Biopacemaking: Clinically Attractive, Scientifically a Challenge - Biopacemaking - page 1

Biopacemaking: Clinically Attractive, Scientifically a
Challenge
Jacques M.T. de Bakker 1,2,3 and Antonio Zaza 4
1 Department of Experimental Cardiology, Heart Failure Research Center,
Academic Medical Center, Meibergdreef 9, 1105AZ
Amsterdam, The Netherlands
[e-mail]
2 The Heart Lung Center, University Medical Center,
Utrecht, The Netherlands
3 The Interuniversity Cardiology Institute of the Netherlands,
Utrecht, The Netherlands
4 Dipartimento di Biotecnologie e Bioscienze,
Università di Milano Bicocca, Milano, Italy
[e-mail]
This special issue gives an overview of the current state-of-the-art of creating a bio-
engineered pacemaker. The subject has potential clinical interest. Indeed, electronic
pacemakers currently available have several limitations, among which inadequate rate
adaptation to physiological needs, problems related to the stimulating and sensing
leads and infection of the pacemaker pocket, which might be overcome by a bio-
pacemaker. Generation of a bio-pacemaker has also scientific interest, because it may
answer the longstanding question of whether the complex structure of the sinus node
is indeed a prerequisite for reliable pacemaking, or simpler structures might work as
well.
Knowledge of normal pacemaker physiology provides the ground for the
development of bio-pacemakers. Various ionic currents contribute to sinoatrial (SA)
node pacemaking; moreover, the sinus node comprises morphologically and
functionally distinct cell types, with different intrinsic rates and response to
autonomic agonists. As outlined by Opthof [11], these differences are relevant to the
width and stability of autonomic modulation of sinus rate. The question may be asked
of whether such complexity, probably the result of evolutionary adaptations, would
also be required to create a bio-pacemaker. For reasons of practicality, the strategies
proposed thus far have adopted a conservative ''one channel'' approach; however, as
genetic manipulation techniques improve, reports of bio-pacemakers based on
combinations of mechanisms start appearing in the literature [3].
Current approaches to bio-pacemaker generation have developed along two main
lines. The first aims to induce pacemaker activity in normally quiescent (''working'')
myocardium. The second involves myocardial implant of exogenous cells, engineered
to sustain pacemaker activity (''cell-based'' approach) once electrically connected to
the host myocardium.
Pacemaking can be induced in working myocardial cells by modification of their
pattern of expression of membrane currents. The required genetic modification is
usually carried out by gene transfer to the site of interest. This can be achieved
theoretically by direct transfection of a plasmid incorporating the gene, or by infecting