Cardiac manifestations of neuromuscular disorders in children

Paediatric Respiratory Reviews 11 (2010) 35–38

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-Symposium: Cardio-Respiratory considerations in CNMD

Cardiac manifestations of neuromuscular disorders in children Daphne T. Hsu * Children’s Hospital at Montefiore and the Albert Einstein College of Medicine, 3415 Bainbridge Avenue, Bronx, New York 10467

S U M M A R Y

Cardiac abnormalities occur in association with many of the neuromuscular disorders that present in childhood. Genetic defects involving the cytoskeleton, nuclear membrane, and mitochondrial function have all been described in patients with skeletal myopathy and cardiac involvement. The most common classes of neuromuscular disorders with cardiac manifestations are the muscular dystrophiesDuchenne, Becker, limb-girdle and Emery Dreifuss. Friedreich Ataxia and myotonic dystrophy also have important cardiac involvement. The type and extent of cardiac manifestations are specific to the type of neuromuscular disorder. The most common cardiac findings include dilated or hypertrophic cardiomyopathy, atrioventricular conduction defects, atrial fibrillation and ventricular arrhythmias. Screening for cardiac involvement should be performed in all children with neuromuscular disorders that have the potential for cardiac involvement. This review discusses the cardiac findings associated with specific neuromuscular disorders and outlines the indications for evaluation and treatment. ß 2009 Elsevier Ltd. All rights reserved.

CARDIAC DISEASE AND THE GENETICS OF NEUROMUSCULAR DISORDERS Cardiomyopathies and arrhythmias are common manifestations of neuromuscular disorders in children. As the gene mutations underlying the neuromuscular disorders are increasingly well-characterized, it has become apparent that a significant overlap exists between the mutations found in the primary skeletal myopathies and those described in primary cardiomyopathies. As a result, the cardiac and neuromuscular manifestations of these mutations share common pathophysiologic processes. For example, specific mutations in the dystrophin gene may be predictive of the development of dilated cardiomyopathy in patients with Duchenne (DMD) or Becker (BMD) muscular dystrophy.1 Furthermore, dystrophin mutations have been found in patients with xlinked dilated cardiomyopathy, a primary cardiomyopathy with no skeletal muscle involvement.2 Research indicates that disruption of the dystrophin glycoprotein complex from external injury such as ischemia may be the final common pathway leading to myocardial dysfunction and end-stage ventricular failure.3 Mutations in other genes that are important to the structural integrity of the cardiac cytoskeleton and nuclear membrane, such as emerin, lamin A/C, fukutin and components of the sarcoglycan complex, also result in cardiac abnormalities that are associated with neuromuscular disorders such as Emery Dreifuss muscular dystrophy and certain of the limb girdle muscular dystrophies.4,5

* Tel.: +1 718 741 2315; Fax: +1 718 920 4351. E-mail address: dhsu@montefiore.org. 1526-0542/$ – see front matter ß 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.prrv.2009.10.004

Hypertrophic cardiomyopathy has been described in 60% of patients with mutations of frataxin (Friedreich ataxia) and, although uncommon, left ventricular noncompaction cardiomyopathy has been described in patients with mutations in the myotonic dystrophy protein kinase, the genetic basis for myotonic dystrophy type 1.6 Although the pathophysiology is less well-defined, cardiac conduction disturbances are common in many of the neuromuscular disorders. In mice heterozygous for a mutation in the lamin A/C gene, there is evidence of apoptosis in the atrioventricular nodal cells and conduction defects are commonly seen.7 In patients with myotonic dystrophy type 1, the most common cardiac abnormalities described are atrial fibrillation and ventricular arrhythmias and these appear to arise from diffuse myocardial fibrosis that preferentially affects the conduction system. Fibrosis of the atrioventricular node leading to atrioventricular block has also been described.8

CARDIAC SCREENING IN PATIENTS WITH NEUROMUSCULAR DISORDERS Screening for cardiac involvement should be performed in all children with neuromuscular disorders that have the potential for cardiac involvement. Recommendations regarding the timing and frequency of initial and follow-up screening have been made by the American Academy of Paediatrics and experts in the field and are based on the onset and course of cardiac involvement in the individual disorders.9–11 Cardiac screening should include a careful history and physical examination for the signs and symptoms of

