Received: 2 September 2021 Revised: 5 February 2022 Accepted: 12 February 2022 DOI: 10.1002/mus.27524 CLINICAL RESEARCH ARTICLE Cardiac and pulmonary findings in dysferlinopathy: A 3-year, longitudinal study Ursula Moore MD1 | Roberto Fernandez-Torron MD1,2 | Marni Jacobs PhD3,4 | 3,4 5,6 Heather Gordish-Dressman PhD | Jordi Diaz-Manera MD PhD | 1 Meredith K. James PT | Anna G. Mayhew PT PhD1 | Elizabeth Harris MBBS, PhD1 | Michela Guglieri MD1 | Laura E. Rufibach PhD7 | Jia Feng MSc3 | Andrew M. Blamire PhD8 | Pierre G. Carlier MD PhD9 | Simone Spuler MD PhD10 | John W. Day MD11 | Kristi J. Jones MD PhD12 | Diana X. Bharucha-Goebel MD13,14 | Emmanuelle Salort-Campana MD15 | Alan Pestronk MD16 | Maggie C. Walter MD MA17 | Carmen Paradas MD PhD18 | Tanya Stojkovic MD19 | Madoka Mori-Yoshimura MD PhD20 | Elena Bravver MD21† | Elena Pegoraro MD PhD22 | Linda Pax Lowes PT PhD23 | Jerry R. Mendell MD23 | Kate Bushby MD1 | The Jain COS Consortium | John Bourke MD24 | Volker Straub MD PhD1 1 The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 2 Neurology Department, Biodonostia Health Research Institute, Neuromuscular Area, Hospital Donostia, Basque Health Service, Donostia-San Sebastian, Spain 3 Center for Translational Science, Division of Biostatistics and Study Methodology, Children's National Health System, Washington, District of Columbia, USA 4 Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, District of Columbia, USA 5 n Biomédica en Red en Enfermedades Raras (CIBERER), Barcelona, Spain Centro de Investigacio 6 Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain 7 The Jain Foundation, Seattle, Washington, USA 8 Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK 9 University Paris-Saclay, CEA, DRF, Service Hospitalier Frederic Joliot, Orsay, France 10 Charite Muscle Research Unit, Experimental and Clinical Research Center, a joint cooperation of the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, Berlin, Germany 11 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA 12 The Children's Hospital at Westmead, and The University of Sydney, Westmead, New South Wales, Australia 13 Department of Neurology Children's National Health System, Washington, District of Columbia, USA Abbreviations: ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blockers; AV, atrioventricular; BMI, body mass index; CPAP, continuous positive airway pressure; COPD, chronic obstructive pulmonary disease; COS, clinical outcomes study; ECG, electrocardiogram; Echo, echocardiogram; FVC, forced vital capacity; LGMD2b, limb girdle muscular dystrophy 2b; LRTI, lower respiratory tract infection; LV, left ventricular; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; MM/MMD1, Miyoshi myopathy; MRI, magnetic resonance imaging; NIV, non-invasive ventilation; NSAD, North Star Ambulatory Assessment for limb girdle type muscular dystrophy; a-NSSA, Amended North Star Ambulatory Assessment; OSA, obstructive sleep apnoea; QTc, QT interval corrected for ventricular rate; RR, relative risk. † Deceased John Bourke and Volker Straub joint last author This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2022 The Authors. Muscle & Nerve published by Wiley Periodicals LLC. Muscle & Nerve. 2022;65:531–540. wileyonlinelibrary.com/journal/mus 531 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 532 MOORE ET AL. 14 National Institutes of Health (NINDS), Bethesda, Maryland, USA 15 Service des maladies neuromusculaire et de la SLA, Hôpital de La Timone, Marseille, France 16 Department of Neurology Washington University School of Medicine, St. Louis, Missouri, USA 17 Friedrich-Baur-Institute, Department of Neurology, Ludwig-Maximilians-University of Munich, Munich, Germany 18 Neuromuscular Unit, Department of Neurology, Hospital U. Virgen del Rocío/Instituto de Biomedicina de Sevilla, Seville, Spain 19 Centre de référence des maladies neuromusculaires, Institut de Myologie, AP-HP, Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France 20 Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan 21 Neuroscience Institute, Carolinas Neuromuscular/ALS-MDA Center, Carolinas HealthCare System, Charlotte, North Carolina, USA 22 Department of Neuroscience, University of Padova, Padua, Italy 23 The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA 24 Department of Cardiology, Freeman Hospital, NUTH NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK Correspondence Volker Straub, John Walton Muscular Abstract Dystrophy Research Centre, Translational and Introduction/Aims: There is debate about whether and to what extent either respira- Clinical Research Institute, Newcastle University, Centre for Life, Newcastle upon tory or cardiac dysfunction occurs in patients with dysferlinopathy. This study aimed Tyne, NE1 3BZ, UK. to establish definitively whether dysfunction in either system is part of the Email: volker.straub@newcastle.ac.uk dysferlinopathy phenotype. Methods: As part of the Jain Foundation's International Clinical Outcome Study (COS) for dysferlinopathy, objective measures of respiratory and cardiac function were collected twice, with a 3-y interval between tests, in 188 genetically confirmed patients aged 11–86 y (53% female). Measures included forced vital capacity (FVC), electrocardiogram (ECG), and echocardiogram (echo). Results: Mean FVC was 90% predicted at baseline, decreasing to 88% at year 3. FVC was less than 80% predicted in 44 patients (24%) at baseline and 48 patients (30%) by year 3, including ambulant participants. ECGs showed P-wave abnormalities indic- ative of delayed trans-atrial conduction in 58% of patients at baseline, representing a risk for developing atrial flutter or fibrillation. The prevalence of impaired left ventric- ular function or hypertrophy was comparable to that in the general population. Discussion: These results demonstrate clinically significant respiratory impairment and abnormal atrial conduction in some patients with dysferlinopathy. Therefore, we recommend that annual or biannual follow-up should include FVC measurement, enquiry about arrhythmia symptoms and peripheral pulse palpation to assess cardiac rhythm. However, periodic specialist cardiac review is probably not warranted unless prompted by symptoms or abnormal pulse findings. KEYWORDS cardiac, dysferlin, limb girdle muscular dystrophy R2, Miyoshi myopathy, respiratory 1 | I N T RO DU CT I O N the myocardium,2 leading to concerns that cardiac and respiratory function may be impaired in some patients with this form of muscular Dysferlinopathy is an autosomal recessively inherited form of limb gir- dystrophy. dle muscular dystrophy, which primarily manifests with skeletal mus- The prevalence of clinically significant cardiac and respiratory cle weakness and wasting, caused by the lack of the protein dysfunction in dysferlinopathy has generally been considered low.3-6 dysferlin.1 The most common clinical diagnoses associated with However, small cohort studies and case reports of patients with dysferlinopathy are limb girdle muscular dystrophy R2 dysferlin dysferlinopathy have described occasional cases of cardiomyopa- related (formerly LGMD 2B) and Miyoshi myopathy (MM or MMD1). thy,4,7 asymptomatic left ventricular (LV) dysfunction, LV hypertrophy The dysferlin protein is highly expressed in skeletal muscle and also in (LVH),3,8 myopathic changes or fibrosis on cardiac MRI,9,10 and early 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MOORE ET AL. 533 respiratory failure.11 In a recent retrospective cohort series of 48 Jap- checked manually. Baseline and 36-mo traces were then compared to anese patients with dysferlinopathy, 41% had minor cardiac conduc- determine consistency of any initial abnormalities and any new tion defects and 21% had a reduced forced vital capacity (FVC) of less changes that developed over time. than 80% predicted.5 Experienced physiotherapists undertook spirometry to measure Rates of cardiac and respiratory dysfunction in patients with FVC at each of six patient evaluation visits (screening, baseline, 6, 12, dysferlinopathy have not previously been compared systematically to 24, and 36 mo). Assessment of change in FVC between sitting and rates seen in the general population. This means that it is not clear lying was also measured, starting from year 2. Particular note was whether findings from small case series can reasonably be generalised made of those with an FVC below the lower limit of normal (80%).15 to the broader dysferlin-deficient population, or if the cardiac or respi- To correlate heart and respiratory measures with skeletal muscle ratory abnormalities described in case reports had unrelated function, we used the North Star Ambulatory Assessment for limb gir- aetiologies. dle type muscular dystrophy (NSAD score).16 This scale was adapted The aim of this study is to determine whether dysferlinopathy is from the a-NSAA for use in ambulant and non-ambulant patients with associated with an increased risk of cardiac or respiratory dysferlinopathy. The NSAD scale was validated using the baseline abnormalities. visits in the Jain COS study and was then used to provide direct motor This work adds to the original report from this large internation- assessment scores by experienced physiotherapists for subsequent ally recruited cohort of patients with dysferlinopathy12 by providing assessments. The full NSAD score was therefore available at year 3, 3-y longitudinal follow-up based on repeat testing, and in relating car- but not at baseline, for correlation with cardiac and respiratory dio-respiratory findings to objective measures of skeletal muscle func- measures. tion and its progression over the same time period. 2.2 | Statistical analysis 2 | METHODS Means and paired t-tests were used to compare normally distributed The protocol and findings at baseline visits have been published FVC data between visits in the patients with FVC results at both base- previously.12 line and at year 3. Non-normally distributed QRS duration was com- This study was approved by the relevant research ethics commit- pared using Wilcoxon signed rank test between those with and tee at each participating institution. Informed consent was obtained without LV dysfunction or LVH. from all research subjects. Chi-squared testing was used to look for significant relationships between reported symptoms, low FVC, and any cardiac abnormality at baseline. To determine independent risk factors for baseline abnor- 2.1 | Assessments