Pacemaker cells account for fewer than 10,000 of the approximately 10 billion cells in the adult mammalian heart, yet the initiation of the heartbeat depends critically upon this small subpopulation of cardiac cells situated in the sinoatrial node (SAN). When the native pacemaker fails, the cardiac rhythm is disrupted, resulting in bradyarrhythmia, a disturbance characterized by an abnormally slow heartbeat. Current treatments for pacemaker failure are costly electronic devices.

After a decade of searching for a biological alternative to electronic SAN therapy, researchers at The Cedars-Sinai Heart Institute (Los Angeles, CA) believe they have found success. The team, led by Eduardo Marbán and Hee Cheol Cho, has successfully converted rodent cardiomyocytes into pacemaker cells both in vitro and in vivo using transduction (Nat. Biotechnol. published online 16 December 2012; doi:10.1038/nbt.2465).

The researchers expressed Tbx18, a gene required for embryonic development of the SAN area, in rodent heart muscle cells. As early as two days after Tbx18 transduction, these reprogrammed cardiomyocytes or 'induced-SAN' (iSAN) cells exhibited all of the key features of native pacemaker cells, including spontaneous automaticity and SAN cell morphology. Furthermore, iSAN cells retained their phenotype even after the expression of Tbx18 had faded, indicating a permanent conversion to a pacemaker phenotype.

Previous efforts to create heart muscle cells that could beat on their own have been partially successful; the modified cells acquired spontaneous automaticity but retained their muscle cell morphology. Other approaches using embryonic stem cells to derive pacemaker cells have shown promise but are burdened by challenges such as heterogeneity of the resultant heart cells and the persistent risk of cancer cell formation.

Marbán and Cho's work demonstrates that a single transcription factor suffices for the direct conversion to iSAN cells. “Although we and others have created primitive biological pacemakers before, this study is the first to show that a single gene can direct the conversion of heart muscle cells to genuine pacemaker cells. The new cells generated electrical impulses spontaneously and were indistinguishable from native pacemaker cells,” Cho notes in a press release.

The results of this study are extremely promising for the development of specific and highly effective alternatives to electronic pacing devices. The authors now plan to conduct longer-term experiments using large-animal models to assess safety and efficacy with the hope of one day being able to use this technology to treat human patients with bradycardia.