36

D.T. Hsu / Paediatric Respiratory Reviews 11 (2010) 35–38

heart failure or arrhythmias.4,8–12 The presence of clinical heart failure can be difficult to ascertain in patients with generalized neuromuscular weakness, because respiratory and peripheral myopathic findings can mimic heart failure symptoms. Signs of low cardiac output, including fatigue, abdominal symptoms, weight loss, anorexia, or sleep disturbance should be evaluated carefully, as they can be indicators of the onset of heart failure. Dizziness or syncope and tachycardia or palpitations can be signs of significant brady- or tachyarrhythmias. At diagnosis, an electrocardiogram and a two-dimensional and Doppler echocardiogram should be performed as part of the cardiac screening process. The electrocardiogram can be diagnostic in certain of the neuromuscular disorders such as DMD or BMD and it is also an important screening tool for the detection of conduction disorders and ventricular hypertrophy or dilatation.13–15 The two-dimensional echocardiogram is the gold standard for the diagnosis of dilated or hypertrophic cardiomyopathy and further examination of myocardial properties with techniques such as tissue Doppler echocardiography have the potential to identify abnormalities of myocardial function in the pre-clinical state.16–19 Additional cardiac testing may be indicated, depending on the level of suspicion for cardiac disease. A 24-hour Holter monitor is recommended in those disorders associated with significant rhythm disturbances. Myocardial function can be difficult to assess by echocardiography in patients who have respiratory failure or who are confined to a wheelchair, because of poor imaging windows. In these situations, non-invasive imaging techniques such as cardiac magnetic resonance imaging (MRI) or computed tomography can be used to assess the degree of ventricular dysfunction and hypertrophy. Cardiac MRI can also provide information regarding the degree of myocardial fibrosis and impairment of myocardial contractility and relaxation. Cardiac MRI techniques such as myocardial delayed enhancement have been proposed as tools to identify patients with Duchenne muscular dystrophy at risk for ventricular dysfunction.20–22 The cardiac biomarkers B-type natriuretic peptide (BNP) and NT pro-BNP are commonly used in adult patients with respiratory distress to distinguish primary pulmonary disease from heart failure. Although BNP and NT pro-BNP levels have not been extensively studied in patients with neuromuscular disorders, these simple screening tests may prove useful in distinguishing respiratory failure from heart failure in patients with respiratory muscle compromise.17,23,24 The following sections address the diagnosis and treatment of cardiac involvement in specific neuromuscular disorders. The genetic mutations and cardiac manifestations associated with the neuromuscular disorders are shown in Table 1. Table 2 summarizes recommendations for cardiac screening in these disorders.9–11 Duchenne and Becker Muscular Dystrophy Cardiomyopathy is common in adolescent and young adult patients with DMD and BMD. By age 20 years, 80-90% of patients with DMD and 50% of patients with Becker BMD will have echocardiographic evidence of a dilated cardiomyopathy and 50% of DMD patients will have clinical signs of heart failure. In DMD, early signs of ventricular dysfunction prior to the development of a decreased ejection fraction or clinical heart failure can be detected with tissue Doppler imaging or cardiac MRI.19–22 The decreased systolic function seen in patients with DMD can be focal or generalized, ranging from wall motion abnormalities localized to the posterior wall and apex of the left ventricular to generalized left ventricular dilation and dysfunction.25 The electrocardiographic changes seen in DMD and BMD appear to be unrelated to

