Atrial arrhythmias in the young: early onset atrial arrhythmias preceding a diagnosis of a primary muscular dystrophy

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1 Europace (2014) 16, doi: /europace/euu141 CLINICAL RESEARCH Electrophysiology and ablation Atrial arrhythmias in the young: early onset atrial arrhythmias preceding a diagnosis of a primary muscular dystrophy Nik Stoyanov, 1, Jeffrey Winterfield 2, Niraj Varma 3, and Michael H. Gollob 1 * 1 Arrhythmia Service, Division of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada K1Y 4W7; 2 Arrhythmia Service, Division of Cardiology, Loyola Center for Heart and Vascular Medicine, Park Ridge, IL, USA; and 3 Arrhythmia Service, Division of Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA Received 25 February 2014; accepted after revision 7 May 2014; online publish-ahead-of-print 17 June 2014 Aims The aetiology of atrial arrhythmias in the otherwise healthy and young is usually unrecognized. We hypothesized that rare cases of atrial arrhythmias in the young may represent the initial manifestation of a muscular dystrophy syndrome.... Methods We describe the clinical characteristics, disease progression, results of electrophysiological study, and genetic findings in and results four patients (age,40 years) presenting with idiopathic atrial arrhythmias who subsequently received a diagnosis of a muscular dystrophy syndrome. The mean age at presentation with atrial arrhythmias was 29.5 years (range, years), and the mean delay to diagnosis of muscular dystrophy was 3.6 years (range, years). Two patients received a subsequent diagnosis of myotonic dystrophy type 1 and 2 a diagnosis of Emery Dreifuss muscular dystrophy. Diseasecausing genetic defects were identified in all four patients. One patient underwent catheter ablation of atrial flutter, experiencing improvement in arrhythmia symptoms. Two patients required device therapy, each receiving cardiac resynchronization therapy-defibrillator implantation for progressive left ventricular dysfunction.... Conclusion Early onset atrial arrhythmias may be the first clinical manifestation of a muscular dystrophy syndrome. Appropriate clinical assessment and surveillance may uncover this primary cause and provide an opportunity for timely genetic counselling and family screening Keywords Atrial fibrillation Genetics Muscular dystrophy Introduction Atrial fibrillation (AF) and atrial flutter are common arrhythmias, especially in the elderly population. 1 Common secondary causes of AF and atrial flutter include hypertension, coronary disease, valvular disease, and other structural heart abnormalities. When atrial arrhythmias occur in otherwise healthy, young individuals, other recognized contributing factors may include a manifest or concealed accessory atrioventricular (AV) pathway, excessive alcohol consumption, sleep apnoea syndrome, or genetic-based channelopathies. 2 4 However, atrial arrhythmia as a first manifestation of a subclinical muscular dystrophy syndrome is not usually considered. In this paper, we describe four patients who presented with atrial arrhythmias (AF, atrial flutter, or atrial standstill) at a young age. Their unique clinical characteristics and progression subsequently led to a diagnosis of a primary muscular dystrophy syndrome, with identification of the genetic aetiology in all four cases (Table 1). Methods We describe four young patients (age,40 years), first presenting with an atrial arrhythmia who later received a diagnosis of a muscular dystrophy syndrome. Clinical records were reviewed, including 12-lead electrocardiograms (ECGs), invasive electrophysiological (EP) studies, clinical progression, and genetic testing results. Genetic testing was performed in commercially available genetic testing centres following written informed consent. Results We identified four patients presenting with an atrial arrhythmia prior to a diagnosis of a muscular dystrophy syndrome. Two patients * Corresponding author. Tel: ; Fax: address: mgollob@ottawaheart.ca These authors contributed equally. Published on behalf of the European Society of Cardiology. All rights reserved. & The Author For permissions please journals.permissions@oup.com.

