Neuromuscular Disorders and Cardiovascular Disease

Genetics and Pathogenesis

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders caused by mutations in one of the largest genes in the human genome, dystrophin (see also Chapter 7, Chapter 52, Chapter 63 ). Dystrophin is located on the short arm of the X chromosome with 79 exons, spanning 2.4 Mb producing a 14 kb mRNA. Variable promoters produce different full-length and shorter versions of dystrophin expressed in muscle and brain, and the short 71 kDa isoform is ubiquitously expressed. Alternative splicing produces other isoforms expressed in the retina, kidney, brain, and peripheral nerves. About 60% of DMD cases are due to deletions of one or more exons; more rarely, duplications, small insertions/deletions, or point mutations produce disease ( eFig.100.2 ). In DMD, mutations usually disrupt the reading frame or introduce a premature stop codon, leading to the absence of dystrophin. Mutations that maintain the reading frame produce internally truncated, relatively functional proteins, resulting in a milder form of the disease, BMD. Although the skeletal muscle symptoms are less severe, the majority of BMD patients also develop a cardiomyopathy, and it is the leading cause of death in patients with BMD.

The dystrophin protein and its associated glycoproteins provide a structural link between the myocyte cytoskeleton and extracellular matrix linking contractile proteins to the cell membrane ( Fig. 100.1B ). Absence of dystrophin leads to membrane fragility resulting in myofiber or cardiomyocyte necrosis and eventual loss of cells with fibrotic replacement. Mutations in the genes encoding dystrophin-associated glycoproteins also present with degeneration of cardiac and skeletal muscle. Cardiac myocytes lacking dystrophin are susceptible to mechanical damage. Cardiac involvement is seen in both DMD and BMD and the severity is not correlated with the severity of skeletal muscle involvement. Mutations in specific domains of the dystrophin gene are associated with a higher risk for cardiomyopathy. X-linked dilated cardiomyopathy arises from mutations that primarily affect cardiac dystrophin production which manifests as cardiac involvement without skeletal muscle dysfunction.

Clinical Presentation

DMD is the most common inherited neuromuscular disease, with an incidence of 1 case in 3600 to 6000 live male births. Patients typically present with skeletal muscle weakness before the age of 5 years, which progresses if untreated such that boys become wheelchair-bound by their early teens ( Fig. 100.2 ) . Without support, death occurs by age 25 years, primarily from a combination of respiratory dysfunction and heart failure. A multidisciplinary treatment approach, including glucocorticoid steroids, ventilatory support, and cardiac therapy has improved survival rates. BMD is less common than DMD, is associated with a highly variable presentation of skeletal muscle weakness compared to Duchenne (see Fig. 100.2 ), and carries a better prognosis, with most patients surviving to the age of 40 to 50 years or longer. In both Duchenne and Becker muscular dystrophies, elevated serum creatine kinase activity is observed, at levels more than 10 and 5 times normal values, respectively. Cardiac troponin T is elevated in up to one-half of patients likely related to immunoreactivity of the assay with diseased skeletal muscle. Cardiac troponin I remains normal in the majority of patients but has been observed to elevate in Duchenne patients with clinical features indicative of cardiomyopathy progression.

Cardiovascular Manifestations

Most patients with DMD develop cardiomyopathy, but symptoms can be masked by activity limits due to skeletal muscle weakness. Sinus tachycardia is the earliest finding in the Duchenne heart, with the onset of clinically apparent cardiomyopathy common after the age of 10. Cardiac involvement can be diagnosed earlier by cardiac magnetic resonance imaging (MRI). The majority of patients with DMD 18 years of age or older develop cardiomyopathy with reduced ejection fraction. Early involvement is observed in the inferobasal and lateral left ventricle (LV) (see Fig. 100.1A ). As with the skeletal muscle weakness, cardiac involvement in Becker muscular dystrophy is more variable than in DMD, ranging from none or subclinical disease to severe cardiomyopathy requiring transplant. More than one-half of patients with subclinical or benign skeletal muscle disease were noted to have cardiac involvement if carefully evaluated. Progression in the severity of cardiac involvement is common. Cardiomyopathy can initially involve solely the right ventricle. The severity of cardiac involvement in both Duchenne and Becker muscular dystrophy can be independent of skeletal muscle involvement.

