Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation

Circulation. 2014 Jan 14;129(2):145-156. doi: 10.1161/CIRCULATIONAHA.113.006641. Epub 2013 Nov 18.


Background: Electrical, structural, and Ca2+ -handling remodeling contribute to the perpetuation/progression of atrial fibrillation (AF). Recent evidence has suggested a role for spontaneous sarcoplasmic reticulum Ca2+ -release events in long-standing persistent AF, but the occurrence and mechanisms of sarcoplasmic reticulum Ca2+ -release events in paroxysmal AF (pAF) are unknown.

Method and results: Right-atrial appendages from control sinus rhythm patients or patients with pAF (last episode a median of 10-20 days preoperatively) were analyzed with simultaneous measurements of [Ca2+]i (fluo-3-acetoxymethyl ester) and membrane currents/action potentials (patch-clamp) in isolated atrial cardiomyocytes, and Western blot. Action potential duration, L-type Ca2+ current, and Na+ /Ca2+ -exchange current were unaltered in pAF, indicating the absence of AF-induced electrical remodeling. In contrast, there were increases in SR Ca2+ leak and incidence of delayed after-depolarizations in pAF. Ca2+ -transient amplitude and sarcoplasmic reticulum Ca2+ load (caffeine-induced Ca2+ -transient amplitude, integrated Na+/Ca2+ -exchange current) were larger in pAF. Ca2+ -transient decay was faster in pAF, but the decay of caffeine-induced Ca2+ transients was unaltered, suggesting increased SERCA2a function. In agreement, phosphorylation (inactivation) of the SERCA2a-inhibitor protein phospholamban was increased in pAF. Ryanodine receptor fractional phosphorylation was unaltered in pAF, whereas ryanodine receptor expression and single-channel open probability were increased. A novel computational model of the human atrial cardiomyocyte indicated that both ryanodine receptor dysregulation and enhanced SERCA2a activity promote increased sarcoplasmic reticulum Ca2+ leak and sarcoplasmic reticulum Ca2+ -release events, causing delayed after-depolarizations/triggered activity in pAF.

Conclusions: Increased diastolic sarcoplasmic reticulum Ca2+ leak and related delayed after-depolarizations/triggered activity promote cellular arrhythmogenesis in pAF patients. Biochemical, functional, and modeling studies point to a combination of increased sarcoplasmic reticulum Ca2+ load related to phospholamban hyperphosphorylation and ryanodine receptor dysregulation as underlying mechanisms.

Keywords: atrial fibrillation; calcium; computational biology; electrophysiology; sarcoplasmic reticulum.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arrhythmias, Cardiac / physiopathology
  • Atrial Appendage / pathology
  • Atrial Appendage / physiopathology
  • Atrial Fibrillation / physiopathology*
  • Calcium / physiology*
  • Calcium Signaling / physiology*
  • Calcium-Binding Proteins / physiology
  • Case-Control Studies
  • Cells, Cultured
  • Computer Simulation
  • Female
  • Heart Atria / physiopathology*
  • Humans
  • Male
  • Membrane Potentials / physiology*
  • Models, Cardiovascular
  • Myocytes, Cardiac / pathology
  • Myocytes, Cardiac / physiology
  • Patch-Clamp Techniques
  • Ryanodine Receptor Calcium Release Channel / physiology
  • Sarcoplasmic Reticulum / physiology*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / physiology
  • Sodium-Calcium Exchanger / physiology


  • Calcium-Binding Proteins
  • Ryanodine Receptor Calcium Release Channel
  • Sodium-Calcium Exchanger
  • phospholamban
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium