Cardiac involvement in muscular dystrophies

Abstract

The muscular dystrophies are a heterogeneous group of conditions with a variable distribution and prognosis. Cardiac complications are common and may significantly alter both quality and quantity of life. Whilst complications are disease specific, many patients will require long-term cardiology follow-up looking for the development of a cardiomyopathic process or conduction problems. Improvements in diagnostic techniques now allow mutation-specific diagnosis to be made in some patients so adequate counselling, management and screening can be put in place for individuals and their families.

Introduction

The muscular dystrophies are a group of muscle disorders characterized by progressive muscle wasting and weakness. Age of onset is variable, as are the distribution and severity of the diseases. Muscular dystrophies are caused by gene abnormalities, which code for a variety of proteins involved in different functions within the muscle cell.¹ Some of these proteins are components of the membrane of the muscle fibre that may have a structural or signalling role, whilst others are components of the nuclear envelope or are muscle-specific enzymes. Cardiac involvement is disease specific and varies from asymptomatic ECG changes to conduction disorders requiring pacing or end-stage dilated cardiomyopathy.

Classification

The muscular dystrophies:

1. Duchenne muscular dystrophy

2. Beckers muscular dystrophy

3. Emery–Dreifuss muscular dystrophy

4. Facioscapulohumoural muscular dystrophy

5. Limb-girdle muscular dystrophy

6. Congenital muscular dystrophy

The myotonic dystrophies:

1. Myotonic dystrophy type I (Curschmann–Steinert dystrophy)

2. Myotonic dystrophy type II (proximal myotonic muscular dystrophy)

Duchenne muscular dystrophy (DMD)

The commonest muscular dystrophy estimated at 1 in 3500 live male births, with a prevalence of 6 in 100 000 males.² DMD is an X-linked recessive disorder caused by a mutation on the dystrophin gene, a 2.5 Mb gene located on chromosome Xp21.1.³ The gene normally codes for a protein, dystrophin, which links cytoplasmic actin to the dystrophin–glycoprotein complex at the cell membrane. Dystrophin loss leads to muscle cell structural instability.^4,5 The disease is characterized by progressive loss of muscle strength, eventually resulting in loss of ambulation, loss of respiratory muscle strength and death from respiratory insufficiency. Onset is usually between the ages of 2–3 years with weakness of the knee and hip extensors, resulting in difficulty in rising to an erect position and late walking. Most boys require a wheelchair by the age of 10 and life expectancy is usually 15–25 years.⁶ A range of 5–10% of female carriers show some degree of muscle weakness with variable clinical progression.

Cardiac involvement

Cardiac involvement is common and increases with age. A range of 10–15% of patients will die from the consequences of left ventricular failure.⁷ The mechanism of cardiac muscle involvement is believed to be similar to that of skeletal muscle with dystrophin deficiency leading to loss in the integrity of the sarcolemmna, fibre necrosis and replacement of myocardium with connective tissue or fat. However, there appears to be no direct correlation between the degree of skeletal and cardiac involvement.⁸

Nigro et al. investigated the evolution of cardiac involvement in DMD.⁹ In children under the age of 10, a variety of asymptomatic ECG changes were found. Previous studies have a found a distinctive ECG in DMD characterized by tall R waves, an abnormal R/S ratio over the right praecordial leads and deep narrow Q waves found in leads 1, aVl, V5 and V6.¹⁰ After the age of 10 many boys will begin to develop a cardiomyopathic process, initially in the form of asymptomatic regional wall motion abnormalities with the posterobasal and lateral walls of the left ventricle most commonly affected.¹¹ A few boys will show evidence of a hypertrophic cardiomyopathy. The conduction system becomes involved as fibrosis becomes more widespread leading to arrhythmias.¹² By 14 years, 50% of patients will show evidence of a cardiomyopathy on echo of which 36% will be symptomatic. Over 18 years, almost all patients will have some form of cardiomyopathy of which 57% will be symptomatic.

Treatment

ACE inhibitors have been shown to have a protective effect in DMD, Duboc et al. studied 57 boys (mean age 10.7 ± 1.2 years) with a normal ejection fraction and found a protective effect of 2/4 mg perindopril over a 5-year period.¹³ Ramciotti investigated the effects of enalapril on LV dysfunction in patients with DMD and found improvement in ejection fraction in 43% of patients.¹⁴ A recent small study has suggested that additional benefit can be gained with the addition of the beta blocker Carvedilol,¹⁵ but beta blocker use should be monitored due to the possibility of conduction system involvement. There is currently no evidence supporting the use of aldosterone antagonists in patients with symptomatic DMD.

Carriers

Carriers of the DMD gene are known to have an increased risk of developing muscle weakness compared with controls. A total of 10–15% will develop skeletal muscle weakness; the so called manifesting carriers. Carriers are at increased risk of cardiac abnormalities including ECG changes and dilated cardiomyopathy with the incidence of echocardiographic abnormalities varying from 10% to 37% across cohort studies.^16,17 A study of childhood carriers found no cardiac abnormalities suggesting changes occur at slower rate than in DMD.¹⁸

Screening

A recent International Workshop has issued guidelines for the screening of patients and carriers with DMD:⁷

Patients should undergo cardiac investigation at diagnosis with an echocardiogram and electrocardiogram (ECG).

DMD patients should have cardiac investigations (Echo and ECG) before any surgery, every 2 years to age 10 and annually after age 10.

All carriers of DMD should have an echo and ECG at diagnosis or after the age of 16 years and at least every 5 years thereafter, or more frequently in patients with abnormalities on investigation.

Becker muscular dystrophy (BMD)

The cumulative birth incidence of BMD is about one-third that of DMD affecting 1 in 18 450 male live births.¹⁹ It is caused by reduced levels or abnormal variants of dystrophin, rather than the absent levels seen in DMD and again is transmitted in an X-linked recessive pattern. Whilst the distribution of muscle weakness is similar to DMD, the age of onset is variable. Some patients present as early as 12 years, but many people with BMD have no symptoms until well into their 30s or 40s. Becker et al. found that only 10% of his patients were wheelchair bound before the age of 40 and none before 16 years.

Cardiac involvement

Cardiac involvement can predate skeletal problems and there can be little correlation between the severity of skeletal and cardiac weakness.²⁰ Nigro et al. evaluated the incidence and evolution of cardiac abnormalities in 134 patients with BMD.²¹ By 20 years of age, 50% of patients were found to have evidence of ECG changes and by 30 years 40% had a dilated cardiomyopathy on echocardiographic screening. During the average 8-year follow-up, seven patients died, five from heart failure and two from respiratory failure indicating that cardiac involvement is the principle cause for the reduced life expectancy in BMD.

Treatment

There are currently no clinical trials looking at the treatment of heart failure in BMD. Advice is generally to use standard heart failure regimes. End-stage cardiac failure is common and there are a number of case reports of the use of cardiac transplantation, which appears to be successful in this group of patients.^22–24

Carriers

Carriers of BMD are at increased risk of developing asymptomatic ECG changes and cardiomyopathy. Carriers should be advised of the risks that are similar to that found in DMD.

Screening

Guidelines similar to that with DMD have been drawn up for the screening of patients with BMD.⁷

BMD patients should have cardiac evaluation (ECG and echo) at diagnosis. They should be screened for the development of cardiomyopathy at least every 5 years.

All carriers of BMD should have echo and ECG at diagnosis or after the age of 16 years and at least every 5 years thereafter, or more frequently in patients with abnormalities on investigation.

Emery–Dreifuss muscular dystrophy (EDMD)

EDMD is an inherited disease characterized by;

1. Contractures of the elbow and Achilles tendon.

2. Progressive muscle wasting and weakness in the scapulo-humero-peroneal distribution.

3. Cardiac involvement including conduction defects, dilated cardiomyopathy and sudden death.

Onset is usually as a child but disease progression is slow and many patients are able to work well into middle age. Prognosis is usually largely influenced by cardiac status.

EDMD was first described as an X-linked recessive condition caused by a mutation coding for a nuclear protein called emerin.²⁵ It is now thought to have a prevalence of 1 in 100 000 of the population. It is known that a less common autosomal dominant and rare autosomal recessive version exist both due to a mutation in a gene coding for the nuclear proteins lamin A and C.²⁶

It is important to make a definitive genetic diagnosis as disease progression is different between the two common forms and carrier status in the X-linked group has important implications for screening and any future cardiac management.

X-linked EDMD

Cardiac involvement

Emerin is a 34 kDa protein of the inner nuclear membrane that forms a link from the nucleoskeleton to the chromatin. This suggests a role in the regulation of DNA synthesis or gene expression. Patients with X-linked EDMD are at high risk of atrioventricular conduction defects and atrial arrhythmias. Atrial fibrillation and flutter are common and a large number of patients will require permanent pacing for brady arrhythmias.²⁷ Cardiomyopathic changes appear to be less common than arrhythmias and the incidence of sudden death appears low once patients are successfully paced.²⁸ Current guidelines suggest the implantation of a permanent pacemaker in asymptomatic individuals who show signs of sinus node or AV node disease.⁷

Screening

Patients should undergo an ECG and Holter monitor at diagnosis and then annually thereafter. Echocardiography should take place on a less regular basis.⁷

Carriers

Cardiac involvement in carriers occurs in a minority of cases although cohort studies are extremely small.²⁸ Carriers should be offered periodic screening with ECGs and Holter monitors.

