In sharp contrast to the other dystrophies, female carriers of Emery-Dreifuss muscular dystrophy may have heart disease that becomes more prevalent with age [2]. Although arrhythmia has been described in carriers, sudden death in a carrier has not been reported. Because female carriers of X-linked diseases usually have no manifestations of the disease, it has not been recognized that female carriers of Emery-Dreifuss muscular dystrophy, like affected men, may have fully developed heart disease without skeletal muscle weakness or contractures. In addition, because Emery-Dreifuss muscular dystrophy is uncommon, the association of potentially fatal arrhythmias with the unique myopathy is not generally appreciated.

We describe the clinical and pathologic findings in a case of sudden cardiac death in a female carrier; compare the cardiac abnormalities with those of two men who were studied at autopsy; emphasize the unique cardiac abnormalities associated with this disorder; and stress the need for careful monitoring and early therapeutic intervention in carriers of the gene who, despite their normal appearance, have a risk for sudden death.

Case Reports

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Clinical and pathologic findings in the described patients are shown in Table 1.

Patient 1

A 45-year-old woman had a son with Emery-Dreifuss muscular dystrophy. She was well until 2 years before death when, during an episode of pneumonia, borderline cardiomegaly was seen on a chest radiograph. During the following 2 years, she had several episodes of dyspnea and experienced chest pain that was thought to be noncardiac in origin. She did not have peripheral edema, classic angina pectoris, or syncope. An evaluation by two cardiologists showed a grade II/VI ejection murmur and an S₄ gallop. Electrocardiograms showed intermittent junctional rhythm with a slightly prolonged QT interval (QT_c, 560 ms) Figure 1 A. A chest radiograph showed borderline cardiomegaly, and a two-dimensional echocardiogram and a Doppler study were normal. Holter monitoring was not done. A family history of Emery-Dreifuss muscular dystrophy was not elicited. The patient improved somewhat while receiving therapy with furosemide (80 mg daily), isosorbide dinitrate (20 mg three times daily), and potassium. The patient was found dead in bed at home.

View larger version (123K): [in this window] [in a new window]   Figure 1 A. Electrocardiographic and pathologic findings in patient 1. Electrocardiographic tracing showing an accelerated junctional escape rhythm (rate, 60 beats/min), QRS voltage suggestive of left ventricular hypertrophy, and a prolonged QT interval of 560 ms (one half the standard calibration of V leads). Figure 1 B and C. Gross photograph of right atrium in patient 1. Panel B. The wall is thin and translucent. Thicker regions are pale because of the replacement of myocytes with adipose tissue (arrow). Panel C. Sections through right (RA) and left (LA) atria to show transmural replacement of myocardium with adipose tissue.

View larger version (84K): [in this window] [in a new window]   Figure 2. Normal and abnormal atrial findings. Panel A. Control right atrial wall from a young trauma victim showing normal musculature. Panel B. Right atrium from patient 1 showing region replaced by adipose tissue. Panel C. Control sinoatrial node region from young trauma victim. Panel D. Sinoatrial node region from patient 1. The most prominent finding is the total absence of myocytes in the atrial tissue surrounding the sinoatrial node. The asterisk indicates the sinoatrial node artery. (Trichrome stain; original magnification, x l0.).

Patient 2

A 43-year-old man had skeletal muscle weakness and contractures typical of Emery-Dreifuss muscular dystrophy since childhood [3]. At age 31 years, his electrocardiograms showed atrial standstill, and an epicardial pacemaker was implanted. Subsequent electrocardiograms showed frequent isolated premature ventricular complexes, but his cardiac status was stable until his sudden death 11 years later, despite the presence of a functioning pacemaker.

At autopsy, both atria were dilated and had thin, pale walls. Endocardial, organizing, mural thrombi were present in both atria. Transmural replacement fibrosis had occurred in the anterolateral and apical walls of the left ventricle, which were thinned in these regions.

Histologic examination of right and left atria showed marked loss of myocardium, with replacement by fibroadipose tissue. A striking finding was marked fibromuscular intimal proliferation with luminal narrowing in the arteries around the atrioventricular node (Figure 3). Sections of the conduction system showed only minimal fibrosis of the sinoatrial node.

