Modeling sex differences in human atrial myocyte structural and Ca2+ handling properties: Impact on Ca2+-driven arrhythmia.

Abstract

Substantial sex differences have been reported in the prevalence, pathophysiology, treatment, and prognosis of atrial fibrillation (AF), the most common cardiac arrhythmia. Knowledge of sex differences in the underlying arrhythmogenic substrate may improve therapy. Recent experimental studies revealed differences in cell geometry, transverse-axial tubule system (TATS) density, and expression, function, and phosphorylation status of Ca2+ handling proteins in female vs. male atrial myocytes, and in their remodeling in AF. However, it remains unknown how these sex-dependent differences contribute (individually or collectively) to arrhythmia propensity in females vs. males. Here, we used our new human atrial myocyte model coupling electrophysiology and spatially-detailed Ca2+ cycling governed by the TATS to integrate these sex-specific features and build sex-specific models of both normal sinus rhythm (nSR) and AF conditions. We tested the responses of the models to a pace-pause protocol and found that in nSR the female myocyte model displays 1) higher Ca2+ spark frequency, and 2) greater and more frequent spontaneous Ca2+ release (SCR) compared to male. These sex differences in Ca2+-driven arrhythmias are exacerbated in AF conditions. A systematic parametric study revealed the precise contribution of each sex-dependent change (i.e., TATS density, cell dimension, and Ca2+-handling protein expression or function) to SCR and Ca2+ spark properties. Both sparse TATS and changes in Ca2+-handling proteins (i.e., larger L-type Ca2+ current, reduced calsequestrin expression, higher RyR phosphorylation, and increased sarcoplasmic reticulum Ca2+-ATPase) promote greater Ca2+-driven arrhythmia in female myocytes, which was slightly attenuated by the smaller cell dimension vs male myocytes. Our study demonstrates the interactive contributions of subcellular structural and ionic sex differences to intracellular Ca2+ instability and provides novel model-based mechanistic insight that may guide future therapeutic sex-specific anti-AF strategies.