neurocardiomyopathy clinic where these
patients have a comprehensive evaluation with heart
failure cardiologists and neuromuscular neurologists.
We believe that increasing attention by heart failure–
trained subspecialists and the establishment of
dedicated neurocardiomyopathy clinics will enhance
our understanding of the mechanisms of DMD car-
diomyopathy and ultimately have an effect on the
morbidity and mortality of this disease.
ACKNOWLEDGMENT The authors are grateful for
artwork assistance by Ms. Cynthia DeKay.
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
Daniel J. Garry, Cardiovascular Division, Lillehei
Heart Institute, University of Minnesota, 2231 6th
Street Southeast, 4-146 CCRB, Minneapolis, Minne-
sota 55455. E-mail: garry@umn.edu.

REFERENCES

1. Meryon E. On granular and fatty degeneration
of the voluntary muscles. Medico-Chirugical Trans
1852;35:73–4.
2. Duchenne GBA. Recherches sur la paralysie
musculaire pseudo-hypertrophique ou paralysie
myo-sclerosique. Arch Gen Med 1868;11:5–25.
3. Gowers WR. A manual of disease of the nervous
system1. London, UK: Churchill, 1886:391–4.
4. Monaco AP, Neve RL, Colletti-Feener C, et al.
Isolation of candidate cDNAs for portions of the
Duchenne muscular dystrophy gene. Nature 1986;
323:646–50.
5. Hoffman EP, Brown RH Jr., Kunkel LM. Dys-
trophin: the protein product of the Duchenne
muscular dystrophy locus. Cell 1987;51:919–28.
6. Emery AE. The muscular dystrophies. Lancet
2002;359:687–95.
7. Cox GF, Kunkel LM. Dystrophies and heart dis-
ease. Curr Opin Cardiol 1997;12:329–43.
8. Mendell JR, Shilling C, Leslie ND, et al.
Evidence-based path to newborn screening for
Duchenne muscular dystrophy. Ann Neurol 2012;
71:304–13.
9. Koenig M, Hoffman EP, Bertelson CJ, et al.
Complete cloning of the Duchenne muscular dys-
trophy (DMD) cDNA and preliminary genomic or-
ganization of the DMD gene in normal and
affected individuals. Cell 1987;50:509–17.
10. Ahn AH, Kunkel LM. The structural and func-
tional diversity of dystrophin. Nat Genet 1993;3:
283–91.
11. Dent KM, Dunn DM, von Niederhausern AC,
et al. Improved molecular diagnosis of dystrophi-
nopathies in an unselected clinical cohort. Am J
Med Genet A 2005;134:295–8.
12. Rybakova IN, Patel JR, Ervasti JM. The dys-
trophin complex forms a mechanically strong link
between the sarcolemma and costameric actin.
J Cell Biol 2000;150:1209–14.
13. Ervasti JM, Campbell KP. A role for the
dystrophin-glycoprotein complex as a trans-
membrane linker between laminin and actin. J Cell
Biol 1993;122:809–23.
14. Cohn RD, Campbell KP. Molecular basis of
muscular dystrophies. Muscle Nerve 2000;23:
1456–71.
15. Klietsch R, Ervasti JM, Arnold W, et al.
Dystrophin-glycoprotein complex and laminin
colocalize to the sarcolemma and transverse tubules
of cardiac muscle. Circ Res 1993;72:349–60.
16. Johnson EK, Zhang L, Adams ME, et al.
Proteomic analysis reveals new cardiac-specific
dystrophin-associated proteins. PloS One 2012;7:
e43515.
17. Cox GA, Cole NM, Matsumura K, et al. Over-
expression of dystrophin in transgenic mdx mice
eliminates dystrophic symptoms without toxicity.
Nature 1993;364:725–9.
18. Petrof BJ, Shrager JB, Stedman HH, et al.
Dystrophin protects the sarcolemma from stresses
developed during muscle contraction. Proc Natl
Acad Sci U S A 1993;90:3710–4.
19. Yasuda S, Townsend D, Michele DE, et al.
Dystrophic heart failure blocked by membrane
sealant poloxamer. Nature 2005;436:1025–9.
20. Konagaya M, Takayanagi T. Regularity in the
change of serum creatine kinase level in Duchenne
muscular dystrophy. A study with long-term
follow-up cases. Jpn J Med 1986;25:2–8.
