Abstract 12646: Cellular Mechanisms Underlying Post-operative Atrial Fibrillation in Patients
Background: Post-operative atrial fibrillation (poAF) after cardiac surgery is a common condition. Although usually self-limiting, poAF increases length of hospital stay and can cause debilitating strokes. A multifactorial pathophysiology involving triggered activity has been hypothesized, but the underlying cellular and molecular mechanisms are unknown and were the subject of this study.
Methods: Multicellular action potentials (APs) were recorded with sharp microelectrodes in right atrial trabeculae obtained from sinus-rhythm patients during open-heart surgery and correlated with subsequent non-poAF (Ctl) or poAF status. Membrane currents (whole-cell voltage clamp) and [Ca2+]i (Fluo-3) were also measured in right atrial cardiomyocytes isolated from Ctl and poAF patient samples. Protein expression was quantified by immunoblot.
Results: In poAF, AP duration at 90% repolarization (APD90) was slightly prolonged (Fig A), whereas AP amplitude, upstroke velocity, APD20, APD50, and resting membrane potential (RMP) were unchanged. ICa,L-triggered [Ca2+]i transient (CaT) amplitude was 37% lower in poAF despite greater Ca2+ influx via L-type Ca2+ current (integral ICa,L), pointing to sarcoplasmic reticulum (SR) dysfunction (Fig B). Na+-Ca2+ exchange (NCX) activity was similar in both groups (Fig C). SR Ca2+ content calculated by integrating NCX current (INCX) during caffeine-induced SR Ca2+ release was decreased by 50% in poAF (Fig C), likely because of smaller expression of SR Ca2+-ATPase-2a (SERCA2a) and decreased Ser16-phosphorylation (stronger SERCA2a inhibition) of the SERCA2a regulator phospholamban (PLB, Fig D). Expression of cardiac SR ryanodine receptor (RyR2) was reduced by 56% (Fig D), consistent with the reduced CaT amplitude.
Conclusions: PoAF is associated with prolonged APD and impaired SR function. These abnormalities likely result in the Ca2+ mishandling that predisposes patients to triggered activity underlying poAF.
- Atrial fibrillation
- Cellular Electrophysiology
- Excitation-contraction coupling (ECC)
- Ion currents
Author Disclosures: A.P. Khan: None. N. Voigt: None. J. Heijman: None. U. Ravens: None. S. Nattel: None. D. Dobrev: Consultant/Advisory Board; Modest; OMEICOS Therapeutics GmbH, Berlin: consultancy fees, research grant, XENTION Limited, Cambridge: consultancy fees, research grant.
- © 2016 by American Heart Association, Inc.