performed malities, factors showing an association on Chi-squared testing were combined with age and body mass index (BMI) into a binary logistic Medical and family history were collected through patient question- regression model for each cardiac abnormality and FVC. To review naires by the site clinicians. This included self-reporting of cardio- the relationship with functional ability, modelling was repeated with respiratory co-morbidities and symptoms, including questions relating year 3 data and with the NSAD score. to sleep apnoea. All concomitant medications were recorded. For longitudinal comparisons, only patients who completed both Echocardiograms (echos) at baseline and at 36 mo were per- assessments were included. formed by experienced cardiac sonographers. The protocol did not dictate a standardised echo examination but simply required the examination used for standard clinical indications at each participating 3 | RE SU LT S centre. Some, therefore, reported a larger range of parameters than others. Technical issues related to positioning of less mobile partici- Baseline demographics and findings in the 188 study participants are pants and reduced echo windows meant that not all measures were summarised in Table 1. Two patients died between baseline and their obtainable from all examinations in some participants.13,14 Standard planned year 3 assessment: one, aged 88 y, of pneumonia and the 12-lead electrocardiograms (ECG) were performed at the same visits. other, aged 68 y, of unknown cause. Ventricular rate and PR intervals were obtained from ECGs at each local site. ECGs were then scanned and transmitted centrally. A more detailed analysis and reporting of ECGs was performed by a neuro- 3.1 | Baseline cardiac symptoms muscular cardiologist centrally. Reports included assessments of P- wave amplitude, morphology and axis, QRS axis and duration, and QT At least one potentially cardiac symptom was reported by almost half intervals. The QTc interval presented in this paper was the one calcu- of patients at baseline (Table 1). Breathlessness was frequently lated automatically by the ECG machine using Bazett's correction. reported by ambulant but not non-ambulant patients and was more ECGs with measurement values outside the normal range were re- common in older ambulant patients with a higher BMI (Supporting 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 534 MOORE ET AL. TABLE 1 Cardiac and respiratory parameters at baseline according to age Median age in years at baseline Under 30– 40– 50– Over All ages 30 39 49 59 59 combined Parameter (N = 51) N (N = 53) N (N = 42) N (N = 31) N (N = 11) N (N = 188) N Median age in years 25 51 34 53 45 42 53 31 64 11 37 188 (range) (11–29) (30–39) (40–49) (50–59) (60–86) (11–86) Median BMI kg/m2 24 46 25 47 23 39 25 30 24 6 24 168 (range) (17–26) (15–50) (17–38) (16–33) (19–41) (15–50) Male gender 28 (55%) 51 24 (45%) 53 21 (50%) 42 12 (39%) 31 3 (27%) 11 88 (47%) 188 b Ambulant (%) 49 (96%) 51 40 (75%) 53 30 (71%) 42 22 (71%) 31 5 (45%) 11 146 (78%) 188 FVC (L) 4.16 50 4.08 52 3.63 41 3.27 30 2.40 11 3.77 ± 1.07 184 Mean (sd) ± 1.10 ± 0.87 ± 0.98 ± 0.97 ± 0.68 FVC 94 (38– 50 95 52 91 41 89 28 80 11 92.00 182 (% predicted) 116) (56–125) (46–140) (49–131) (43–105) (38–140) NIV usersa 0 (0%) 51 1 (2%) 53 2 (5%) 41 1 (3%) 31 0 (0%) 11 4 (2%) 188 Echo “abnormal” a 8 (17%) 46 6 (12%) 52 8 (21%) 39 9 (32%) 28 6 (60%) 10 37 (21%) 175 LVEF <55% 4 (9%) 43 6 (14%) 44 3 (8%) 35 2 (7%) 27 2 (25%) 8 17 (11%) 157 LVEF <50% 1 (2%) 43 0 (0%) 44 2 (6%) 35 0 (0%) 27 0 (0%) 8 3 (2%) 157 LVHa 2 (5%) 41 1 (2%) 41 1 (3%) 32 5 (21%) 24 2 (22%) 9 11 (8%) 146 P-wave abnormality 17 (65%) 26 15 (48%) 34 13 (57%) 23 12 (67%) 18 4 (50%) 8 61 (58%) 106 QRS >120 ms 0 (0%) 37 1 (3%) 39 1 (3%) 29 1 (5%) 20 1 (14%) 7 4 (3%) 132 a Hypertension 3 (6%) 51 3 (6%) 53 11 (26%) 42 6 (19%) 31 4 (36%) 11 27 (14%) 188 Palpitations 5 (10%) 51 3 (6%) 53 9 (21%) 42 5 (16%) 31 1 (9%) 11 23 (12%) 188 Ankle swelling 6 (12%) 51 11 (21%) 53 12 (29%) 42 11 (35%) 31 8 (73%) 11 48 (26%) 188 Breathlessness 9 (18%) 51 9 (17%) 53 12 (29%) 42 8 (26%) 31 1 (9%) 11 39 (21%) 188 Dizzy episodes 5 (10%) 51 6 (11%) 53 7 (17%) 42 4 (13%) 31 2 (18%) 11 24 (13%) 188 Fainting history 2 (4%) 51 0 (0%) 53 1 (2%) 42 0 (0%) 31 0 (0%) 11 3 (2%) 188 Sleep apnoea 3 (6%) 51 2 (4%) 53 4 (10%) 42 4 (13%) 31 2 (18%) 11 15 (8%) 188 a Factors that showed significant association with age in binary logistic regression modelling. b Ambulant patients were those who reported not using a wheelchair full time at the time of assessment. Information Table S1, which is available online). Patients who reported blockers (ARBs), beta-blockers, diuretics, anti-platelets or anti-coagu- any of these non-specific symptoms were not more likely to have lants, statins, calcium channel blockers, and other anti-arrhythmic echo or ECG abnormalities than those who were asymptomatic drugs. Between baseline and 3-y assessments, eight patients had (Supporting Information Table S1). ACEi, beta-blocker, calcium channel blocker, or diuretics initiated and Leg swelling was more common in non-ambulant than in ambu- another three had the doses of pre-existing medications increased. lant patients, but was not associated