History and physical examination

Patients with DMD are rarely symptomatic unless they are ambulatory. An apical S3 and S4 may be present in advanced cardiomyopathy. Additionally, a mitral regurgitation murmur may be audible. Patients with advanced disease may have signs of heart failure, including neck vein distention, sacral edema, peripheral edema, and hepatomegaly.

Pathology

Cardiac involvement in DMD is caused by fibrosis and scarring that proceeds from the epicardium to the endocardium, starting generally at the region behind the posterior mitral valve apparatus. This scarring spreads downward progressively toward the apex and around the heart, ultimately leading to cardiomyopathy. The myopathy is not always dilated, because the scarred areas do not have expansile properties. This process has been confirmed in vivo by MRI studies. A similar process is seen in Becker muscular dystrophy, and a recent study has shown that determining the exon deletion site has predictive value in estimating the timing of cardiomyopathy onset.

Electrocardiography

The classic findings in DMD include a shortened PR interval, right ventricular hypertrophy (RVH), and Q waves in the inferolateral leads. Previous literature suggested that Q waves in leads I and aVL were common and that RVH was proportional to the degree of myopathy, suggesting that LV fibrosis interfered with LV forces. A large study showed that findings are present in approximately half of patients (43% short PR, 37% RVH, 34% Q wave in V5, V6) ( Fig. 3 ), with no relationship to the degree or presence of cardiomyopathy as defined by an echocardiography-derived ejection fraction of less than 55%. Furthermore, the presence of Q waves was more often seen in the inferolateral leads than the anterior leads. An unpublished serial evaluation of R wave amplitudes in V1 showed no significant progression of that waveform over time in patients with cardiomyopathy of DMD (Thrush PT, Allen HD, unpublished data, 2012).

Electrocardiogram in DMD showing shortened PR, RVH, and Q waves in leads II, III, aVF, V5, and V6 (inferolateral leads).

Holter monitoring

Several studies have shown abnormally fast average heart rates in patients with DMD, regardless of the presence of cardiomyopathy. This condition is termed disordered automaticity , which is generally defined as an average heart rate exceeding 100 beats per minute in patients older than 12 years. It is attributed to a sympathetic imbalance. Older boys (and some younger ones) can have atrial and ventricular ectopy, heart block, and either atrial or ventricular tachydysrhythmias.

Doppler echocardiography studies

Anatomically, LV posterior wall thinning can occasionally be appreciated, along with contractile and relaxation abnormalities. Using the parameters mentioned earlier, as the disease advances, areas of akinesis or dyskinesis can be seen, accompanied by some with LV dilation, decreased shortening fraction, rounding (remodeling) shown by a sphericity index approaching unity, and decreased ejection fraction. Diastolic abnormalities can be seen with increasing mitral valve inflow Doppler E and A wave ratios and lateral and medial tissue Doppler ratios approaching unity.

MRI studies

MRI can show the presence and distribution of myocardial fibrosis and offer a measurement of contractility and circumferential strain ( Fig. 4 ). These findings precede the cardiomyopathy defined by an ejection fraction of less than 55% shown on echocardiographic studies. Careful analysis of ejection fraction is also possible with MRI.

MRI in patient with DMD. Note the whitened areas ( arrows ) reflecting fibrosis in the LV posterior wall.

Laboratory analysis: biomarkers

Serum brain natriuretic peptide (BNP) and α-atrial natriuretic peptide (α-ANP) levels are elevated in the presence of LV dysfunction in adults and in some boys with DMD and advanced heart failure.

Timing of treatment initiation

Ideally, boys with DMD should be referred to a cardiologist for an initial evaluation at the time of diagnosis. Changes in the heart have been documented from an early age, with 53% of children aged 5 years and younger showing an abnormality on electrocardiogram. Follow-up surveillance should continue every other year until the child begins to have symptoms or reaches the age of 10 years, when yearly follow-up should be initiated.

When to begin treating these patients with pharmacologic management is debated. Because these boys may not have symptoms, the standard has been to commence therapy if the echocardiography-derived ejection fraction is less than 55%. This timing is parallel with that of treatment of other forms of cardiomyopathy. Some have initiated treatment if, in addition to the presence of echocardiographic abnormalities, biomarkers (α-ANP, BNP) are abnormal.