21. Eagle M, Baudouin SV, Chandler C, et al.
Survival in Duchenne muscular dystrophy:
improvements in life expectancy since 1967 and
the impact of home nocturnal ventilation. Neuro-
muscul Disord 2002;12:926–9.
22. Nigro G, Comi LI, Politano L, et al. The inci-
dence and evolution of cardiomyopathy in
Duchenne muscular dystrophy. Int J Cardiol 1990;
26:271–7.
23. Angelini C. The role of corticosteroids in
muscular dystrophy: a critical appraisal. Muscle
Nerve 2007;36:424–35.
24. Bushby K, Finkel R, Birnkrant DJ, et al., for the
DMD Care Considerations Working Group. Diag-
nosis and management of Duchenne muscular
dystrophy, part 1: diagnosis, and pharmacological
and psychosocial management. Lancet Neurol
2010;9:77–93.
25. Manzur AY, Kuntzer T, Pike M, et al. Gluco-
corticoid corticosteroids for Duchenne muscular
dystrophy. Cochrane Database Syst Rev 2008:
CD003725.
26. Bonifati MD, Ruzza G, Bonometto P, et al.
A multicenter, double-blind, randomized trial of
deflazacort versus prednisone in Duchenne
muscular dystrophy. Muscle Nerve 2000;23:
1344–7.
27. Bushby K, Finkel R, Birnkrant DJ, et al., for the
DMD Care Considerations Working Group. Diag-
nosis and management of Duchenne muscular
dystrophy, part 2: implementation of multidisci-
plinary care. Lancet Neurol 2010;9:177–89.
28. Gozal D. Pulmonary manifestations of neuro-
muscular disease with special reference to
Duchenne muscular dystrophy and spinal muscular
atrophy. Pediatr Pulmonol 2000;29:141–50.
29. Eagle M, Bourke J, Bullock R, et al. Managing
Duchenne muscular dystrophy—the additive effect
of spinal surgery and home nocturnal ventilation
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
in improving survival. Neuromuscul Disord 2007;
17:470–5.
30. Finder JD, Birnkrant D, Carl J, et al. Respira-
tory care of the patient with Duchenne muscular
dystrophy: ATS consensus statement. Am J Respir
Crit Care Med 2004;170:456–65.
31. American Academy of Pediatrics Section on
Cardiology and Cardiac Surgery. Cardiovascular
health supervision for individuals affected by
Duchenne or Becker muscular dystrophy. Pediat-
rics 2005;116:1569–73.
32. Markham LW, Spicer RL, Khoury PR, et al.
Steroid therapy and cardiac function in Duchenne
muscular dystrophy. Pediatr Cardiol 2005;26:
768–71.
33. Jefferies JL, Eidem BW, Belmont JW, et al.
Genetic predictors and remodeling of dilated car-
diomyopathy in muscular dystrophy. Circulation
2005;112:2799–804.
34. Romfh A, McNally EM. Cardiac assessment in
Duchenne and Becker muscular dystrophies. Curr
Heart Fail Rep 2010;7:212–8.
35. Thrush PT, Allen HD, Viollet L, et al. Re-
examination of the electrocardiogram in boys with
Duchenne muscular dystrophy and correlation
with its dilated cardiomyopathy. Am J Cardiol
2009;103:262–5.
36. Perloff JK, Roberts WC, de Leon AC Jr., et al. The
distinctive electrocardiogram of Duchenne’s progres-
sive muscular dystrophy. An electrocardiographic-
pathologic correlative study. Am J Med 1967;42:
179–88.
37. Sanyal SK, Johnson WW, Thapar MK, et al. An
ultrastructural basis for electrocardiographic
alterations associated with Duchenne’s progres-
sive muscular dystrophy. Circulation 1978;57:
1122–9.
38. Frankel KA, Rosser RJ. The pathology of the
heart in progressive muscular dystrophy: epi-
myocardial fibrosis. Human Pathol 1976;7:375–86.
39. Markham LW, Michelfelder EC, Border WL,
et al. Abnormalities of diastolic function precede
dilated cardiomyopathy associated with Duchenne
muscular dystrophy. J Am Soc Echocardiogr 2006;
19:865–71.
40. Boas EP, Lowenburg H. The heart rate in
progressive muscular dystrophy. Arch Intern Med
1931;47:376–83.
