Biomedical Engineering Reference
In-Depth Information
Fig. 2.
Suppression of Kir2.1 channels liberates pacemaker activity.
a
Stable action potentials
initiated by external depolarizing stimuli in control ventricular myocytes.
b
Spontaneous action
potentials with a SA nodal phenotype in Kir2.1AAA transduced myocytes.
c
Control
electrocardiogram of normal sinus rhythm.
d
Electrocardiogram of ventricular rhythms 72 h
after transduction with Kir2.1AAA. P waves (
arrow A
) and wide QRS complexes (
arrow V
) are
uncoupled, demonstrating that ventricular activation does not proceed along the normal
conduction pathway (from reference [26], with permission).
The first in vivo proof-of-concept of this approach was provided in 2002 by Miake et
al. [26], who built a dominant negative construct by replacing three amino acid residues
in the pore of Kir2.1. Four Kir2.1 subunits normally assemble to form tetrameric inward
rectifier potassium channels. Adenoviral (Ad) vectors were used to target the left
ventricular cavity of guinea pigs. After 3-4 days, in vivo Kir2.1AAA transduced
myocytes were isolated and a reduction of about 80% of
I
K1
was found. Successfully
transduced cells increased their pacing rate in response to
ȕ
-adrenergic stimulation, and
in 40% of the animals, premature ventricular beats occurred. Figure 2 b illustrates the
development of spontaneous activity in a ventricular myocyte after reducing
I
K1
. The
action potential of an untreated myocyte is depicted in panel a. Panel d shows the
ensuing rhythm in the intact animal after treatment, while panel c is the ECG of a
control animal. One major concern regarding this strategy is that reduction in
repolarizing currents may result in excess prolongation of repolarization which
constitutes a proarrhythmic effect, potentially causing torsades de pointes ventricular
tachyarrhythmias that could degenerate to ventricular fibrillation [46]. Loss-of-
function mutations in Kir2.1 are clinically manifested in Andersen-Tawil syndrome
(also known as Long-QT Syndrome type 7). This syndrome consists of mild QT
interval prolongation, prominent ECG U waves, frequent ventricular ectopy and
polymorphic ventricular tachycardia, in conjunction with extracardiac features such as
