Po-02-123 knockdown of two atrial fibrillation associated genes heighten arrhythmia substrates

Expression quantitative trait locus analysis identified significant associations between two AF susceptibility loci and expression of the SYNE2 and FAM13B genes, with the risk alleles associated with lower expression. However, the relationship between these risk alleles and arrhythmia is unknown. To determine the effects of decreased expression of SYNE2 and FAM13B genes on cardiomyocyte arrhythmia substrates. siRNA mediated knockdown of the SYNE2 or FAM13B genes, compared to scrambled control siRNAs, was performed in confluent monolayers of human induced pluripotent stem cell-derived cardiomyocytes (iCells). Optical mapping methods were used to determine action potential duration and conduction velocity in knockdown vs. control cells. RNAseq was performed to explore the potential mechanisms for the gene knockdown effects. SYNE2 knockdown, vs. control, resulted in significantly slower conduction velocity (0.099 vs.0.157 m/sec, p=0.0009) and significantly shorter action potential duration (1975 vs. 2282 msec, p=0.0059). RNAseq after SYNE2 knockdown revealed changes in potassium and calcium-related genes, with increased expression of KCNQ, KCNJ3, KCNJ12, KCNJ4, KCNQ3, CASQ2, and ATP2A2. Conduction velocity for FAM13B knockdown vs. control was not different; however, action potential duration was significantly shorter (1688 vs 2278 msec, p=0.026). RNAseq after FAM13B knockdown revealed changes in sodium and calcium-related genes, with increased expression of CASQ2 and decreased expression of SCN2B. AF risk is associated with decreased expression of the SYNE2 and FAM13B genes, and their knockdown led to shorter action potential duration and slower conduction velocity (SYNE2), which can shorten cardiac wavelength and increase the likelihood of reentrant excitation, an important cause of AF. Drugs that target the downstream ion channels altered by low expression of SYNE2 or FAM13B may be worth evaluating as personalized therapy for patients inheriting the risk alleles at these loci.