Proarrhythmic and antiarrhythmic actions of ion channel blockers on
arrhythmias in the heart: model study.
Chay, Teresa Ree.
Department of Biological Sciences, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260, E-Mail Address:
TRC1@VM2.CIS.PITT.EDU, Telephone: 412-624-4656 FAX Number: 412-624
-4759
APStracts 2:0496H, 1995.
In this paper, we explain why (i) some Classe I and IV antiarrhythmic
drugs could exert proarrhythmic action, (ii) some Class III drugs are
effective in controlling reentrant arrhythmias, and (iii) cycle
length oscillation is involved in the termination or initiation of
reentry. To explain these, we employ the following three means:
bifurcation analysis, simulation, and model construction.
Antiarrhythmic drugs are modeled by varying the maximal conductances
of sodium, calcium, time-dependent delayed rectifying potassium, and
time-independent inward rectifying potassium channels in the Beeler
-Reuter model, where the model cells are arranged in a ring. The
bifurcation analysis predicts that there is a critical ring size
(CRS) at which the infinite ring behavior suddenly breaks down. The
channel blockers can affect CRS in different manners -- both the
sodium and calcium blockers shorten the CRS, while the delayed
rectifying K+ channel blockers as well as the inward K+ channel
blockers lengthen the CRS. This differential explains why some
antiarrhythmic drugs are proarrhythmic (i.e., those drugs which
shorten the CRS) while others are antiarrhythmic (those which
lengthen the CRS). Simulation is then used to investigate how the
drugs affect reentrant rhythms in the neighborhood of the critical
ring size. We find that in this region, cycle length (CL), conduction
velocity (CV), and the action potential duration (APD) become
oscillatory. As the ring size shrinks, the pattern of the oscillation
becomes more and more complex. When the ring size shrinks to a
certain size, reentry can no longer be sustained, and it terminates
after a few oscillatory cycles. To explain the basic mechanism
involved in the cycle length oscillation, we then construct a minimal
model which contains a low-threshold fast inward current and a high
-threshold slow inward current. With this model, we show that the two
inward currents with vastly different activation and inactivation
kinetics are the cause of the CL oscillations. Our results thus give
theoretical explanations for the experimental finding of Frame's
group in canine atrial tricuspid ring in vitro that Class IC drugs
can bring about stable reentry from non-sustained transient reentry,
whereas Class III drugs transform stable reentry to complex
oscillations in cycle length. Our results also support the result of
Frame's group in that in "adjustable" tricuspid rings the CL
oscillation becomes more and more complex and its period becomes
shorter and shorter as an excitable gap is shortened.
Received 8 September 1994; accepted in final form 30 October
1995.
APS Manuscript Number H812-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 November 95