2 Atrial arrhythmias in the young 1815 What s new? Atrial arrhythmias in the young may represent the first sign of a systemic muscular dystrophy disorder. Unique electrocardiogram and electrophysiological observations may be a clue to an underlying subclinical muscular dystrophy syndrome. Recognition of this rare cause of atrial arrhythmias will lead to appropriate genetic counselling and family screening. received a diagnosis of myotonic dystrophy type 1 (DM1), and two patients a diagnosis of Emery Dreifuss muscular dystrophy (EDMD). The mean age at presentation with atrial arrhythmias was 29.5 years (range, years), and the mean delay to diagnosis of muscular dystrophy was 3.6 years (range, years). Disease-causing genetic defects were identified in four of four patients. Genetic counselling and cascade family screening have been initiated in each case. Electrophysiological studies were performed in three of four patients and demonstrated a range of abnormalities. One patient underwent catheter ablation of atrial flutter and has remained minimally symptomatic of palpitations. Two patients required device therapy, each receiving cardiac resynchronization therapy-defibrillator (CRT-D) implantation for progressive left ventricular (LV) dysfunction. Case details Patient 1 A previously well 22-year-old female presented to her local emergency room complaining of an irregular heart rhythm and palpitations. Electrocardiogram confirmed the presence of AF (Figure 1A). Despite the absence of atrioventricular nodal (AVN) blocking medications, her average ventricular rate was only in the range of 80 85b.p.m. Elective electrical cardioversion was performed revealing a normal baseline ECG (Figure 1B), and outpatient referral to the arrhythmia clinic requested. Echocardiography was normal in all parameters, including LV function and atrial size. Cardiac examination was normal. In light of only a single episode, the patient was commenced on daily aspirin. At the age of 25, the patient presented with nausea, vomiting, and headache. Imaging revealed a venous sinus thrombosis and a right thalamic stroke. She completely recovered. However, neurological examination elicited percussion myotonia of the thenar eminences. Further inspection suggested atrophy of the temporalis muscles and mild bilateral ptosis. In retrospect, the patient recalled myotonic symptoms of both hands during hand grip activities over the previous 5 10 years. Electromyography studies demonstrated classical myotonic discharges and the patient received a diagnosis of myotonic dystrophy. No family history of muscular dystrophy or AF was present. Genetic testing confirmed the presence of a heterozygous triplet repeat expansion (250 CTG repeats) in the DMPK (Dystrophia Myotonica protein kinase) gene, consistent with the diagnosis of DM1. At age 28, the patient perceived an increased symptom burden of palpitations. Electrocardiogram documented typical atrial flutter, again with a relative slow ventricular rate (75 80 b.p.m.) in the absence of AVN blocking agents (Figure 1B). The patient underwent Table 1 Clinical characteristics of Patients 1 4 Muscle disease ECG 2D echo EP study Genetic testing Age at diagnosis of myopathy Age at atrial arrhythmia Patients Diagnosis Atrial arrhythmia CTG repeats in DMPK gene Normal Normal HV 65 ms A flutter (CTI) ablation Myotonia; mild distal weakness; ptosis; SCM and temporalis wasting 1 DM1* Paroxysmal AF, AFL Normal N/A 500 CTG repeats in DMPK gene First-degree AV block 2 DM1 Paroxysmal AF Myotonia; mild distal weakness; ptosis; SCM and temporalis wasting Deletion mutation (c.83-3_97) EMD gene RA standstill CS fibrillation LA flutter AV block N LV size, EF 55% 35%; LA + RA dilated Fine fibrillatory activity, junctional escape Elbow contractures Elevated CK 3 EDMD** RA standstill, CS fibrillation LA flutter 484 C T (Q162X) truncating mutation EMD gene RA + LA standstill AV block LVEF 35%; LVEDD 8.2 cm; LA + RA dilated Atrial standstill, junctional escape 4 EDMD Atrial standstill Elbow contracture Elevated CK AF, atrial fibrillation; AFL, atrial flutter; AV, atrioventricular; DM1, myotonic dystrophy type 1; EDMD, Emery Dreifuss muscular dystrophy; RA, right atrium; LA, left atrium; SCM, sternocleidomastoid.

