A sexy approach to pacemaking: Differences in function and molecular make up of the sinoatrial node

Background. Functional properties of the sinoatrial node (SAN) are known to differ between sexes. Women have higher resting and intrinsic heart rates. Sex determines the risk of developing certain arrhythmias such as sick sinus syndrome, which occur more often in women. We believe that a major contributor to these differences is in gender specific ion channel expression. Methods. qPCR was used to compare ion channel gene expression in the SAN and right atrium (RA) between male and female rats. Histology, immunohistochemistry and signal intensity analysis were used to locate the SAN and determine abundance of ion channels. The effect of nifedipine on extracellular potential recording was used to determine differences in beating rate between sexes. Results. mRNAs for Ca_v 1.3, K_ir 3.1, and Nkx2-5, as well as expression of the L-Type Ca²⁺ channel protein, were higher in the female SAN. Females had significantly higher intrinsic heart rates and the effect of nifedipine on isolated SAN preparations was significantly greater in male SAN. Computer modelling using a SAN cell model demonstrated a higher propensity of pacemaker-related arrhythmias in females. Conclusion. This study has identified key differences in the expression of Ca_v 1.3, K_ir 3.1 and Nkx2-5 at mRNA and/or protein levels between male and female SAN. Ca_v 1.3 plays an important role in the pacemaker function of the SAN, therefore the higher intrinsic heart rate of the female SAN could be caused by the higher expression of Ca_v 1.3. The differences identified in this study advance our understanding of sex differences in cardiac electrophysiology and arrhythmias.