Autosomal dominant EDMD (the laminopathies)

Cardiac involvement

Lamin A and C are proteins in the nucleoplasm that provide structure to the nuclear membrane.²⁹ Mutations in the genes at locus 1p1-q21 that code for these proteins produce autosomal dominant EDMD, which has a more variable cardiac picture than X-linked EDMD. Left ventricular involvement is common and increases with age, whilst conduction defects and arrhythmias remain an ongoing problem. Severe cardiac involvement can occur even when musculoskeletal problems are slight.³⁰ Patients should have a permanent pacemaker implanted if asymptomatic sinus node or AV node disease develops. The incidence of sudden cardiac death is relatively high and does not appear to be reduced by the implantation of a permanent pacemaker suggesting a ventricular arrhythmogenic cause.³¹ Careful consideration should be given for the implantation of an implantable cardio defibrillator (ICD) if a pacemaker is required. Cardiac failure should be treated with standard regimes, but pacemaker implantation should be carefully considered if beta blockers are to be used and the effects of treatment closely monitored.

Screening

As with X-linked EDMD patients should undergo an ECG and Holter monitor at diagnosis and then annually thereafter. Echocardiography, however, should take place on a more regular basis.

Facioscapulohumeral muscular dystrophy (FSHMD)

FSHMD is characteristically inherited in an autosomal dominant fashion, although sporadic cases are not infrequent. Current prevalence data suggests that it occurs in 1 in 20 000 of the population. It is typically associated with a normal lifespan and cardiac involvement appears uncommon. FSHMD causes a progressive loss of all skeletal muscle, with weakness starting with facial, scapular/back and upper arm muscles. A loss of mobility occurs in about 20% of the cases and the age of onset is variable as is the disease rate of progression.

Cardiac involvement

In the largest cohort study to date, Laforet et al. investigated 100 patients with FSHMD for evidence of cardiac abnormalities. Only five were found to show abnormalities with two having supraventricular tachycardias and intraventricular conduction delay, one only showing supraventricular arrhythmias, one severe AV block requiring pacing and one VT associated with RV dysplasia.³² Studies by De Visser, Stevenson and Trevasin confirm that there is a preponderance towards atrial arrhythmias but conduction abnormalities and cardiomyopathies are rare.^33–35

Limb-girdle muscular dystrophy (LGMD)

The LGMDs are a heterogeneous group of disorders that are inherited either recessively or less commonly in an autosomal dominant pattern. There are currently seven autosomal dominant types numbered LGMD1A to 1G and 13 autosomal recessive types numbered LGMD 2A to 2M. The frequency of LGMD is thought to be 5–70 per million people of which the recessive type accounts for 90% of cases.³⁶ The LGMDs are characterized by proximal muscle weakness with onset, distribution and rate of progression being highly variable and disease specific.³⁷

Cardiac involvement

Cardiac complications are disease specific and it important that a genetic diagnosis is made to allow adequate guidance about future complications. Type 2A and 2B appear to be the most common accounting for ∼50% of cases and typically are not associated with significant cardiac complications.³⁸ The sarcoglycanopathies account for types 2C to 2F and cardiac involvement is common. They should be investigated for cardiomyopathies with regular echocardiograms, but the incidence of arrhythmias appears low.^39,40 Patients with the autosomal dominant form appear predisposed to arrhythmias and conduction block rather than cardiomyopathies.⁴¹

Congenital muscular dystrophy (CMD)

The CMDs are a group of genetic disorders caused by a mutation in the gene coding for α2 chain of Laminin. Laminin is a protein that is an important part of the structural scaffolding of the basement membrane. In CMDs, weakness and abnormal muscle histological features are present at birth. They are mostly inherited in an autosomal dominant pattern and the incidence is thought to be about 4.7 per 100 000 live births.⁴² There are currently at least 10 different CMDs described with variable muscle weakness, rate of progression and mental retardation.⁴³ Cardiac involvement is disease specific with the development of a dilated cardiomyopathy described in type MDC1C.⁴⁴

Myotonic dystrophy

Myotonic dystrophy is caused by an expansion of the cytosine–thymine–guanine (CTG) repeat in certain areas of DNA. It is the most common adult form of muscular dystrophy and is inherited in an autosomal dominant pattern. It has a prevalence of 2–14 per 100 000 and is found in 1 in 8000 live births.⁴⁵

There are currently two recognized types of myotonic dystrophy, DM1 and the less common DM2.

In DM1, a mutation in the phosphokinase (DMPK) gene located at chromosome 19q13.3 leads to reduced production of myosin kinase expressed in muscle. Myosin kinase is an important enzyme in the myosin/actin interaction needed for muscle contraction. The genetic mutation is caused by a variable CTG repeat. As cell division occurs during gametogenesis, an extra CTG repeat is added and so anticipation occurs with the child of an affected adult often having an earlier onset of the disorder. DM1 is split into three types: a congenital form that is severe with a high risk of death in the neonatal period; a minimal form that usually presents over the age of 50 and is associated with mild weakness and a normal lifespan and a classical form that is the most common, and usually presents between the ages of 20–40 years. Patients typically present with ptosis, facial weakness and weakness of the distal limbs. This usually progresses to proximal muscle involvement, myotonia as well as the development of complications including cataracts, endocrine abnormalities and progressive neurological problems.

