Circulation, Vol 89, 1839-1850, Copyright © 1994 by American Heart Association
JM Di Diego and C Antzelevitch
BACKGROUND: Elevated intracellular calcium activity is thought to play an
important role in arrhythmia induction, particularly during ischemia and
reperfusion. Delayed after-depolarization-induced triggered activity and
intracellular communication problems are thought to be responsible. METHODS
AND RESULTS: Increased extracellular calcium levels and rapid pacing are
interventions known to elevate intracellular calcium activity. The present
study, conducted using standard microelectrode techniques, was designed to
compare the effects of increased [Ca2+]o (1.8 to 5.4 mmol/L) in isolated
canine ventricular epicardial and endocardial tissues and to test the
hypothesis that elevated intracellular calcium activity contributes to
arrhythmogenesis in working ventricular myocardial tissues by promoting
electrical heterogeneity. High [Ca2+]o caused a slight abbreviation of
action potential duration (APD90) in endocardium but more dramatic rate-
dependent and dynamic changes in epicardium. Under steady-state conditions,
epicardium displayed a marked abbreviation of APD90 at fast rates but no
significant changes at slow rates. A significant augmentation of phase 1
was evident at the faster stimulation rates. Vmax and conduction velocity
were only slightly reduced. The marked abbreviation of the epicardial
response at the factor rates was due to loss of the action potential dome.
Recovery of the dome after deceleration was not synchronous throughout the
preparation. As a consequence, a sudden slowing of rate caused marked
dispersion of repolarization among neighboring epicardial sites, giving
rise to ectopic activity via a phase 2 reentry mechanism. These effects of
high [Ca2+]o were mimicked by exposure of the preparations to low [Na+]o.
Electrical homogeneity was restored and arrhythmias were abolished after
addition of the Ito blocker 4-aminopyridine 1 mmol/L. 4- Aminopyridine also
eliminated the differential response of epicardium and endocardium to high
[Ca2+]o. CONCLUSIONS: Our data demonstrate the induction of marked
electrical heterogeneity and reentrant activity by high [Ca2+]o and rapid
stimulation, conditions known to elevate [Ca2+]i. The results suggest that
increased intracellular calcium activity, as occurs during ischemia and
reperfusion, may contribute to the development of electrical inhomogeneity
in the ventricle and thus to the genesis of ventricular arrhythmias through
a mechanism other than triggered activity, namely, phase 2 reentry. Our
data point to an increase in net outward current as the underlying
mechanism for the calcium-induced changes. Our results also suggest that
the presence of a prominent transient outward current (Ito) in epicardium
sensitizes that tissue to the effects of high calcium. Finally, the results
suggest that Ito blockers can reverse high calcium-induced electrical
heterogeneity and thus can exert antiarrhythmic actions.
ARTICLES
High [Ca2+]o-induced electrical heterogeneity and extrasystolic activity in isolated canine ventricular epicardium. Phase 2 reentry
Masonic Medical Research Laboratory, Utica, NY 13504.
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