Management of Cardiac Involvement in NeuroMuscular Diseases: Review

Neuromuscular Diseases are a heterogeneous molecular, clinical and prognosis group. Progress has been achieved in the understanding and classification of these diseases. Cardiac involvement in neuromuscular diseases namely conduction disorders, ventricular dilatation and dilated cardiomyopathy with its impact on prognosis, is often dissociated from the peripheral myopathy. Therefore, close surveillance is mandatory in the affected patients. In this context, preventive therapy (beta-blockers and angiotensin converting enzyme inhibitors) has been recently recommended in the most common Neuromuscular Diseases, Duchenne Muscular Dystrophy and Myotonic Dystrophy.


INTRODUCTION
During last years, progress has been achieved in the understanding and classification of neuromuscular diseases.
Cardiac involvement (Table 1) in the neuromuscular diseases namely conduction disorders, ventricular dilatation and dilated cardiomyopathy with its impact on prognosis, is often dissociated from the peripheral myopathy. Therefore, close surveillance is mandatory in affected patients. In this context, preventive therapy has been recently recommended in the most common forms the Duchenne Muscular Dystrophy and the Myotonic Dystrophy.

Duchenne (DMD) and Becker (BMD) Muscular Dystrophy
In the DMD, prognosis depends on the ventilatory assistance (respiratory muscle dysfunction is the main reason for death, survival thus depend on the ventilatory support). In BMD, prognosis rather depends on the existence of a cardiomyopathy.
Both diseases are X-linked recessive disorders due to the Dystrophine gene abnormality with almost absence of Dystrophine in DMD and reduced Dystrophine in BMD [1][2]. (Table 2) DMD is the most common inherited neuromuscular disorder with an incidence of 30/100000 live male births. A cardiomyopathy is always present but is masked by severe muscle weakness. The electrocardiogram (ECG) is often abnormal. Death occurs by the age of 20 years old in DMD versus 40-50 years old in BMD [3]. (Table 3) Angiotensin Converting Enzyme Inhibitors (ACEI) have been shown to be effective in preventing left ventricular (LV) remodeling in ischemic cardiomyopathy and reducing LV hypertrophy and fibrosis which contribute to ventricular arrhythmias and sudden cardiac death (SCD) [4]. Recently, ACEI have been studied in patients with muscular dystrophies. Early initiation of treatment with perindopril was associated with lower mortality in patients with DMD with normal LV ejection fraction at study entry [5]. Likewise, others [6] found that a beta-blocker (BB), in addition to ACEI improves LV systolic function in patients with muscular dystrophy.

Cardiac Management
In the light of these positive results, many authors [5][6] recommend initiation of ACEI and/or BB early after diagnosis of the muscular dystrophy especially in DMD.
Some studies suggested that corticosteroids might have a beneficial effect in DMD [7].
Males with DMD must be followed-up more closely than female with DMD or those with BMD [7].
The mean age survival is 53 years old. Cardiovascular Events (LV dysfunction, ischemic heart disease, pulmonary emboli or SCD) represents 30% of all cause mortality [10].
Moreover, cardiac involvement may be the first expression of the disease [10].

Conduction Disorders
First degree AV bloc is seen in up to 40% cases. Bundle branch blocs, a long QT, ST-T modifications and axis deviations are other possible findings [10][11].
Because progression of these conduction disorders is unpredictable, in addition to the high prevalence of infra-His defects (conduction impairment below the His bundle), an electrophysiology study (EPS) should always be performed.
Late potentials (LP), rather than a risk indicator for ventricular arrhythmias, seems to correlate with a delayed activation along the His-Purkinje system [10][11][12]. LP can thus be used for selection of candidates for an EPS ( Table 5).

Management of Cardiac Involvement in NeuroMuscular Diseases
The Open Cardiovascular Medicine Journal, 2008, Volume 2 95 Asymptomatic sinus bradycardia has been reported in pediatric series [13].
-Ventricular tachycardias (VT) are frequent, thus any symptomatic patient should undergo an EPS ( Table 5). 50% of patients who had a pace-maker (PM) for AV bloc, develop VT and are at risk of SCD. Different mechanisms are described for the VT, a particular one is the bundle branch rerentry (BBR) VT since it can be cured by radiofrequency ablation [10,12,14].

Cardiomyopathy and other Disorders
Patients present symptoms of heart failure in only 1.8% cases because they are usually limited in their daily activity. In fact, cardiac imaging can unmask 14% of asymptomatic LV dysfunction [10][11][12].

Cardiac Management [10,12,13]
While waiting for several ongoing studies that will evaluate arrhythmias and cardiac manifestations of DM1, suggestions for management of cardiovascular complications in DM1 patients are as follows: An ECG every 6 to 12 months is advised in asymptomatic patients with a normal baseline ECG.
EPS is indicated as previously mentioned in Table 5.
According to recent guidelines [15], PM implantation is a class1 indication in the presence of a third degree and advanced second degree AV block at any anatomic level with or without symptoms. If a VT at EPS is only a BBRVT, radiofrequency ablation of 1 BB (usually the right BB) is probably curative and the patient may not need an implant-able cardioverter defibrillator (ICD) if he/she does not meet the classical criteria for ICD placement and if there is no other inducible VT with a mechanism other than BBR.
Echocardiography is recommended in symptomatic patients and in those patients with conduction disturbances or arrhythmia.

Epidemiology and Clinical Presentation
Two forms are described; EDMD2 is the autosomal dominant type caused by mutations of the LMNA gene at 1q21 (which encodes lamins A and C); EDMD1 is the Xlinked form caused by mutations of the STA gene at Xq28 (which encodes the nuclear membrane protein emerin) [1][2].
ECG is abnormal by age 20 to 30 years old with sinoatrial or auriculo-ventricular conduction disorders, atrial arrhythmias, ventricular arrhythmias (particularly in EDMD2) [13]. Cardiomyopathy (CMP) represents 2% of CMP in children and may develop earlier in the EDMD2 [13].
Survival is 35% at the age of 45 years old with a high risk of SCD [1-2-11].

Cardiac Management
Family members of the EDMD, especially EDMD2, must be screened after the age of 10 years old, even in the absence of symptoms [13].
It is advised to perform during follow-up, an ECG, a Holter ECG and an Echocardiography once a year. An exercise test may be helpful in children and an EPS will be indicated as for the MD1.
Cardiomyopathy is possible except in alpha-sarcoglycanopathy.
Fanin reported cardiomyopathy in 10 patients with LGMD type 2E from 6 different families [11]; atrial fibrillation was found in 2 out of these 10 patients.
Though guidelines are lacking in these dystrophies, it is advised to repeat ECG/Holter and echocardiography every 2 to 5 years. Empirical therapy by ACEI and /or BB is used in the setting of LV dysfunction [13].

CONCLUSIONS
Advances in the understanding of the incidence, the type, the pathophysiology and molecular biology of the various peripheral myopathies and their cardiac complications had allowed recommendations for the cardiological follow-up of the patients especially in the commonest diseases (Steinert's disease, Duchenne and Becker muscular dystrophies and EDMD). Little is known regarding the management of cardiac complications in children with the same diseases; prospective studies in this age group of patients are therefore mandatory. This may lead to early screening in affected families and adjustment of guidelines for device implantation in adults for this young population.