41. Fitch CW, Ainger LE. The Frank vectorcardio-
gram and the electrocardiogram in Duchenne
progressive muscular dystrophy. Circulation 1967;
35:1124–40.
42. Kovick RB, Fogelman AM, Abbasi AD, et al.
Echocardiographic evaluation of posterior left
ventricular wall motion in muscular dystrophy.
Circulation 1975;52:447–54.
43. Nomura H, Hizawa K. Histopathological study
of the conduction system of the heart in Duchenne
progressive muscular dystrophy. Acta Pathol Jpn
1982;32:1027–33.
44. Yotsukura M, Sasaki K, Kachi E, et al. Circadian
rhythm and variability of heart rate in Duchenne-
type progressive muscular dystrophy. Am J Car-
diol 1995;76:947–51.
45. Yotsukura M, Fujii K, Katayama A, et al. Nine-
year follow-up study of heart rate variability in
patients with Duchenne-type progressive muscular
dystrophy. Am Heart J 1998;136:289–96.
46. Thomas TO, Morgan TM, Burnette WB, et al.
Correlation of heart rate and cardiac dysfunction in
Duchenne muscular dystrophy. Pediatr Cardiol
2012;33:1175–9.
47. Dalmaz Y, Peyrin L, Mamelle JC, et al. The
pattern of urinary catecholamines and their me-
tabolites in Duchenne myopathy, in relation to
disease evolution. J Neural Transm 1979;46:17–34.
48. Villa CR, Czosek RJ, Ahmed H, et al. Ambula-
tory monitoring and arrhythmic outcomes in
pediatric and adolescent patients with Duchenne
muscular dystrophy. J Am Heart Assoc 2015;5:
e002620.
49. Corrado G, Lissoni A, Beretta S, et al. Prog-
nostic value of electrocardiograms, ventricular
late potentials, ventricular arrhythmias, and left
ventricular systolic dysfunction in patients with
Duchenne muscular dystrophy. Am J Cardiol
2002;89:838–41.
50. Yotsukura M, Yamamoto A, Kajiwara T, et al.
QT dispersion in patients with Duchenne-type
progressive muscular dystrophy. Am Heart J
1999;137:672–7.
51. Yancy CW, Jessup M, Bozkurt B, et al. 2013
ACCF/AHA guideline for the management of heart
failure: a report of the American College of Car-
diology Foundation/American Heart Association
Task Force on Practice Guidelines. J Am Coll Car-
diol 2013;62:e147–239.
52. Rapezzi C, Leone O, Biagini E, et al. Echocar-
diographic clues to diagnosis of dystrophin related
dilated cardiomyopathy. Heart 2007;93:10.
53. Markham LW, Kinnett K, Wong BL, et al.
Corticosteroid treatment retards development of
ventricular dysfunction in Duchenne muscular
dystrophy. Neuromuscul Disord 2008;18:365–70.
54. Silva MC, Meira ZM, Gurgel Giannetti J, et al.
Myocardial delayed enhancement by magnetic
resonance imaging in patients with muscular dys-
trophy. J Am Coll Cardiol 2007;49:1874–9.
55. Hagenbuch SC, Gottliebson WM, Wansapura J,
et al. Detection of progressive cardiac dysfunction
by serial evaluation of circumferential strain in
patients with Duchenne muscular dystrophy. Am J
Cardiol 2010;105:1451–5.
56. Hor KN, Wansapura J, Markham LW, et al.
Circumferential strain analysis identifies strata of
cardiomyopathy in Duchenne muscular dystrophy:
a cardiac magnetic resonance tagging study. J Am
Coll Cardiol 2009;53:1204–10.
57. Puchalski MD, Williams RV, Askovich B, et al.
Late gadolinium enhancement: precursor to car-
diomyopathy in Duchenne muscular dystrophy? Int
J Cardiovasc Imaging 2009;25:57–63.
58. Verhaert D, Richards K, Rafael-Fortney JA,
et al. Cardiac involvement in patients with
muscular dystrophies: magnetic resonance imag-
ing phenotype and genotypic considerations. Circ
Cardiovasc Imaging 2011;4:67–76.
59. Hor KN, Taylor MD, Al-Khalidi HR, et al.
Prevalence and distribution of late gadolinium
enhancement in a large population of patients
Kamdar and Garry 2545
DMD and BMD Cardiomyopathy
with Duchenne muscular dystrophy: effect of age
and left ventricular systolic function. J Cardiovasc
Magn Reson 2013;15:107.
