Sudden cardiac death (SCD) is defined as unexpected natural death from a cardiac cause heralded by abrupt loss of consciousness within a short time period, generally less than 1 hour from the onset of symptoms.1 Pre-existing heart disease may or may not have been known to be present, but the time and mode of death are unexpected. Current estimates place the incidence of sudden cardiac death (SCD) between 180,000 to 400,000 per year.2–4 Ischemic cardiomyopathy, nonischemic cardiomyopathy, and primary electrical disorders are well-recognized causes of SCD.2,5 In addition, there are a number of under- or unrecognized medical conditions that place the affected individual at a higher risk for SCD. Of these rare and unusual causes of SCD, muscular dystrophies (MD), and fibromuscular dysplasia (FMD) are perhaps the most significant. While a comprehensive review, including specific cardiac recommendations in patients with MD and FMD, is beyond the scope of this article, we aim to highlight the importance of recognizing MD and FMD as potential causes for SCD.
Muscular DystrophiesMuscular dystrophies (MD) are a constellation of genetically and clinically distinct disorders characterized by dystrophic changes in skeletal muscle and skeletal muscle weakness of varying severity and distribution.6,7 Hermens et al, in their recent review, provide a comprehensive list of the conditions included under the broad heading of muscular dystrophies.8 Not all muscular dystrophies are associated with cardiac involvement. In some, cardiac manifestations could be the lone presenting manifestation with no skeletal muscle involvement.6,8 For the purpose of this review, MD with known cardiac involvement will be discussed below and are listed in Table 1. Dystrophinopathies Dystrophinopathies are characterized by mutations in the dystrophin gene located on chromosome Xp21.1 and resultant defective dystrophin production.9 Dystrophin is a part of the transmembrane dystrophin associated protein complex, which plays an important role in the maintenance of structural and functional integrity of the sarcolemma from exercise-induced damage.6 Cardiac manifestations in dystrophinopathies are thought to be due to progressive replacement of the cardiac myocytes and the Purkinje system by connective tissue or fat.9 Three distinct entities are included in this group, namely Duchenne Muscular Dystrophy, Becker Muscular Dystrophy and X-linked dilated cardiomyopathy. Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, affecting 1 in 3,500 male births and characterized by weakness of the muscles of the lower extremities and the pelvis and shoulder girdle.8 Cardiac manifestations among patients with DMD can vary from no involvement to severe involvement, including dilated cardiomyopathy, cardiac arrhythmias and SCD.9 Electrocardiographic (ECG) studies reveal a variety of conduction system abnormalities in DMD. More importantly, SCD has been well documented. Over a 33-month period, 12 of 45 DMD patients had SCD. Six of the 12 patients who died suddenly had known complex ventricular ectopic beats. Left ventricular systolic dysfunction and left ventricular dilatation was associated with an increased risk of SCD.10 In another study, 80 DMD patients were followed over a 5-year period. In this study, ventricular premature beats were found in 30% (24 of 80) and their incidence increased as the clinical severity of skeletal muscle involvement advanced. SCD occurred in four of the 80 patients. Ventricular couplets, ventricular tachycardia, and R-on-T-type ventricular premature beats were observed in three of four patients with SCD.11 In recent years, there has been a marked improvement in the respiratory care of DMD patients, and as a result, death due to cardiac causes could potentially be on the rise.12 Becker Muscular Dystrophy (BMD) is a milder variant of DMD. Most patients with BMD have some evidence of cardiac involvement8 and a variety of ECG abnormalities including sinus tachycardia, atrial fibrillation, AV nodal block of varying severity and ventricular arrhythmias.13 In a study of 19 BMD patients, 74% showed abnormal ECG, 42% demonstrated interventricular conduction delay, 37% showed left ventricular dilatation and 63% had reduced left ventricular systolic function.14 SCD is also documented in BMD. In a case series of 31 patients, one patient experienced SCD due to polymorphic ventricular tachycardia and three patients had significant life-threatening arrhythmias.15 X-linked dilated cardiomyopathy (XLCM) is a primary myocardial dystrophinopathy and is characterized by rapidly progressive cardiomyopathy and cardiac death from biventricular failure within one to two years from diagnosis.9,15,16 Emery-Dreifuss Muscular Dystrophy Emery-Dreifuss Muscular Dystrophy (EDMD) is characterized by early contractures of the Achilles tendons, elbows and posterior cervical muscles, progressive muscle wasting and weakness along the humeroperoneal distribution, and cardiomyopathy. Evidence of cardiac disease is usually present by age 30. Based on underlying genetic defects, EDMD can be further classified as EDMD 1 and EDMD 2,17 and both variants have clinically similar phenotype.18 EDMD 1 has a X-linked recessive mode of inheritance and can be seen in 1 in 100,000 males.8 Cardiac involvement usually manifests as cardiac conduction defects, ranging from first degree AV block to complete heart block.19 Atrial paralysis with absent P waves on electrocardiography should always prompt exclusion of this muscular dystrophy.17 SCD is the most common cause of death in EDMD 1 patients. SCD can be very unpredictable and could often be the presenting manifestation of cardiac disease.20 Furthermore, SCD due to pulseless electrical activity has been documented in patients with an implanted cardiac defibrillator.21 Even carriers of the EDMD 1 genetic defect are at an increased risk of SCD. In a case series of 16 carriers of the EDMD 1 genetic defect, 3 male patients experienced SCD, and 7 male and 2 female carriers required pacemakers for bradyarrhythmias.22 EDMD 2 has autosomal dominant (common) and autosomal recessive (uncommon) modes of inheritance.17 The true prevalence of EDMD 2 is unknown. The primary genetic defect in EDMD 2 is due to a mutation in the Lamin A/C gene. Cardiac involvement in EDMD 2 is phenotypically similar to cardiac manifestation in limb girdle muscular dystrophy 1B (LGMD 1B).8 The burden of cardiac disease is clearly shown in a meta-analysis of 299 patients with Lamin A/C gene mutation. After 30 years of age, 92% of patients showed some form of cardiac dysrhythmia, and after 50 years of age, 64% developed heart failure. In both the cardiac and neuromuscular phenotype, 46% experienced SCD and this was the most frequent cause of death. In addition, 28% of carriers of Lamin A/C gene mutations received a pacemaker, but this did not change the rate of SCD.23 Limb Girdle Muscular Dystrophies Limb girdle muscular dystrophies (LGMD) are a heterogeneous group of disorders characterized by involvement of the muscles of the shoulder and pelvic girdle. Based on inheritance patterns, LGMD can be subclassified into two groups: autosomal dominant LGMD (type 1) and autosomal recessive LGMD (type 2). The prevalence of LGMD seems to range from 1 in 23,000 to 1 in 150,000.8 LGMD 1 includes 7 disease entities, of which LGMD 1B has cardiac manifestations very similar to EDMD 2, and has been described above. LGMD 1E has been reported in one family and cardiac manifestations are similar to LGMD 1B. Cardiac conduction defects, dilated cardiomyopathy and SCD despite pacemaker therapy have been described.24 Cardiac manifestations including SCD are rare in other forms of LGMD 1. LGMD 2 includes 13 disease entities. LGMD 2C, 2D, 2E, and 2F result due to defects in the transmembrane sarcoglycan complex and are collectively called sarcoglycanopathies. Sarcoglycanopathies are associated with a variety of cardiac manifestations,25 particularly LGMD 2E, which has been known to be associated with severe dilated cardiomyopathy and lethal ventricular arrhythmias.26 LGMD 2I is caused by mutations in the fukutin-related protein gene. While reports of dilated cardiomyopathy and symptomatic cardiac failure have been reported, SCD has not yet been reported in LGMD 2I.8 Myotonic Dystrophy Myotonic dystrophy, or dystrophia myotonica (DM), is the most common muscular dystrophy of adults, with a prevalence of 1 in 8,000.27 DM is a multisystem disease and is characterized by somnolence, myotonia, involvement of smooth and cardiac muscle, and weakness of facial, temporal, sternocleidomastoid and distal limb musculature. Two disease variants exist: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2).8 Cardiac manifestations seem to be due to myocyte hypertrophy, interstitial fibrosis and fatty infiltration.28 Overt myocardial disease is rare but the brunt of cardiac involvement seems to be related to involvement of the cardiac conduction system. Nguyen et al report fibrosis of the sinus node and atrioventricular node, infiltration of His bundle and the left bundle branch.29 It is this involvement of the conduction system which can lead to complete heart block and SCD.27 Furthermore, both atrial and ventricular arrhythmias have been documented in DM with resultant SCD despite pacemaker and antiarrhythmic therapy.30 The prevalence of SCD seems to vary in case series; one study of 12 patients revealed SCD in 3 patients,29 another study of 37 patients revealed SCD in 1 patient.31
