Abstract P1088: Polycystin-1 Protects Against Experimental Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a 1 in 4 lifetime risk. AF impairs cardiac function and increases the risk of stroke and heart attack. Although this is a common and harmful disease, little is known about the molecular mechanisms driving this disease. We have previously demonstrated that the protein polycystin-1 (PC1) plays a role in atrial cardiomyocyte excitation-contraction coupling in ventricular cardiomyocytes. Interestingly, patients with mutations in PC1 encoding gene have increased rates of atrial arrhythmias, including atrial fibrillation. Here, we sought to study the role of PC1 in atrial cardiomyocyte function and atrial fibrillation inducibility. We performed intracardiac electrophysiology with burst pacing in two mouse models with impaired PC1 function: 1) a mouse model harboring R3277C mutation (RC/RC) known to cause autosomal polycystic kidney disease, and 2) cardiomyocyte-specific PC1 KO (CKO). We observed increased rates of atrial fibrillation inducibility in both RC/RC and PC1 CKO mice compared to their respective control littermates (76.9% in RC/RC and 81.8% in CKO vs 20.0% and 11.1% in their respective WT controls). To elucidate molecular mechanisms driving increased susceptibility to atrial fibrillation, we determined whether PC1 affects excitation-contraction coupling in atrial cardiomyocytes. Human induced pluripotent stem cells-derived atrial cardiomyocytes (hiPSC-aCM) were treated with control or PC1 siRNA. Action potentials and intracellular calcium were measured using Fluovolt and Fluo-4, respectively. PC1 ablation decreased action potential duration and calcium transient peak amplitude elicited by electrical stimulation in hiPSC-CM. Decreased calcium transient peaks were also observed in HL-1 atrial cell line treated with siRNA and adult atrial cardiomyocytes isolated from RC/RC mice compared to their control counterparts. Unexpectedly, RNA-sequencing revealed altered DNA Damage Response gene expression. DNA damage has been implicated in the pathogenesis of atrial fibrillation. Therefore, we studied whether tachypacing elicited DNA damage in hiPSC-aCM. We observed increased levels of H2AX phosphorylation (gamma H2AX) in hiPSC-aCM with reduced PC1 expression. Our data show that PC1 mutations increase atrial fibrillation inducibility in multiple mouse models, likely due to impaired DNA damage response and altered action potential and calcium handling.