Biological Pacemaker: Science Fiction or a Feasible Project?

Abstract

Artificial electronic pacemakers have been successfully driving the hearts and reliably saving the lives of millions by providing cardiac pacing for a variety of cardiac bradyarrhythmias. However, there are several caveats to this technology not merely limited to procedural and hardware complications associated with its usage. These hurdles have prompted research in the development of a biological counterpart which could replace or supplement its electronic version. The concept of the biological pacemaker is very appealing, albeit most challenging. If normal working myocytes or conduction system cells could be transformed to perform the pacemaker function, there would be no need to replace pulse generator, and no issues with circuit or lead failure, size mismatch or foreign body infection would ever arise. Two general approaches have been pursued in the development of biological pacemakers, gene transfer into cardiac myocytes to create or enhance the pacemaker function, and cell transplantation into the heart that can perform the pacemaker function on their own or in conjunction with native cardiac myocytes. There are always pros and cons of these different approaches. Importantly, in order to develop such a biologic pacemaker, two elements are deemed essential: to select a gene that can direct cells of non-automatic tissue to induce spontaneous phase 4 depolarization in a reliable and automatic manner, similar to the native sinus node cells or other conduction tissue with inherent automaticity; and subsequently to develop a technique to deliver this gene into the target tissue. Gene transfer methods may use injection of adenoviral vectors, of genetically engineered stem cells or use of gene-carrying mesenchymal stem cells. Thus, biologic pacing could be accomplished either by genetic engineering, cellular therapy or a combination of both. Over the past decade, gene therapy has been explored to upregulate β2-adrenergic receptors, to downregulate inward rectifier current, and to overexpress pacemaker current as potential sources of biological pacemakers. Cell therapy approaches have explored the ‘‘forcing’’ of embryonic stem cells to evolve along cardiac pacemaker cell lines and the use of adult mesenchymal stem cells as platforms for delivery of specific gene therapies... (excerpt)