Fibromuscular DysplasiaFibromuscular dysplasia (FMD) is a non-atherosclerotic, non-inflammatory vascular disease which was first described in 1938 by Leadbetter and Burkland. FMD commonly affects renal and internal carotid arteries and is a recognized cause of renovascular hypertension and disorders of intracerebral perfusion.32 The precise prevalence of FMD is not well known,33 but sources estimate a prevalence of up to 5% in the US population.34 Further, many physicians consider FMD to be a rare clinical entity and often misdiagnose or under-diagnose FMD. FMD can involve virtually any artery in the human body.35 Depending on the vasculature affected, symptoms can include dizziness, headaches, neck pain, nausea, vertigo, or tinnitus. The most commonly affected arteries are the renal artery and internal carotid artery, which often manifest as hypertension and stroke, respectively. When FMD involves the coronary arteries, it can result in SCD. One of the first reports of coronary involvement with FMD occurred in 1964.36 Since then, there have been several reports of SCD secondary to FMD.37,38 More recently, an article in the mainstream media described SCD in a 10-year-old girl secondary to FMD.34 While the precise prevalence of SCD secondary to FMD is unknown, a recent study of 1,647 SCDs revealed 4% of cases to be secondary to FMD.39 The underlying pathology of SCD in patients with FMD seems to be secondary to occlusion of coronary blood flow to the myocardium37 and the cardiac conduction system, with resultant fatal arrhythmias.40,41
DiscussionSCD is an important and increasing cause of mortality. Robust clinical evidence and well established clinical management guidelines exist to guide primary prevention interventions for ischemic and non-ischemic cardiomyopathies. While a comprehensive understanding of the above is paramount, it is equally important to recognize that there exists other conditions in the population which may predispose an individual to SCD. As stated above, patients with muscular dystrophy and fibromuscular dysplasia are at an increased risk for SCD based on the type of MD and the specific arterial involvement in FMD. A recent international workshop including 16 international participants set about to establish a consensus statement for the management of cardiac manifestations of MD.42 This group called for further research to strengthen the existing evidence base. A similar guideline for the management of patients with FMD does not exist. Given this large void in evidence, more research is required to guide future primary prevention strategies. Clinicians should be aware that these less common diseases exist and are associated with SCD.
1. Reynolds MR, Pinto DS, Josephson ME. In: Fuster V, O'Rourke RA, Walsh RA, Poole-Wilson P (eds). Hurst's The Heart. 12 ed. 2. Chugh SS, Reinier K, Teodorescu C, et al. Epidemiology of sudden cardiac death: Clinical and research implications. Prog Cardiovasc Dis 2008;51:213-228. 3. Noseworthy PA, Newton-Cheh C. Genetic determinants of sudden cardiac death. Circulation 2008;118:1854-1863. 4. Ali S, Antezano ES. Sudden cardiac death. South Med J 2006;99:502-510. 5. Zipes DP. Epidemiology and mechanisms of sudden cardiac death. Can J Cardiol 2005;21(Suppl A):37A-40A. 6. Muntoni F. Cardiomyopathy in muscular dystrophies. Curr Opin Neurol 2003;16:577-583. 7. Goodwin FC, Muntoni F. Cardiac involvement in muscular dystrophies: Molecular mechanisms. Muscle Nerve 2005;32:577-588. 8. Hermans MC, Pinto YM, Merkies IS, et al. Hereditary muscular dystrophies and the heart. Neuromuscul Disord 2010;20:479-492. 9. Finsterer J, Stollberger C. The heart in human dystrophinopathies. Cardiology 2003;99:1-19. 10. Chenard AA, Becane HM, Tertrain F, et al. Ventricular arrhythmia in Duchenne muscular dystrophy: Prevalence, significance and prognosis. Neuromuscul Disord 1993;3:201-206. 11. Yanagisawa A, Miyagawa M, Yotsukura M, et al. The prevalence and prognostic significance of arrhythmias in Duchenne type muscular dystrophy. Am Heart J 1992;124:1244-1250. 