3 1816 N. Stoyanov et al. Figure 1 Electrocardiogram and EP tracings for Patient 1. (A) Electrocardiogram during AF with relatively slow ventricular rate response. (B) Electrocardiogram during sinus rhythm showing no evidence of overt conduction disease. (C) Electrocardiogram during atrial flutter. (D) Intracardiac electrograms (EGMs) during EP study demonstrating typical counterclockwise RA flutter. Halo positioning with Halo bipole 1 2 just lateral to cavotricuspid isthmus, and Halo bipole at low interatrial septum. an EP study confirming the presence of typical counter-clockwise, cavotricuspid isthmus-dependent flutter (Figure 1D), and she underwent subsequent successful radiofrequency catheter ablation of the cavotricuspid isthmus. Her HV interval was measured at 65 ms, but no evidence of PR prolongation has been evident on ECG. The patient has remained minimally symptomatic of palpitations and remains solely on daily aspirin. Now aged 33, she has not shown progressive cardiac disease, experiences obstructive sleep apnoea, and has mild myotonic symptoms. Patient 2 A 21-year-old male was referred to the arrhythmia service following presentation to his local hospital with symptomatic palpitations and confirmed AF. Past medical history was remarkable only for a selfreported history of tachycardia in early childhood. Presenting ECG during AF was remarkable for a slow ventricular rate response in the absence of medications (Figure 2A). Baseline ECG was abnormal for the presence of a first-degree AV block (PR 280 ms) (Figure 2B). Echocardiography was unremarkable, noting normal biventricular function and chamber dimensions. In view of a minimum symptom burden, the patient was treated conservatively with aspirin and low-dose beta-blocker (metoprolol 12.5 mg twice daily) and was followed annually for re-assessment of symptom burden. During routine follow-up in the arrhythmia clinic, the patient was noted to have moderate bilateral ptosis. The patient was requested to perform hand grip and arm flexion isotonic exercises and displayed delayed muscle relaxation. Myotonia was evident on percussion of the deltoid. A diagnosis of DM1was suspected and genetic testing was arranged. Genetic testing revealed a heterozygous triplet repeat expansion of 500 CTG repeats in the DMPK gene, confirming a diagnosis of DM1. Patient 3 A previously well 36-year-old male physician, formerly a collegiate distance runner, was referred for a new diagnosis of atrial fibrillation following routine physical examination and 12-lead ECG. The patient reported a long-standing history of asymptomatic, persistent slow heart rate (40 50 b.p.m.). Initial referring ECG demonstrated no visible P-waves, but later possibly flutter or fine fibrillatory activity, and a ventricular rate of 42 b.p.m. with apparent regular R R intervals (Figure 3A). Echocardiography revealed normal LV function but severe bi-atrial enlargement. No intracardiac shunts were evident. Doppler recordings across the AV valves showed complete absence of A-waves, indicating loss of right and left atrial mechanical activity. The patient underwent an EP study. 5 Regular flutter activity was noted within the coronary sinus (CS) likely responsible for the evanescent fine electrical activity observed on ECG. This arrhythmia could be pace-terminated (Figure 3B). Electroanatomical mapping revealed extremely low voltage throughout the right atrium (RA) with some sparing of the septum, and preserved voltage in the CS (Figure 3C). Despite high output pacing from multiple sites, electrical capture of the RA was not possible. Further mapping in the region of the sinus node showed slow electrical activity (30 b.p.m.) that did not depolarize adjacent tissue (Figure 3C). Direct mapping of the left atrium was not attempted. Ventricular depolarization resulted

4 Atrial arrhythmias in the young 1817 Figure 2 Electrocardiogram tracings for Patient 2. (A) Monitor tracing of paroxysmal AF with slow ventricular rate response in the absence of AVN blocking agents. (B) Sinus rhythm with baseline PR prolongation of 320 ms. Figure 3 Electrocardiograms, intracardiac EGMs, and 3D electroanatomic mapping observations for Patient 3. (A) Presenting ECG showing regular junctional escape rhythm and low amplitude baseline deflections suggestive of atrial fibrillatory or flutter activity. (B) Atrial flutter noted in CS terminated with overdrive pacing. (C) Bipolar voltage map of RA and CS showing extreme low voltage throughout RA and preserved CS voltage. Silver dots indicate the region where sinus activity was explored. EGMs below show cyclic electrical activity in sinus node region (3000 ms, black arrows). (D) EGM recordings during second EP study showing atrial flutter (CL 274 ms) within the CS. Fine flutter activity is noted on surface ECG (arrows).

