Heart Rate Mystery Unveiled: Sex Differences in Human Sinoatrial Node Genes and Female Tachycardia

BACKGROUND: Despite over a century of clinical electrocardiographic studies showing that females exhibit a faster resting heart rate (HR), the mechanisms underlying sex differences in HR remain unresolved. Moreover, inappropriate sinus tachycardia primarily affects females, whereas males are at a higher risk for conduction block and atrial fibrillation. We hypothesized that the sexual dimorphism of genes responsible for sinoatrial node (SAN) pacemaking and signaling pathways may contribute to the sex differences in HR and susceptibility to arrhythmias. METHODS: Human SAN central pacemaker and right atrial tissue were isolated from nondiseased ex vivo donor hearts. Gene expressions were quantified and validated using the transcriptomic panel and quantitative polymerase chain reaction. Gene set enrichment analysis, Ingenuity Pathway Analysis, and human-specific SAN models were utilized to define regulatory mechanisms and functional impacts of sex-biased gene transcription. RESULTS: We identified differentially expressed region- and sex-specific genes, with gene sets enriched in HR regulation (eg, TBX3 , HCN1 ) and metabolism (eg, ADIPOQ , LEP ) pathways in female SAN. In contrast, differential genes and gene sets involved in collagen biosynthetic processes, fibrogenesis (eg, EGR1 ), and immune response (eg, IL6 , CXCL8 ) pathways were enriched in males SAN and right atrial. Ingenuity Pathway Analysis predicted significant roles for TBX3 and estradiol in the sex-specific expression of genes involved in SAN function. Computational simulations showed that the sex-specific SAN differences in I f (HCN1) and I Ca,L (CACNA1D) can explain the faster HR in females, with females having a lower threshold for inappropriate sinus tachycardia, whereas males are more vulnerable to sinus arrest. CONCLUSIONS: The human SAN exhibits region-specific sexual dimorphism in pacemaking gene sets. Higher expression of TBX3 and HCN1 in females may underlie their faster HR and increased susceptibility to inappropriate sinus tachycardia, whereas enriched gene sets related to inflammation and collagen biosynthesis in males may predispose them to conduction impairments and atrial fibrillation risk.