with cardiac abnormalities (Supporting Information Table S1). Hypertension was the most fre- quent cardiovascular co-morbidity identified, increasing in incidence 3.3 | Baseline ECG findings with age (Table 1) but not independently related to muscle function at year 3 (Supporting Information Table S1). Of the 180 baseline ECGs performed (Figure 1), 177 (98%) were in sinus rhythm and 3, aged 54, 67 and 71 y, respectively, were in atrial fibrillation (AF) with controlled ventricular response rates. The PR 3.2 | Cardioactive medications interval was abnormally short (i.e., <120 ms) in six and abnormally pro- longed in three (PR intervals 204–230 ms) of the 168 ECGs where PR Thirty-six (19%) participants were taking one or more cardioactive interval was recorded at site (Table 2).17 All three had either long- medications for diagnoses other than dysferlinopathy. These included standing hypertension and/or coronary artery disease (2) or prior hypertension, arrhythmias, ischemic heart disease, diabetes mellitus, myocardial infarction (1) accounting for the atrioventricular (AV) block. and leg oedema. In none was therapy initiated for LV dysfunction. QRS-duration was greater than 120 ms in four patients who had Medications listed were ACE-inhibitors (ACEi) or angiotensin receptor hypertension or old myocardial infarction (Table 2). None of the six 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MOORE ET AL. 535 Patients Patients completing 20 patients missed, or were out of completing baseline visit Window for the year 3 visit year 3 visit N = 188 N = 168 Local investigations and reporting Echocardiogram ECG Electrocardiogram Echocardiogram performed (echo) performed (ECG) performed (echo) performed performed in 153 locally and reported locally and reported locally patients at both N = 147 locally N = 180 N = 175 visits (87%) N = 157 (96%) (93%) (93%) Ventricular Echo report Echo report Ventricular PR interval included included PR interval rate rate documented estimation of Reported for 125 estimation of documented documented Patients at both documented at site LVEF LVEF at site at site visits at site N = 168 N = 157 N = 137 N = 135 N = 180 N = 143 (89%) (84%) (73%) (80%) (96%) (85%) Echo report included Echo report included presence/absence of Reported for 54 presence/absence of LVH Patients at both LVH N = 146 visits N = 58 (78%) (35%) Lead site reporting ECG scanned to lead site and ECG scanned to lead site and legibile enough for calculation of legibile enough for calculation of Reported for 64 electrophysiological intervals Patients at both visits electrophysiological intervals N = 132 N = 76 (70%) (45%) ECG quality sufficient for p-wave ECG quality sufficient for p-wave morphology interpretation by the morphology interpretation by the lead site neuromuscular Reported for 51 lead site neuromuscular cardioogist Patients at both visits cardioogist N = 106 N = 71 (56%) (42%) FIGURE 1 Flow chart of cardiac assessments included in analysis ECGs, identified by automated reporting as showing QTc interval pro- hypertension, nor in those reporting palpitations or other, potentially longation, were confirmed on manual re-measurement.21 cardiac, symptoms (Supporting Information Table S1). ECG trace quality and scan resolution were variable, such that full interpretation of all ECGs was not possible (Figure 1). In the 106 base- line ECGs legible enough for P-wave morphology interpretation by 3.4 | Changes in ECG findings between the lead site neuromuscular cardiologist, one or more P-wave abnor- assessments malities were evident in 61 patients (58%) (Table 1). Abnormalities comprised low-amplitude, peaked or varying P-wave morphology in Of the 64 patients whose ECGs were available from both assessments 14 (13%), prolonged P-wave duration in 36 (34%), or P-wave notching (Figure 1), 62 showed sinus rhythm and 2 (3%) (aged 54 and 71 y) AF at in 23 (22%) (Supplementary Figure S1). The finding of abnormal P- both visits. Another patient (aged 67 y), who was in AF at baseline, died waves did not correlate with echo measures of atrial enlargement, of unknown cause before having the repeat recording. Of the 51 reduced LV-ejection fraction (LVEF <55%), LVH, or diastolic dysfunc- patients with ECGs available from both assessments, P-waves had tion. Prevalence of abnormal P-waves did not increase with age become abnormal in 6 but initial abnormalities were not reported in 9 (Table 1) or BMI and were not more common in subjects with known (Table 3). 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 536 MOORE ET AL. TABLE 2 ECG parameters at baseline and normal ranges N Median (range) Normal rangea,b Patients below normal range (%) Patients above normal range (%) Sinus rate (beats/min) 180 71 (46–150) 60–100 5 (3) 3 (2) PR interval (ms) 168 150 (110–230) 120–200 6 (4) 3 (2) QRS duration (ms) 132 92 (70–145) 70–120 0 (0) 4 (3) Bazett's QTc (ms) 131 417 (362–570) 350–450 (male) 0 (0) 4 (6) 350–470 (female) 0 (0) 2 (3) Abbreviation: IQR, interquartile range. Note: All durations are given in milliseconds (ms). a Borys Surawicz TK, Chou's Electrocardiography in Clinical Practice. 6th edition. 2008. b Viskin S. The QT interval: too long, too short or just right. Heart Rhythm. 