Recently, optogenetics has provided interesting insights into cardiovascular research, leading to cardiac pacing, re-synchronization therapy and cardioversion. Although these interventions have clearly demonstrated the feasibility of cardiac pathway manipulation, optical stimulation has not been directly driven by the cardiac electrical dynamics, limiting the full potential of such a new technology. Here, we developed an all-optical platform complemented by integrated, newly developed software to monitor and control whole mouse heart electrical activity. The system combines an ultrafast wide-field mesoscope with a digital micro-mirror device (Texas Instruments Lightcrafter), capable of drawing arbitrarily-chosen patterns, thus allowing optogenetic activation. Cardiac functionality can be manipulated either in free-run mode with sub-millisecond temporal resolution or in a closed-loop fashion: an ad hoc hardware and software platform allows real-time intervention capable of reacting to threatening anomalous electrical conditions within 2 ms. The methodology has been applied to restore atrioventricular block, by triggering the optical stimulation of the ventricle according to optically mapped atrial activity. Furthermore, real-time intra-ventricular manipulation of the propagating electrical wave-front has been demonstrated, opening the prospect for real-time resynchronization therapy and cardiac defibrillation. The development of this innovative optical methodology provides the first proof-of-concept that a real-time, self-sustaining, optical-based stimulation can efficiently control cardiac rhythm in normal and abnormal conditions, promising a new approach to the investigation of (patho)physiology of the heart.
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