Outward K + Current Densities and Kv1.5 Expression Are Reduced in Chronic Human Atrial Fibrillation

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Abstract
Chronic atrial fibrillation is associated with a shortening of the atrial action potential duration and atrial refractory period. To test the hypothesis that these changes are mediated by changes in the density of specific atrial K + currents, we compared the density of K + currents in left and right atrial myocytes and the density of delayed rectifier K + channel α-subunit proteins (Kv1.5 and Kv2.1) in left and right atrial appendages from patients (n=28) in normal sinus rhythm with those from patients (n=15) in chronic atrial fibrillation (AF). Contrary to our expectations, nystatin–perforated patch recordings of whole-cell K + currents revealed significant reductions in both the inactivating ( I TO ) and sustained ( I Ksus ) outward K + current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the I TO and I Ksus densities in myocytes isolated from patients in normal sinus rhythm. Quantitative Western blot analysis revealed that although there was no change in the expression of the Kv2.1 protein, the expression of Kv1.5 protein was reduced by >50% in both the left and the right atrial appendages of AF patients. The finding that Kv1.5 expression is reduced in parallel with the reduction in delayed rectifier K + current density is consistent with recent suggestions that Kv1.5 underlies the major component of the delayed rectifier K + current in human atrial myocytes, the ultrarapid delayed rectifier K + current, I Kur . The unexpected finding of reduced voltage-gated outward K + current densities in atrial myocytes from AF patients demonstrates the need to further examine the details of the electrophysiological remodeling that occurs during AF to enable more effective and safer therapeutic strategies to be developed.