the presence of dilated cardiomyopathy. The most common findings are a short PR interval and right ventricular hypertrophy. Prominent Q waves in leads II, III aVF, V5 and V6 are also seen.14 Ventricular arrhythmias can occur in association with ventricular dysfunction and can be associated with increased mortality. In BMD the degree of cardiac involvement is often out of proportion to the level of skeletal muscle impairment. Findings of right ventricular dilation are present prior to the development of left ventricular dysfunction.26 Heart failure develops later in life, with > 70% of patients affected by age 40 years.27 Ventricular arrhythmias in association with ventricular dysfunction have also been described, similar to those seen in DMD. Screening for cardiac involvement in DMD is recommended between the ages of 6 to 10 years or at presentation and at age 10 years or at presentation in BMD patients.9,12 The recommended frequency of follow-up screening is between 1-2 years, with more frequent evaluation indicated if abnormalities are noted. Six-year survival in DMD patients following the diagnosis of dilated cardiomyopathy was 58% in a large series reported by the Paediatric Cardiomyopathy Registry and a 55% transplant-free survival was reported for BMD patients in the same series.28 The efficacy of medical therapy in the prevention and treatment of ventricular dysfunction in DMD and BMD patients remains to be determined. In adult patients without neuromuscular disease at risk for the development of left ventricular dysfunction, the prophylactic use of angiotensin converting enzyme (ACE) inhibitors and beta-blockers is recommended.29 In 2005, Duboc et al published the results of a small, multicenter, randomized, double blind trial of the ACE inhibitor perindopril vs. placebo in DMD patients with normal ejection fraction. A significantly higher proportion of the perindopril subjects maintained a normal ejection fraction five years after therapy.30 This benefit was seen despite the fact that all subjects received open label perindopril during the last two years of the study. A 10-year follow-up report found a lower mortality in the subjects randomized initially to perindopril.31 In a retrospective study of adolescent patients with DMD, normalization of the shortening fraction occurred in 10 of 26 patients treated with enalapril.32 Use of the beta blocker carvedilol in 22 DMD patients resulted in a small but statistically significant improvement in cardiac MRI ejection fraction and echocardiographic measures of myocardial performance.33 A few retrospective series have been published describing outcomes in patients with DMD and BMD who receive combined ACE inhibition and beta-blocker therapy. In a series of DMD patients, a beneficial effect of the combined therapy was found on long term survival compared to historic controls.34 Nineteen of 25 DMD and BMD patients treated with an ACE inhibitor and betablocker after the diagnosis of a dilated cardiomyopathy demonstrated normalization of left ventricular size and function.1 Although these small series are suggestive of a beneficial effect of conventional heart failure therapies in DMD and BMD patients the evidence provided is not sufficient to support recommendations for their routine use. A long term, large randomised controlled trial is needed to address this issue. If congestive heart failure develops, treatment with diuretics and inotropic agents may provide symptomatic improvement. Other therapies have been described in BMD patients, including biventricular pacing and heart transplantation.28,35–37 The presence of significant ventricular arrhythmias may be an indication for placement of an automatic implantable cardiac defibrillator (AICD) to prevent sudden death. Female Carriers of Duchenne Muscular Dystrophy Cardiac abnormalities are commonly described in females heterozygous for DMD and BMD, although the development of

D.T. Hsu / Paediatric Respiratory Reviews 11 (2010) 35–38

37

Table 1 Gene mutations and cardiac manifestations of the neuromuscular disorders Neuromuscular Disorder

Gene Mutation

Cardiomyopathy

ECG

Arrhythmia

Duchenne Muscular Dystrophy

Dystrophin

Dilated

Short PR interval, prolonged QT interval, increased QT:PT ratio, Right ventricular hypertrophy, deep Q waves II, III, aVF, %, v6

Duchenne Muscular Dystrophy-female carrier Becker’s muscular dystrophy Emery Dreifuss autosomal dominant or proximal dominant limb-girdle muscular dystrophy IB Limb Girdle muscular dystrophy

Dystrophin Dystrophin Lamin A/C

Dilated Dilated Dilated

a, b, g, d sarcoglycans

Dilated

Congenital Muscular Dystrophy Limb Girdle muscular dystrophy 21

Laminin alpha 2 Fukutin

Dilated Dilated

Emery Dreifuss X-linked

Emerin

Rare

Friedriech ataxia

Frataxin gene

Hypertrophic

Myotonic dystrophy type 1, infantile

Myotonic dystrophy protein kinase gene

Hypertrophic

Myotonic dystrophy type 1

Myotonic dystrophy protein kinase gene

LV noncompaction

None Conduction system disease Conduction abnormalities: prolonged PR interval and sinus bradycaria Incomplete right bundle-branch block, tall R waves in VI and V2 or left anterior hemiblock None AV node and bundle branch block, age at onset late teens and early 2Q’s, Conduction abnormalities: prolonged PR interval and sinus bradycaria T wave inversion, left axis deviation and repolarization abnormalities Conduction disease, Prolonged PR interval, widening of the QRS complex Conduction disease, Prolonged PR interval, widening of the QRS complex

Increased baseline HR, decreased rate variability, premature ventricular beats (58% of patients by 24 years of age) Uncommon Similar to DMD Atrial fibrillation or flutter and atrial standstill. Ventricular dysrhythmias Uncommon

heart failure is rare. It has been recommended to initially screen carriers with an echocardiogram and electrocardiogram between the ages of 16 to 25 years and perform follow-up screening every five years.9