Preventive treatment

Some centers advocate beginning treatment before echocardiographic abnormalities manifest, arguing that all of these boys have cardiomyopathy (raising the question, what is a cardiomyopathy?) regardless of the later-stage echocardiographic abnormalities. Duboc and colleagues conducted a trial of placebo versus angiotensin-converting enzyme inhibitor (ACE-I) in boys with DMD who had normal ejection fraction on radioisotope analysis, with all boys placed on the ACE-I after 3 years. Although all patients showed progressive deterioration in function, no significant difference was seen between the groups in their ejection fractions over time, regardless of whether they were treated. More patients in the placebo group died than in the treated group at a 10-year follow-up. Because of the increased death rate (Kaplan-Meyer survival lower in the placebo group; P = .13), the investigators concluded that boys should be treated prophylactically after the age of 9.5 years. Although the causes of deaths were not detailed, the study has resulted in many centers adopting a preventive treatment approach.

An important MRI study by Hor and colleagues showed that boys with normal echocardiographic ejection fraction had fibrosis and decreased peak circumferential strain on MRI. Patients younger than 10 years showed abnormal strain, and older boys showed a further decline in strain, with abnormal ejection fraction appearing at a mean age of 15.8 years.

A mouse model of DMD showed a protective effect of Aldactone in combination with an ACE-I on both skeletal and cardiac muscle. This effect may be from the antifibrotic effects of these medications (transforming growth factor β inhibition) in treated mice versus controls. Clinical trials are obviously needed before this may be potentially translatable to boys with DMD.

Drugs and treatments used in cardiomyopathy of DMD

In the past, standard treatment was with digoxin and diuretics; however, because of the arrhythmogenic potential of digoxin, it has largely fallen out of favor.

The standard treatment of cardiomyopathy in adults has been ACE-I, and several centers have used the same concept in boys with cardiomyopathy of DMD. At the authors’ center, an analysis of 42 boys showed that the mean age of onset of cardiomyopathy was 14.1 years, with a range of 7 to 27.3 years. Use of ACE-I resulted in ejection fraction improvement from a mean of 44% to 52% ( P ≤.001). Addition of, or initial use of, a β-blocker before ACE-I initiation (usually for disordered automaticity) did not change the result ( P = .947).

Angiotensin receptor blocker treatment can be effective and is associated with less cough (a rare complication of ACE-I). Furthermore, at least in the mdx mouse, skeletal and cardiac muscle regeneration has been seen. Clinical studies are needed to determine whether this occurs in humans. One such Muscular Dystrophy Association–sponsored study is underway.

Whether eplerenone or aldactone (both aldosterone antagonists) is effective in treating cardiomyopathy or reducing skeletal muscle degeneration requires careful and prospective double-blinded clinical studies.

For severe heart failure, hospitalization and treatment with milrinone may be useful. One study has advocated using intravenous milrinone as home therapy, but this is not without potential adverse events, and most centers reserve this treatment for the inpatient arena.

Idebenone (a benzoquinone with antioxidant properties) improves respiratory chain function and cellular energy production and was found to be beneficial in a trial in patients with DMD. Improvement in pulmonary function was also seen. A larger trial is ongoing. Trials are also underway assessing the use of sildenafil and carvedilol.

Atrial and ventricular arrhythmias are treated as per standard. For disordered automaticity, β-blocker therapy is used. If ventricular tachydysrhythmias are present, sotalol (a class III antiarrhythmic) or flecainide (a class Ic antiarrhythmic) may be used.

Automatic implantable cardioverter defibrillator placement may be helpful in patients with ventricular tachydysrhythmias, and is also considered in patients with an ejection fraction less than 15%, similar to the approach used in adults with severe congestive heart failure.

Another observation has been that boys with DMD can have hyperkalemic or hyperthermic reactions to inhalant anesthetic agents or muscle relaxants, suggesting that these agents should be avoided during general anesthesia.

Use of nocturnal bilevel positive airway pressure (BiPAP) for respiratory support also benefits boys with cardiomyopathy. Although BiPAP results in decreased preload, the primary benefit is secondary to decreased LV transmural pressure and, ultimately, decreased afterload. With advances in pulmonary and cardiac treatment, these patients, although lacking skeletal muscle function, now survive longer.

Some providers consider using destination therapy (eg, extracorporeal membrane oxygenation, acutely, or left ventricular–assist devices, which can be used over a long term) in patients with DMD with severe cardiomyopathy, using the survival argument, although the ethics of this approach can be debated. The same argument can be made for cardiac transplantation. The ultimate hope is that gene therapy may reverse or stop the disease. Whether the cardiac myocyte response to gene therapy will be the same as the skeletal muscle response remains to be seen.