Abstract 13977: Mechanisms Underlying Delayed Afterdepolarisations and Triggered Activity in Human Atrial Fibrillation
Introduction: Delayed afterdepolarizations (DADs) and triggered activity are believed to contribute to clinical atrial fibrillation (AF) but their presence and mechanisms have never been assessed in humans, which was the object of this study.
Methods: Membrane voltage/currents (patch clamp) and [Ca2+]i (Fluo-3) were recorded in right atrial myocytes from sinus rhythm (Ctl) or AF patients. Caffeine was used to release SR Ca2+ and quantify Na+-Ca2+-exchange current (INCX).
Results: Action potential (AP) duration at 90% repolarization was shorter in AF vs Ctl (378±41 vs 493±38* ms; *p<0.05). Diastolic [Ca2+]i of current clamped myocytes was comparable, whereas amplitude of AP triggered Ca2+ transients (CaTs) was decreased by 48%* in AF. Despite reduced CaTs, spontaneous SR Ca2+ releases (SCaRs) were more frequent (6/13 cells, 46%) in AF than Ctl (1/16 cells*, 6%, Fig A). Ni2+ (10 mM), a NCX blocker, prevented DADs in AF without altering underlying SCaRs, suggesting NCX involvement. In voltage clamped myocytes, susceptibility to SCaRs was enhanced in AF (8/10 cells, 80% vs 5/15 cells*; 33%) with amplitude of SCaEs being 3-fold higher and coupling intervals between the first SCaR and the last regular CaT being shorter in AF vs Ctl (Fig B). The amplitude of inward currents accompanying SCaRs was 2.5-fold greater in AF vs Ctl suggesting larger INCX for any given [Ca2+]i. During the decay of caffeine-induced CaT, a given SR Ca2+ release produced larger inward currents in AF, in accordance with 77% higher NCX expression in AF (Fig C). These currents were suppressed by Ni2+, but not by the Ca2+-activated Cl--channel blocker niflumic acid, confirming the currents as INCX (Fig D).
Conclusions: Atrial myocytes from AF patients are susceptible to DAD-induced triggered activity because of increased incidence and amplitude of SCaRs, which trigger DADs, along with larger DADs because of enhanced INCX. These DADs and triggered activity likely contribute to atrial ectopy and AF promotion.
- © 2011 by American Heart Association, Inc.