Influence of sex on intracellular calcium homeostasis in patients with atrial fibrillation.

AIMS Atrial fibrillation (AF) has been associated with intracellular calcium disturbances in human atrial myocytes, but little is known about the potential influence of sex and we here aimed to address this issue. METHODS AND RESULTS Alterations in calcium regulatory mechanisms were assessed in human atrial myocytes from patients without AF or with long-standing persistent or permanent AF. Patch-clamp measurements revealed that L-type calcium current (ICa) density was significantly smaller in males with than without AF (-1.15±0.37 vs. -2.06±0.29 pA/pF) but not in females with AF (-1.88±0.40 vs. -2.21±0.0.30 pA/pF). In contrast, transient inward currents (ITi) were more frequent in females with than without AF (1.92±0.36 vs. 1.10±0.19 events/min) but not in males with AF. Moreover, confocal calcium imaging showed that females with AF had more calcium spark sites than those without AF (9.8±1.8 vs. 2.2±1.9 sites/µm2) and sparks were wider (3.0±0.3 vs. 2.2±0.3 µm) and lasted longer (79±6 vs. 55±8 ms), favoring their fusion into calcium waves that triggers ITIs and afterdepolarizations. This was linked to higher ryanodine receptor phosphorylation at s2808 in women with AF, and inhibition of adenosine A2A or beta-adrenergic receptors that modulate s2808 phosphorylation was able to reduce the higher incidence of ITI in women with AF. CONCLUSION Perturbations of the calcium homeostasis in AF is sex-dependent, concurring with increased spontaneous SR calcium release-induced electrical activity in women but not in men, and with diminished ICa density in men only. TRANSLATIONAL PERSPECTIVE Statistical analysis taking into account confounding effects of concurrent disease, risk factors and treatments revealed differential sex-dependent alterations of the calcium homeostasis in AF. The analysis suggests that suppression of calcium release-induced membrane depolarizations with adenosine receptor antagonists may be efficient in women with AF only while therapies aiming to restore L-type calcium current may be more efficient in males with AF.