Intracellular calcium cycling, early afterdepolarizations, and reentry in simulated long QT syndrome.
OBJECTIVE
The purpose of this study was to investigate interactions between early afterdepolarizations (EADs) and reentry in long QT (LQT) syndromes.


BACKGROUND
EADs, a characteristic feature of congenital and acquired LQT syndromes, are classically bradycardia dependent. Mechanisms by which they promote tachyarrhythmias such as torsades de pointes and ventricular fibrillation are not fully understood. Recent evidence suggests that EADs also may occur at rapid heart rates as a sequela of spontaneous sarcoplasmic reticulum (SR) Ca(2+) release related to intracellular Ca(2+) overload. Here, we performed computer simulations to explore the arrhythmogenic consequences of this phenomenon.


METHODS
We used a modified version of the Luo-Rudy dynamic model in one-dimensional and two-dimensional cardiac tissue with the time-dependent K(+) currents I(Kr) or I(Ks) reduced by 50% to simulate acquired and congenital LQT syndromes.


RESULTS
(1) Spontaneous SR Ca(2+) release prolonged action potential duration but did not induce overt EADs unless K(+) current density was reduced to simulate acquired and congenital LQT syndromes. (2) In simulated LQT syndromes, EADs were capable of both terminating and reinitiating one-dimensional reentry. (3) A similar phenomenon in simulated 2D tissue led to reinitiation of spiral wave reentry that otherwise would have self-terminated. (4) Reentry reinitiation occurred only when the L-type Ca(2+) current and SR Ca(i) cycling were potentiated to simulate moderate sympathetic stimulation, consistent with the known arrhythmogenic effects of sympathetic activation (and protection by beta-blockers) in LQT syndromes.


CONCLUSIONS
These computer simulations suggest that EADs related to spontaneous SR Ca(2+) release can enhance arrhythmogenesis in LQT syndromes by reinitiating reentry.
Huffaker
Ray
R
Department of Computer Science, University of California, Los Angeles, 90095, USA.
Lamp
Scott T
ST
Weiss
James N
JN
Kogan
Boris
B
D000200:Action Potentials; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D022062:Electrophysiologic Techniques, Cardiac; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D008133:Long QT Syndrome / Q000151:congenital / Q000503:physiopathology*; D008955:Models, Cardiovascular; D017180:Tachycardia, Ventricular / Q000503:physiopathology*
D020746:Calcium Channels, L-Type; D002118:Calcium