Early Atrial Remodeling Drives Arrhythmia in Fabry Disease.

Abstract

Background: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-Gal A (α-galactosidase A) deficiency, resulting in multiorgan accumulation of sphingolipid, namely globotriaosylceramide. This triggers ventricular myocardial hypertrophy, fibrosis, and inflammation, driving arrhythmia and sudden death. Atrial fibrillation is common, yet the cellular mechanisms accounting for this are unknown.

Methods: To address this, we conducted ECG analysis from a large cohort of 115 adults with FD at varying cardiomyopathy stages. ECG P-wave characteristics were compared with non-FD controls. Cellular contractile and electrophysiological function were examined in a novel atrial cellular FD model developed and imputed into in silico atrial models to provide insight into mechanisms of arrhythmia. Induced pluripotent stem cells were genome-edited using Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 to introduce the GLA p.N215S variant and differentiated into induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-CMs). Contraction, calcium handling, and electrophysiology experiments were conducted. Bi-atrial in silico models were developed with cellular changes as in GLA p.N215S iPSC-CMs.

Results: ECG analysis demonstrated P-wave duration and PQ interval shortening in FD adults before the onset of cardiomyopathy. Patients with FD exhibited a higher incidence of premature atrial contractions and increased risk of atrial fibrillation compared with healthy controls. GLA p.N215S iPSC-CMs were deficient in α-Gal A and exhibited globotriaosylceramide accumulation. Atrial GLA p.N215S iPSC-CMs demonstrated a more positive diastolic membrane potential, faster action potential upstroke velocity, greater incidence of delayed afterdepolarizations, greater contraction force, and alterations in calcium handling compared with wild-type iPSC-CMs. Simulations with these changes in the in silico models resulted in similar P-wave morphology changes to those seen in early FD cardiomyopathy and increased atrial fibrillation vulnerability.

Conclusions: These findings provide novel insights into underpinning mechanisms for atrial arrhythmia and a rationale for early P-wave changes in FD. These may be targeted to develop therapeutic strategies to reduce the arrhythmic burden in FD.