Biomedical Engineering Reference
In-Depth Information
hypothesis [57] on the functioning of the normal pacemaker has been proposed, by
integrating, via activation of I
CaL
(as the common event), the ''external loop'' of the
''membrane clock'' (
I
k
,
I
st
,
I
f
,
I
CaT
,
I
CaL
) with the ''internal loop'' of the intracellular
calcium clock. Briefly, by this theory [57], backed up by solid experimental data [4,
52, 56, 88], the SAN cells calcium clock is both entrained by an action potential
(during early diastolic depolarization) and ''free running'' (during the later part of the
preaction potential phase, when LCRs of significant frequency and strength initiate
the SAN ''duty cycle'' [57] by SCaRIE of the NCX, and subsequent initiation of an
action potential by the
I
CaT
) [88]. A more detailed discussion of these mechanisms is
presented in other sections of this journal, but it is clear that a
unified theory
of
pacemaking is still in the making. The role of the calcium clock has been downplayed
or ignored in most of the theoretical pacemaker models, and it is expected that its
inclusion, along with its characteristic modulation by PKA-dependent phosphorylation,
in such models will broaden our theoretical armamentarium in the quest for the
creation of a biological pacemaker. To date, though, there have been no attempts, to
our knowledge, of genetic manipulation of submembrane calcium mechanisms for the
purpose of obtaining a biopacemaker per se.
4 Autonomic Modulation of Pacemaker Activity
As noted above, the main pacemaker current carriers,
I
f
and
I
CaL
are modulated by the
sympathetic and parasympathetic nervous systems, but this neurohumoral influence
on the rate of discharge of the pacemaker cells is more concerted. In principle, the
discharge rate may be increased by lowering the maximum diastolic potential (MDP),
increasing the slope of phase 4, or increasing the threshold potential; the opposite
changes may decelerate discharge rate. Sympathetic and parasympathetic activation
alters SAN pacemaker rates in two ways: (a) they shift the primary site of the
pacemaker within the SAN, and (b) they modify the kinetics of the currents
that control pacemaker activity. Sympathetic stimulation, mediated primarily by
ȕ
-adrenergic-receptor (
ȕ
-AR) activation, has a positive chronotropic effect through a
shift of the site of the primary pacemaker toward the cephalad region of the SAN and
by increasing
I
CaT
,
I
f
,
I
st
and I
ks
[7, 16, 79]. Acetylcholine and vagal stimulation have
the opposite effect on the activation of
I
f
and
I
CaL
, and the negative chronotropic effect
is enhanced by
I
KAch
activation and caudal displacement of the primary pacemaker site
within the SAN. Thus, attempts at genetically modifying the influence of the
autonomic nervous system on preexistent structures of the cardiac conduction system
implicitly rely on normal innate pacemaking structures. Enhancing the autonomic
influence of a diseased pacemaker could conceivably have deleterious effects such as
arrhythmias. It is thus likely that this approach would have a rather peripheral role in
the synthesis of a biopacemaker.
5 Gene Transfer to the Heart
Recent advances in cardiac gene therapy have shown great promise for the eventual
treatment of cardiac disease [3, 20, 21]. Moreover, cardiac gene transfer has been