Thoracic deformities and a high diaphragm can alter the cardiovascular examination in patients with DMD. A reduction in the anterior-posterior chest dimension is commonly responsible for a systolic impulse displaced to the left sternal border, a grade 1 to 3/6 short midsystolic murmur in the second left interspace, and a loud pulmonary component of the second heart sound. In both Duchenne and Becker types of muscular dystrophy, mitral regurgitation is observed. The presence of mitral regurgitation is related to posterior papillary muscle dysfunction in DMD and to mitral annular dilation in BMD. Female carriers of Duchenne and Becker muscular dystrophy are at increased risk for dilated cardiomyopathy ^, and is consistent with increased susceptibility to cardiac injury in DMD carrier mice.

Electrocardiography

In a majority of patients with DMD, the electrocardiogram (ECG) is abnormal (see Chapter 14 ). The classically described electrocardiographic pattern shows distinctive tall R waves and increased R/S amplitude in V ₁ and deep narrow Q waves in the left precordial leads possibly related to the posterolateral left ventricular involvement ( Fig. 100.3 ). Other common findings include a short PR interval and right ventricular hypertrophy. No association between the presence of a dilated cardiomyopathy and electrocardiographic abnormalities has been established. In BMD, electrocardiographic abnormalities are present in up to 75% of the patients. The electrocardiographic abnormalities observed include tall R waves and an increased R/S amplitude in V ₁ , akin to that seen in DMD. In patients with dilated cardiomyopathy, a left bundle branch block is also common.

Imaging

Clinical care guidelines recommend using screening echocardiography at diagnosis or by the age of 6 years; subsequently every 2 years until the age of 10; and annually thereafter in boys with DMD (this and other cardiac imaging modalities are described more fully in Chapter 16, Chapter 17, Chapter 18, Chapter 19, Chapter 20 ). Cardiac MRI, especially with gadolinium contrast, is more sensitive in detecting subclinical ventricular involvement and fibrosis. The presence of fibrosis as indicated by late gadolinium enhancement on MRI predicted a subsequent decrement in left ventricular function. Regional abnormalities in the posterobasal and lateral wall typically occur earlier than in other areas (see Fig. 100.1A ). A process akin to left ventricular noncompaction can be observed, possibly resulting from compensatory mechanisms in response to the failing dystrophic myocardium. Mitral regurgitation can result from dystrophic changes in the posterior leaflet papillary muscles.

Arrhythmias

In DMD, persistent or labile sinus tachycardia is the most common arrhythmia recognized (see Chapter 65 ). Atrial arrhythmias, including atrial fibrillation and atrial flutter (see Chapter 66 ), occur in the setting of respiratory dysfunction and cor pulmonale or are associated with progression of dilated cardiomyopathy. Abnormalities in atrioventricular conduction have been observed, with both short and prolonged PR intervals recognized. Ventricular arrhythmias occur on monitoring in 30% of patients, primarily ventricular premature beats. Complex ventricular arrhythmias have been reported, more commonly in patients with advanced DMD. Sudden death occurs in DMD, typically in patients with end-stage muscular disease, and may occur due to arrhythmias or events like fat emboli. Several follow-up studies have shown a correlation between sudden death and the presence of complex ventricular arrhythmias. The presence of ventricular arrhythmias was not a predictor for all-cause mortality. Arrhythmia manifestations in BMD are typically related to the severity of the associated structural cardiomyopathy. Distal conduction system disease with complete heart block and bundle branch reentry ventricular tachycardia has been observed (see Chapter 67 ).

