Early atrial remodelling drives arrhythmia in Fabry Disease

ABSTRACT 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 inducing AF. Conclusions These findings enhance our understanding of atrial myopathy in FD by providing novel insights into underpinning mechanisms for atrial arrhythmia and a rationale for early P-wave changes. These may be targeted in future research to develop therapeutic strategies to reduce the arrhythmic burden in FD and other atrial cardiomyopathies.