Unusual Causes of Sudden Cardiac Death

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 Dystrophies

Muscular 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 Dysplasia

Fibromuscular 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

Discussion

SCD 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.

References

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