Treatment and Prognosis

DMD is a progressive skeletal and cardiac muscle disorder. Glucocorticoid steroids and steroid derivatives are effective in delaying skeletal muscle disease progression and appear to decrease the progression to a dilated cardiomyopathy. They constitute the mainstay of treatment for DMD and are part of the Care Considerations. Deflazacort is an FDA approved glucocorticoid for DMD, although prednisone is still commonly used. A retrospective analysis supports steroid benefit to the heart. The adverse side effects from long-term glucocorticoid treatment include obesity, osteoporosis, and metabolic syndrome. A novel dissociative steroid, vamolorone, is being investigated with initial promising results. Steroid treatment is not routinely recommended in BMD.

A cardiac cause for morbidity and mortality is playing an increasingly significant role in DMD because of improved multidisciplinary support for respiratory issues. There is an equal distribution of cardiac death from heart failure and sudden death. With evidence of reduced left ventricular function, even mildly reduced function, it is reasonable to offer guideline-directed heart failure management. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers can improve left ventricular function in patients treated early. Angiotensin receptor blockers can be used if the patient cannot tolerate ACE inhibitors. The aldosterone antagonist, eplerenone, showed benefit in maintaining cardiac magnetic resonance left ventricular circumferential strain in boys already receiving ACE inhibitors or angiotensin receptor blockers. ^, Dosing, age, or clinical status at which pharmacotherapy should be initiated is unclear (see Chapter 49, Chapter 50 ). Other advanced types of therapy such as implantable cardioverter-defibrillators (ICDs) play an uncertain role but should be considered individually based on clinical presentation using a shared decision-making approach (see Chapter 69 ). The use of left ventricular mechanical assist devices has been described. Whether heart failure therapies improve long-term outcomes is unclear. However, the age at death has increased, with the majority of patients surviving into their 30s, and recognition and treatment of the associated cardiomyopathy likely plays a role in that success. In patients with Becker muscular dystrophy, an improvement in left ventricular function also is observed after treatment with ACE inhibitors and beta blockers. Screening with left ventricular imaging is recommended as in DMD. Advanced heart failure therapy, including primary prevention ICDs, is appropriate in patients with cardiomyopathy. Patients with Becker muscular dystrophy with advanced heart failure can undergo cardiac transplantation, with expected outcomes similar to those for non–muscular dystrophy cohorts of age-matched patients with dilated cardiomyopathy. Female carriers of Duchenne and BMD do not develop a cardiomyopathy during childhood, and screening can be delayed until later in adolescence. Cardiac transplantation also has been reported in carriers.

Mutation-targeted treatment for Duchenne includes three forms of antisense mediated exon skipping that have been FDA approved, eteplirsen, golodirsen, and casimersen, and these agents treat different primary gene mutations (see eFig. 100.1 ). Adeno-associated viral gene therapy is in later stages of clinical investigation using micro-dystrophin, which is designed to convert Duchenne into Becker muscular dystrophy. On the horizon, CRISPR-Cas9-mediated gene editing is being designed to mediate more permanent exon skipping. ^,