5 1818 N. Stoyanov et al. from a regular junctional escape rhythm, with a normal HV interval (50 ms). The patient underwent placement of a single chamber pacemaker (VVI with lower rate limit of 40 paces per minute) and was commenced on warfarin. The patient continued endurance exercise with no limitations. Six years following initial presentation, the patient presented with exercise-induced palpitations as well as a new complaint of increased fatigue. A 7-day ambulatory monitor demonstrated frequent ventricular ectopy and non-sustained ventricular tachycardia (VT), including a 17 beat run of VT at 246 b.p.m. His average resting heart rate measured 49 b.p.m. with bradycardia documented 92% of time. He reported increased fatigue with his daily activities, and he queried whether bradycardia might explain his symptoms. He paced 40% of time with a setting of VVI 40. Clinical examination revealed mild bilateral elbow contractures. In hindsight, the patient recalled this abnormality since his late teens, which were attributed to previous arm fractures in childhood. Upon further questioning, he confirmed a history of elevated creatine kinase (CK) levels in the past (as high as 1000 IU/L) attributed to endurance running. Echocardiography now revealed mild left and right ventricular enlargement with LV ejection fraction of 50%, moderate tricuspid regurgitation, and marked bi-atrial enlargement. Invasive EP testing was repeated in view of the LV dilation and documented symptomatic ventricular arrhythmias. Programmed ventricular stimulation with up to triple extra-stimuli induced repeated non-sustained polymorphic VT. As observed in the previous EP study, the RA remained electrically silent with left atrial flutter (cycle length 251 ms) noted on the CS electrograms (Figure 3D). Notably, AV block at the level of the AV node was observed with spontaneous junctional rhythm (HV 51 ms) responsible for ventricular activity. Voltage mapping of left and right ventricles demonstrated normal voltage with only patchy areas of low voltage in the peri-valvular regions. Taken together, the constellation of history, examination, imaging, and EP findings suggested a diagnosis of EMDM. Following genetic counselling, the patient underwent testing of the EMD gene, which encodes the muscle-specific emerin protein, and of the LMNA gene. Genetic testing revealed an 18 bp deletion mutation within the EMD gene spanning over the latter sequence of intron 1, the splice junction and initial region of exon 2 (c.83-3_97del18), resulting in a frame-shift mutation and predicted premature truncation of the emerin protein. The patient underwent CRT-D implant, and he continued anticoagulation for left atrial flutter and RA standstill. With pacing set to VVI 60, he noted an initial functional improvement in symptoms of fatigue and improved energy for daily activity. Patient 4 A 37-year-old asymptomatic male was noted to have significant bradycardia on routine physical examination and an abnormal ECG, prompting referral to the arrhythmia clinic. Electrocardiogram demonstrated no visible P-waves, regular R R interval, and a heart rate of 40 b.p.m. (Figure 4A). A Holter monitor again showed no evidence of atrial activity through 24 h monitoring, and noted a high burden of premature ventricular contractions (PVCs), accounting for 32% of QRS complexes. Echocardiogram was remarkable for biventricular enlargement and an estimated LV ejection fraction of 30 35% (global hypokinesis). Severe bi-atrial enlargement was also apparent, and there was no significant valvular disease. Despite the clinical findings and an active lifestyle, the patient had no complaints of shortness of breath. An invasive EP study was undertaken, and there was no evidence of appreciable atrial electrograms in the RA free wall as well as within the CS (Figure 4B). As observed in Patient 3, a junctional rhythm was observed with an HV interval of 52 ms. Right atrial capture was unsuccessful even at high output (20 ma, 9 ms). Voltage mapping confirmed extreme low voltage throughout most of the RA (,0.10 mv), further confirming electrical standstill (Figure 4C). Ventricular mapping indicated a PVC origin in the region of aortomitral continuity; however, earliest activation measured 25 ms despite excellent pace map match. Mapping from the junction of the anterior interventricular vein and great cardiac vein yielded earliest activation of 0 ms with a poor pace map match. Application of radiofrequency energy to the endocardial site resulted in thermal facilitation of the PVC with acceleration to rapid VT of similar