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

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 alpha-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 (ITO) and sustained (IKsus) outward K+ current densities in left and right atrial myocytes isolated from patients in chronic AF, relative to the ITO and IKsus 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, IKur. 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.

Dynamics of human atrial cell models: Restitution, memory, and intracellular calcium dynamics in single cells

“…In some cases, more significant rate adaptation can be observed at the shortest CLs (Kim et al, 2002;Dobrev and Ravens, 2003). Similar alterations to those given by Courtemanche et al (1999) have been observed in other experiments as well (Dobrev and Ravens, 2003), including substantial reductions in I Ca,L (Bosch et al, 1999;Van Wagoner et al, 1999;Skasa et al, 2001;Workman et al, 2001) and I to (Van Wagoner et al, 1997;Bosch et al, 1999;Brandt et al, 2000;Grammer et al, 2000;Workman et al, 2001). The reduction in I Kur proposed by Courtemanche et al (1999) has been found in some studies (Van Wagoner et al, 1997;Brandt et al, 2000) but not in others (Grammer et al, 2000;Workman et al, 2001).…”

Novel KCNA5 loss-of-function mutations responsible for atrial fibrillation

“…31 Specifically functioning in the atria, I kur, is a crucial determinant for phase I repolarization during action potentials. 32,33 The strong evidence that KCNA5 expresses much more extensively in human atria than in ventricles, and that I Kur has not been recorded in the human ventricle, 32,34 implicates Kv1.5 as a potential selective target for the medical management of AF. 35 Importantly, it should be noted that traditional therapeutics for AF are based on inhibition of I Kur , 31 and would not be applicable in patients with loss of function of Kv1.5.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…One may tentatively speculate that circulating anti-VGKC autoantibodies, which were present in 14% of our cohort and are known to impair K V 1 channel function, may contribute to chagasic oesophageal and heart disease by impairing K V 1.5 channel function. In support of this hypothesis is the fact that down-regulation of expression of this channel has been found to be associated with arrhythmia (Van Wagoner et al 1997;Lai et al 1999;Brundel et al 2001) which is a common feature of chagasic heart disease (Elizari 2002). Due to their function of regulating cellular excitability, impairment of K V 1.5 oesophageal smooth muscle would be expected to interfere with oesophageal contractility, and this may be relevant to the loss of normal peristalsis and failure of smooth muscle relaxation characteristic of oesophageal achalasia.…”