Fabry Disease Triggers Atrial Arrhythmia Before Heart Enlargement Begins

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to deficiency of the enzyme α-galactosidase A (α-GAL A). This results in toxic accumulation of glycosphingolipid globotriaosylceramide (Gb3) across multiple organs, with cardiovascular disease being the leading cause of death. While ventricular hypertrophy and fibrosis are well characterized, the mechanisms driving atrial arrhythmia — particularly atrial fibrillation (AF), which affects over 12% of FD patients — have remained largely unknown.

The research team conducted signal-averaged ECG analysis in 115 adults with FD at a specialist rare disease center, comparing P-wave characteristics across cardiomyopathy stages against 40 age- and sex-matched healthy controls. Notably, FD patients demonstrated significantly shorter P-wave duration and PQ interval even prior to the onset of cardiomyopathy, alongside a higher incidence of premature atrial contractions (PACs) and elevated AF risk compared to controls. This suggests the atrial substrate for arrhythmia is established very early in the disease course.

To investigate cellular mechanisms, the team developed the first atrial iPSC-derived cardiomyocyte (iPSC-CM) model of FD using CRISPR-Cas9 genome editing to introduce the GLA p.N215S variant — the most prevalent FD mutation in the United Kingdom — into a validated iPSC line. The edited cells were confirmed to be α-GAL A deficient with Gb3 accumulation. Electrophysiological patch-clamp recordings revealed that GLA p.N215S atrial iPSC-CMs exhibited a more positive diastolic membrane potential, faster action potential upstroke velocity, and a significantly greater incidence of delayed afterdepolarizations (DADs) compared to wildtype controls. Calcium handling experiments showed altered transient dynamics and increased spontaneous calcium release, consistent with a pro-arrhythmic substrate. Contractile force measurements also demonstrated increased contraction amplitude.

These cellular findings were then incorporated into bi-atrial in-silico computational models. Simulations reproduced the ECG P-wave morphology changes observed in early FD patients and demonstrated markedly increased vulnerability to AF initiation. Together, this multi-scale experimental framework — from ECG cohort analysis through cellular electrophysiology to whole-atrium simulations — provides a mechanistically coherent explanation for why AF arises early in FD, driven by intrinsic atrial cardiomyocyte dysfunction rather than solely as a downstream consequence of ventricular remodeling.

These findings open new avenues for early therapeutic intervention in FD. Since atrial electrical remodeling precedes structural cardiomyopathy, P-wave changes on routine ECG could serve as early biomarkers for AF risk stratification. Targeting the ionic and calcium-handling abnormalities identified in this model may represent a novel strategy for reducing arrhythmic burden in FD patients before irreversible structural damage occurs.