Genetics and Pathogenesis

The myotonic dystrophies are autosomal dominant disorders characterized by myotonia, which is a delayed muscle relaxation after contraction, weakness, and atrophy of skeletal muscles, and systemic manifestations, including endocrine abnormalities, cataracts, cognitive impairment, and cardiac involvement ( Fig. 100.4 ). Two distinct mutations are responsible for the myotonic dystrophies. In myotonic dystrophy type 1 (Steinert disease), the mutation is an amplified trinucleotide cytosine-thymine-guanine (CTG) repeat on chromosome 19 in the 3′ untranslated region of dystrophia myotonica protein kinase (DMPK) . Normal individuals have 5 to 37 copies of the repeat, whereas patients with myotonic dystrophy have 50 to several thousand repeats. A direct correlation exists between an increasing number of CTG repeats and earlier age at onset and increasing severity of neuromuscular involvement ( Table 100.1 ). Cardiac involvement including conduction disease, arrhythmias, and age at cardiovascular death also correlate with the length of repeat expansion ( Fig. 100.5 ). It is typical for the CTG repeat to expand as it is passed from parents to offspring, resulting in the characteristic worsening clinical manifestations in subsequent generations, termed anticipation . Myotonic dystrophy type 2, also called proximal myotonic myopathy (PROMM), has generally less severe skeletal muscle and cardiac manifestations than type 1. Both congenital presentation and cognitive impairment are lacking in myotonic dystrophy type 2—typically, the most severely involved subsets of the type 1 patients. The genetic mutation responsible for myotonic dystrophy type 2 is a tetranucleotide repeat expansion, cytosine-cytosine-thymine-guanine (CCTG), found on chromosome 3 in intron 1 of the cellular nucleic acid binding protein ( CNBP aka ZNF9 ). Intergenerational repeat contraction and expansion has been reported, and there is no apparent relationship between the degree of expansion and clinical severity. The prominent molecular mechanism by which both myotonic dystrophies exert their similar phenotypic presentations is by a toxic RNA gain-of-function effect. Large RNA expansions sequester and alter the function of nuclear RNA–binding proteins, resulting in aberrant mRNA splicing and polyadenylation. Cardiac involvement is related to the resultant dysregulation of multiple cardiac proteins that underlie contraction, calcium handling, excitability, and cell connectivity ( Fig. 100.6 ).

Clinical Presentation

The myotonic dystrophies are the most common inherited neuromuscular disorders in patients presenting as adults. Type 1 is more commonly diagnosed than type 2, except in certain areas of northern Europe. The global incidence of myotonic dystrophy type 1 has been estimated to be 1 in 8000 but higher in certain populations, such as French Canadians. The age at onset of symptoms and diagnosis averages 20 to 25 years. A congenital presentation is seen in severely affected patients with myotonic dystrophy type 1. Common early manifestations are related to weakness in the muscles of the face, neck, and distal extremities. Muscle weakness is progressive. On examination, myotonia can be demonstrated in the grip, thenar muscle group, and tongue ( Fig. 100.7 ). A diagnosis can be made in asymptomatic patients using electromyography and genetic testing. Subcapsular (“Christmas tree”) cataracts and early male-pattern baldness are common. Hyperinsulinemia, hyperglycemia, insulin resistance, diabetes, testicular failure, and adrenocortical dysregulation are seen in myotonic dystrophy type 1. Cardiac symptoms typically appear after the onset of skeletal muscle weakness but can be the initial manifestation. Patients with myotonic dystrophy type 2 exhibit muscle weakness, myotonia, cataracts, and endocrine abnormalities, as in type 1; however, age at symptom onset is typically older.

Cardiovascular Manifestations

Histopathology in the myotonic dystrophies shows cardiac myocyte hypertrophy and degeneration with fibrosis and fatty infiltration preferentially targeting the specialized conduction tissue, including the sinus node, atrioventricular node, and His-Purkinje system ( Fig. 100.8 ). Degenerative changes are observed in working atrial and ventricular tissue but only rarely progress to a symptomatic dilated cardiomyopathy. It is not clear if there are differences in the cardiac pathology observed between myotonic dystrophy type 1 and 2. Patients with type 2 myotonic dystrophy typically demonstrate cardiac involvement later in life or not at all. The primary cardiac manifestations of the myotonic dystrophies are arrhythmias.

Electrocardiography

A majority of adult patients with myotonic dystrophy type 1 exhibit electrocardiographic abnormalities. In a general middle-aged US myotonic population, abnormal electrocardiographic patterns were seen in 65% of the patients. Abnormalities included first-degree atrioventricular block in 42%, right bundle branch block in 3%, left bundle branch block in 4%, and nonspecific intraventricular conduction delay in 12%. Q-waves not associated with a known myocardial infarction are common. Electrocardiographic abnormalities are less common in younger patients. Conduction disease worsens with advancing age ( Fig. 100.9 ). Electrocardiographic abnormalities are less common in myotonic dystrophy type 2, occurring in approximately 20% of middle-aged patients.

