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Study of Indications for Cardiac Device Implantation and Utilisation in Fabry

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Study of Indications for Cardiac Device Implantation and Utilisation in Fabry Arrhythmias and sudden death ORIGINAL RESEARCH ARTICLE Heart: first published as 10.1136/heartjnl-2019-315229 on 24 August 2019. Downloaded from Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy Ravi Vijapurapu, 1,2,3 Tarekegn Geberhiwot,3,4 Ana Jovanovic,5 Shanat Baig,1,2,3 Sabrina Nordin,6 Rebecca Kozor,7 Francisco Leyva,8 Dipak Kotecha, 1,2 Nigel Wheeldon,9 Patrick Deegan,10 Rosemary A Rusk,11 James C Moon,6 Derralynn A Hughes,12 Peter Woolfson,13 Richard P Steeds1,2 ► Additional material is ABSTRact of FD, with cardiovascular disease now the main published online only. To view Background Fabry disease is a treatable X-linked cause of morbidity and mortality.4 Cardiac involve- please visit the journal online (http:// dx. doi. org/ 10. 1136/ condition leading to progressive cardiomyopathy, ment includes progressive left ventricular hyper- heartjnl- 2019- 315229). arrhythmia and premature death. Atrial and ventricular trophy (LVH), myocardial inflammation, fibrosis, arrhythmias contribute significantly to adverse prognosis; arrhythmia, congestive cardiac failure and sudden For numbered affiliations see however, guidance to determine which patients require death.5 Sphingolipids accumulate in all cardiac cells end of article. cardiovascular implantable electronic devices (CIEDs) is including the conduction system.6 This triggers a sparse. We aimed to evaluate indications for implantation cascade of cellular reactions leading to a proinflam- Correspondence to practice in the UK and quantify device utilisation. matory microenvironment with local tissue injury Dr Tarekegn Geberhiwot, 7 Endocrinology, Queen Methods In this retrospective study, we included and apoptosis. The ensuing damage to conductive Elizabeth Hospital Birmingham, demographic, clinical and imaging data from patients tissue contributes to electrical instability and subse- Birmingham B15 2GW, UK; in four of the largest UK Fabry centres. Ninety patients quent development of arrhythmia. Although symp- tarekegn. geberhiwot@ uhb. with Fabry disease were identified withCIE Ds implanted toms such as palpitations and syncope are common nhs. uk between June 2001 and February 2018 (FD-CIED group). in FD, little is known regarding the true frequency Received 11 April 2019 To investigate differences in clinical and imaging markers of arrhythmia.4 Registry data and small single centre Revised 25 June 2019 between those with and without devices, these patients studies suggest that the rate of atrial arrhythmias Accepted 3 July 2019 were compared with 276 patients without a CIED (FD- such as atrial fibrillation (AF) could be as high as control). 13%,8 while the reported incidence of ventricular Results In the FD-CIED group, 92% of patients with arrhythmia varies widely from 5% to 30%,9–11 with permanent pacemakers but only 28% with implantable a progressive increase with advancing age.12 cardioverter-defibrillators had a class 1 indication for A number of clinical and imaging parame- implantation. A further 44% of patients had defibrillators ters have been identified as markers of poten- http://heart.bmj.com/ inserted for primary prevention outside of current tial arrhythmia,13 14 but no criteria exist to guide guidance. The burden of arrhythmia requiring treatment implantation of cardiovascular implantable elec- in the FD-CIED group was high (asymptomatic atrial tronic devices (CIEDs) for primary prevention. fibrillation: Furthermore, FD is specifically excluded from the 29%; non-sustained ventricular tachycardia requiring risk prediction tool for sudden cardiac death used medical therapy alone: 26%; sustained ventricular in hypertrophic cardiomyopathy (HCM),15 despite tachycardia needing anti-tachycardia pacing/ 16 similarities in risk factors between FD and HCM. on October 2, 2021 by guest. Protected copyright. defibrillation: 28%).T hose with devices were older, had Data are lacking on the reasons for implantation of greater LV mass, more scar tissue and larger atrial size. CIEDs in FD and on device utilisation following Conclusions Arrhythmias are common in Fabry implantation.17 18 patients. Those with cardiac devices had high rates of The aims of our study were to evaluate the atrial fibrillation requiring anticoagulation and ventricular indications for CIEDs applied in clinical practice, arrhythmia needing device treatment. These are as high to quantify arrhythmia burden and device usage as those in hypertrophic cardiomyopathy, supporting in patients with FD and to investigate differences the need for Fabry-specific indications for device in clinical characteristics between those with and implantation. without a device. METHODS © Author(s) (or their INTRODUCTION Study population employer(s)) 2019. Re-use permitted under CC BY. Fabry disease (FD) is an X-linked lysosomal storage This study conformed to the principles of Good Published by BMJ. disorder caused by a deficiency in the enzyme Clinical Practice guidelines. The study consisted of α-Galactosidase A,1 which leads to progressive patients with genetically confirmed FD followed up To cite: Vijapurapu R, accumulation of sphingolipids.2 This leads to at national specialist centres within the UK: Queen Geberhiwot T, Jovanovic A, et al. Heart Epub ahead of cellular dysfunction and life-threatening cardio- Elizabeth Hospital, Birmingham; Salford Royal print: [please include Day vascular, renal and neurological complications.3 Hospital, Salford; Royal Free Hospital, London; Month Year]. doi:10.1136/ The advent of enzyme replacement (ERT) and oral and Addenbrookes Hospital, Cambridge. We heartjnl-2019-315229 chaperone therapy has altered the natural history included all patients who had a therapeutic CIED, Vijapurapu R, et al. Heart 2019;0:1–7. doi:10.1136/heartjnl-2019-315229 1 Arrhythmias and sudden death including a permanent pacemaker (PPM), implantable cardio- and Mann-Whitney U testing for non-parametric data. χ2 or verter-defibrillator (ICD) or cardiac resynchronisation therapy Fisher’s exact testing was used to compare proportions within Heart: first published as 10.1136/heartjnl-2019-315229 on 24 August 2019. Downloaded from (CRT), implanted between 1 June 2001 and 1 February 2018 two independent groups. Comparisons between multiple groups (FD-CIED group). The clinical notes of all patients both current were performed using analysis of variance testing with post hoc and historical under follow-up within each centre were manu- Tukey correction. Time-to-event analysis was performed to eval- ally reviewed to identify whether a cardiac device had been uate the presence of arrhythmic events. Kaplan-Meier curves implanted and to define the study cohort. A comparator group were used to show time to first new diagnosis of AF, ventric- included patients recruited to the Fabry400 study ( ClinicalTrials. ular arrhythmia and first appropriate ICD therapy, whereas a gov: NCT03199001), which is a separate observational study multivariable Cox model was used for the occurrence of any evaluating the role of cardiovascular magnetic resonance (CMR) arrhythmia requiring treatment during follow-up (online supple- imaging in FD.19 mentary table 1). Proportionality of hazards was assessed by visual inspection of Kaplan-Meier curves for each predictor vari- Baseline assessment able. A p value of <0.05 was considered statistically significant. Baseline FD specific information included genetic muta- tion (classical or non-classical variant), other FD-target organ 20 RESULTS involvement and the Mainz Severity Score Index (MSSI). Study cohort characteristics The presence of ischaemic heart disease (IHD) was defined as Of the UK population of 880 Fabry patients in the four national evidence of a flow-limiting lesion on coronary angiography centres, 90 (10%) had a therapeutic cardiac device implanted requiring treatment (surgical, percutaneous or medical). In the between 1 June 2001 and 1 February 2018. The FD-CIED group FD-CIED group, cardiac investigations were recorded if these had a median follow-up of 4.3 years (IQR 2.2–7.7 years). These had been performed before or within 3 months following device patients are compared with detailed cardiac data from 276 Fabry implantation. These included transthoracic echocardiography, patients without a device in the FD-control group. Baseline char- CMR imaging and a 12-lead electrocardiogram (ECG), which acteristics are described in table 2. The FD-CIED cohort was were performed in accordance with standardised protocols. In older, more often male and more frequently had a non-classical the FD-control cohort, the most recent investigations during the mutation (predominantly with a cardiac variant, N215S protein Fabry400 study period were captured through clinical record sequence change). Furthermore, disease severity was more analysis. Classification of an ECG as abnormal included the pres- advanced in the FD-CIED patients, reflected by higher mean ence of the following: prolonged or shortened PR interval, QRS MSSI score, increased prevalence of LVH, ECG abnormalities duration >120 ms, minor conduction disturbances (intraventric- and late gadolinium enhancement (LGE) on CMR (see table 2). ular conduction abnormalities and bundle branch block patterns Eighteen patients (20%) in the FD-CIED group had chronic <120 ms), the presence of LVH by Sokolow-Lyon criteria, T kidney disease stage 3 or above, with two of these patients wave inversion in at least two contiguous leads and the presence having undergone renal transplantation, compared with two of multifocal
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