60. Tandon A, Villa CR, Hor KN, et al. Myocardial
fibrosis burden predicts left ventricular ejection
fraction and is associated with age and steroid
treatment duration in Duchenne muscular dystro-
phy. J Am Heart Assoc 2015;4:e001338.
61. Dec GW. Steroid therapy effectively delays
Duchenne’s cardiomyopathy. J Am Coll Cardiol
2013;61:955–6.
62. Silversides CK, Webb GD, Harris VA, et al. Ef-
fects of deflazacort on left ventricular function in
patients with Duchenne muscular dystrophy. Am J
Cardiol 2003;91:769–72.
63. Mavrogeni S, Papavasiliou A, Douskou M, et al.
Effect of deflazacort on cardiac and sternocleido-
mastoid muscles in Duchenne muscular dystrophy:
a magnetic resonance imaging study. Eur J Pae-
diatr Neurol 2009;13:34–40.
64. Barber BJ, Andrews JG, Lu Z, et al. Oral cor-
ticosteroids and onset of cardiomyopathy in
Duchenne muscular dystrophy. J Pediatr 2013;163:
1080–4.e1.
65. Schram G, Fournier A, Leduc H, et al. All-cause
mortality and cardiovascular outcomes with pro-
phylactic steroid therapy in Duchenne muscular
dystrophy. J Am Coll Cardiol 2013;61:948–54.
66. Duboc D, Meune C, Lerebours G, et al. Effect
of perindopril on the onset and progression of left
ventricular dysfunction in Duchenne muscular
dystrophy. J Am Coll Cardiol 2005;45:855–7.
67. Duboc D, Meune C, Pierre B, et al. Perindopril
preventive treatment on mortality in Duchenne
muscular dystrophy: 10 years’ follow-up. Am
Heart J 2007;154:596–602.
68. Allen HD, Flanigan KM, Thrush PT, et al.
A randomized, double-blind trial of lisinopril and
losartan for the treatment of cardiomyopathy in
Duchenne muscular dystrophy [published correction
appears in PLoS Curr 2015;7]. PLoS Curr 2013;5.
69. Saito T, Matsumura T, Miyai I, Nozaki S,
Shinno S. [Carvedilol effectiveness for left
ventricular-insufficient patients with Duchenne
muscular dystrophy]. Rinsho Shinkeigaku 2001;41:
691–4.
70. Rhodes J, Margossian R, Darras BT, et al.
Safety and efficacy of carvedilol therapy for pa-
tients with dilated cardiomyopathy secondary to
muscular dystrophy. Pediatr Cardiol 2008;29:
343–51.
71. Kajimoto H, Ishigaki K, Okumura K, et al. Beta-
blocker therapy for cardiac dysfunction in patients
with muscular dystrophy. Circ J 2006;70:991–4.
72. Viollet L, Thrush PT, Flanigan KM, et al. Effects
of angiotensin-converting enzyme inhibitors
and/or beta blockers on the cardiomyopathy in
Duchenne muscular dystrophy. Am J Cardiol 2012;
110:98–102.
73. Raman SV, Hor KN, Mazur W, et al. Eplerenone
for early cardiomyopathy in Duchenne muscular
dystrophy: a randomised, double-blind, placebo-
controlled trial. Lancet Neurol 2015;14:153–61.
74. Rees W, Schüler S, Hummel M, et al.
Heart transplantation in patients with muscular
2546 Kamdar and Garry
DMD and BMD Cardiomyopathy
dystrophy associated with end-stage cardiomy-
opathy. J Heart Lung Transplant 1993;12:804–7.
75. Ruiz-Cano MJ, Delgado JF, Jiménez C, et al.
Successful heart transplantation in patients with
inherited myopathies associated with end-stage
cardiomyopathy. Transplant Proc 2003;35:1513–5.
76. Patanè F, Zingarelli E, Attisani M, et al. Suc-
cessful heart transplantation in Becker’s muscular
dystrophy. Eur J Cardiothorac Surg 2006;29:250.
77. Wu RS, Gupta S, Brown RN, et al. Clinical
outcomes after cardiac transplantation in muscular
dystrophy patients. J Heart Lung Transplant 2010;
29:432–8.