View larger version (167K): [in this window] [in a new window]   Figure 3. Atrial findings in patients 2 and 3. Panel A. Atrial wall of patient 2 has been replaced by fibroadipose tissue, with no myocardium present. Panel B. Region of the atrioventricular node showing marked intimal proliferation of arteries. Myocardium is absent in this region of the right atrium. Panel C. The left atrial wall of patient 3 is thin and has few remaining myocytes within dense fibrous tissue. Panel D. The atrioventricular node (N) appears normal. The arteries are normal in this region (compared with the arteries in the region of the atrioventricular node in patient 2). (Trichrome stain; original magnification, x l0.).

Patient 3

Progressive congestive heart failure developed in a 25-year-old man and eventually was responsible for his death. At age 19 years, he developed atrial fibrillation and atrial standstill. He had a transvenous right ventricular pacemaker inserted. During the next 6 years, recurrent ventricular tachycardia and progressive left ventricular dysfunction with an ejection fraction of less than 20% developed. Severe mitral and tricuspid regurgitation were also present. His clinical course was complicated by ventricular fibrillation, from which he was resuscitated, and pulmonary and systemic thromboemboli.

At autopsy, both atria were dilated and the atrial myocardium appeared pale, thin, and translucent. Histologic sections showed bilateral absence of atrial myocardium, with replacement by fibroadipose tissue (Figure 3). Sections of the conduction system showed mildly increased fibrous tissue in the sinoatrial node and bundle of His.

Discussion

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Emery-Dreifuss muscular dystrophy, the third most common X-linked recessive dystrophy, is unique in that the skeletal myopathy may be extremely mild, even asymptomatic, in patients who have a cardiomyopathy that may cause sudden death [1]. Myopathies classically affect the most proximal muscles, but in Emery-Dreifuss muscular dystrophy the distribution is distinctive because it affects the arm muscles more than the shoulder muscles, and the calf muscles more than hip and pelvic muscles. Patients with Emery-Dreifuss muscular dystrophy also have unusual, easily recognizable skeletal contractures. They have fixed elbow flexion that prevents the relaxed arm posture, and they cannot flex the spine because of neck and lower back contractures; forward bending is accomplished entirely by hip flexion. When the elbow contractures are combined with contractures of the spine and Achilles tendons, the patient's appearance is unique. Cardiac findings in the disease are also unique.

The clinical cardiac manifestations are protean, and the severity of heart disease does not correlate with the degree of skeletal muscle involvement. In asymptomatic patients, an electrocardiogram may show low-amplitude P waves and first-degree heart block. These changes may progress to atrial fibrillation or flutter and then to second- and third-degree heart block with a slow junctional rhythm. Atrial standstill is a pathognomonic finding [4]. Patients may have syncope in the second to third decades of life. Late in the course, manifestations of a generalized cardiomyopathy may become evident. The rate of progression and severity of cardiac disease is extremely variable. Death may be sudden or caused by progressive congestive failure or complications of thromboemboli from the heart.

The cardiac morphologic features of Emery-Dreifuss muscular dystrophy appear to be pathognomonic. In 1975, Waters and colleagues [4] predicted that the atria in patients with Emery-Dreifuss muscular dystrophy would show fibrosis and degeneration and that changes in the conduction system might be present. Myocardial hypertrophy and interstitial fibrosis have been described, with the atria showing earlier and more severe involvement than the ventricles [2]. Female carriers of Emery-Dreifuss muscular dystrophy, who are usually free of peripheral myopathy and do not have contractures, are known to have arrhythmias and to require pacemakers for heart block; however, the presence of cardiac abnormalities in a carrier has not been previously reported.

The marked loss of atrial myocardium and its replacement by fibrous and adipose tissue are the most prominent and consistent abnormalities in Emery-Dreifuss muscular dystrophy. These striking changes are similar to those in the right ventricle of patients with arrhythmogenic right ventricular dysplasia [5]. The loss of atrial musculature and the resulting isolation of the sinoatrial and atrioventricular nodes appear sufficient to explain the atrial arrhythmias (fibrillation, flutter, standstill) and atrioventricular block observed in patients with Emery-Dreifuss muscular dystrophy. The mild changes observed in the conduction system support the notion that the atrial arrhythmias and conduction defects were due to changes seen in the atrial myocardium rather than the sinoatrial and atrioventricular nodes. All three patients also had sudden death.

The one carrier we studied was found dead in bed (patient 1), had electrocardiographic evidence of an accelerated junctional rhythm, and a prolonged QT interval. Whether the sudden death was related to bradyarrhythmias associated with the atrial abnormalities, or to ventricular tachyarrhythmias associated with ventricular hypertrophy and fibrosis is unknown. The electrocardiographic finding of a prolonged QT interval, not previously associated with Emery-Dreifuss muscular dystrophy, also complicates the evaluation of the mechanism of death in this patient.

