Altered atrial cytosolic calcium handling contributes to the development of postoperative atrial fibrillation

Abstract

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.

Evaluating Serum Heat Shock Protein Levels as Novel Biomarkers for Atrial Fibrillation

“…Additionally, undiagnosed, silent and/or very short-lasting AF episodes might have been overlooked in control patients and during follow-up of ECV or PVI patients by using ECG measurements. As previous studies revealed exhaustion of HSP levels in atrial tissue of persistent AF patients [ 18 ], in future research projects it is recommended to investigate human HSP levels in both serum and atrial tissue and their relationship to parameters related to AF-induced electrical and/or structural remodeling and also structural remodeling-induced (post-operative) AF [ 37 ]. Thus, a lack of correlation between HSPs and AF stage in the current study does not negate a role for HSPs as potential biomarker in AF.…”

Cellular and mitochondrial mechanisms of atrial fibrillation

“…This is presumably due to the close coupling of [Ca 2+ ] i with Ca 2+ -dependent ion channels and transporters such as L-type Ca 2+ channel and NCX1. [Ca 2+ ] i -driven alternans is enhanced by factors increasing SR Ca 2+ release and by factors reducing Ca 2+ sequestration from the cytosol, such as increased SR Ca 2+ leak and reduced SERCA expression or activity (for example due to reduced ATP levels) [ 34 , 37 ]. Since electrical alternans has been linked to metabolic oscillations, it is plausible that mitochondrial dysfunction-related alternans may also contribute to arrhythmogenesis in AF [ 98 ].…”

Modulation of SK Channels: Insight Into Therapeutics of Atrial Fibrillation

“…Spontaneous Na 1 -Ca 21 exchange current is increased and acts as a trigger of AF in patients with severe LV dysfunction, which subsequently promotes the maintenance of AF [64]. Expression of SERCA2a, an ATP-dependent calcium pump, is reduced in postoperative AF patients, suggesting that Ca 21handling abnormalities contribute to development of postoperative AF [65].…”