2009;6:711–715. TABLE 3 Cardiac and respiratory parameters of patients with assessments at both visits Baseline Year 3 Median (range) Mean ± SD Patient Median (range) Mean ± SD Patient Number tested at both number (%) number (%) visits Demographics Age (y) 37 (11–71) 40 (14–74) 168 % male 46% 46% 168 2 BMI (kg/m ) 25 ± 5.9 26 ± 6.2 153 Motor function NSAD score Not performed 14 (0–54) 159 (y 3 only) Ambulant (%) ^ 131 (78) 125 (75) 168 Respiratory FVC (L) 3.80 ± 1.04 3.67 ± 0.98 162 % predicted FVC 90 ± 18 88 ± 19 162 Sitting – Lying drop Not performed 0.08 ± 0.24 153 (L) (y 3 only) Nocturnal NIV 4 (2%) 7 (4%) 163 Sleep apnoea 13 (8%) 11 (7%) 167 Morning headaches 13 (8%) 24 (14%) 167 Frequent LRTI 6 (3%) 2 (1%) 167 Cardiovascular Echo “abnormal” 30 (20%) 17 (11%) 153 LVEF <55% 10 (8%) 9 (7%) 125 LV hypertrophy 3 (6%) 4 (7%) 54 P-wave abnormality 33 (65%) 30 (59%) 51 QRS > 120 ms 3 (5%) 3 (5%) 64 Hypertension 21 (12%) 24 (14%) 168 Palpitations 20 (12%) 23 (14%) 167 Leg swelling 39 (23%) 55 (33%) 167 Breathlessness 35 (21%) 34 (20%) 166 Dizzy episodes 19 (11%) 24 (14%) 167 Syncope 3 (2%) 2 (1%) 167 3.5 | Arrhythmia prevalence tachycardia in one, ventricular ectopy in one, and “unspecified” in three. Six of the patients reporting arrythmias had other co-morbidities includ- A prior history of arrhythmias was reported by eight patients at baseline ing hypertension (four), sleep apnoea requiring NIV (one), and mitral ste- (4%): AF in three (the same three in whom it was noted on ECG), sinus nosis (one). Abnormal echos were also noted in three. The patient with 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MOORE ET AL. 537 sinus tachycardia showed a LV impairment with reduced ejection frac- 3.8 | Respiratory findings tion. One patient with AF (aged 54 y) had mitral stenosis, pulmonary hypertension, and left atrial dilatation on echo, while another (aged Mean FVC was mildly reduced at baseline and fell by 2% of the 67 y) had a LV impairment with reduced ejection fraction. predicted value by year 3 (Tables 1, 3). An FVC of <80% was observed in 44 patients (24%) at baseline and 48 patients (30%) by year 3. A sit- ting to lying drop in FVC of more than 0.5 L was observed in six 3.6 | Baseline echo findings patients (4%) at year 3, and five of these also had an FVC of <80%. In a model of percent predicted FVC with patient age, BMI, dis- LV systolic dysfunction (LV ejection fraction <55%) was found in 17 ease duration, and NSAD score, only the functional ability denoted by (11%) subjects. LV fractional shortening and chamber dimension were the NSAD score was significantly related to FVC (Figure 2). 18 within population normal ranges (Supporting Information Table S2). Supporting this, FVC was lower in non-ambulant patients (mean LVH was found on 11 baseline echos. Its prevalence increased with FVC = 81.6%, median age 45) than in those with retained ambulation age (relative risk [RR], +0.1/y) and increasing BMI (RR, +0.14/unit) (mean FVC = 92%, median age 35) (p < 0.01) at baseline. However, but not with hypertension (p = 0.45) or diabetes mellitus (p = 0.24). although there was a significant positive correlation between a lower Left atrial enlargement was found in 11 patients and right atrial NSAD score and lower FVC, variability in FVC measures between enlargement in 4. Echo abnormalities were more common in older those of the same functional level was common (Figure 2). FVC of patients (RR, 0.05/y) and in those with a higher BMI (RR, 0.12/unit), <80% predicted was found in 27 ambulant patients at baseline. Respi- but were not independently associated with skeletal muscle function, ratory co-morbidities did not account for the lower measures and, as measured by NSAD scoring, at the year 3 assessment. although seven patients (4%) had asthma and one had chronic obstructive pulmonary disease (COPD), the FVC in these eight patients was >80% predicted. Symptoms of nocturnal hypoventilation 3.7 | Changes in echo findings between (morning headaches, frequent lower respiratory tract infections assessments [LRTIs] and/or breathlessness)19,20 were not reported more frequently in those with a lower FVC. Echo abnormalities were seen in 30 patients at baseline. These were Non-invasive ventilation (NIV) requirement was rare, with a all graded as mild and resolved by year 3 in 13 (43.3%) (Table 3). small increase by the year 3 assessment (Table 3). A diagnosis of Eleven of these patients were already on cardiac medications, and five “sleep apnoea” was reported by six of these seven patients and others had medications added between the two assessments. In four, COPD in one patient. These seven patients, aged 19–55 y (median, resolution of abnormality coincided with the introduction or adjust- 34.5 y), had more advanced muscle weakness, as evidenced by an ment of anti-hypertensive medications. However, abnormal findings NSAD score of 12 or less. A low FVC of <80% was seen in six of had resolved without therapy changes in 13, including borderline low these NIV users. However, neither NSAD scores nor spirometry LVEF in one. New abnormalities developed in four patients: LA dilata- measures were independent predictors of NIV use at the year 3 tion in two, LV diastolic dysfunction in