Optogenetic investigation of cardiac arrhythmia mechanisms

Abstract

Cardiac arrhythmias are one

of the major causes of morbidity and mortality in the world. The clinical

management of cardiac arrhythmias relies on several anti-arrhythmic therapies,

e.g. drugs, ablation, and device implantation that, unfortunately, are often unspecific, irreversible and/or traumatizing, respectively. Recently, to overcome these side effects, gene therapy has been introduced as an alternative option to treat cardiac arrhythmias by specifically targeting the biological defect. However, gene therapy alone is lacking the possibility to gain precise spatiotemporal and quantitative control over a certain target. Interestingly, more recently, such precise control could be achieved with an innovative strategy, called optogenetics. Here, gene therapy is combined with optics allowing expression of light-activatable proteins that are specifically activate and deactivate by simply turning light on and off, respectively. This now opens new and unique possibilities for cardiac arrhythmias research based on optical modulation of excitability with superb spatiotemporal resolution. Therefore, in the studies presented in this thesis, the unique features of optogenetics were employed for investigating the underlying mechanism of arrhythmia initiation, maintenance, and termination in order to identify novel biological anti-arrhythmic strategies.