Biological pacemaker

The heart is endowed with specialized excitatory and conducting cells that are responsible for the generation and conduction of rhythmic impulses and contractions throughout the heart. If these cells are damaged by disease, the implantation of an artificial cardiac pacemaker becomes necessary. However, despite the successes of artificial pacemakers several limitations and problems have emerged during the past decades such as electrode fracture or damage to insulation, infection, re-operations for battery exchange and vein thrombosis. The need for an alternative is most obvious in children including premature newborn babies where size mismatch and the fact that pacemaker leads do not grow with children are a problem.The first successful experiment with biological pacemakers was carried out by Arjang Ruhparwar's group at Hannover Medical School in Germanyc using transplanted fetal heart muscle cells, first introduced at the scientific sessions of the American Heart Association in Anaheim in 2001 and published in 2002 (1). A few months later Eduardo Marban's group from Johns Hopkins University published the first successful gene-therapeutic approach towards the generation of pacemaking activity in otherwise non-pacemaking adult cardiomyocytes using a guinea pig model (2). The investigators postulated latent pacemaker capability in normal heart muscle cells. This potential ability is suppressed by the inward-rectifier potassium current Ik1 encoded by the gene Kir2 which is not expressed in pacemaker cells. By specific inhibition of Ik1 below a certain level, spontaneous activity of cardiomyocytes was observed with resemblance to the action potential pattern of genuine pacemaker cells. Meanwhile other genes and cells have been discovered, including heart muscle cells derived from embryonic stem cells, "HCN" genes which encode the wild-type pacemaker current I(f). Michael Rosen's group demonstrated that transplantation of HCN2-transfected human mesenchymal stem cells (hMSCs) leads to expression of functional HCN2 channels in vitro and in vivo, mimicking overexpression of HCN2 genes in cardiac myocytes (3). Again, Ruhparwar's group demonstrated that by injection of the "Adenylate Cyclase" gene into the heart muscle a biological cardiac pacemaker can be created (4).

Biological safety

Until this young field of research finds access to the clinic, the durability and potential ability of transplanted cells or transfected genes to cause arrhythmia must be excluded in long-term studies with cardiac mapping experiments at various time points and with a large population of animals.

References

1. Ruhparwar A, Tebbenjohanns J, Niehaus M et al. Transplanted fetal cardiomyocytes as cardiac pacemaker. Eur J Cardiothor Surg. 2002; 21: 853-857

2. Miake J, Marban E, Nuss HB. Gene therapy: Biological pacemaker created by gene transfer. Nature 2002; 419: 132-133

3. Plotnikov AN, Sosunov EA, Qu J et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation. 2004; 109: 506-512

4. Ruhparwar A, Kallenbach K, Klein G et al. Adenylate-Cyclase VI Transforms Ventricular Cardiomyocytes Into Biological Pacemaker Cells. Scientific Sessions of the American Heart Association 2007, Orlando, Florida.