None Atrial arrhythmias and/or ventricuar arrhythmias Atrial fibrillation or flutter and atrial standstill. Ventricular arrhythmias

Atrial fibrillation and flutter, complete heart block Atrial fibrillation and flutter, complete heart block

every 3-5 years.11 Therapy is directed at the signs and symptoms of heart failure. Cardiac transplantation has been described in this population.36 X- linked Emery Dreifuss Muscular Dystrophy

Limb-Girdle Muscular Dystrophy The limb-girdle muscular dystrophies are a genetically heterogeneous group of disorders. Several of the limb-girdle muscular dystrophies (LGMD) are associated with cardiac diseases (Table 1). Dilated cardiomyopathy is found in the LGMD associated with Lamin A/C, the sarcoglycans a, b, g, d, fukutin, and laminin alpha 2.11 Atrial and ventricular arrhythmias are seen in the lamin A/C and sarcoglycan forms, with atrial standstill occurring in the patients with autosomal dominant form of Emery Dreifuss muscular dystrophy associated with lamin A/C.5 Screening with an ECG and echocardiogram is recommended at diagnosis and

X-linked Emery Dreifuss muscular dystrophy results from mutations in the emerin gene. The most significant cardiac manifestations of X-linked Emery Dreifuss muscular dystrophy are atrioventricular conduction defects including complete heart block.5 The X-linked form has also been associated with atrial paralysis and atrial flutter. Pacemaker placement is indicated for bradycardia associated with heart block or atrial paralysis. Dilated cardiomyopathy is not common in the X-linked form of Emery Dreifuss muscular dystrophy. Yearly screening with an ECG and 24-hour Holter monitor is recommended. An echocardiogram is recommended at diagnosis and every five years.11

Table 2 Cardiac screening recommendations for neuromuscular disorders Neuromuscular Disorder

Echocardiogram

ECG

24 hour Hotter Monitor

Duchenne Muscular Dystrophy

Initial at 6 years of age, biannually until 10 years of age, then annually Initial at 16 years then every 5 years Initial at 10 years, then biannually At diagnosis and annually At diagnosis and annually At diagnosis and annually At diagnosis At diagnosis, then every five years At diagnosis At diagnosis

Initial at 6 years of age, biannually until 10 years of age, then annually Initial at 16 years then every 5 years Initial at 10 years, then biannually At diagnosis and annually At diagnosis and annually At diagnosis and annually At diagnosis At diagnosis and annually At diagnosis and annually At diagnosis and annually

As indicated

Duchenne Muscular Dystrophy-female carrier Becker’s muscular dystrophy Emery Dreifuss autosomal dominant Limb Girdle muscular dystrophy, sarcoglycans Limb Girdle muscular dystrophy 21, fukutin Congenital Myopathy Emery Dreifuss x-linked Myotonic dystrophy type 1, infantile Myotonic dystrophy type 1

As indicated As indicated As indicated As indicated As indicated As indicated At diagnosis and annually As indicated As indicated, EP study to measure HV intervalshould be performed in borderline cases of heart block

