Biomedical Engineering Reference
In-Depth Information
Creation of a Biological Pacemaker by Gene- or
Cell-Based Approaches
Eduardo Marbán and Hee Cheol Cho
Institute of Molecular Cardiobiology, Division of Cardiology,
Johns Hopkins University School of Medicine, 858 Ross Bldg,
720 Rutland Ave, Baltimore, MD 21205, USA
marban@jhmi.edu
Abstract.
Cardiac rhythm-associated disorders are caused by malfunctions of impulse
generation and conduction. Present therapies for the impulse generation span a wide array of
approaches but remain largely palliative. The progress in the understanding of the biology of
the diseases with related biological tools beckons for new approaches to provide better
alternatives to the present routine. Here, we review the current state of the art in gene and cell-
based approaches to correct cardiac rhythm disturbances. These include genetic suppression of
an ionic current, stem cell therapies, adult somatic cell-fusion approach, novel synthetic
pacemaker channel, and creating a self-contained pacemaker activity in non-excitable cells. We
then conclude by discussing advantages and disadvantages of the new possibilities.
1 Introduction
The heart requires a steady rhythm and rate in order to fulfill its physiological role as
the pump for the circulation. An excessively rapid heart rate (tachycardia) allows
insufficient time for the mechanical events of ventricular emptying and filling.
Cardiac output drops, the lungs become congested, and, in the extreme, the circulation
collapses. An equally morbid chain of events ensues if the heart beats too slowly
(bradycardia). Serious disturbances of cardiac rhythm, known as arrhythmias, afflict
more than three million Americans and account for >479,000 deaths annually [71]. In
2001, $2.7 billion ($6,634 per discharge) was paid to Medicare beneficiaries for
cardiac arrhythmia-related diseases [71].
Current therapy has serious limitations: antiarrhythmic drugs can sometimes be
effective, but their utility is limited by their propensity to create new arrhythmias
while suppressing others [17, 19, 66, 74]. Ablation of targeted tissue can readily cure
simple wiring errors, but is less effective in treating more complex and common
arrhythmias, such as atrial fibrillation or ventricular tachycardia [20, 59]. Implantable
devices can serve as surrogate pacemakers to sustain heart rate, or as defibrillators to
treat excessively rapid rhythms. Such devices are expensive, and implantation
involves a number of acute and chronic risks (pulmonary collapse, bacterial infection,
lead or generator failure [6]). In short, arrhythmias are a serious threat of public health
proportions, and current treatment is inadequate. Given these limitations, we have
begun to develop gene or cell therapy as an alternative to conventional treatment.