one, and concentric LV- assessment. NIV treatment at year 3 was independently associated remodelling in one. with increasing patient age (RR, +0.1/y) and higher BMI (RR, F I G U R E 2 Correlation between skeletal muscle function and respiratory assessment. NSAD score: NSAD is an objective functional scale. Percent predicted FVC: FVC result expressed as a percentage of normal for an age- and height-matched population. Correlation coefficient: Pearson's correlation coefficient. R2: coefficient of determination 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 538 MOORE ET AL. +0.14/unit), and six of the seven patients were significantly over- demands of remaining ambulant with worsening muscle function, weight (BMI, 32.2–51.9). rather than of cardiac aetiology, particularly as these breathless patients tended to be older with a higher BMI than those not reporting breathlessness and were not more likely to have echo or 4 | DISCUSSION ECG abnormalities. The main cardiac abnormality identified was of atrial electrical The main findings from this cohort of patients were, first, that 24– conduction, evidenced by dysmorphic P-waves observed at higher 30% had respiratory impairment as assessed by FVC of <80% rates than in the general population.29 Prolonged P-waves indicate predicted, without alternative explanation, and second, 58% had atrial slowed electrical conduction across and between atria and have not electrical abnormalities as evidenced by P-wave abnormalities on sur- been reported previously in dysferlinopathy patients. The findings are face ECGs at baseline. compatible with an atrial electropathy being part of the Reduced FVC measures were mostly seen in non-ambulant dysferlinopathy phenotype.29,30 In cohort studies, unrelated to mus- patients, supporting findings of a previous Japanese study.5 However, cular dystrophy, prolonged, notched, or otherwise dysmorphic P- FVC was also reduced in some ambulant patients with no identifiable waves on ECG are associated with the development of atrial tachy- co-morbidities, suggesting that reduction in respiratory reserve can be arrhythmias (atrial tachycardia, flutter, or fibrillation).31,32 Sinus node part of dysferlinopathy, perhaps relating to mild diaphragmatic dystro- disease and atrial tachy-arrhythmias are a well-recognised part of phy.5,21 Patients with respiratory impairment rarely reported symp- other muscular dystrophies, such as Emery-Dreifuss muscular dystro- toms of respiratory insufficiency, demonstrating that symptoms alone phy.32 The clinical implication for patients with dysferlinopathy is that should not be used to monitor respiratory function. Assessment of they may be more prone to develop AF. However, the RR does not respiratory muscle strength, with sitting and lying FVC measurement, appear to be high, as the prevalence of AF at baseline was not higher should therefore be included in surveillance of these patients. How- than in the adult population in the USA.33 ever, since respiratory function did not decline significantly between While progressive abnormalities in AV and infra-Hisian conduc- assessments, FVC monitoring once every 2 y should be sufficient to tion are seen in patients with myotonic dystrophy, laminopathies, and detect significant changes. in some muscular dystrophies, this was not found in this Despite identifying some patients with low FVC, advanced respi- dysferlinopathy cohort.34,35 Although PR prolongation and bundle ratory impairment requiring NIV does not seem to occur in branch block were noted in a minority of our cohort, this was only in dysferlinopathy. The prevalence of sleep apnoea in this cohort is no association with co-morbidities. We therefore conclude that these higher than in the general population.22 UK guidelines recommend abnormalities were unlikely to be attributable to dysferlinopathy.5,17 continuous positive airway pressure (CPAP) for symptomatic patients On the basis of the echo findings of the study, any structural abnor- with moderate or severe obstructive sleep apnoea (OSA),23 giving a malities were either inconsistent or mild and of doubtful clinical signif- CPAP use prevalence in the general population similar to that seen in icance or explained by subject age or known co-morbidities. Clinically this study. NIV requirement can be due to obstructive or restrictive significant cardiomyopathy, as opposed to atrial electropathy, is prob- causes or a combination of both.24 In other forms of muscular dystro- ably not part of the dysferlinopathy phenotype. phy with respiratory involvement, increasing diaphragmatic involve- ment contributes to a restrictive respiratory impairment as disease progresses20 and this has been suggested in dysferlinopathy.21 How- 4.1 | Limitations of the study ever, in this cohort, NIV use was not frequent, even in those with advanced skeletal muscle involvement. Those who did require NIV This observational study was conducted over a period of 3 y, which is were more likely to be older with a higher BMI or have COPD, factors a relatively short period of follow-up for patients with a slowly pro- that are related to OSA and NIV use in the general population.25 This gressive condition. Longer follow-up may allow more definitive