Published Online
on March 17, 2003

A more recent version of this article appeared on April 8, 2003

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Submitted on October 18, 2002
Revised on December 16, 2002
Accepted on December 17, 2002

Intracellular Chloride Accumulation and Subcellular Elemental Distribution During Atrial Fibrillation

Joseph G. Akar MD, Thomas H. Everett PhD, Ruoya Ho PhD, Joseph Craft BS, David E. Haines MD, Andrew P. Somlyo MD, and Avril V. Somlyo PhD^*

From the Department of Molecular Physiology and Biological Physics and the Cardiovascular Division, University of Virginia Health Sciences Center, Charlottesville.

^* To whom correspondence should be addressed. E-mail: avs5u{at}virginia.edu.

Background--Ion channel remodeling occurs during atrial fibrillation (AF); however, the extent of alteration in the subcellular distribution of elements (Na, K, Cl, Ca, Mg, P) is unknown. Electron probe microanalysis was used to determine the total (free+bound) in vivo subcellular concentration of these elements during AF.

Methods and Results--The left atrial appendage (LAA) was snap-frozen in situ after pacing (640 bpm) for 3 minutes (n=5 dogs), 30 minutes (n=3), or 48 hours (n=5). Dogs in sinus rhythm (n=3) served as controls. Whole-cell, cytosolic, and mitochondrial elemental concentrations were measured in cryosections. LAA effective refractory period (ERP) was measured before and after pacing. LAA ERP decreased significantly after 48 hours (116±3 to 88±10 ms, P=0.02). Whole-cell Cl increased by 9.0 mmol/L and 17 mmol/L after 3 and 30 minutes of pacing, respectively (P<0.0001), without a concomitant increase in Na. However, at 48 hours, whole-cell Na was reduced by 51% (P<0.01). Cytosolic Ca increased by 1.1 mmol/kg dry wt after 3 minutes (P<0.005), but mitochondrial Ca remained low and unchanged. Cell size measured in transverse cryosections increased after 3 minutes of pacing (75±5 to 109±11 µm², P=0.007) but returned to baseline by 30 minutes (66±5 µm²).

Conclusions--Intracellular Cl accumulation induced by rapid pacing is a novel finding and may play a role in AF pathogenesis by causing resting membrane depolarization and ERP reduction. There was no evidence of cellular or mitochondrial Ca overload despite the development of electrical remodeling and transient increase in cytoplasmic Ca.

Key words: fibrillation • electron probe microanalysis • chloride • calcium • pacing

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