Genetics and Cardiac Pathophysiology

Duchenne and Becker muscular dystrophies are X-linked recessive disorders caused by mutations in the dystrophin gene. The dystrophin protein and dystrophin-associated glycoproteins provide a structural link between the myocyte cytoskeleton and extracellular matrix. Dystrophin is nearly absent in Duchenne muscular dystrophy, whereas dystrophin is present but reduced in size or amount in Becker muscular dystrophy. This leads to the characteristic early presentation and rapidly progressive muscle disease in Duchenne and the more benign course in Becker muscular dystrophy.

Clinical Presentation

Duchenne is the most common muscular dystrophy. Symptoms typically begin before the age of 5 years with proximal muscle weakness that is progressive, leading to a loss of ambulation and later to respiratory failure. Invasive ventilation and spinal surgery has improved outcomes with a median survival of 35 years. Becker muscular dystrophy is less common, has a more variable presentation of skeletal muscle weakness, and has a better prognosis.

The majority of patients with Duchenne muscular dystrophy develop a cardiomyopathy, but clinical recognition can be masked by severe skeletal muscle weakness.¹ Cardiac magnetic resonance (CMR) imaging detects early myocardial fibrosis. Predilection for involvement in the posterobasal and posterolateral left ventricle has been observed. Electrocardiograms are abnormal in 90% of patients with Duchenne muscular dystrophy, demonstrating a distinctive pattern of tall R waves and increased R/S amplitude in V1 and deep narrow Q waves in the left precordial leads related to the regional ventricular involvement. Up to 40% of individuals have PR intervals less than 120 ms. Cardiac involvement in Becker muscular dystrophy is more variable, ranging from none or subclinical to severe cardiomyopathy requiring transplant. Electrocardiographic abnormalities similar to that in Duchenne muscular dystrophy are present in up to 75% with echocardiographic abnormalities in 50%. The severity of cardiac involvement does not correlate with the degree of skeletal muscle weakness.

Arrhythmia Manifestations

Persistent or labile sinus tachycardia is the most common rhythm abnormality observed in Duchenne muscular dystrophy. Atrial arrhythmias including fibrillation and flutter occur in the setting of a dilated cardiomyopathy or as a preterminal rhythm. Complete heart block requiring pacing is rare but has been reported. Ventricular arrhythmias primarily ventricular premature beats are seen on ambulatory monitoring. Monomorphic ventricular tachycardia has been described. A primary cardiac etiology for death occurs in approximately one fourth of individual with an equal distribution of death from progressive heart failure and sudden death. Whether the sudden death is due to arrhythmias is unclear. The presence of left ventricular systolic dysfunction is a risk factor for all-cause mortality. Arrhythmia manifestations in Becker muscular dystrophy correspond to the degree of associated cardiomyopathy, but are poorly characterized. Complete heart block has been observed. The prevalence of ventricular arrhythmias is not well documented. Bundle branch reentry tachycardia has been reported in a patient with cardiomyopathy.

Treatment and Prognosis

Duchenne muscular dystrophy is a progressive disorder with death from respiratory or cardiac failure. Steroids delay the progression of skeletal and cardiac muscle dysfunction. Angiotensin-converting enzyme inhibitors and β-blockers delay the onset of and can possibly improve left ventricular systolic dysfunction. The role of implantable cardioverter defibrillators (ICDs) or biventricular pacing in Duchenne patients with heart failure and left ventricular systolic dysfunction is unclear. Fatal respiratory failure after sedation for ICD placement has been reported. Patients with Becker muscular dystrophy benefit from angiotensin-converting enzyme inhibitors and β-blockers and may be better candidates for ICDs or biventricular pacing than Duchenne patients because of better respiratory status; however, little has been published. Cardiac transplant has been reported in highly select patients primarily with Becker muscular dystrophy.

Genetics and Cardiac Pathophysiology

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 that include cardiac involvement. Two distinct mutations are responsible for the myotonic dystrophies. In myotonic dystrophy type 1, a trinucleotide, cytosine-thymine-guanine (CTG) repeat expansion occurs in an untranslated region of chromosome 19. In myotonic dystrophy type 2, also called proximal myotonic myopathy, a tetranucleotide, CCTG repeat expansion occurs on chromosome 3. The mechanism responsible for the similar phenotype despite two different mutations is that the amplified DNA repeat sequence is transcribed into an amplified RNA that affects nuclear RNA binding proteins (RNA toxic gain-of-function) and subsequent downstream protein synthesis. A recent study suggests that cardiac pathology in both myotonic dystrophies is related to gap junction and calcium channel protein overexpression.² The cardiac pathology observed includes preferential degeneration of the conduction system from the sinus node to the His-Purkinje fibers. Degenerative changes are observed in other atrial and ventricular tissue, but progression to a symptomatic structural cardiomyopathy is less common. Myocardial fibrosis and conduction system degeneration is progressive, leading to an age-dependent risk of arrhythmias. Although the pathology appears similar in types 1 and 2, type 1 typically has earlier and more severe cardiac involvement.

Clinical Presentation

Myotonic dystrophy is the most common inherited muscular dystrophy in adults with type 1, significantly more prevalent than type 2. In type 1, the age at onset of symptoms and diagnosis averages 20 to 25 years, and patients often die prematurely in the fifth or sixth decade.³ In type 1, a congenital presentation marked by severe involvement including neurocognitive abnormalities can occur. Patients with type 2 and less affected patients with type 1 live longer.