38

D.T. Hsu / Paediatric Respiratory Reviews 11 (2010) 35–38

FRIEDREICH ATAXIA Hypertrophic cardiomyopathy has been described in up to 2/3 of patients with Friedreich Ataxia.38 Although the hypertrophy is described as asymmetric with septal hypertrophy greater than the free wall, left ventricular outflow obstruction is not described. ECG changes are consistent with ventricular hypertrophy and atrial and ventricular arrhythmias can occur. Later in the course of the disease, the hypertrophied heart can develop systolic dysfunction and heart failure and arrhythmias are common causes of death in these patients.38 MYOTONIC DYSTROPHIES The myotonic dystrophies, type 1 and type 2, are associated with heart block, significant tachyarrhythmias and risk of sudden death. Cardiac involvement is more common in type 1. Hypertrophic cardiomyopathy and noncompaction cardiomyopathy are described in neonates presenting with myotonic dystrophy type 1.39 Atrioventricular block is a cause of sudden death in these patients and a pacemaker should be placed in the presence of significant atrioventricular conduction defects. Atrial fibrillation and ventricular arrhythmias have been described and implantation of an AICD is an important consideration to prevent sudden death in these patients. Screening should include yearly ECG and consideration of a 24-hour Holter monitor if there is a suspicion of tachyarrhythmias. An echocardiogram is recommended at diagnosis in neonates and infants.11 SUMMARY Cardiomyopathy, atrioventricular conduction defects and tachyarrhythmias are the most common cardiac manifestations of neuromuscular disorders. Screening for cardiac disease should be performed at diagnosis and regular intervals, depending on the specific type of disorder. Anti-congestive therapy may help alleviate symptoms in patients with a dilated cardiomyopathy. The efficacy of ACE inhibitors and/or beta-blocker therapy in the pre-clinical or clinical state has not been well-established. In patients with significant atrioventricular conduction disease, pacemaker implantation is indicated. In cases at risk for tachyarrhythmias, such as the autosomal dominant form of myotonic dystrophy, an automatic implantable cardioverter-defibrillator should be considered. Heart transplantation has been performed in patients with stable neuromuscular disease and end-stage heart failure. REFERENCES 1. Jefferies JL, Eidem BW, Belmont JW, Craigen WJ, Ware SM, Fernbach SD et al. Genetic predictors and remodeling of dilated cardiomyopathy in muscular dystrophy. Circulation 2005; 112: 2799–2804. 2. Ferlini A, Sewry C, Melis MA, Mateddu A, Muntoni F. X-linked dilated cardiomyopathy and the dystrophin gene. Neuromuscul Disord 1999; 9: 339–346. 3. Vatta M, Stetson SJ, Perez-Verdia A, Entman ML, Noon GP, Torre-Amione G et al. Molecular remodelling of dystrophin in patients with end-stage cardiomyopathies and reversal in patients on assistance-device therapy. Lancet 2002; 359: 936–941. 4. Sachdev B, Elliott PM, McKenna WJ. Cardiovascular Complications of Neuromuscular Disorders. Curr Treat Options Cardiovasc Med 2002; 4: 171–179. 5. Manzur AY, Muntoni F. Diagnosis and new treatments in muscular dystrophies. J Neurol Neurosurg Psychiatry 2009; 80: 706–714. 6. Finsterer J. Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol 2009; 30: 659–681. 7. Holaska JM. Emerin and the nuclear lamina in muscle and cardiac disease. Circ Res 2008; 103: 16–23. 8. Dellefave L, McNaly E. Cardiomyopathy in neuromuscular disorders. Prog Ped Card 2007; 24: 35–46. 9. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics 2005; 116:1569–73. 10. Beynon RP, Ray SG. Cardiac involvement in muscular dystrophies. Qjm 2008; 101: 337–344.

