Biological Pacemakers Based on I - Biopacemaking - page 63

Biological Pacemakers Based on I f
Michael R. Rosen 1,2,3 , Peter R. Brink 3 , Ira S. Cohen 1,3 , and Richard B. Robinson 1
1 Department of Pharmacology, Center for Molecular Therapeutics,
College of Physicians and Surgeons of Columbia University,
630 West 168 Street, PH7West-321,
New York, NY 10032, USA
[e-mail]
2 Department of Pediatrics, Columbia University,
New York, NY, USA
3 Departments of Physiology and Biophysics,
Institute of Molecular Cardiology, SUNY Stony Brook,
Stony Brook, NY, USA
Abstract. Biological pacemaking as a replacement for or adjunct to electronic pacemakers has
been a subject of interest since the 1990s. In the following pages, we discuss the rational for
and progress made using a hyperpolarization activated, cyclic nucleotide gated channel isoform
to carry the I f pacemaker current in gene and cell therapy approaches. Both strategies have
resulted in effective biological pacemaker function over a period of weeks in intact animals.
Moreover, the use of adult human mesenchymal stem cells as a platform for carrying
pacemaker genes has resulted in the formation of functional gap junctions with cardiac
myocytes in situ leading to effective and persistent propagation of pacemaker current. The
approaches described are encouraging, suggesting that biological pacemakers based on this
strategy can be brought to clinical testing.
Keywords: HCN isoforms, Electronic pacemakers, Sinoatrial node, Atrioventricular block,
Gene therapy, Cell therapy.
1 Introduction
Agreeing to prepare this manuscript implies acceptance of the proposition that
biological pacemakers are a need of the community. Yet, this is less than a tested and
proven proposition. In fact, given the availability of superb electronic pacemaker
technology, it might be argued that biological pacemaking should be low on the list of
priorities for new therapeutic ventures. However, there are compelling reasons for
proceeding in this direction [3, 12, 13]. In part, the reasons are therapeutic: as good as
electronic pacemakers are, they remain palliatives; to develop a biological pacemaker
means to embark on discovering a cure. In part, the reasons are educational: because
electronic pacemakers are as good as they are, there is no need for a biological
pacemaker today, tomorrow is soon enough. The key is that sufficient time can and
must be taken to
(1) learn what is needed to get the method right, and
(2) to be certain that the therapy is as good as it is expected to be (and superior to
electronic pacemaking) before bringing it to the clinic.