# Sex differences in human atrial electrophysiology: the dark side of the moon? Will engineered heart tissue help to bring light into the darkness?

## TL;DR

This paper reviews sex differences in human atrial electrophysiology and explores how engineered heart tissues could improve understanding of these differences.

## Contribution

The paper introduces engineered heart tissues as a novel approach to study sex-specific atrial electrophysiology and hormone effects.

## Key findings

- Sex differences in atrial electrophysiology are under-researched despite clinical evidence like lower AF incidence in women.
- Current models lack ECG markers for atrial repolarization and fail to account for sex-specific ion currents like IKs.
- Engineered heart tissues may help distinguish genetic and non-genetic hormone effects in atrial function.

## Abstract

Sex-related differences in cardiac electrophysiology are well established in the ventricle and have reached textbook level. In contrast, our understanding of sex effects in the human atrium remains limited, despite clear clinical observations such as the lower incidence of atrial fibrillation (AF) in women. In this review, we summarize sex differences and discuss potential reasons for the imbalance in knowledge, including the lack of ECG markers for atrial repolarization, the minimal contribution of IKs in atrial tissue, and possible sex differences in inward rectifier currents. We also address the role of aging and hormonal changes, the complexity of studying the perimenopausal transition, and the current limitations of available models. Finally, we highlight the potential of engineered heart tissues to detect genetically encoded differences and to dissect genomic versus non-genomic hormone effects.