11. Muntoni F. Cardiac complications of childhood myopathies. J Child Neurol 2003; 18: 191–202. 12. English KM, Gibbs JL. Cardiac monitoring and treatment for children and adolescents with neuromuscular disorders. Dev Med Child Neurol 2006; 48: 231–235. 13. Hindfelt B. Electrocardiographic findings in motor neurone disease. Eur Neurol 1976; 14: 433–438. 14. Thrush PT, Allen HD, Viollet L, Mendell JR. Re-examination of the electrocardiogram in boys with Duchenne muscular dystrophy and correlation with its dilated cardiomyopathy. Am J Cardiol 2009; 103: 262–265. 15. Stollberger C, Winkler-Dworak M, Blazek G, Finsterer J. Association of electrocardiographic abnormalities with cardiac findings and neuromuscular disorders in left ventricular hypertrabeculation/non-compaction. Cardiology 2007; 107: 374–379. 16. Smith GC, Kinali M, Prasad SK, Bonne G, Muntoni F, Pennell DJ et al. Primary myocardial dysfunction in autosomal dominant EDMD. A tissue doppler and cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2006; 8: 723– 730. 17. Mori K, Manabe T, Nii M, Hayabuchi Y, Kuroda Y, Tatara K. Plasma levels of natriuretic peptide and echocardiographic parameters in patients with Duchenne’s progressive muscular dystrophy. Pediatr Cardiol 2002; 23: 160–166. 18. Utsunomiya T, Mori H, Shibuya N, Oku Y, Matsuo S, Hashiba K. Long-term observation of cardiac function in Duchenne’s muscular dystrophy. Evaluation using systolic time intervals and echocardiography. Jpn Heart J 1990; 31: 585–597. 19. Mertens L, Ganame J, Claus P, Goemans N, Thijs D, Eyskens B et al. Early regional myocardial dysfunction in young patients with Duchenne muscular dystrophy. J Am Soc Echocardiogr 2008; 21: 1049–1054. 20. Hor KN, Wansapura J, Markham LW, Mazur W, Cripe LH, Fleck R et al. Circumferential strain analysis identifies strata of cardiomyopathy in Duchenne muscular dystrophy: a cardiac magnetic resonance tagging study. J Am Coll Cardiol 2009; 53: 1204–1210. 21. Puchalski MD, Williams RV, Askovich B, Sower CT, Hor KH, Su JT et al. Late gadolinium enhancement: precursor to cardiomyopathy in Duchenne muscular dystrophy? Int J Cardiovasc Imaging 2009; 25: 57–63. 22. Silva MC, Meira ZM, Gurgel Giannetti J, da Silva MM, Campos AF, Barbosa Mde M et al. Myocardial delayed enhancement by magnetic resonance imaging in patients with muscular dystrophy. J Am Coll Cardiol 2007; 49: 1874–1879. 23. Martins E, Silva-Cardoso J, Silveira F, Nadais G, Goncalves FR. Left ventricular function in adults with muscular dystrophies: genotype-phenotype correlations. Rev Port Cardiol 2005; 24: 23–35. 24. Ramaciotti C, Scott WA, Lemler MS, Haverland C, Iannaccone ST. Assessment of cardiac function in adolescents with Duchenne muscular dystrophy: importance of neurohormones. J Child Neurol 2002; 17: 191–194. 25. Ishikawa K. Cardiac involvement in progressive muscular dystrophy of the Duchenne type. Jpn Heart J 1997; 38: 163–180. 26. Melacini P, Fanin M, Danieli GA, Villanova C, Martinello F, Miorin M et al. Myocardial involvement is very frequent among patients affected with subclinical Becker’s muscular dystrophy. Circulation 1996; 94: 3168–3175. 27. Kirchmann C, Kececioglu D, Korinthenberg R, Dittrich S. Echocardiographic and electrocardiographic findings of cardiomyopathy in Duchenne and Becker-Kiener muscular dystrophies. Pediatr Cardiol 2005; 26: 66–72. 28. Connuck DM, Sleeper LA, Colan SD, Cox GF, Towbin JA, Lowe AM et al. Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J 2008; 155: 998–1005. 29. Hunt SA. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol 2005; 46: e1–82. 30. Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Becane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol 2005; 45: 855–857. 31. Duboc D, Meune C, Pierre B, Wahbi K, Eymard B, Toutain A et al. Perindopril preventive treatment on mortality in Duchenne muscular dystrophy: 10 years’ followup. Am Heart J 2007; 154: 596–602. 32. Ramaciotti C, Heistein LC, Coursey M, Lemler MS, Eapen RS, Iannaccone ST et al. Left ventricular function and response to enalapril in patients with duchenne muscular dystrophy during the second decade of life. Am J Cardiol 2006; 98: 825–827. 33. Rhodes J, Margossian R, Darras BT, Colan SD, Jenkins KJ, Geva T et al. Safety and efficacy of carvedilol therapy for patients with dilated cardiomyopathy secondary to muscular dystrophy. Pediatr Cardiol 2008; 29: 343–351. 34. Ogata H, Ishikawa Y, Ishikawa Y, Minami R. Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy. J Cardiol 2009; 53: 72–78. 35. Stollberger C, Finsterer J. Left ventricular synchronization by biventricular pacing in Becker muscular dystrophy as assessed by tissue Doppler imaging. Heart Lung 2005; 34: 317–320. 36. Kichuk Chrisant MR, Drummond-Webb J, Hallowell S, Friedman NR. Cardiac transplantation in twins with autosomal dominant Emery-Dreifuss muscular dystrophy. J Heart Lung Transplant 2004; 23: 496–498. 37. Quinlivan RM, Dubowitz V. Cardiac transplantation in Becker muscular dystrophy. Neuromuscul Disord 1992; 2: 165–167. 38. Kipps A, Alexander M, Colan SD, Gauvreau K, Smoot L, Crawford L et al. The longitudinal course of cardiomyopathy in Friedreich’s ataxia during childhood. Pediatr Cardiol 2009; 30: 306–310. 39. Finsterer J, Stollberger C. Neuromuscular disorders associated with apical hypertrophic cardiomyopathy. Acta Cardiol 2009; 64: 85–89.