Abstract 19064: Sex Specific Gene Profile in Canine Sinoatrial Node

Abstract

Introduction: Biological sex plays an important role in cardiac function and occurrence of cardiac arrhythmias. Clinical reports show that adult females have faster resting and intrinsic heart rate (HR) while males have faster HR peak and larger HR reserve. Furthermore, inappropriate sinus tachycardia primarily occurs in females, suggesting sex-specific function and/or structure of the sinoatrial node (SAN). The aim of the study is to define sex-specific molecular features of the SAN complex. Methods: mRNA was isolated from SAN pacemaker tissue of healthy adult canines (male=4, female=4). Differential RNA expression patterns of >400 genes, including fibrosis, inflammation, and metabolism markers were quantified with nCounter Nanostring fibrosis panel. Quantitative PCR was used to compare mRNAs of key ion channels related to SAN pacemaker function. Results: Nanostring panel revealed sex-specific and SAN-specific gene profiles of inflammation and fibrotic markers with multiple mRNAs higher in male (e.g. NLRP3, CD86, COL3A1, TGFB1) and several higher in females (e.g. MARCOL, IL20RB). mRNAs responsible for SAN pacemaking e.g. HCN1, HCN4, Cav1.3, and GIRK4 are higher expressed in female SAN. Sex-specific retrospective analysis of published gene profiles from non-failing human hearts showed a similar pattern to canine with HCN1, HCN4, Cav1.3 expression higher in female SAN. Conclusions: The study revealed significantly different gene expressions of fibrosis, inflammation, and pacemaking in male vs female SAN. The higher expression of HCN1/4 and Cav1.3 may explain the faster intrinsic sinus rhythm and susceptibility to SAN arrhythmias in females. The elevated fibrosis and inflammation genes in male SAN may suggest higher vulnerability to fibrotic remodeling during cardiac disease.