Biomedical Engineering Reference
In-Depth Information
mRNA [42]. The activity of HCN channels is controlled by the cyclic adenosine
monophophate (cAMP)-binding site which allows alteration of activation kinetics by
ȕ
-adrenergic and muscarinic stimulation (Fig. 1b). By this mechanism, channel
activity might be increased or decreased. This plays an important role in the
autonomic regulation of heart rate [7]. However,
I
f
is not the only current contrib-
uting to the pacemaker cell membrane potential. Other inward and outward currents
are involved as well. Any increase in inward and/or decrease in outward current may
initiate or accelerate the process of phase 4 depolarization [2].
3 How Can a Biological Pacemaker Be Created?
To induce the spontaneous release of action potentials in normal cardiac cells three
main gene therapy strategies have been developed: (1) upregulation of
ȕ
2
-adrenergic
receptors (
ȕ
2
-AR) [11]; (2) knock-down of outward potassium current (
I
K1
) [26]; (3)
overexpression of inward cation current (If) [35]. In addition to these strategies, we
will discuss two cell therapy approaches.
3.1 Upregulation of
ȕ
2
-Adrenergic Receptors
The proof of concept for the creation of a biopacemaker by modulating chronotropy
was provided in 2001 by Edelberg et al [11]. They showed for the first time increased
contraction rates in murine cardiac myocytes after introduction of a plasmid with the
human
ȕ
2
-AR gene into these cells [10]. Later in vivo experiments in mouse and
swine were conducted in which injections of the
ȕ
2
-AR carrying construct into the
right atrium increased heart rates by ~40 and ~50%, respectively [10, 11]. Although
these experiments demonstrated that gene therapy is able to alter cardiac rhythm in
intact hearts of large animals, this approach was designed as a proof-of-principle and,
accordingly, lacked a design appropriate for clinical applicability. First, only transient
expression is induced by the use of these delivery platforms. Second, modulation of
ȕ
-adrenergic responsiveness will only modulate the rate at which the native
pacemaker system fires. In case of a diseased SA node, this altered responsiveness
might worsen the situation, resulting in additional arrhythmias. Patients with sick
sinus syndrome, now treated with electronic pacemakers, have a disrupted sinus node
function, resulting in disease causing bradycardias (slow heart rates) in conjunction
with atrial tachycardias (fast heart rates). This condition cannot be treated with
upregulation of
ȕ
2
-adrenergic receptors, since this may worsen the tachycardias.
3.2 Knock Down of Outward, Hyperpolarizing Current (
I
K1
)
There are two strategies by which the resting membrane potential (RMP) may be
disturbed to generate spontaneous slow diastolic depolarization. One is the knock-
down of the hyperpolarizing inward rectifier potassium channels. These channels are
abundantly expressed in the working myocardium of the atrium and ventricle but not
in the SA node and they play an important role in repolarization and stabilization of
the RMP. A knock down of these channels results in depolarization of the RMP,
which liberates endogenous pacemaker activity [27].