The patient with Emery-Dreifuss muscular dystrophy who died suddenly, despite the presence of a pacemaker (patient 2), also had extensive ventricular fibrosis possibly related to infarction secondary to thromboembolic phenomena from a left atrial mural thrombus. The profound obliterative small-vessel disease, in the region of the atrioventricular node in this patient, has not been described in Emery-Dreifuss muscular dystrophy. Its frequency and significance are unknown. Interestingly, the similar small-vessel disease described in patients with Duchenne muscular dystrophy is also limited to arteries close to the conduction system [6].

The patient who died of progressive congestive heart failure (patient 3) had been resuscitated from ventricular fibrillation (sudden death). The study at autopsy showed characteristic atrial findings and patchy interstitial fibrosis of the ventricles. In this case, as in others previously reported, a primary ventricular myopathic process was manifest clinically.

The cardiac clinicopathologic abnormalities in Emery-Dreifuss muscular dystrophy differ from those of other childhood myopathies. Friedreich ataxia, an autosomal recessive disorder, is associated with hypertrophic cardiomyopathy [7]. Duchenne and Becker muscular dystrophies are X-linked disorders associated with left ventricular fibrosis, usually of the posterobasal wall, and small-vessel disease [6]. Cases of familial forms of dilated cardiomyopathy [8], including those with X-linked inheritance [9], have also been reported. In these patients, the pathologic findings are identical to those seen in patients with nonfamilial idiopathic dilated cardiomyopathy.

Myotonic dystrophy [10-13] and a group of disorders called mitochondrial myopathies [14-19] are multisystem diseases with protean manifestations and are easily distinguished from Emery-Dreifuss muscular dystrophy. Bradyarrhythmias may be observed in these conditions. Conduction defects in both conditions appear to be primarily infranodal, and left or right bundle branch block is common. The cardiac abnormalities associated with these two conditions have not been well characterized.

In patients with myotonic dystrophy, syncope and sudden death, when monitored, were associated with ventricular tachyarrhythmias [10-13]. Although subclinical cardiac abnormalities are common, clinical evidence of heart disease is rare. Autopsy findings reported in myotonic dystrophy include coronary artery disease, mitral valve prolapse, myocardial fibrosis and vacuolization, and focal fatty infiltration of the conduction system [10, 11].

In mitochondrial myopathies, tachyarrhythmias occur but are most often supraventricular [14]. In three fatal cases, death was caused by high-degree infranodal heart block [14]. In mitochondrial myopathy, autopsy diagnoses include dilated [15], hypertrophic [16], and histiocytoid [17] cardiomyopathy. The working myocardium may be normal, with pathologic changes primarily affecting the bundle of His and bundle branches [18].

Emery-Dreifuss muscular dystrophy is the only muscular dystrophy known to cause atrial paralysis. It should be considered in any young person with progressive loss of P-wave amplitude or prolongation of the PR interval leading to slow junctional rhythm. In patients with heart block, pacemaker therapy may improve symptoms and be lifesaving. For patients with documented life-threatening ventricular tachyarrhythmias, antiarrhythmic therapy and an implantable defibrillator should be considered. In patients with severe dilated cardiomyopathy, cardiac transplantation may be indicated^[20], especially if the skeletal myopathy is mild, as it so often is. For asymptomatic patients, 24-hour monitoring of the rhythm is warranted to detect intermittent arrhythmias and heart block. Anticoagulation therapy should be considered for patients with atrial fibrillation or standstill, because mural thrombi commonly form, and systemic embolization can be a cause of disability or death.

The standard genetic theory for why certain women might show clinical manifestations of an X-linked recessive disorder is that skewed inactivation of the normal X chromosome occurs in key cells of affected tissues. In Emery-Dreifuss muscular dystrophy, the heart appears to be the tissue that manifests this change [1]. Cardiac involvement of female carriers increases progressively with age [2]. As our case shows, women who are heterozygous carriers of the Emery-Dreifuss gene (that is, mothers and sisters of affected men) may have subtle clinical cardiac disease yet still be at risk for sudden death. Because of this lethal potential of Emery-Dreifuss muscular dystrophy, a thorough family history must be obtained so that carriers can be identified and studied. Cardiac function and conduction, as well as the potential for bradyarrhythmias and tachyarrhythmias, must be assessed not only in men who are affected or at risk but also in their mothers and sisters because they may be carriers of the Emery-Dreifuss muscular dystrophy gene.