Imaging and Heart Failure

Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, mitral valve prolapse, regional wall motion abnormalities, and left atrial dilatation have been reported in patients with myotonic dystrophy type 1 at moderate prevalence rates. Clinical heart failure is observed but is less common than are arrhythmias. Left ventricular hypertrophy and ventricular dilation have been reported in myotonic dystrophy type 2. Cardiac MRI is more sensitive than echocardiography for detection of early cardiac involvement. Myocardial fibrosis is often observed in myotonic dystrophy and is associated with regional abnormalities in LV function. The association of global LV function and conduction abnormalities is more variable.

Arrhythmias

A cardiac etiology is second only to respiratory failure as a cause of death in patients with myotonic dystrophy type 1. The major goal of management is evaluation of the risk for serious arrhythmias and sudden death ( eFig. 100.3 ). Patients with myotonic dystrophy type 1 demonstrate a wide range of arrhythmias. At cardiac electrophysiologic study, the most common abnormality found is a prolonged His-ventricular (H-V) interval ( Chapter 68 ). Conduction system disease can progress to symptomatic atrioventricular block and necessitate pacemaker implantation. The prevalence of permanent cardiac pacing in patients with myotonic dystrophy type 1 varies widely between studies based on referral patterns and the indications used for implant. Updated practice guidelines have recognized that asymptomatic conduction abnormalities in neuromuscular diseases such as myotonic dystrophy may warrant special consideration for pacing ( Chapter 69 ). Atrial arrhythmias, primarily atrial fibrillation and atrial flutter ( Chapter 66 ), are the most common arrhythmias observed. Ventricular tachycardia can occur. Patients with myotonic dystrophy type 1 are at risk for ventricular tachycardia occurring as a consequence of reentry in the diseased distal conduction system, as characterized by bundle branch reentry and interfascicular reentry tachycardia ( Fig. 100.10 ). Therapy with right bundle branch or fascicular radiofrequency ablation can be curative ( Chapter 67 ). Sudden death is responsible for 18% to 33% of deaths in myotonic dystrophy type 1; presumably, most are due to arrhythmias. Annual rates of sudden death in population studies vary between 0.25% and 2%. The mechanisms leading to sudden death are not clear. Distal conduction disease producing atrioventricular block can result in the lack of an appropriate escape rhythm and asystole or bradycardia-mediated ventricular fibrillation. Sudden death can occur in myotonic dystrophy type 1 despite pacing, implicating ventricular arrhythmias. Non-arrhythmic causes of sudden death, probably acute respiratory issues, play some role. Arrhythmias and sudden death have been reported in myotonic dystrophy type 2 but seem to be rarer than in type 1.