Cardiac involvement

Cardiac involvement is common in type DM1 and is often the cause of reduced life expectancy.⁴⁶ The relationship between CTG repeat size and cardiac severity is less clear than with involvement of other systems.^47,48 Supraventricular arrhythmias in the form of atrial flutter, atrial fibrillation and atrial tachycardias are noted in up to 25% of individual. Ventricular arrhythmias occur regularly and can include monomorphic and polymorphic VT as well as VF.⁴⁹ Arrhythmias appear to be more significant in people who are diagnosed at a relatively young age.⁵⁰ ECG abnormalities in the form of a long PR interval or bundle branch block are often noted. Mean age of death is 53 years and cardiac causes account for up to 20% of cases with sudden death accounting for a further 10%.⁶ Given the high rate of sudden death, syncope and pre-syncope should be thoroughly investigated, if necessary with an electrophysiological study to assess HV times and the ability to induce VT.⁵¹ Bundle branch block re-entry ventricular tachycardia (BBRVT) has been described and is important to rule out as it is amenable to catheter ablation.⁵² The use of an ICD or pacemaker should be carefully considered in symptomatic patients. Left ventricular function does not, however, appear to be affected with DM1.⁵³

Myotonic dystrophy type 2 (DM2) is less common than DM1 and has recently been described. Phenotypically it appears similar to DM1 but no congenital form has yet been identified. There are currently no significant cohort studies investigating cardiac complications in this group, but the early signs are that it shares similar traits to DM1 with arrhythmias and syncope.^54,55

Cardiac screening

Left ventricular dysfunction

Over the last 20 years, cardiac screening has relied on transthoracic echocardiography to assess the development of cardiomyopathy. Recently, the introduction of Tissue Doppler Imaging has identified patients with subclinical left ventricular dysfunction that have previously been assessed as normal.⁵⁶ The increasing availability of Cardiac MRI scanning has shown benefit in identifying patients with the early stages of cardiomyopathy,^57,58 and MRI is more accurate and reproducible than traditional echocardiographic techniques.⁵⁹

Cardiac arrhythmias

Many of the muscular dystrophies result in an increase incidence of cardiac arrhythmias. The risk of conduction block requiring pacing is highest in EDMD but significant bradycardias can be noted in many of the other diseases as the conduction system becomes involved. Cardiac tachyarrhythmias become more common as left ventricular impairment increases and sudden cardiac death is a possibility. The presence of conduction defects raises the necessity for prophylactic cardiac pacing and episodes of sustained or non-sustained ventricular tachycardia (NSVT) may suggest the need for an ICD. Cardiac autonomic dysfunction is thought to be common with reductions in heart rate variability (HRV) noted in BMD, DMD and myotonic dystrophy.^60,61 Poor heart rate variability has been shown to be a risk factor for sudden death in patients with BMD.⁶² Increased QT dispersion is known to be a marker of abnormal ventricular repolarization and this can be assessed from a 12 lead ECG. Increased QT dispersion has been found to be a marker for ventricular arrhythmias in both BMD and DMD, and should prompt an increase in the regularity of monitoring. The presence of abnormal HRV and QT dispersion may help when assessing the potential benefits from an ICD.

Conclusion

The muscular dystrophies are a heterogeneous group of conditions with widely different clinical features and prognosis. Cardiac involvement is disease specific, may be severe and regular communication is needed between the cardiologist, neurologist and geneticist to provide the patient with optimal care. Whilst some of the diseases are present primarily as disorders of skeletal muscle, cardiac involvement may be the dominant feature in carriers and patients with BMD or myotonic dystrophy. This may mean the primary diagnosis is overlooked and only comes to light at a later stage. Clinical trials are progressively showing the benefit of cardiac interventions with ACE inhibitors and possibly β-blockers slowing the progression of any cardiomyopathic process with an associated impact on potential prognosis. Pacemakers can extend life expectancy in patients with significant conduction defects, in particular in those with EDMD and myotonic dystrophy, and ICD are appropriate in some patients. Improvements in genetic techniques are now allowing mutation-specific diagnoses to be made and so adequate counselling, management and screening can be put in place for individuals and their families. The importance of regular cardiac screening for carriers and patients is now recognized, in order to prevent sudden death and optimize patient morbidity and mortality, and screening is becoming increasingly more sophisticated with the availability of Tissue Doppler Imaging and Cardiac MRI.

References