Abstract Body (Do not enter title and authors here): Background: Biological sex plays an important role in cardiac function and the occurrence of arrhythmias. Females have faster resting and intrinsic heart rate (HR), and a higher prevalence of inappropriate sinus tachycardia (IST), while males have a higher risk of atrial fibrillation (AF).
Hypothesis: Sexual dimorphism of gene expression and hormones may underlie the sex-related differences in sinoatrial node (SAN) function and arrhythmia’s prevalence
Methods: Cardioplegically-arrested non-failing donor hearts (male=5, 52±10 y.o., female=7, 48±16 y.o.) were dissected and total RNA was isolated from SAN pacemaker tissue and paired right atria (RA). Differential mRNA expression of ~800 genes in male vs female SAN and RA were quantified with a customized nCounter gene panel (Nanostring). Ingenuity Pathway Analysis (IPA, Qiagen) was conducted to infer the underlying causes of the differential express genes (DEG) related to SAN development, HR regulation, and atrial arrhythmia susceptibility.
Results: Nanostring gene panel revealed sex-biased DEG in SAN (n=42) and RA (n=30) (p<0.05 and absolute fold change >1.2). 25 mRNAs (eg. HCN1, TBX3, COL6A3) were higher in female SAN, and 17 mRNAs (eg. EGR1, IL6, COL14A1) were higher in male SAN. Gene set enrichment analysis showed enriched genes in Gene Ontology (GO) pathways related to HR regulation, cardiac conduction, and metabolic process in female SAN. In contrast, gene sets related to collagen biosynthetic process and immune response are enriched in male SAN and RA. IPA predicted the key role of TBX3 in maintaining SAN function, and significantly higher estradiol but lower testosterone levels in female than male SAN, which may indirectly enhance the expression of pacemaking ion channels and ANS receptors.
Conclusions: Higher estradiol but lower testosterone in females may enhance the expression of TBX3 and HCN1, and enriched gene sets in HR regulation pathways, resulting in a faster HR and increased risk of IST. In males, the enriched gene sets related to inflammation and collagen biosynthetic process in the atria may predispose them to conduction impairments and a higher risk of AF.