78. Rose EA, Gelijns AC, Moskowitz AJ, et al., for
the Randomized Evaluation of Mechanical Assis-
tance for the Treatment of Congestive Heart
Failure (REMATCH) Study Group. Long-term use
of a left ventricular assist device for end-stage
heart failure. N Engl J Med 2001;345:1435–43.
79. Slaughter MS, Rogers JG, Milano CA, et al., for
the HeartMate II Investigators. Advanced heart
failure treated with continuous-flow left ventric-
ular assist device. N Engl J Med 2009;361:
2241–51.
80. Amodeo A, Adorisio R. Left ventricular assist
device in Duchenne cardiomyopathy: can we
change the natural history of cardiac disease? Int J
Cardiol 2012;161:e43.
81. Ryan TD, Jefferies JL, Sawnani H, et al. Im-
plantation of the HeartMate II and HeartWare left
ventricular assist devices in patients with
Duchenne muscular dystrophy: lessons learned
from the first applications. ASAIO J 2014;60:
246–8.
82. Becker PE, Kiener F. [A new x-chromosomal
muscular dystrophy]. Archiv Psychiatr Nervenkr Z
Gesamte Neurol Psychiatr 1955;193:427–48.
83. Becker PE. Two families of benign sex-linked
recessive muscular dystrophy. Rev Can Biol 1962;
21:551–66.
84. Kingston HM, Sarfarazi M, Thomas NS, et al.
Localisation of the Becker muscular dystrophy
gene on the short arm of the X chromosome by
linkage to cloned DNA sequences. Hum Genet
1984;67:6–17.
85. Koenig M, Beggs AH, Moyer M, et al. The
molecular basis for Duchenne versus Becker
muscular dystrophy: correlation of severity with
type of deletion. Am J Hum Genet 1989;45:
498–506.
86. Worton R. Muscular dystrophies: diseases of
the dystrophin-glycoprotein complex. Science
1995;270:755–6.
87. Monaco AP, Bertelson CJ, Liechti-Gallati S,
et al. An explanation for the phenotypic differ-
ences between patients bearing partial deletions
of the DMD locus. Genomics 1988;2:90–5.
88. Bradley WG, Jones MZ, Mussini JM,
Fawcett PR. Becker-type muscular dystrophy.
Muscle Nerve 1978;1:111–32.
89. Melacini P, Fanin M, Danieli GA, et al.
Myocardial involvement is very frequent among
patients affected with subclinical Becker’s
muscular dystrophy. Circulation 1996;94:3168–75.
90. Finsterer J, Stöllberger C. Cardiac involvement
in Becker muscular dystrophy. Can J Cardiol 2008;
24:786–92.
91. Hoogerwaard EM, de Voogt WG, Wilde AA,
et al. Evolution of cardiac abnormalities in Becker
muscular dystrophy over a 13-year period.
J Neurol 1997;244:657–63.
92. Nigro G, Politano L, Nigro V, et al. Mutation of
dystrophin gene and cardiomyopathy. Neuromusc
Disord 1994;4:371–9.
93. Yilmaz A, Gdynia HJ, Baccouche H, et al. Car-
diac involvement in patients with Becker muscular
dystrophy: new diagnostic and pathophysiological
insights by a CMR approach. J Cardiovasc Magn
Reson 2008;10:50.
94. Norman A, Harper P. A survey of manifesting
carriers of Duchenne and Becker muscular dys-
trophy in Wales. Clin Genet 1989;36:31–7.
95. Comi LI, Nigro G, Politano L, et al. The car-
diomyopathy of Duchenne/Becker consultands. Int
J Cardiol 1992;34:297–305.
96. Hoogerwaard EM, van der Wouw PA,
Wilde AA, et al. Cardiac involvement in carriers of
Duchenne and Becker muscular dystrophy. Neu-
romusc Disord 1999;9:347–51.
97. Hoogerwaard EM, Bakker E, Ippel PF, et al.
Signs and symptoms of Duchenne muscular dys-
trophy and Becker muscular dystrophy among
carriers in The Netherlands: a cohort study. Lancet
1999;353:2116–9.
98. Schade van Westrum SM, Hoogerwaard EM,
Dekker L, et al. Cardiac abnormalities in a follow-
up study on carriers of Duchenne and Becker
muscular dystrophy. Neurology 2011;77:62–6.
