Early Atrial Remodeling Drives Arrhythmia in Fabry Disease

Area of Science:

• Cardiology
• Genetics
• Biochemistry

Background:

• Fabry disease (FD) is an X-linked lysosomal storage disorder due to alpha-galactosidase A (α-Gal A) deficiency.
• This deficiency causes sphingolipid accumulation, leading to cardiac hypertrophy, fibrosis, inflammation, and potentially sudden death.
• Atrial fibrillation is common in FD, but its underlying cellular mechanisms remain unclear.

Purpose of the Study:

• To investigate the cellular mechanisms of atrial arrhythmia in Fabry disease.
• To analyze electrocardiogram (ECG) P-wave characteristics in FD patients.
• To develop and utilize an in vitro and in silico model of FD atrial cardiomyocytes.

Main Methods:

• ECG analysis of 115 adults with FD and comparison with controls.
• Development of a novel atrial cellular model using genome-edited induced pluripotent stem cells (iPSCs) with the GLA p.N215S variant.
• Electrophysiological and contractile assessments of iPSC-derived atrial cardiomyocytes (iPSC-CMs) and in silico atrial modeling.

Main Results:

• FD patients showed P-wave duration and PQ interval shortening before cardiomyopathy onset.
• FD iPSC-CMs exhibited α-Gal A deficiency, globotriaosylceramide accumulation, altered membrane potential, faster action potential upstroke, and increased delayed afterdepolarizations.
• In silico models replicated early FD ECG changes and demonstrated increased atrial fibrillation vulnerability.

Conclusions:

• Early P-wave changes in FD are linked to specific cellular electrophysiological alterations.
• The study provides novel insights into the mechanisms driving atrial arrhythmia in Fabry disease.
• These findings support the development of targeted therapeutic strategies to mitigate the arrhythmic burden in FD.