Abstract

Fabry Disease (FD) is an X-linked disease due to enzyme deficiency of α-galactosidase A resulting in multi-organ accumulation of globotriaosylceramide (Gb3). Cardiac accumulation triggers myocardial hypertrophy, inflammation, and fibrosis, predisposing to ventricular and atrial arrhythmia. Atrial fibrillation (AF) is common, yet the direct effects of FD on the atrial myocyte are unclear. Using genome-edited induced pluripotent stem-cell derived atrial cardiomyocytes (iPSC-CMs) with a cardiac variant of FD (N215S), we quantified atrial contraction, calcium handling, and intracellular electrophysiology. These were correlated with signal averaged P-wave analysis from the electrocardiograms (ECG) of adults with FD and left atrial (LA) volume on echocardiography. We confirmed greater accumulation of Gb3 in N215S iPSC-CMs with under-expression of α-galactosidase A compared with wild type (WT) controls. We demonstrated greater contraction force, slower beat rate and greater transients of calcium in N215S iPSC-CMs compared to WT. From atrial action potentials (AP) we demonstrated greater upstroke velocity, amplitude and diastolic membrane potential compared to WT. ECG analysis revealed shorter P-wave duration and PQ interval in adults with FD and no apparent cardiomyopathy compared to healthy controls which prolonged as cardiomyopathy developed. Patients with AF had prolonged P-wave duration when in sinus rhythm compared to those without AF. P-wave duration and PQ interval correlated with increasing LA volume as cardiomyopathy progressed. These findings suggest that enzyme deficiency and Gb3 accumulation associate with changes in atrial contractility, intracellular calcium kinetics and action potential morphology. The ECG changes observed of shorter P-wave duration and PQ interval in FD patients without cardiomyopathy, mimics the cellular data of greater upstroke velocity in atrial action potentials. The identified early electrophysiological changes may provoke arrhythmia through increased excitability due to greater calcium cycling alterations to inward sodium currents. These early changes in atrial electrophysiology suggest that risk of AF in FD may be exacerbated by the direct impact of enzyme deficiency and Gb3 accumulation on atrial cardiomyocytes rather than the secondary effects of ventricular disease.