Abstract 14767: Mechanism of Proarrhythmic Spontaneous Ca2+ Release Events in Patients With Paroxysmal Atrial Fibrillation
Introduction: Chronic atrial fibrillation (AF) is associated with increased spontaneous Ca2+ release events (SCaEs) causing ectopic (triggered) activity. Ectopic activity plays a greater role in paroxysmal AF (pAF), but whether Ca2+-handling changes occur in pAF is unknown and was investigated here.
Methods: Membrane currents (patch clamp), [Ca2+]i (Fluo3) and protein levels (Western blot) were measured in right atrial myocytes/tissue from sinus rhythm (Ctl, n = 24 pts) and pAF (n = 18 pts) patients in sinus rhythm. A new computational model of the human atrial myocyte was used to study SCaE mechanisms.
Results: During steady state pulsing, L-type Ca2+ current and Ca2+ transient (CaT) amplitude were unchanged in pAF, indicating a lack of AF-induced remodeling. Susceptibility to and frequency of SCaEs were enhanced in pAF (Fig A). The amplitude of SCaEs and associated transient inward NCX currents were also enhanced. Caffeine induced CaT (cCaT) amplitude and integrated NCX current were larger in pAF, indicating increased sarcoplasmic reticulum (SR) Ca2+ load (Fig B). NCX function (decay of cCaT) and NCX expression were unchanged in pAF but decay of ICa,L triggered CaT (SERCA+NCX) was faster, suggesting enhanced SR Ca2+ uptake through SERCA2a. Phosphorylation (inhibition) of SERCA2a-inhibitory phospholamban at Ser16 was enhanced (+84%, P<.01) explaining increased SERCA2a activity. RyR2 expression was increased in pAF (+154%, P<.02) but RyR2 phosphorylation was unaltered. Simulations showed that increased RyR2 levels and SERCA2a activity enhance SR Ca2+ leak in an additive manner, accounting for the experimentally observed effects on SCaEs.
Conclusions: Increased RyR2 expression, SERCA2a activity and SR Ca2+ load contribute to enhanced SCaEs in pAF, in the absence of AF-induced remodeling. These results suggest for the first time that pAF patients have discrete atrial myocyte Ca2+ handling abnormalities predisposing them to SCaE-induced triggered activity.
- © 2013 by American Heart Association, Inc.