morphology; however, the rhythm rapidly degenerated to ventricular fibrillation requiring defibrillation. In the setting of marked LV dilation (7.2 cm end-diastolic dimension), further ablation was abandoned. The patient subsequently underwent implantation of a CRT-D device. Based on similarities to the previous case, further questioning revealed a family history of a skeletal muscular disorder in a male first cousin (age 45) and in a maternal great uncle who required a permanent pacemaker and experienced sudden death at age 33 years. Follow-up neurological assessment noted mild bilateral elbow contractures. Blood work indicated an elevated CK of 1400 IU/L and the patient received a diagnosis of EDMD. Genetic testing demonstrated a 484C.T nucleotide change leading to a premature stopcodon mutation (Q162X) of the EMD gene and a predicted truncation of the emerin protein. Discussion Atrial arrhythmias in presumably healthy, young individuals (age,40 years) occur in,0.1% of the population. 6,7 In isolation, episodes are often attributed to a metabolic disturbance or alcohol excess. When atrial arrhythmias occur in the young, secondary causes such as previously unrecognized structural heat disease or familial, genetic-based primary arrhythmia syndromes may be considered but are frequently unyielding. The association of atrial arrhythmias with primary muscular dystrophy syndromes is well recognized, although typically the natural course of these conditions begins with skeletal muscle symptoms and onset of cardiac pathology in later years. 8 In this case series, we describe our experience and the clinical characteristics of four previously asymptomatic patients who first came to medical attention for review of atrial arrhythmias, and who later were recognized to have an underlying primary muscular dystrophy syndrome. Two patients in their early 20s were referred for management of AF by family physicians following clinical presentation with symptomatic palpitations and documented AF. Uniquely, both patients presented with a controlled ventricular rate response in the context of their arrhythmia and in the absence of any AVN blocking agents. This observation, in hindsight, may have been a clinical clue to their underlying condition, in light of the common association of

6 Atrial arrhythmias in the young 1819 Figure 4 Electrocardiograms, intracardiac EGMs, and 3D electroanatomic mapping observations for Patient 4. (A) Presenting ECG showing the absence of atrial activity, regular junctional escape, and ventricular ectopy. (B) Intracardiac EGM during junctional rhythm with PVC; no atrial electrical activity is appreciated in the RA or CS poles of the duo-decapolar catheter. (C, D) Left anterior oblique and posteroanterior projections of CARTO voltage map of RA showing diffuse low voltage with a small area of preserved voltage posteriorly. Yellow points denote location of His EGM. conduction system disease in muscular dystrophy syndromes. 8 In Patient 1, a subsequent ablation procedure for atrial flutter noted a prolonged HV interval of 65 ms, while Patient 2 was noted to have a first-degree AV block on ECG. These patients had a delay of 3 and 6 years, respectively, to an ultimate diagnosis of DM1. Contributing to this delay was the absence of any significant functional limitations in both patients secondary to their underlying skeletal muscle disorder. The absence of symptoms in DM1 may occur in individuals who choose to live a more sedentary lifestyle, as was the case for these patients. Despite the lack of physical complaints, the objective findings of myotonia were evident on physical examination of both patients. Although it is not usual to consider neurological assessment during evaluation for AF management, simple examination observations and manoeuvres in the clinic may elicit findings consistent with DM1 if clinical suspicion arises. Both patients had evidence of mild bilateral ptosis, although a continuum of this phenotypic feature may be a challenge for the unrefined in neurological examination. More substantially, both patients exhibited the characteristic stiffness and delay in release following a firm hand grip, an easily performed assessment. Gentle percussion to the thenar eminence (Case 1) or deltoid muscle (Case 2) showed characteristic contraction and delayed relaxation (myotonia). Genetic testing confirmed the diagnosis of MD1 in both patients, allowing for a more focused clinical surveillance and cascade family screening. Myotonic dystrophy type 1 occurs in 1 of 8000 individuals and is the most common adult-onset muscular dystrophy. 