Left-to-right atrial inward rectifier potassium current gradients in patients with paroxysmal versus chronic atrial fibrillation.
BACKGROUND
Recent evidence suggests that atrial fibrillation (AF) is maintained by high-frequency reentrant sources with a left-to-right-dominant frequency gradient, particularly in patients with paroxysmal AF (pAF). Unequal left-to-right distribution of inward rectifier K(+) currents has been suggested to underlie this dominant frequency gradient, but this hypothesis has never been tested in humans.


RESULTS
Currents were measured with whole-cell voltage-clamp in cardiomyocytes from right atrial (RA) and left (LA) atrial appendages of patients in sinus rhythm (SR) and patients with AF undergoing cardiac surgery. Western blot was used to quantify protein expression of I(K1) (Kir2.1 and Kir2.3) and I(K,ACh) (Kir3.1 and Kir3.4) subunits. Basal current was ≈2-fold larger in chronic AF (cAF) versus SR patients, without RA-LA differences. In pAF, basal current was ≈2-fold larger in LA versus RA, indicating a left-to-right atrial gradient. In both atria, Kir2.1 expression was ≈2-fold greater in cAF but comparable in pAF versus SR. Kir2.3 levels were unchanged in cAF and RA-pAF but showed a 51% decrease in LA-pAF. In SR, carbachol-activated (2 μmol/L) I(K,ACh) was 70% larger in RA versus LA. This right-to-left atrial gradient was decreased in pAF and cAF caused by reduced I(K,ACh) in RA only. Similarly, in SR, Kir3.1 and Kir3.4 proteins were greater in RA versus LA and decreased in RA of pAF and cAF. Kir3.1 and Kir3.4 expression was unchanged in LA of pAF and cAF.


CONCLUSIONS
Our results support the hypothesis that a left-to-right gradient in inward rectifier background current contributes to high-frequency sources in LA that maintain pAF. These findings have potentially important implications for development of atrial-selective therapeutic approaches.
Voigt
Niels
N
Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
Trausch
Anne
A
Knaut
Michael
M
Matschke
Klaus
K
Varró
András
A
Van Wagoner
David R
DR
Nattel
Stanley
S
Ravens
Ursula
U
Dobrev
Dobromir
D
D000368:Aged; D001281:Atrial Fibrillation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western; D002463:Cell Membrane Permeability / Q000502:physiology; D002908:Chronic Disease; D005260:Female; D005500:Follow-Up Studies; D006325:Heart Atria / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques / Q000379:methods; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D013614:Tachycardia, Paroxysmal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
C099489:KCNJ4 protein, human; C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying