Transcript (Verapamil) on atrioventricular nodal reentrant tachycardia (AVNRT)

Computational modeling of the effects of L-type calcium channel blockers
(Verapamil) on atrioventricular nodal reentrant tachycardia (AVNRT)
Kevin Chung, Elliot Howard, & Chris MacDonald
June 15th, 2007
Department of Bioengineering, University of California, San Diego, CA
INTRODUCTION
Atrioventricular (AV) nodal reentrant tachycardia (AVNRT) is a
condition which causes elevated heart rates in patients of up to 250
beats per minute. The focus of this study was to simulate the
pathological events at the molecular, cellular, and tissue levels that
ultimately result in AVNRT. Additionally, the effects of L-type Ca2+
channel blockers, such as the drug Verapamil on regulating AV nodal
reentrant tachycardia was studied.
At the molecular level, drug-receptor interactions are modeled,
which allows for an assessment on the efficacy of the drug in blocking
L-type calcium channels. At the cellular level, the effect of ion channel
transport inhibition on the propagation of the action potential was
modeled, and the information on the propagation of these waves was
then used to simulate the propagation of the action potential on the
tissue/organ scale. The effect of Verapamil on AVNRT was then
evaluated at the whole tissue level.
METHODS
RESULTS
Ca2+ Channel Blocking Model
Molecular Kinetics
Cellular Dynamics
Beeler-Reuter Model
BACKGROUND
AVNRT affects about 60% of adult patients suffering from
supraventricular tachycardia. [1] AVNRT arises from the presence of
multiple conduction pathways within the AV node, one with a short
refractory period and one with a longer refractory period. The pathway with
the short refractory period conducts slowly compared to the other pathway.
The onset of an AVNRT event is caused by a premature heartbeat which
reaches the AV node before the pathway with the longer refractory period
has come back to the resting state; the result is that the impulse conducts
forward through the AV node in the slow pathway and then reenters the
faster pathway in the retrograde direction, which has reset by the time the
impulse passes through the AV node. This begins a re-entrant spiral wave
which results in elevated heart rates of up to 250 beats per minute. Calcium
channel blockers, such as Verapamil, are commonly used for prevention.
Tissue Dynamics
Normal electrical pacing in AV node with AVNRT
AV Node Electrophysiological Model
Premature beat initiates arrhythmia
Verapamil increases refractory period and restores normal activity
Effective
refractory period
Verapamil is an L-type calcium channel blocker.
It binds to
active/open calcium channels and prevents these affected channels from
allowing any flux of calcium. The inhibition of calcium flux extends the
absolute (effective) refractory periods (ERP), causing an interruption of the
recycling electrical impulse. This mechanism of interrupting the reentrant
impulse from recycling by prolonging the refractory period will be explored
in the models described in the following section.
CONCLUSIONS
Numerical Simulations
The L-type calcium channel gating parameters were obtained from the molecular
simulation at varying Verapamil concentrations, which directed the alterations made in BeelerReuter (BR) model in order to include the effects of drug-channel interactions. The resulting
BR model simulation yielded the calcium transient and action potential profiles, which varied
with Verapamil concentration. Finally, from the AP profile, the absolute (effective) refractory
period was determined and inputted into the AV node model to simulate normal, pathological,
and Verapamil-regulated pacing at an AVNRT site.
The molecular kinetics of Verapamil affected the calcium transients by reducing the maximum number of
open calcium channels as well as increasing the length of time that channels remained open. When
implemented into the Beeler-Reuter cell level model, this resulted in an extension of the length of the action
potential, thus a lengthening of the refractory period. When this refractory period was implemented into a
model for a conductive AV node, it resulted in the interruption of a simulated arrhythmia.
The implementation of the models In this study must be considered qualitative at best. They are the
simplest models that will propagate the effects of Verapamil up the scale levels. While this has the advantage
of describing the physiological effects of the drug at the tissue scale with a simple representation, the results
can be considered qualitative in nature. The Beeler-Reuter model is known to be inaccurate with respect to
calcium dynamics. Therefore, an alternative model which better describes calcium dynamics would be
necessary for accurate numerical results.
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