Spatial Distribution of Calcium Sparks Determines Their Ability to Induce Afterdepolarizations in Human Atrial Myocytes

•A newly developed analysis methodology uncovers a preferential increase in calcium sparks near the sarcolemma in myocytes from patients with AF, which is linked to higher ryanodine receptor (RyR2) phosphorylation at s2808 and lower calsequestrin-2 levels.•A novel mathematical human atrial myocyte model, incorporating modulation of RyR2 gating, shows that only the observed combination of changes in RyR2 phosphorylation and calsequestrin-2 levels can account for the shift in the spatio-temporal distribution of sparks in patients with AF.•Preferential calcium release near the sarcolemma is the key to a higher incidence and amplitude of afterdepolarizations in atrial myocytes from patients with AF.