Cholinergic atrial fibrillation: I(K,ACh) gradients determine unequal left/right atrial frequencies and rotor dynamics.
OBJECTIVE
We tested the hypothesis that left atrial (LA) myocytes are more sensitive to acetylcholine (ACh) than right atrial (RA) myocytes, which results in a greater dose-dependent increase in LA than RA rotor frequency, increased LA-to-RA frequency gradient and increased incidence of wavelet formation during atrial fibrillation (AF).


RESULTS
AF was induced in seven Langendorff-perfused sheep hearts in the presence of ACh (0.1-4.0 microM) and studied using optical mapping and bipolar recordings. Dominant frequencies (DFs) were determined in optical and electrical signals and phase movies were used to identify rotors and quantify their dynamics. DFs in both atria increased monotonically with ACh concentration until saturation, but the LA frequency predominated at all concentrations. Rotors were also seen more often in the LA, and although their life span decreased, their frequency and number of rotations increased. Patch-clamp studies demonstrated that ACh-activated potassium current (I(K,ACh)) density was greater in LA than RA sheep myocytes. Additionally, ribonuclease protection assay demonstrated that Kir3.4 and Kir3.1 mRNAs were more abundant in LA than in RA.


CONCLUSIONS
A greater abundance of Kir3.x channels and higher I(K,ACh) density in LA than RA myocytes result in greater ACh-induced speeding-up of rotors in the LA than in the RA, which explains the ACh dose-dependent changes in overall AF frequency and wavelet formation.
Sarmast
Farzad
F
Institute for Cardiovascular Research and Department of Pharmacology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.
Kolli
Arun
A
Zaitsev
Alexey
A
Parisian
Keely
K
Dhamoon
Amit S
AS
Guha
Prabal K
PK
Warren
Mark
M
Anumonwo
Justus M B
JM
Taffet
Steven M
SM
Berenfeld
Omer
O
Jalife
José
J
D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D006325:Heart Atria; D032383:Myocytes, Cardiac / Q000187:drug effects*; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects; D012756:Sheep; D012815:Signal Processing, Computer-Assisted
D015221:Potassium Channels; D000109:Acetylcholine