Rapid stimulation causes electrical remodeling in cultured atrial myocytes.
OBJECTIVE
Rapid stimulation causes electrical remodeling in the intact atrium, with shortening of action potential duration (APD), down-regulation of L-type Ca2+ currents (I(Ca,L)), and increased vulnerability to atrial fibrillation (AF). The essential elements required for this process are currently unknown. We tested the hypothesis that rapid stimulation of cardiomyocytes in vitro is sufficient to recapitulate the remodeling process, and that atrial cells subjected to rapid pacing in culture would display changes similar to those that occur in vivo.


METHODS
Atrial (HL-1) cells were cultured in the presence of rapid field stimulation (300 beats per min) for 24 h. Action potentials and ionic currents were recorded from stimulated cells, as well as control cells cultured in parallel, using whole-cell voltage-clamp techniques.


RESULTS
Rapid stimulation of atrial cells for 24 h significantly shortened APD. HL-1 cells displayed both I(Ca,L) blocked by nimodipine, and T-type Ca2+ currents (I(Ca,T)) sensitive to mibefradil. Rapid activation in culture caused down-regulation of I(Ca,L), while I(Ca,T) was similarly reduced. Multiple outward currents were present in response to a depolarizing voltage-clamp protocol, and rapid pacing resulted in up-regulation of the rapidly-activating delayed rectifier K+ current, I(Kr).


CONCLUSIONS
Rapid stimulation of atrial cells in culture produces electrical remodeling, recapitulating principal phenotypic features of atrial tachycardia remodeling in vivo. Our results demonstrate that an important component of this process is cell autonomous, given that in vivo conditions are not required for the development of electrical remodeling.
Yang
Zhenjiang
Z
Department of Medicine, Vanderbilt University School of Medicine, Room 559 Preston Research Building, 23rd Avenue South at Pierce Avenue, Nashville, TN 37232-6602, USA.
Shen
Wangzhen
W
Rottman
Jeffrey N
JN
Wikswo
John P
JP
Murray
Katherine T
KT
D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D004553:Electric Conductivity; D004558:Electric Stimulation; D006325:Heart Atria / Q000166:cytology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D013997:Time Factors
D015761:4-Aminopyridine; D002118:Calcium