Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease

Vijapurapu, Ravi; Roy, Ashwin; Demetriades, Polyvios; Warfield, Adrian; Hughes, Derralynn; Moon, James; Woolfson, Peter; Bono, Joseph De; Geberhiwot, Tarekegn; Kotecha, Dipak; Steeds, Richard P.

doi:10.1136/openhrt-2023-002316

Cited by 6 publications

(1 citation statement)

References 38 publications

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“…Our findings suggest that patients undergoing ILR implantation on clinical grounds have advanced disease, which is evidenced by an increased indexed left ventricular mass, MWT, and supranormal LVEF, and the majority of them have evidence of LGE on CMR indicative of myocardial fibrosis. Unsurprisingly, because of this, the arrhythmia detection rate is high, as these factors are shown to predispose to tachy-and bradyarrhythmia in FD (6,21). There were no differences in mass, MWT, LVEF, and presence of LGE in those with or without arrhythmia, and this largely reflects the heterogeneity of the cohort, with the majority of patients already having advanced disease at the time of ILR implantation.…”

Section: Discussionmentioning

confidence: 97%

Clinical utilisation of implantable loop recorders in adults with Fabry disease—a multi-centre snapshot study

Roy,

Vijapurapu,

Kurdi

et al. 2023

Front. Cardiovasc. Med.

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Fabry disease (FD) is an X-linked deficiency of alpha-galactosidase-A, leading to lysosomal storage of sphingolipids in multiple organs. Myocardial accumulation contributes to arrhythmia and sudden death, the most common cause of FD mortality. Therefore, there is a need for risk stratification and prediction to target device therapy. Implantable loop recorders (ILRs) allow for continual rhythm monitoring for up to 3 years. Here, we performed a retrospective study to evaluate current ILR utilisation in FD and quantify the burden of arrhythmia that was detected, which resulted in a modification of therapy. This was a snapshot assessment of 915 patients with FD across three specialist centres in England during the period between 1 January 2000 and 1 September 2022. In total, 22 (2.4%) patients underwent clinically indicated ILR implantation. The mean implantation age was 50 years and 13 (59%) patients were female. Following implantation, nine (41%) patients underwent arrhythmia detection, requiring intervention (six on ILR and three post-ILR battery depletion). Three patients experienced sustained atrial high-rate episodes and were started on anticoagulation. Three had non-sustained tachyarrhythmia and were started on beta blockers. Post-ILR battery depletion, one suffered complete heart block and two had sustained ventricular tachycardia, all requiring device therapy. Those with arrhythmia had a shorter PR interval on electrocardiography. This study demonstrates that ILR implantation in FD uncovers a high burden of arrhythmia. ILRs are likely to be underutilised in this pro-arrhythmic cohort, perhaps restricted to those with advanced FD cardiomyopathy. Following battery depletion in three patients as mentioned above, greater vigilance and arrhythmia surveillance are advised for those experiencing major arrhythmic events post-ILR monitoring. Further work is required to establish who would benefit most from implantation.

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Section: Discussionmentioning

confidence: 97%

Clinical utilisation of implantable loop recorders in adults with Fabry disease—a multi-centre snapshot study

Roy,

Vijapurapu,

Kurdi

et al. 2023

Front. Cardiovasc. Med.

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Arrhythmogenesis in Fabry Disease

Roy,

Cumberland,

O’Shea

et al. 2024

Curr Cardiol Rep

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Purpose of Review Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. Recent Findings There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual’s risk of arrhythmia in FD. Summary In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.

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Early atrial remodelling drives arrhythmia in Fabry Disease

Roy,

O’Shea,

Dasi I Martinez

et al. 2024

Preprint

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Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A (α-Gal A) deficiency, resulting in multi-organ accumulation of sphingolipid, namely globotriaosylceramide (Gb3). This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death, a common cause of FD mortality. Atrial fibrillation (AF) is common in FD, yet the cellular mechanisms accounting for this are unknown. To address this, we conducted electrocardiography (ECG) analysis from a large cohort of adults with FD at varying stages of cardiomyopathy. Cellular contractile and electrophysiological function were examined in an atrial FD model, developed using gene-edited atrial cardiomyocytes and imputed into in-silico atrial models to provide insight into arrhythmia mechanisms. Methods: In 115 adults with FD, ECG P-wave characteristics were compared with non-FD controls. Induced pluripotent stem cells (iPSCs) were genome-edited using CRISPR-Cas9 to introduce the GLA p. N215S variant and differentiated into atrial cardiomyocytes (iPSC-CMs). Contraction, calcium handling and electrophysiology experiments were conducted to explore proarrhythmic mechanisms. A bi-atrial in-silico model was developed with the cellular changes induced by GLA p. N215S iPSC-CMs. Results: ECG analysis demonstrated P-wave duration and PQ interval shortening in FD adults before onset of cardiomyopathy on imaging and biochemical criteria. FD patients exhibited a higher incidence of premature atrial contractions and increased risk of developing AF. In our cellular model, GLA p. N215S iPSC-CMs were deficient in α-Gal A and exhibited Gb3 accumulation. Atrial GLA p. N215S iPSC-CMs demonstrated a more positive diastolic membrane potential, faster action potential upstroke velocity, greater burden of delayed afterdepolarizations, greater contraction force, slower beat rate and dysfunction in calcium handling compared to wildtype iPSC-CMs. Inputting these changes into the in-silico model resulted in similar P-wave morphology changes to those seen in early FD cardiomyopathy and increased the action potential duration (APD) restitution slope, causing APD alternans and

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Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease

Cited by 6 publications

References 38 publications

Clinical utilisation of implantable loop recorders in adults with Fabry disease—a multi-centre snapshot study

Clinical utilisation of implantable loop recorders in adults with Fabry disease—a multi-centre snapshot study

Arrhythmogenesis in Fabry Disease

Early atrial remodelling drives arrhythmia in Fabry Disease

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