Intracellular calcium dynamics and acetylcholine-induced triggered activity in the pulmonary veins of dogs with pacing-induced heart failure.
BACKGROUND
Heart failure increases autonomic nerve activities and changes intracellular calcium (Ca(i)) dynamics.


OBJECTIVE
The purpose of this study was to investigate the hypothesis that abnormal Ca(i) dynamics are responsible for triggered activity in the pulmonary veins (PVs) during acetylcholine infusion in a canine model of heart failure.


METHODS
Simultaneous optical mapping of Ca(i) and membrane potential was performed in isolated Langendorff-perfused PV-left atrial (LA) preparations from nine dogs with ventricular pacing-induced heart failure. Mapping was performed at baseline, during acetylcholine (1 micromol/L) infusion (N = 9), and during thapsigargin and ryanodine infusion (N = 6).


RESULTS
Acetylcholine abbreviated the action potential. In four tissues, long pauses were followed by elevated diastolic Ca(i), late phase 3 early afterdepolarizations, and atrial fibrillation (AF). The incidence of PV focal discharges during AF was increased by acetylcholine from 2.4 +/- 0.6 beats/s (N = 4) to 6.5 +/- 2.2 beats/s (N = 8; P = .003). PV focal discharge and PV-LA microreentry coexisted in 6 of 9 preparations. The spatial distribution of dominant frequency demonstrated a focal source pattern, with the highest dominant frequency areas colocalized with PV focal discharge sites in 35 (95%) of 37 cholinergic AF episodes (N = 8). Thapsigargin and ryanodine infusion eliminated focal discharges in 6 of 6 preparations and suppressed the inducibility of AF in 4 of 6 preparations. PVs with focal discharge have higher densities of parasympathetic nerves than do PVs without focal discharges (P = .01), and periodic acid-Schiff (PAS)-positive cells were present at the focal discharge sites.


CONCLUSIONS
Ca(i) dynamics are important in promoting triggered activity during acetylcholine infusion in PVs from pacing-induced heart failure. PV focal discharge sites have PAS-positive cells and high densities of parasympathetic nerves.
Chou
Chung-Chuan
CC
Department of Medicine, Second Section of Cardiology, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taoyuan, Taiwan.
Nguyen
Bich Lien
BL
Tan
Alex Y
AY
Chang
Po-Cheng
PC
Lee
Hui-Ling
HL
Lin
Fun-Chung
FC
Yeh
San-Jou
SJ
Fishbein
Michael C
MC
Lin
Shien-Fong
SF
Wu
Delon
D
Wen
Ming-Shien
MS
Chen
Peng-Sheng
PS
D000109:Acetylcholine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects*; D023421:Models, Animal; D011667:Pulmonary Veins / Q000187:drug effects* / Q000503:physiopathology*; D012433:Ryanodine / Q000494:pharmacology; D013318:Stroke Volume; D019284:Thapsigargin / Q000494:pharmacology; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D016277:Ventricular Function, Left
D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D012433:Ryanodine; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium