Abstract 1369: Gender-related Differences In Non-diseased Human Epicardial-endocardial Ion-channel Expression Heterogeneity
Background: Gender-related and transmural differences in ventricular electrophysiology are important determinants of human arrhythmic risk, but underlying molecular mechanisms are poorly understood.
Objectives and Methods: By using a high-throughput quantitative approach, we studied at a genome scale the expression of 79 genes encoding ion-channel and transporter subunits in non-diseased human cardiac samples from donor hearts of either sex.
Results: Hierarchical clustering demonstrated that transcript expression dissimilarities between endocardium (Endo) and epicardium (Epi) or between samples from males (Ms) and females (Fs) are subtle but involve key genes involved in conduction and repolarization. Significant transmural ventricular expression gradients were seen for 8/79 genes (Epi/Endo ratios: Nav1.5 â €″37%, Cav1.2 +27%, CavÎ±2Î′1 −19%, Cx40 −47%, SERCA2 +27%, Kv1.4 −50%, Kv4.2 +132% and KChIP2 +138%), with only two of these (KChIP2 and Kv1.4) showing sex-related divergences (F/M expression ratios −39%, −43%). The expression of the Iroquois transcription factors IRX3 and IRX5 was opposite that of KChIP2, both in relation to endocardium/epicardium and gender differences, suggesting that negative transcriptional regulation of KChIP2 in humans may occur via IRX3 and/or IRX5. In addition, 6 other ion channel transcripts encoding K+ channel subunits and connexins without transmural gradients showed lower-level expression in women (F/M ratios Cx43 −36%, Kir6.2 −46%, SUR2 −23%, Kir2.3 −42%, HERG −34% and MinK −33%). For selected genes, protein expression patterns were confirmed by Western blots.
Conclusions: Women have lower-level ventricular expression of key repolarizing ion-channel subunit transcripts than men, providing a potential molecular basis for their smaller repolarization reserve and predisposition to acquired long QT syndrome. The significantly stronger expression of KChIP2 in the right epicardium of men could explain why reduced INa in Brugada patients leads more readily to premature repolarization and arrhythmias in males than females. These results are important for understanding clinically significant sex-related differences in the susceptibility to ventricular arrhythmias.