12. Cardiovascular health supervision for individuals affected by Duchenne or Becker muscular dystrophy. Pediatrics 2005;116:1569-1573. 13. Finsterer J, Stollberger C. Cardiac involvement in Becker muscular dystrophy. Can J Cardiol 2008;24:786-792. 14. Steare SE, Dubowitz V, Benatar A. Subclinical cardiomyopathy in Becker muscular dystrophy. Br Heart J 1992;68:304-308. 15. Melacini P, Fanin M, Danieli GA, et al. Cardiac involvement in Becker muscular dystrophy. JAMA 1993;22:1927-1934. 16. Berko BA, Swift M. X-linked dilated cardiomyopathy. N Engl J Med 1987;316:1186-1191 . 17. Emery AE. The muscular dystrophies. Lancet 2002;359:687-695. 18. Vohanka S, Vytopil M, Bednarik J, et al. A mutation in the X-linked Emery-Dreifuss muscular dystrophy gene in a patient affected with conduction cardiomyopathy. Neuromuscul Disord 2001;11:411-413. 19. Waters DD, Nutter DO, Hopkins LC, Dorney ER. Cardiac features of an unusual X-linked humeroperoneal neuromuscular disease. N Engl J Med 1975;293:1017-1022. 20. Merlini L, Granata C, Dominici P, Bonfiglioli S. Emery-Dreifuss muscular dystrophy: Report of five cases in a family and review of the literature. Muscle Nerve 1986;9:481-485. 21. Zaim S, Bach J, Michaels J. Sudden death in an Emery-Dreifuss muscular dystrophy patient with an implantable defibrillator. Am J Phys Med Rehabil 2008;87:325-329. 22. Sakata K, Shimizu M, Ino H, et al. High incidence of sudden cardiac death with conduction disturbances and atrial cardiomyopathy caused by a nonsense mutation in the STA gene. Circulation 2005;111:3352-3358. 23. van Berlo JH, de Voogt WG, van der Kooi AJ, et al. Meta-analysis of clinical characteristics of 299 carriers of LMNA gene mutations: Do lamin A/C mutations portend a high risk of sudden death? J Mol Med 2005;83:79-83. 24. Messina DN, Speer MC, Pericak-Vance MA, McNally EM. Linkage of familial dilated cardiomyopathy with conduction defect and muscular dystrophy to chromosome 6q23. Am J Hum Genet 1997;61:909-917. 25. van der Kooi AJ, de Voogt WG, Barth PG, et al. The heart in limb girdle muscular dystrophy. Heart 1998;79:73-77. 26. Fanin M, Melacini P, Boito C, et al. LGMD2E patients risk developing dilated cardiomyopathy. Neuromuscul Disord 2003;13:303-309. 27. Phillips MF, Harper PS. Cardiac disease in myotonic dystrophy. Cardiovascular Res 1997;33:13-22. 28. Motta J, Guilleminault C, Billingham M, et al. Cardiac abnormalities in myotonic dystrophy. Electrophysiologic and histopathologic studies. Am J Med 1979;67:467-473. 29. Nguyen HH, Wolfe JT 3rd, Holmes DR Jr, Edwards WD. Pathology of the cardiac conduction system in myotonic dystrophy: A study of 12 cases. J Am Coll Cardiol 1988;11:662-671. 30. Grigg LE, Chan W, Mond HG, et al. Ventricular tachycardia and sudden death in myotonic dystrophy: clinical, electrophysiologic and pathologic features. J Am Coll Cardiol 1985;6:254-256. 31. Hawley RJ, Milner MR, Gottdiener JS, Cohen A. Myotonic heart disease: A clinical follow-up. Neurology 1991;41(2 (Pt 1)):259-262. 32. Slovut DP, Olin JW. Fibromuscular dysplasia. N Engl J Med 2004;350:1862-1871. 33. Plouin PF, Perdu J, La Batide-Alanore A, et al. Fibromuscular dysplasia. Orphanet J Rare Dis 2007;2:28. 34. Burton TM. The 'Rare' Disease That Isn't. Often Undiagnosed, FMD May Afflict Up to 5% of Americans. The Wall Street Journal 2009 June 27. 35. Olin JW. Recognizing and managing fibromuscular dysplasia. Cleve Clin J Med 2007;74:273-4, 7-82. 36. Hill LD, Antonius JI. Arterial dysplasia: An important surgical lesion. Arch Surg 1965;90:585-595. 37. Ropponen KM, Alafuzoff I. A case of sudden death caused by fibromuscular dysplasia. J Clin Pathol 1999;52:541-542. 38. Maresi E, Becchina G, Ottoveggio G, et al. Arrhythmic sudden cardiac death in a 3-year-old child with intimal fibroplasia of coronary arteries, aorta, and its branches. Cardiovasc Pathol 2001;10:43-48. 39. Hill SF, Sheppard MN. Non-atherosclerotic coronary artery disease associated with sudden cardiac death. Heart 2010;96:1119-1125. 40. Nichols GR 2nd, Davis GJ, Lefkowitz JB. Sudden death due to fibromuscular dysplasia of the sinoatrial nodal artery. J Ky Med Assoc 1989;87:504-505. 41. James TN, Riddick L. Sudden death due to isolated acute infarction of the His bundle. J Am Coll Cardiol 1990;15:1183-1187. 42. Bushby K, Muntoni F, Bourke JP. 107th ENMC international workshop: The management of cardiac involvement in muscular dystrophy and myotonic dystrophy. 7th-9th June 2002, Naarden, the Netherlands. Neuromuscul Disord 2003;13:166-172.