9 Cardiac abnormalities may occur in up to 80% of affected cases, including dilated cardiomyopathy and conduction disease. The most common manifestation is first-degree AV block although up to one-third of patients may develop atrial arrhythmias later in life. 9,10 Reports of AF preceding overt symptoms of DM1 are rare. A single report by Bassez et al. 11 describes two patients presenting with cardiac arrhythmia prior to the recognition of DM1. One patient suffered a cardiac arrest due to ventricular fibrillation, and another was symptomatic of atrial flutter. 11 Interestingly, skeletal muscle symptoms in DM1 patients are commonly mild, although debilitating cases leading to progressive respiratory muscle weakness and death may occur. 12 Management is focused on education, genetic counselling, and regular monitoring for heart rhythm disorders. 8,9 Issues related to genetic counselling are particularly relevant. Myotonic dystrophy type 1 is a trinucleotide repeat genetic disease characterized by the genetic phenomenon of anticipation. 12 This impliesthatoffspring of affected individuals areat risk of developing earlier onset and more severe features of the disease. This results from trinucleotide repeat expansion within the affected DMPK gene, which occurs during the repeated meiosis events generating germ cells. Inheritance from an affected father is generally less severe, likely related to the lack of viability of sperm cells harbouring a large number of trinucleotide repeats. 12 The pathogenesis of muscle disease, both skeletal and cardiac, is believed to be related to the toxic cellular effects of the DMPK mrna containing high numbers of CTG repeats, leading to impairment in the gene regulation and subsequent architecture of myofibril development. 13 Histopathology in affected hearts commonly show myocyte hypertrophy, fatty infiltration, and interstitial fibrosis. 14

7 1820 N. Stoyanov et al. Emery Dreifuss muscular dystrophy was subsequently diagnosed in two additional patients who first presented with symptomatic palpitations and abnormal ECGs interpreted as AF. These patients shared numerous clinical features, including age of onset (age 37 years), the absence of visible P-waves on ECG, severe bi-atrial enlargement and mechanical standstill on echo, and invasive EP evidence of atrial electrical standstill with the inability to pace atrial myocardium. In both patients, there was evidence of AV block at the level of the AV node with a junctional escape, a common finding in certain inherited cardiomyopathies. 15 Both patients developed LV impairment (indicating that the disease process is not limited to the atria), and subsequently received CRT-D devices. Genetic testing confirmed novel genetic defects in the EMD gene (encoding the emerin protein), confirming a diagnosis of EDMD. Emery Dreifuss muscular dystrophy is a relatively rare muscle disorder affecting 1 of individuals. 16 Typically, clinical onset is recognized in the second or third decade of life, characterized by muscle weakness or wasting and development of contractures of the elbows, ankles, or neck. 16,17 Cardiac involvement is common, with cardiomyopathy and the risk of sudden death a frequent sequelae in later years. 8,16 Emery Dreifuss muscular dystrophy may be autosomal dominant in nature when caused by genetic defects in the LMNA gene, or X-linked recessive in inheritance when caused by mutations in the EMD gene. In the more common X-linked recessive form, as present in our patients, manifestation of the condition typically skips females in the pedigree. However, rare reports of cardiac involvement in female gene carriers of EMD mutations exist, indicating that clinical and genetic screening should extend to all family members. 16 The specific mechanism of muscle disease related to emerin defects remains unclear. 18 Emerin is known to bind directly to cardiac actin, and defective emerin proteins are suggested to disrupt the normal molecular framework associated with myofibril function, including impairment of integral membrane proteins and junctional complexes. 18 Histopathological description at autopsy has described a marked loss of atrial myocardium and its replacement by fibrous and fat tissue, as well as various degrees of interstitial fibrosis in the ventricular myocardium. 19 Conclusion Early onset atrial arrhythmias may be the first clinical manifestation of a muscular dystrophy syndrome, albeit rare in light of the low prevalence of these conditions and the uncommon scenario of early onset atrial arrhythmias. 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