Therapy Insight: Cardiovascular Complications Associated With Muscular Dystrophy

Elizabeth M McNally; Heather MacLeod

Disclosures

Nat Clin Pract Cardiovasc Med. 2005;2(6):301 

In This Article

Therapy

Practice guidelines for the management of heart failure have been derived based on data from clinical trials.[42] Most of these trials were conducted in adult patients with reduced systolic function and the symptoms of heart failure. Similar studies to address mortality benefit in the muscular dystrophy population are difficult because of the small number of patients. Nonetheless, in the absence of studies that demonstrate specific mortality benefits for muscular dystrophy patients, it seems reasonable to adopt these practices. The benefit of afterload reduction achieved by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers plus â-receptor blockade is clear for cardiomyopathy patients without muscular dystrophy, and there is no reason to avoid this standard regimen in muscular dystrophy patients. The use of the aldosterone agonist spironolactone and the cardiac glycoside digoxin should also be considered because these agents might also be of benefit. Diuretics should be pursued as needed for the management of fluid overload.

A central question that dominates the cardiomyopathy care of muscular dystrophy patients is when to initiate medical therapy. Recently, a prospective study demonstrated beneficial effects of angiotensin-convertingenzyme inhibitors in young Duchenne patients, suggesting that early intervention can actually prevent the development of dilated cardiomyopathy and reduced systolic function.[43] The muscular dystrophy population, particularly patients with Duchenne muscular dystrophy or limb-girdle muscular dystrophy caused by sarcoglycan gene mutations, is at high risk of developing cardiomyopathy; therefore, additional studies investigating the effectiveness of early afterload reduction, â-receptor blockade and the effect of steroids should be performed to determine whether onset of cardiomyopathy can be slowed or eliminated with pharmacologic therapy. Cardiac transplantation has been effective in patients with the milder variant Becker muscular dystrophy and in the maternal carriers of dystrophin gene mutations.[44,45]

Arrhythmia management is an equally important aspect of managing cardiomyopathy patients, and the cardiomyopathy that accompanies muscular dystrophy is no exception. Careful surveillance through history taking, as well as Holter and event monitoring, should be routinely performed. Both bradycardic and tachycardic rhythm disturbances occur and can be treated with device implantation. Because this clinical need frequently arises late in the life of many muscular dystrophy patients, device implantation might be limited by kyphoscoliosis and muscle wasting. For some patients, the use of external home defibrillators is an alternative approach. In Duchenne and the limb-girdle muscular dystrophies caused by sarcoglycan gene mutations, irregular heart rhythms tend to parallel the onset and course of progressive ventricular dilation and dysfunction.[46]

In two forms of muscle disease, irregular heart rhythms arise at an early stage in the disease, or even at presentation. The first of these diseases is myotonic dystrophy, a myopathic process commonly associated with first-degree atrio-ventricular heart block, bundle-branch block or both, reflecting involvement of the cardiac conduction system.[47] Myotonic dystrophy type I, more common than myotonic dystrophy type II, arises from a trinucleotide expansion on chromosome 19 that alters gene function and produces messenger RNA-mediated cytotoxic effects.[48] More recently, the cardiac involvement in myo tonic dystrophy type II has been described.[49] Myotonic dystrophy is a class II indication for pacemaker implantation, and patients should be monitored regularly for lengthening PR intervals.[50] Individuals with muscular dystrophy associated with mutations in the LMNA gene are also at risk of cardiac arrhythmia events, and close monitoring and prophylactic device implantation should be considered for these patients.[28]

Compromise of respiratory musculature leads to hypoventilation and is a contributor to right heart dysfunction, particularly in Duchenne muscular dystrophy. Guidelines for the management of pulmonary complications in Duchenne muscular dystrophy have been outlined and should be adopted to diminish cardiac complications that arise from respiratory dysfunction.[51]

New experimental therapies for muscular dystrophies are now emerging (Box 1). Gene replacement therapy relies on a range of viral vectors for delivery. For example, broad transduction of skeletal and cardiac muscle in mouse models has been achieved by use of adeno-associated virus serotypes.[52] Cell-based therapies are also being explored for the regeneration of skeletal and cardiac muscle;[53,54] skeletal muscle stem cells, when delivered systemically, might also home to cardiac muscle and result in muscle regeneration. Caution is advised, however, because skeletal muscle-like differentiation could occur within the heart, which would alter electrical properties and cardiac function. Finally, growth-factor-based gene therapy is emerging as a successful approach for stimulating muscle growth. Growth factors that are currently being studied for effects on skeletal muscle regeneration include insulin-like growth factor 1, and factors that inhibit myostatin.[55,56] Data generated thus far indicate that insulin-like growth factor 1-based therapies might have direct effects on the stimulation of cardiac growth. The effect of myostatin on cardiac growth is not known. Further work is required, and these therapies should be evaluated for their beneficial and adverse effects on the heart.

Growth-factor-based and cell-based therapies might be broadly applicable to all muscle degenerative disorders. Certain gene-based therapies, however, will require a precise genetic diagnosis before the designing of gene-specific therapy. For example, it was recently shown that HEREGULIN can upregulate utrophin in mice carrying a mutation in dystrophin.[57] In this model, heregulin treatment was effective in improving muscle mass. Because some therapies are directed at certain genetic forms of muscular dystrophy but not others, the molecular mutations responsible for each case of muscular dystrophy will need to be defined prior to initiating these therapies. Muscular dystrophy patients frequently present to the cardiologist without a clear molecular diagnosis. Genetic tests for many muscular dystrophies are commercially available, and most require only a simple blood draw. Muscle biopsy is used regularly to augment genetic diagnosis, and should be performed, if needed, for molecular diagnosis. A correct molecular diagnosis is highly useful to predict which muscular dystrophy patients are at risk of cardiac complications. Molecular diagnoses are also of great benefit for potentially at-risk relatives, who might not be obviously affected by muscle weakness but could still be at risk of cardiac complications (e.g. carrier mothers of Duchenne muscular dystrophy patients). Careful family history should be taken paying strict attention to history of sudden cardiac death.

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