con- suggests that NIV requirement was of obstructive cause and clusions and identification of additional risk factors for progression in unrelated to dysferlinopathy, although it is possible that mild dia- respiratory or cardiac conduction deficits. phragmatic involvement is compounding hypopnoea in these patients From a respiratory perspective, the diagnosis of sleep apnoea and and contributing to NIV requirement. ventilation need was self-reported. While we conclude that cases Dysferlinopathy does not appear to be associated with cardiac requiring ventilation were most likely obstructive in nature, rather co-morbidities or symptoms in this cohort. Although hypertension than due to diaphragmatic or intercostal weakness, a definitive con- was frequent, it was not more common than in the general popula- clusion would require more detailed respiratory assessment, including tion.26 Leg swelling was commonly encountered in non-ambulant polysomnography, to determine the cause. patients, but did not appear to be related to cardiac function and is From a cardiac perspective, while we identified frequent dys- well known to occur in cases of reduced mobility of many causes.27 morphic P-waves that may increase the risk of atrial arrythmias, Breathlessness was the only potentially cardiac symptom that was we did not include Holter-ECG monitoring in our study. The 1.7% reported more frequently than in the general population.28 We prevalence of AF in this population may, therefore, be an under- postulate that this may be related to the increased exertional estimate, as it does not capture patients with intermittent or non- 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MOORE ET AL. 539 sustained AF. We plan to assess AF risk further in a sub-study trademark of the University of Washington, Seattle. All rights that will include signal averaging of P-wave and Holter-ECG reserved; 1993. 2. Human Protein Atlas Dysferlin RNA and protein expression, 2020. recordings. The Human Protein Atlas Web site, https://www.proteinatlas.org/ Two patients died during the study. We were unable to clarify ENSG00000135636-DYSF/tissue. the cause of death in the younger patient (aged 68 y) and cannot 3. Takahashi T, Aoki M, Suzuki N, et al. Clinical features and a mutation definitively state whether it had a primary cardiac or respiratory with late onset of limb girdle muscular dystrophy 2B. J Neurol Neuro- surg Psychiatry. 2013;84:433-440. cause. Allowing for previous known medical history, however, we 4. Wenzel K, Geier C, Qadri F, et al. Dysfunction of dysferlin-deficient consider death directly due to dysferlinopathy unlikely. hearts. J Mol Med. 2007;85:1203-1214. 5. Nishikawa A, Mori-Yoshimura M, Segawa K, et al. Respiratory and cardiac function in Japanese patients with dysferlinopathy. Muscle Nerve. 2016;53:394-401. 5 | C O N CL U S I O N S 6. Ten Dam L, Frankhuizen WS, Linssen W, et al. Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in The Netherlands: the In this large, multi-national cohort of patients with dysferlinopathy, clinical and molecular spectrum of 244 patients. Clin Genet. 2019;96: severe respiratory muscle weakness was rare, but mild impairment was 126-133. 7. Suzuki N, Takahashi T, Suzuki Y, et al. An autopsy case of a sufficiently common to justify screening for it routinely at follow-up by dysferlinopathy patient with cardiac involvement. Muscle Nerve. FVC measurements every 2 y. Dysferlinopathy did not cause clinically 2012;45:298-299. significant LV dysfunction or LVH. However, more than half of the 8. Guglieri M, Magri F, D'Angelo MG, et al. Clinical, molecular, and pro- patients showed atrial electrical conduction abnormalities on ECG. An tein correlations in a large sample of genetically diagnosed Italian limb atrial electropathy seems to be part of the dysferlinopathy phenotype; girdle muscular dystrophy patients. Hum Mutat. 2008;29:258-266. 9. Choi ER, Park S-J, Choe YH, et al. Early detection of cardiac involve- so, patients may be at increased risk of developing AF compared to the ment in Miyoshi myopathy: 2D strain echocardiography and late gad- general population. We recommend routine enquiry about arrhythmia olinium enhancement cardiovascular magnetic resonance. J symptoms at neuromuscular reviews, routine pulse checking for asymp- Cardiovasc Magn Reson. 2010;12:31. tomatic AF and standard Holter ECG testing, if pulse abnormalities are 10. Rosales XQ, Moser SJ, Tran T, et al. Cardiovascular magnetic reso- detected or when palpitation symptoms are reported. However, spe- nance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I. J Cardiovasc Magn Reson. 2011;13:39. cialist cardiac review and more detailed testing is probably not 11. Mahjneh I, Marconi G, Bushby K, Anderson LV, Tolvanen-Mahjneh H, warranted unless prompted by symptoms or abnormal pulse findings. Somer H. Dysferlinopathy (LGMD2B): a 23-year follow-up study of 10 patients homozygous for the same frameshifting dysferlin muta- E THI CAL P UBLI CATI ON S TAT EME NT tions. Neuromuscul Disord. 2001;11:20-26. 12. Harris E, Bladen CL, Mayhew A, et al. The clinical outcome study for We confirm that we have read the Journal's position on issues dysferlinopathy: an international multicenter study. Neurol Genet. involved in ethical publication and affirm that this report is consistent 2016;2:e89. with those guidelines. 