Altered Atrial Cytosolic Calcium Handling Contributes to the Development of Postoperative Atrial Fibrillation.

AIMS Atrial fibrillation is a commonly occurring arrhythmia after cardiac surgery (postoperative AF, poAF) and is associated with poorer outcomes. Considering that reduced atrial contractile function is a predictor of poAF and that Ca2+ plays an important role in both excitation-contraction coupling and atrial arrhythmogenesis, this study aims to test whether alterations of intracellular Ca2+ handling contribute to impaired atrial contractility and to the arrhythmogenic substrate predisposing patients to poAF. METHODS AND RESULTS Right atrial appendages were obtained from patients in sinus rhythm undergoing open-heart surgery. Cardiomyocytes were investigated by simultaneous measurement of [Ca2+]i and action potentials (AP, patch-clamp). Patients were followed-up for 6 days to identify those with and without poAF. Speckle-tracking analysis of preoperative echocardiography revealed reduced left atrial contraction strain in poAF patients. At the time of surgery, cellular Ca2+ transients (CaT) and the sarcoplasmic reticulum (SR) Ca2+ content were smaller in the poAF group. CaT decay was slower in poAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting preserved NCX function. In agreement, western blots revealed reduced SERCA2a expression in poAF patients but unaltered phospholamban expression/phosphorylation. Computational modeling indicated that reduced SERCA activity promotes occurrence of CaT- and AP-alternans. Indeed, alternans of CaT and AP occurred more often and at lower stimulation frequencies in atrial myocytes from poAF patients. Resting membrane potential and AP duration were comparable between both groups at various pacing frequencies (0.25-8 Hz). CONCLUSIONS Biochemical, functional and modeling data implicate reduced SERCA-mediated Ca2+ reuptake into the SR as a major contributor to impaired preoperative atrial contractile function and to the pre-existing arrhythmogenic substrate in patients developing poAF. TRANSLATIONAL PERSPECTIVE Development of atrial fibrillation (AF) within the immediate postoperative period (poAF), represents one of the most frequent complications after cardiac surgery and is associated with poorer outcomes. Our results suggest that reduced Ca2+ uptake into the sarcoplasmic reticulum (SR), associated with increased cellular susceptibility to Ca2+-transient (CaT)- and action potential (AP)-alternans, contributes to the arrhythmogenic substrate predisposing patients to the development of poAF. Therefore, modulation of SERCA activity may represent a novel mechanistic target to prevent development of poAF.Furthermore, we show that the impaired SR Ca2+ uptake contributes to reduced systolic Ca2+ release and impaired atrial contractility in poAF patients. Atrial contractility may therefore represent an important factor for identification of patients at risk for poAF development.