The Long Way to Enlightenment

Electronic cardiac pacemakers are the primary therapy for sinus node dysfunction and high-degree AV block. Although uncommon, infections, lead failures, and vascular complications do result in mortality and morbidity for some patients.1 Battery life limitations require device changes, which contribute to infection risk. In addition, providing adequate rate adaptation to physical activity as well as pacing the developing heart of pediatric patients is technically challenging. Because of these and other shortcomings, the use of biological pacemakers is of great interest. Several approaches have been studied, including direct gene transfer in native cardiomyocytes to express the 2-adrenoreceptor,2 a dominant-negative form of the Kv2.1 potassium channel,3 or the classical pacemaker channels of the HCN family.4 Despite some promising experimental results, there are still technical limitations, and biological pacemakers are not yet suited to replace implantable pacemakers in the clinic (see Rosen et al5 and Boink and Rosen6 for an extensive review and discussion). In addition to difficulty in achieving pacing at high heart rates, major challenges relate to the fact that gene transfer must be safe; reliable; and ideally, life lasting. An alternative to gene transfer in native cardiomyocytes is the transplantation of cells with pacemaking activity. Such cells are not necessarily excitable themselves because they only need to generate a pacemaking current that is transferred to neighboring cardiomyocytes through gap junctions to evoke an action potential. This concept is called a tandem cell unit (TCU) strategy and has been analyzed previously by in vitro studies and transplantation of mesenchymal stem cells expressing the pacemaker channel HCN2.7