Muscular dystrophy (MD) is a heterogenous group of diseases that vary in their pattern of skeletal and cardiac muscle involvement.1 They are classified by their specific gene defect, pattern of skeletal muscle involvement, and unique clinical features.1 It is intuitive that the heart would be affected in many of the muscular dystrophies, given the similarities that exist between cardiac and skeletal muscle. However, there is often discord between skeletal and cardiac involvement. This phenotypic disparity likely results from biological differences between cardiac and skeletal tissue, differences in protein isoforms, and differences in workload between the two tissue types.
The pathological process observed in the heart in muscular dystrophy is similar to that observed in skeletal muscle and consists of necrosis, fibrosis, and fatty replacement of muscle.2'3 MD can affect the myocardial contractile elements and the cardiac conduction system. Involvement of the myocardium can lead to the development of a cardiomyopathy and heart failure. Conduction system abnormalities result in a wide range of clinical dysrhythmias and place the patient at risk for sudden death from either complete heart block or malignant arrhythmias.
Traditionally, the cardiac evaluation in MD was performed in the teenage years, late in the disease process after significant cardiac abnormalities had developed. However, the contemporary interdisciplinary care of the patient with MD should include appropriate cardiac surveillance and treatment of the patient at risk before the onset of significant cardiac ; abnormalities. With advances in supportive care, those with childhood-onset MD are living beyond pediatrie care into young adulthood.4
This article summarizes the signs and symptoms of cardiac dysfunction and outlines the diagnostic and therapeutic approaches to the failing heart We discuss the four muscular dystrophies known to have cardiac involvement - Duchenne, Becker, limb-girdle, and congenital MD.
EVALUATION AND TREATMENT
History and Physical Examination
A number of signs and symptoms of cardiac dysfunction are unique to the MD population. Patients with underlying musculoskeletal disease often have significant physical limitations that result in an underreporting of the typical signs and symptoms of cardiac dysfunction, such as activity intolerance or shortness of breath.
Cardiac dysfunction in a patient with MD often manifests as pronounced fatigue, altered duration and quality of sleep, and unexplained weight loss or gain. Special attention should be paid to subtle changes in the patient's daily activities. Symptoms such as chest pain, dizziness, or palpitations require additional investigation. Syncope warrants particular attention, as it may reflect disruption of normal atrioventricular conduction.
Accurate documentation of weight also is essential, although challenging in a wheelchair-bound patient, often requiring special scales. Other important signs of cardiac dysfunction include abnormal cardiac rate or rhythm, tachypnea, diminished pulses, murmurs, hepatomegaly, edema, abdominal pain, or vomiting.
Echocardiography is useful to assess cardiac anatomy, chamber size, and ventricular function. Because body habitus and scoliosis may limit the utility of echocardiography, alternate modalities such as magnetic resonance imaging (MRI) or multi-gated acquisition imaging (MUGA) may provide important information regarding cardiac function (Sidebar 1).
Standard tools to assess heart rhythm include resting electrocardiogram, 24hour ambulatory Holter monitoring, and event monitor (Sidebar 1). The resting electrocardiogram is an electrical snapshot of the heart that provides essential information about heart rate and rhythm. Patients with MD that involves the conduction system may have electrocardiographic abnormalities and are at risk for arrhythmias. Several of the muscular dystrophies have very specific electrophysiologic profiles, but a wide variety of rhythm abnormalities may occur, including premature atrial or ventricular beats, atrial or ventricular tachyarrhythmia, and heart block.5
The Holter monitor, an ambulatory monitoring device, is used to record heart rate and rhythm for a 24- to 48hour period of time. The event monitor is patient-activated, allowing capture of heart rate and rhythm during a symptomatic event and can be used for weeks to months if necessary.
Although management of cardiac dysfunction remains challenging, advances in the understanding of heart failure pathophysiology6 have led to new therapies that improve symptoms and outcomes7 (Sidebar 2). Neurohormonal activation occurs in patients with heart failure, including those with MD,8 and acutely augments myocardial contractility, raises heart rate and blood pressure, and causes intravascular fluid shifts.
Although initially leading to improved cardiac output, over time, these same neurohormonal influences become detrimental. The deterioration occurs via direct heart muscle hypertrophy, fibrosis, and, ultimately, cell death. Cardiac enlargement (remodeling) progresses and cardiac function worsens, along with the symptoms of heart failure. Therapies to interrupt these neurohormonal influences in heart failure patients have led to remarkable improvement in cardiac function, symptomatic status, and survival.8"10
Angiotensin-converting enzyme inhibitors and beta-blockers, two well-known modulators of neurohormone excess, are now considered first-line heart failure therapy, joining diuretics and occasionally digoxin as therapeutic mainstays.11 Although clinical trials of neurohormonal heart failure therapy in pediatrie patients are lacking, improved cardiac function and outcomes have been reported in patients with MD treated with ACE inhibitors, beta-blockers,orboth.10'12
When initiating cardiac therapy in patients with MD, consideration should be given to the most recent guidelines for heart failure management as published by the American College of Cardiology and the American Heart Associatioa 13 Of significance in these guidelines is the classification of heart failure as Stages A-D (Table 1). All patients with MD, at any age, should be considered in Stage A heart failure before evaluatioa The development of ventricular enlargement or diminished contractility should move the patient into Stage B. ACE inhibitors and beta-blockers are recommended for heart failure patients in these stages and should be given to MD patients as well. With further progression of disease to symptomatic status, diuretics and inotropes can be added. Patients with refractory end-stage heart failure can, in selected cases with preserved skeletal muscle function, be considered for cardiac transplantation.14'15
Treatment regimens for heart failure associated with MD are applicable to treatment of heart failure of any etiology and include angiotensin-converting enzyme inhibitors, digoxin, diuretics, betablockers, and inotropes (Sidebar 2). Neurohormonal therapy, which includes ACE inhibitors, angiotensin-receptor blockers, and beta-blockers, improves morbidity and mortality in patients with heart failure.9'16 However, there has been a single prospective trial showing benefit from administering ACE inhibitor therapy to asymptomatic patients with Duchenne MD and normal heart function.12 Heart transplantation has been used in patients with MD with preserved skeletal muscle function and for carriers of MD.14'15 Antiarrhythmic therapy should be directed at the specific dysrhythmia and could include pharmacologie treatment or devices (eg, pacemaker, internal defibrillator).
Heart Failure Classification
Limb-girdle Muscular Dystrophies
SPECIFIC NEUROMUSCULAR DISORDERS
Duchenne MD is the most frequent inherited MD, with an estimated incidence of 1 in 3,500 boys independent of ethnicity. Becker MD is less frequent, with an estimated incidence of 1 in 30,000 boys. The gene responsible for both Duchenne and Becker MD is located on the short arm of the X chromosome and encodes the protein dystrophin. The mutation of this gene leads to deficiency of dystrophin, which affects cardiac contractile function17'18 (Table 2, see page 533). By being X-linked, the mutation is passed from maternal carrier to child. Male offspring with the dystrophin mutation present with the disease while female offspring with the mutation are carriers of the disease. Survival with the most severe form, Duchenne MD, is now into the late teens to 20s and is largely dependent on cardiopulmonary status.4
Electrocardiographic abnormalities are present in 90% of patients with Duchenne MD.19'22 The classic electrocardiogram in an older patient with Duchenne MD demonstrates tall R waves in the right precordial leads and prominent Q waves in the left precordial and limb leads.20'21 Ventricular hypertrophy, interventricular conduction delay, ventricular pre-excitation, ST segment changes, atrial enlargement, and prolonged corrected QT interval have been described but do not correlate with development of cardiac dysfunction.22
Congenital Muscular Dystrophies
Interestingly, approximately 30% to 50% of boys with Duchenne MD have sinus tachycardia independent of cardiac function abnormalities.19"21 This resting tachycardia may reflect autonomie dysfunction or early cardiac dysfunction. Sudden death in Duchenne MD has been attributed to ventricular arrhythmia and usually occurs in patients with myocardial dysfunction.
Dilated cardiomyopathy typically manifests in the second decade of life.22 Early cardiac evaluation and regular follow-up should be part of the interdisciplinary care of patients with Duchenne MD or Becker MD.
The limb-girdle muscular dystrophies (LGMDs) are phenotypically and genotypically heterogeneous and classified into at least 13 types.23 The onset, progression, and nature of clinical manifestations vary among the subtypes (Table 3). Recommendations regarding the need for cardiac surveillance are dependent on subtype. Patients with LGMDlB, 2E, 2F, and 21 require routine cardiac evaluation. Currently, cardiac surveillance is not recommended for patients with LGMD2A, 2B, 2G, 2H, 2J, IA, and 1C.24
Cardiac involvement is characterized by electrocardiographic abnormalities, conduction defects, supraventricular tachycardia, atrial and ventricular premature beats, and dilated cardiomyopathy leading to early death.25 Although cardiac manifestations typically develop after adolescence, increased awareness among pediatrie primary care providers and cardiologists is likely to uncover a larger number of patients with cardiac involvement.
Congenital MD is a heterogeneous group of autosomal recessive diseases, many of which have cardiac involvement26 (Table 4, see page 534). Fukuyama congenital MD patients frequently manifest cardiac dysfunction. Severity of the skeletal muscle involvement in congenital MD varies and is dependent on type. Of individuals with merosin (laminin ct-2) deficient congenital MD, approximately half develop significant scoliosis and nocturnal hypoventilation.27
The impairment of pulmonary function can affect cardiac function as well. Approximately 30% of patients with congenital MD die of cardiopulmonary complications. Because laminin-2 is expressed in cardiac muscle, cardiac pathology as manifested by electrocardiographic abnormalities and potential dilated cardiomyopathy should be expected, and prospective cardiac involvement is warranted.27
Pediatricians and other healthcare professionals need to be alert to the presence and progression of cardiac involvement in patients with MD. The signs and symptoms of cardiac involvement may be minimal, necessitating careful interval history, physical examination, and noninvasive cardiac testing. Available treatment strategies may reduce disease morbidity and mortality.
It is reasonable to expect that a child who has skeletal muscle weakness from MD may have cardiac involvement, even if it is subclinical. Treatment of the muscular dystrophies through genetic engineering is a future dream. However, the improvements in clinical care, evaluation and treatment standards, and multidisciplinary supportive care are able to benefit the current generation of children.
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Heart Failure Classification
Limb-girdle Muscular Dystrophies
Congenital Muscular Dystrophies