13. Poonja S, Power A, Mah JK, Fine NM, Greenway SC. Current cardiac imaging approaches in Duchenne muscular dystrophy. J Clin Neuromuscul Dis. 2018;20:85-93. CONF LICT S OF INTE R ES T 14. Wharton G, Steeds R, Allen J, et al. A minimum dataset for a stan- This study was financed through a grant from the Jain Foundation. dard adult transthoracic echocardiogram: a guideline protocol from Apart from this grant, none of the authors has any conflict of interests the British society of echocardiography. Echo Res Pract. 2015;2: to disclose. G9-G24. 15. Liou TG, Kanner RE. Spirometry. Clin Rev Allergy Immunol. 2009;37: 137-152. DATA AVAI LAB ILITY S TATEMENT 16. Jacobs MB, James MK, Lowes LP, et al. Assessing dysferlinopathy Anonymised aggregate data will be provided on reasonable request. patients over three years with a new motor scale. Ann Neurol. 2021; Requests should be made to the clinical outcomes study steering com- 89:967-978. mittee by contacting the corresponding author. 17. Surawicz B, Knilans T. Chou's Electrocardiography in Clinical Practice. 6th ed. Philadelphia, PA: Elsevier; 2008. 18. Kou S, Caballero L, Dulgheru R, et al. Echocardiographic reference ORCID ranges for normal cardiac chamber size: results from the NORRE study. Eur Heart J Cardiovasc Imaging. 2014;15:680-690. Marni Jacobs https://orcid.org/0000-0001-6649-6692 19. Krachman S. Hypoventilation syndromes. BMJ Best Pract. 2019. Jordi Diaz-Manera https://orcid.org/0000-0003-2941-7988 https://bestpractice.bmj.com/topics/en-gb/1153 Meredith K. James https://orcid.org/0000-0001-8078-7744 20. Aboussouan LS. Sleep-disordered breathing in neuromuscular dis- Volker Straub https://orcid.org/0000-0001-9046-3540 ease. Am J Respir Crit Care Med. 2015;191:979-989. 21. Barton ER, Wang BJ, Brisson BK, Sweeney HL. Diaphragm displays early and progressive functional deficits in dysferlin-deficient mice. RE FE R ENC E S Muscle Nerve. 2010;42:22-29. 1. Aoki M. Dysferlinopathy. In: Adam MP et al., eds. GeneReviews®. Seat- 22. Senaratna CV, Perret JL, Lodge CJ, et al. Prevalence of obstructive tle, WA: University of Washington, Seattle Copyright © 1993-2020, sleep apnea in the general population: a systematic review. Sleep Med University of Washington, Seattle. GeneReviews is a registered Rev. 2017;34:70-81. 10974598, 2022, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/mus.27524 by Readcube (Labtiva Inc.), Wiley Online Library on [29/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 540 MOORE ET AL. 23. Continuous positive airway pressure for the treatment of obstructive 32. Holmqvist F, Platonov PG, McNitt S, et al. Abnormal P-wave mor- sleep apnoea/hypopnoea syndrome, 2008. National Institute for phology is a predictor of atrial fibrillation development and cardiac Health and Care Excellence Web site, https://www.nice.org.uk/ death in MADIT II patients. Ann Noninvasive Electrocardiol. 2010;15: guidance/ta139/chapter/About-this-guidance. 63-72. 24. Kushida CA, Littner MR, Morgenthaler T, et al. Practice parameters 33. Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of for the indications for polysomnography and related procedures: an atrial fibrillation and flutter in the United States. Am J Cardiol. 2009; update for 2005. Sleep. 2005;28:499-523. 104:1534-1539. 25. Liu Y, Zou J, Qian Y, et al. The association between obesity indices 34. Ismail H, Raynor E, Zimetbaum P. Neuromuscular disorders and the and obstructive sleep apnea is modified by age in a sex-specific man- role of the clinical electrophysiologist. JACC Clin Electrophysiol. 2017; ner. Sleep Breath. 2020;25:189-197. 3:1069-1079. 26. Heart Statistics, 2020. British Heart Foundation Web site, https:// 35. Parry-Williams G, Malhotra A, Dhutia H, et al. The short PR interval in www.bhf.org.uk/what-we-do/our-research/heart-statistics. young athletes. Heart. 2019;105:A25-A26. 27. Partsch H. Intermittent pneumatic compression in immobile patients. Int Wound J. 2008;5:389-397. 28. Ihlebæk C, Eriksen HR, Ursin H. Prevalence of subjective health com- plaints (SHC) in Norway. Scand J Public Health. 2002;30:20-29. SUPPORTING INF ORMATION 29. Lehtonen AO, Langén VL, Puukka PJ, et al. Incidence rates, correlates, Additional supporting information may be found in the online version and prognosis of electrocardiographic P-wave abnormalities: a nation- wide population-based study. J Electrocardiol. 2017;50:925-932. of the article at the publisher's website. 30. Centurio  n OA. Clinical implications of the P wave duration and dis- persion: relationship between atrial conduction defects and abnor- mally prolonged and fractionated atrial endocardial electrograms. Int J How to cite this article: Moore U, Fernandez-Torron R, Cardiol. 2009;134:6-8. Jacobs M, et al. Cardiac and pulmonary findings in 31. Ooie T, Wakisaka O, Hujita T, et al. A specific combination of P wave dysferlinopathy: A 3-year, longitudinal study. Muscle & Nerve. duration and morphology accurately predicts the presence of left 2022;65(5):531-540. doi:10.1002/mus.27524 atrial low voltage area in patients with atrial fibrillation. J Ele- ctrocardiol. 2020;63:173-180.