Treatment and Prognosis

Cardiac manifestations occur in both myotonic dystrophy types 1 and 2, and therefore diagnostic evaluation is essential in both. Cardiac disease is observed at a younger age in myotonic dystrophy type 1 compared with type 2. Annual ECGs are recommended even in patients without symptoms or conduction disease. Echocardiography or other imaging modalities can determine if structural abnormalities are present. Cardiac imaging in adults should be done at diagnosis or with new symptoms. In the absence of significant abnormalities and symptoms, repeat evaluation every 3 to 5 years is appropriate. In the patient with reduced left ventricular function, standard therapy including ACE inhibitors and beta blockers has improved symptoms. There are no data on the role of ACE inhibitors or beta blockers in preventing the development of a cardiomyopathy in myotonic dystrophy. Patients presenting with symptoms indicative of arrhythmias such as syncope and palpitations should undergo an evaluation, often including a cardiac electrophysiologic study, to determine an underlying causative disorder. The role and interval for ambulatory ECG (Holter) monitoring are not clear although periodic surveillance even in the absence of conduction system disease is prudent ( Chapter 61 ). The presence of significant or progressive electrocardiographic abnormalities despite a lack of symptoms is an indication for consideration of prophylactic pacing. The presence of severe electrocardiographic conduction abnormalities and atrial arrhythmias were independent risk factors for sudden death. The strategy of pacing when the H-V interval is 70 milliseconds or more decreased sudden death in a large observational trial using propensity analysis for risk stratification. Patients with significant conduction defects who are candidates for pacemaker implantation should be evaluated for their risk of ventricular arrhythmias. If cardiac MRI reveals fibrosis or if LV dysfunction is present, programmed stimulation of the ventricle may be appropriate. If a ventricular tachyarrhythmia is inducible with a non-aggressive protocol, an ICD may be the preferred cardiac rhythm management device. In patients presenting with wide complex tachycardia, cardiac electrophysiologic study with particular evaluation for bundle branch reentry tachycardia should be done ( Chapter 67 ). The use of cardiac resynchronization therapy may be appropriate in patients requiring ventricular pacing.

Treatment of myotonia, weakness, and muscle pain with sodium channel blocking drugs (mexiletine) in patients with myotonic dystrophy may be required. In the setting of a normal resting ECG and no evidence for cardiac involvement, mexiletine can be used without further evaluation. If the ECG demonstrates any conduction system disease, pacing may be required to safely use sodium channel blocking drugs. In situations in which pacing is not possible or desired, instituting drug therapy with electrocardiographic monitoring may be considered recognizing the risk of progressive conduction system disease. Similarly, the use of Na channel blocking drugs for the treatment of atrial fibrillation is contraindicated in patients with conduction system disease in the absence of a pacemaker.

Anesthesia in patients with myotonic dystrophy increases the risks of decreased gastrointestinal motility, respiratory failure, and arrhythmias. Patients may have unpredictable responses to neuromuscular blocking agents and careful monitoring during the perioperative period is mandatory. Monitored anesthesia during cardiac device implants should be done under an anesthesiologist’s care.

The course and prognosis of neuromuscular abnormalities in the myotonic dystrophies is variable ( eTable 100.1 ). Respiratory failure from progressive muscle dysfunction is the most common cause of death. Some patients, however, are only minimally limited by weakness up to the age of 60 to 70 years. Sudden death can reduce survival rates in patients with myotonic dystrophies, including those minimally symptomatic neuromuscular involvement. Decisions regarding primary prevention cardiac devices need to be made with full consideration of all aspects for the care of the myotonic patient.

Genetics and Cardiac Pathology

Emery-Dreifuss muscular dystrophy (EDMD) is a spectrum of rare inherited disorders in which skeletal muscle symptoms are often mild but with cardiac involvement that is both common and serious. The disease (EDMD1) is classically inherited in an X-linked recessive fashion and the gene responsible, STA , encodes a nuclear membrane protein termed emerin ( Table 100.2 ). EDMD is also inherited in an autosomal manner, the result of mutations in the LMNA gene that encodes the nuclear membrane proteins, lamins A and C. LMNA mutations also cause a spectrum of other diseases, including dilated cardiomyopathy and conduction system disease without skeletal muscle involvement and lipodystrophy ( Chapter 52 ). Nuclear membrane proteins such as emerin and lamins A and C provide structural support for the nucleus and interact with the cell’s cytoskeletal proteins. The most common pattern of inheritance of LMNA mutations is autosomal dominant with variable expressivity and penetrance. Mutations throughout the LMNA gene have been documented in EDMD.

