29-02: Optogenetic termination of anatomical reentry in rat myocardial slices

Purpose: Anatomical reentry is an important mechanism of ventricular tachycardia (VT) in patients with structural heart disease. Current approaches for studying and treating VT rely on drugs, devices, and ablation. As a result, electrophysiological properties can only be controlled to some extent in terms of magnitude, time and space, thereby hampering progress. However, optogenetics, based on light-gated ion channel expression and activation, can modulate such properties with unmatched precision in all three terms. Therefore, we studied whether and how optogenetic interventions can influence anatomical reentry. Methods: Neonatal rat hearts and a vibratome were used to produce 150-μm-thick transverse ventricular tissue slices, which were genetically modified with lentiviral vectors encoding a depolarizing channelrhodopsin (CatCh), or yellow fluorescent protein (eYFP) as control. CatCh activation in these slices was precisely controlled by using a 470-nm LED-based patterned illuminator, while the effects were studied by optical voltage mapping. Summary of results: CatCh and control groups behaved similarly upon electrical stimulation (n = 30 and n = 7). However, only in CatCh-group, 10-ms light pulses evoked propagating waves. Stable reentry was induced in both groups by electrical stimulation but only in CatCh-expressing slices it could be terminated by global exposure to 500-ms light (p < 0.01). Furthermore, local transmural exposure of the slice over a width of 600 and 300 µm, resulted in 100% and 54% arrhythmia termination, respectively (p < 0.01). Mechanistically, arrhythmias were terminated by CatCh activation-induced temporary conduction block leading to reentrant wave extinction allowing normal activation to regain. Conclusions: This is the first study to show that stable anatomical reentry in ventricular tissue slices can be terminated effectively by creation of a temporary and fully reversible conduction block through local activation of light-gated ion channels. These results can provide novel practical and mechanistic insights into the optogenetic control of arrhythmic activity in ventricular tissue.