Biomedical Engineering Reference
In-Depth Information
6 Biological Pacemakers
6.1 State of the Art
Thus far moderate success has been achieved with biological pacemakers either along
the lines of a genetic or a cellular approach (Rosen et al., this issue [53]). Successful
introduction of human ß2-adrenoceptor constructs has been reported in the murine
heart [19] and in the porcine heart [20]. As far as the in vivo parts of these studies are
involved, I wish to underscore that demonstrating that heart rate can be increased after
the introduction of components of the adrenergic system is not the same as
demonstrating that the heart is able to respond to catecholamines. Secondly, the
response to injection of these constructs persisted for 2-3 days in the mice [19]) and
for less than 2 days in the pigs [20]. Obviously, these responses are transient. In the
case of cellular approaches it is important to know what happens to the implanted or
injected biomaterials in case of loss of function. The biological function is simply
lost, when the implant disappears (is 'eaten'), but when it is still sitting in the
myocardium and has lost pacemaker potency, a proarrhythmic risk may ensue.
In the dog substantial success has been achieved thus far (Rosen et al., this issue
[53]) both by a gene therapy approach [47, 50] and by a cellular approach based on
adult human mesenchymal stem cells [48]. In the former approach injection of
adenoviral contructs with mouse HCN2 constructs into the left canine atrium [47]
yielded spontaneous rhythms during vagal stimulation (in order to silence the native
sinus node). This occurred 3-4 days after injection. Left atrial myocytes isolated from
these hearts showed prominent
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current. In a comparable study HCN2 adenovirus
contructs were injected in the posterior limb of the left bundle branch of canine hearts
[50]. Again, during vagal stimulation ventricular escape rhythms were demonstrated
at least 7 days after the injection. There was a brief period of arrhythmias after the
injection, but this appears to be related to the injection not to the construct, because
the arrhythmias were also prominent in the control group and ceased after days.
Although these results are encouraging, it is emphasized that positive chronotropy in
response to catecholamines was not demonstrated. Along the cellular approach human
mesenchymal stem cells transfected with the murine HCN2 gene were injected in the
epicardium of the left canine ventricle [48]. Again, during sinus arrest pacemaker
activity was observed. In the in vitro part of this study [48], acetylcholine did not
affect
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f
current, although it could mitigate the response to isoproterenol. Although it
had been reported that human mesenchymal stem cells can form functional gap
junctions with freshly isolated canine ventricular myocytes [58], this was also
demonstrated in vivo at the actual site of injection of the engineered mesenchymal
stem cells [48].
An experimental proof for the putative scheme as shown in Fig. 7 of Rosen et al.
[53] (this issue), in which a genetically engineered stem cell is able to deliver
pacemaker current to a myocyte is provided in another paper in this issue [13]. Thus,
the spontaneous beating rate of neonatal rat cardiomyocytes can be tuned by
coculturing them with HEK-293 cells which stably express murine inward rectifier
channels (Fig. 3 in [13], this issue). Although the beating rate of the neonatal rat
cardiomyocytes rapidly decreases with a small proportion (only 5%) of engineered
HEK-293 cells, spontaneous beating did not cease even when the large majority of