99. Schelhorn J, Schoenecker A, Neudorf U, et al.
Cardiac pathologies in female carriers of Duchenne
muscular dystrophy assessed by cardiovascular
magnetic resonance imaging. Eur Radiol 2015;25:
3066–72.
100. Lang SM, Shugh S, Mazur W, et al. Myocardial
fibrosis and left ventricular dysfunction in
Duchenne muscular dystrophy carriers using car-
diac magnetic resonance imaging. Pediatr Cardiol
2015;36:1495–501.
101. Berko BA, Swift M. X-linked dilated cardio-
myopathy. N Engl J Med 1987;316:1186–91.
102. Muntoni F, Cau M, Ganau A, et al. Brief
report: deletion of the dystrophin muscle-
promoter region associated with X-linked dilated
cardiomyopathy. N Engl J Med 1993;329:921–5.
103. Towbin JA, Hejtmancik JF, Brink P, et al.
X-linked dilated cardiomyopathy. Molecular
genetic evidence of linkage to the Duchenne
muscular dystrophy (dystrophin) gene at the Xp21
locus. Circulation 1993;87:1854–65.
104. Aartsma-Rus A, Fokkema I, Verschuuren J,
et al. Theoretic applicability of antisense-mediated
exon skipping for Duchenne muscular dystrophy
mutations. Hum Mutat 2009;30:293–9.
JACC VOL. 67, NO. 21, 2016
MAY 31, 2016:2533–46
105. Goemans NM, Tulinius M, van den Akker JT,
et al. Systemic administration of PRO051 in
Duchenne’s muscular dystrophy. N Engl J Med
2011;364:1513–22.
106. Cirak S, Arechavala-Gomeza V, Guglieri M,
et al. Exon skipping and dystrophin restoration in
patients with Duchenne muscular dystrophy after
systemic phosphorodiamidate morpholino olig-
omer treatment: an open-label, phase 2, dose-
escalation study. Lancet 2011;378:595–605.
107. Pichavant C, Aartsma-Rus A, Clemens PR,
et al. Current status of pharmaceutical and genetic
therapeutic approaches to treat DMD. Mol Ther
2011;19:830–40.
108. England SB, Nicholson LV, Johnson MA, et al.
Very mild muscular dystrophy associated with the
deletion of 46% of dystrophin. Nature 1990;343:
180–2.
109. Harper SQ, Hauser MA, DelloRusso C, et al.
Modular flexibility of dystrophin: implications for
gene therapy of Duchenne muscular dystrophy.
Nat Med 2002;8:253–61.
110. Gregorevic P, Allen JM, Minami E, et al.
rAAV6-microdystrophin preserves muscle function
and extends lifespan in severely dystrophic mice.
Nat Med 2006;12:787–9.
111. Banks GB, Chamberlain JS, Froehner SC.
Truncated dystrophins can influence neuromus-
cular synapse structure. Mol Cell Neurosci 2009;
40:433–41.
112. Mendell JR, Campbell K, Rodino-Klapac L,
et al. Dystrophin immunity in Duchenne’s muscular
dystrophy. N Engl J Med 2010;363:1429–37.
113. Bowles DE, McPhee SW, Li C, et al. Phase 1
gene therapy for Duchenne muscular dystrophy
using a translational optimized AAV vector. Mol
Ther 2012;20:443–55.
114. Jinek M, Chylinski K, Fonfara I, et al.
A programmable dual-RNA-guided DNA endonu-
clease in adaptive bacterial immunity. Science
2012;337:816–21.
115. Cong L, Ran FA, Cox D, et al. Multiplex
genome engineering using CRISPR/Cas systems.
Science 2013;339:819–23.
116. Long C, McAnally JR, Shelton JM, et al. Pre-
vention of muscular dystrophy in mice by CRISPR/
Cas9-mediated editing of germline DNA. Science
2014;345:1184–8.
117. Long C, Amoasii L, Mireault AA, et al. Post-
natal genome editing partially restores dystrophin
expression in a mouse model of muscular dystro-
phy. Science 2016;351:400–3.
118. Nelson CE, Hakim CH, Ousterout DG, et al.
In vivo genome editing improves muscle function
in a mouse model of Duchenne muscular dystro-
phy. Science 2016;351:403–7.
KEY WORDS Becker muscular dystrophy
cardiomyopathy, Duchenne muscular
dystrophy cardiomyopathy, muscular
dystrophy cardiomyopathy