Arrhythmia Manifestations

Patients with myotonic dystrophy type 1 demonstrate a wide range of arrhythmias. Electrocardiograms are abnormal in 60% of middle-aged adults primarily showing abnormalities in conduction with prolonged PR interval and QRS duration. On an electrophysiological study, a prolonged His-ventricular interval is often present.⁴

Conduction system disease can progress to symptomatic heart block and necessitate pacing. The prevalence of pacemakers varies widely between studies based on referral patterns and indications.3,4 Atrial arrhythmias, primarily fibrillation and flutter, are common. Patients with atrial arrhythmias are often asymptomatic possibly because of a controlled ventricular response from concomitant conduction disease. Up to one third of individuals with myotonic dystrophy type 1 die suddenly. The mechanisms leading to sudden death are not clear, but are believed to be related primarily to arrhythmia. Asystole, owing to complete heart block without an appropriate escape rhythm, has been considered a probable cause. Sudden death can occur despite pacemakers implicating ventricular arrhythmias. Patients with myotonic dystrophy type 1 are at risk for bundle branch reentry tachycardia because of associated conduction disease. Arrhythmias are observed in patients with myotonic dystrophy type 2, but are less frequent and occur later in life. Unexplained sudden death has been reported.⁵

Treatment and Prognosis

Neurologists and neuromuscular specialists appropriately refer myotonic patients to cardiology or electrophysiology for assessment and treatment. In patients with symptoms consistent with arrhythmias, electrophysiological evaluation to determine an etiology is mandatory. Annual electrocardiograms and consideration for 24-hour ambulatory monitoring have been recommended as screening evaluations in asymptomatic patients. In a large, myotonic dystrophy type 1 cohort, the presence of severe electrocardiographic conduction abnormalities (non–sinus rhythm, PR interval ≥ 240 ms, QRS duration ≥ 120 ms, or second- or third-degree atrioventricular block) and a clinical diagnosis of atrial arrhythmias were independent factors predicting sudden death.³ The 2008 guideline update for device-based therapy of cardiac rhythm abnormalities has recognized that asymptomatic electrocardiographic conduction abnormalities, including first degree atrioventricular or fascicular block in neuromuscular diseases such as myotonic dystrophy, warrant special consideration for prophylactic pacing.⁶ Electrophysiological study for determination of the severity of His-Purkinje disease has been recommended. In a retrospective observational evaluation performed in a referred myotonic dystrophy type 1 cohort, an invasive strategy using electrophysiologic study to guide pacing if the H-V interval is 70 ms or greater decreased the frequency of sudden death compared with a noninvasive strategy observational group.⁴ Sudden death occurs despite pacemakers, and the ICD may be the preferential therapy in patients being considered for a prophylactic device.⁷ In patients with wide complex tachycardia, an electrophysiologic study with particular evaluation for bundle branch reentry tachycardia should be done.

Anesthesia in patients with myotonic dystrophy can increase the risk of conduction block and other arrhythmias. Careful monitoring during the perioperative period with a low threshold for temporary pacing is recommended.

Respiratory failure owing to progressive neuromuscular disease is the most common cause of death in myotonic dystrophy. Nonambulatory patients and those receiving respiratory support should be considered high risk for pulmonary complications of procedural sedation. Prophylactic devices might not be justifiable if the likelihood of long-term survival is poor.

Genetics and Cardiac Pathophysiology

Emery-Dreifuss muscular dystrophy is an inherited disorder in which skeletal muscle involvement is often mild, but with cardiac and arrhythmia involvement that is common and life threatening. The disease is classically inherited in an X-linked recessive fashion, but heterogeneity is observed with an autosomal dominant inheritance that is, in fact, more common. The gene abnormality responsible for the X-linked recessive Emery-Dreifuss muscular dystrophy is a deficiency in a nuclear membrane protein termed emerin. Mutations in the LMNA gene found on chromosome 1 encoding two other nuclear membrane proteins, lamin A and C, have been identified as responsible for a multitude of degenerative disorders collectively termed laminopathies with a cardiac phenotype similar to that of the X-linked Emery-Dreifuss muscular dystrophy.⁸ Less than half of patients with Emery-Dreifuss muscular dystrophy have mutations in emerin or lamin A/C, and mutations affecting other nuclear membrane proteins have been identified. The nuclear membrane proteins provide structural support for the nucleus and interact with the cell’s cytoskeleton. Abnormalities in the nuclear proteins might not allow the nucleus and cell to tolerate mechanical stress (the nuclear fragility mechanism), and chromatin structure and subsequent downstream proteins can be adversely affected (the gene expression mechanism).⁹ Pathologic studies have shown fibrotic replacement of cardiac muscle and conduction tissue.

Clinical Presentation

A triad of early contractures of the elbow, Achilles tendon, and posterior cervical muscles, slowly progressing muscle weakness and atrophy, and cardiac involvement characterizes Emery-Dreifuss muscular dystrophy. There is a significant variation in the phenotypic expression of the various other subtypes of laminopathies.⁸ Both arrhythmias and a dilated cardiomyopathy occur in Emery-Dreifuss muscular dystrophy and the associated disorders. Often the first manifestation is conduction disease and heart block requiring pacing. The dilated cardiomyopathy tends to be observed later.

Arrhythmia Manifestations