Biomedical Engineering Reference
In-Depth Information
Embryological Development of Pacemaker Hierarchy and
Membrane Currents Related to the Function of the Adult
Sinus Node: Implications for Autonomic Modulation of
Biopacemakers
Tobias Opthof
Experimental and Molecular Cardiology Group, Academic Medical Center,
Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
t.opthof@med.uu.nl
Department of Medical Physiology, University Medical Center Utrecht,
Utrecht, The Netherlands
Abstract.
The sinus node is an inhomogeneous structure. In the embryonic heart all myocytes
have sinus node type pacemaker channels (
I
f
) in their sarcolemma. Shortly before birth, these
channels disappear from the ventricular myocytes. The response of the adult sinus node to
changes in the interstitium, in particular to (neuro)transmitters, results from the interplay
between the responses of all of its constituent cells. The response of the whole sinus node
cannot be simply deduced from these cellular responses, because all cells have different
responses to specific agonists. A biological pacemaker will be more homogeneous. Therefore it
can be anticipated that tuning of cycle length may be problematic. It is discussed that efforts to
create a biological pacemaker responsive to vagal stimulation, may be counterproductive,
because it may have the potential risk of 'standstill' of the biological pacemaker. A normal
sinus node remains spontaneously active at high concentrations of acetylcholine, because it has
areas that are unresponsive to acetylcholine. The same is pertinent to other substances with a
negative chronotropic effect. Such functional inhomogeneity is lacking in biological
pacemakers.
1 Introduction
Whether or not there will be a place for
biological pacemakers
in addition to or as a
substitute for technically very effective pacemakers, is discussed in another paper in
this issue [53]. The biological material for
biological pacemakers
is derived from
embryonic stem cells or from other types of cells with an undifferentiated status, or,
alternatively, stems from geneticengineering techniques. Therefore, it is relevant to
consider the pacemaker characteristics of embryonic hearts and myocytes.
2 The Embryonic Heart
2.1 The Initiation of the Heart Rhythm: Early Sinus Node Control
The embryonic heart develops by the fusion of two primordia into one single tube
[60]. This tube bends and septates, eventually leading to the four-chambered heart [8].
