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

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

Author information

1
Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
2
Division of Experimental Cardiology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
3
Cardiovascular Research Institute, Department of Molecular Physiology and Biophysics and Department of Medicine, Baylor College of Medicine, Houston, USA.
4
Department of Cardiac Surgery, Heidelberg University, Heidelberg, Germany.
5
Department of Medicine, Montreal Heart Institute and Université de Montréal and Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada.
#
Contributed equally

Abstract

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

PMID:
24249718
PMCID:
PMC4342412
DOI:
10.1161/CIRCULATIONAHA.113.006641
[Indexed for MEDLINE]
Free PMC Article

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