Clinical Presentation

EDMD is characterized by a triad of early contractures of the elbow, Achilles tendon, and posterior cervical muscles; slowly progressing muscle weakness and atrophy, primarily in humeroperoneal muscles; and cardiac involvement ( Fig. 100.11 ). The disorder has been labeled “benign X-linked muscular dystrophy” to differentiate the slowly progressive muscular weakness from that of DMD. In the autosomal dominant and recessive inheritance of EDMD, a more variable phenotypic expression and penetrance are typically observed. Mutations in the lamin A/C gene are also responsible for an autosomal dominant familial partial lipodystrophy characterized by marked loss of subcutaneous fat, diabetes, hypertriglyceridemia, and cardiac abnormalities.

Cardiovascular Manifestations

In most patients with EDMD, the cardiac manifestations are the cause of mortality. Arrhythmias and dilated cardiomyopathy are the major manifestations of cardiac disease in EDMD and its associated disorders (see eFig. 100.1 ). In X-linked recessive EDMD, abnormalities in impulse generation and conduction are common. Electrocardiographic abnormalities are usually apparent by age 20 to 30 years, commonly showing first-degree atrioventricular block. The atria appear to be involved earlier than the ventricles, with atrial fibrillation and atrial flutter, or more classically, permanent atrial standstill and junctional bradycardia. Abnormalities in impulse generation or conduction are present in virtually all patients by age 35 to 40 years, and requirement for pacing is typical. Ventricular arrhythmias occur, including sustained ventricular tachycardia and ventricular fibrillation. Sudden death, presumably due to cardiac disorders, before age 50 is observed and has informed the use of primary prevention ICDs. ^, Female carriers of X-linked recessive EDMD due to emerin mutations do not exhibit skeletal muscle disease but exhibit late cardiac disease, including conduction abnormalities, and more rarely sudden death. Although arrhythmias are the most common presentation of cardiac involvement in X-linked recessive EDMD, a dilated cardiomyopathy does occur. The dilated cardiomyopathy is more common in patients in whom the survival time has been improved with cardiac device implantation. Both autopsy and endomyocardial biopsy specimens have shown cardiac fibrosis.

Patients with disorders caused by lamin A and C mutations typically present at 20 to 40 years of age with cardiac conduction disease, atrial fibrillation, and dilated cardiomyopathy. Skeletal muscle disease typically is subclinical or absent. Progressive cardiomyopathy severe enough to require heart transplantation has been reported. Sudden death in those patients with dilated cardiomyopathy occurs. Pacing often is required for symptomatic heart block. ICDs are the appropriate cardiac device for a majority of these patients.

Treatment and Prognosis

Patients should be monitored for development of electrocardiographic conduction abnormalities and arrhythmias. Annual evaluation including an ECG is appropriate ( eFig. 100.4 ). Sinus node dysfunction and atrial standstill are associated with AF often before the development of bradyarrhythmias. AF is associated with a relatively high frequency of embolic stroke, even in the absence of ventricular dysfunction; therefore, anticoagulation should be considered in patients with EDMD with atrial standstill or AF. Sudden death even in patients with pacemakers has been observed. Primary prevention ICD is recommended in patients with EDMD and its associated disorders if significant electrocardiographic conduction disease is present and pacing is being considered. ^, The use of biventricular pacing should be considered in patients that require ventricular pacing. Whether ICDs should be considered only in certain subgroups of patients or in all patients with significant conduction disease or cardiomyopathy is not clear. In a large observational European series, risk factors for sudden death and appropriate ICD therapy included nonsustained ventricular tachycardia, left ventricular ejection fraction less than 45% at presentation, male sex, and lamin A or C non–missense mutations. Routine imaging for evaluation of left ventricular function is appropriate in all patients with EDMD and the associated disorders. Although data are limited in this cohort, patients with LV dysfunction should be managed with guideline-recommended medical therapies, including ACEIs or ARBs, neprilysin inhibitors, beta blockers, and diuretics. Advanced HF treatment, including mechanical cardiac support (ventricular assist devices) and heart transplantation should be considered in appropriate patients. Female carriers of X-linked recessive EDMD develop conduction disease, and electrocardiographic monitoring on a routine basis is appropriate. Atrioventricular block can occur with anesthesia.