Optogenetic cardiac pacemakers: science or fiction?

Optogenetics is a novel technology that allows cell-specific controlling of membrane potential with light by expressing light-sensitive proteins in cells of interest [1]. This method is extensively used for optical stimulation of specific cell types in well-defined brain regions in vivo. Optogenetic cardiac pacing in vivo has also been demonstrated in adult mouse hearts [2] and embryonic zebrafish hearts [3] using transgenic animals expressing the blue light-sensitive cation channel Channelrhodopsin 2 (ChR2). In this issue of Trends in Cardiovascular Medicine, Boyle et al. [4] review the existing literature on optogenetic control of heart muscle in vitro, in silico, and in vivo and discuss the potential clinical use to treat cardiac arrhythmia. Because optogenetic stimulation has distinct advantages over electrical stimulation such as low energy consumption, cell-specific stimulation, uniform deor hyperpolarization, and high spatial precision, optogenetic cardiac pacing or defibrillation can be envisioned in the future. It is important to note that before raising hope for future therapies, the potential, effectiveness, advantages, and disadvantages of optogenetic pacing or defibrillation have to be investigated in vivo in native non-transgenic hearts. Therefore, the most important issue to be solved is how to make native hearts light sensitive. The authors discuss two fundamentally different approaches [4], either transplantation of cells expressing optogenetic proteins (cell delivery) or viral gene transfer of optogenetic proteins into native cardiomyocytes (gene delivery). In comparison to transgenic animals, both approaches will result in a lower percentage and patterned distribution of ChR2-expressing cells within the myocardium. Because all cardiomyocytes are well coupled through gap junctions, the three-dimensional ventricle, which represents a large