Optical ventricular cardioversion by local optogenetic targeting and LED implantation in a cardiomyopathic rat model

Abstract

Aims Ventricular tachyarrhythmias (VTs) are common in the pathologically remodelled heart. These arrhythmias can be lethal, necessitating acute treatment like electrical cardioversion to restore normal rhythm. Recently, it has been proposed that cardioversion may also be realized via optically controlled generation of bioelectricity by the arrhythmic heart itself through optogenetics and therefore without the need of traumatizing high-voltage shocks. However, crucial mechanistic and translational aspects of this strategy have remained largely unaddressed. Therefore, we investigated optogenetic termination of VTs 1) in the pathologically remodelled heart using a 2) implantable multi-LED device for 3) in vivo closed-chest, local illumination. Methods and Results In order to mimic a clinically relevant sequence of events, transverse aortic constriction (TAC) was applied to adult male Wistar rats before optogenetic modification. This modification took place three weeks later by intravenous delivery of adeno-associated virus vectors encoding red-activatable channelrhodopsin (ReaChR) or Citrine for control experiments. At 8 to 10 weeks after TAC, VTs were induced ex vivo and in vivo, followed by programmed local illumination of the ventricular apex by a custom-made implanted multi-LED device. This resulted in effective and repetitive VT termination in the remodelled adult rat heart after optogenetic modification, leading to sustained restoration of sinus rhythm in the intact animal. Mechanistically, studies on the single cell and tissue level revealed collectively that, despite the cardiac remodelling, there were no significant differences in bioelectricity generation and subsequent transmembrane voltage responses between diseased and control animals, thereby providing insight into the observed robustness of optogenetic VT termination. Conclusion Our results show that implant-based optical cardioversion of VTs is feasible in the pathologically remodelled heart in vivo after local optogenetic targeting because of preserved optical control over bioelectricity generation. These findings add novel mechanistic and translational insight into optical ventricular cardioversion.

Wireless, fully implantable cardiac stimulation and recording with on-device computation for closed-loop pacing and defibrillation

“…While treating VT does not require multiple stimulation points, having the capacity to actuate from any required point on the heart is essential to stopping re-entry, because cardiac failure is a dynamic process with magnitude and locality of infarction changing from case to case clinically ( 21 ). In current technology, the computation of heart rate and the delivery of stimulation by these devices are achieved using multiple pieces of equipment or require researchers to interpret the data to determine and deliver the appropriate stimulus ( 22 , 23 ). The spatiotemporal accuracy of these devices is often limited by the size of the interface that delivers stimulus to the heart, which, in turn, is limited by the lack of flexibility of the biointerface.…”

Ultra‐low power deep sustained optogenetic excitation of human ventricular cardiomyocytes with red‐shifted opsins: a computational study

“…Prolonged illumination of ventricular areas leads to disturbance in the regular sinus rhythm with the generation of spontaneous ventricular extrabeats or complete block of electrical activity, used to terminate ventricular tachycardia in mouse heart (Bruegmann et al., 2010; Nyns et al., 2014). Earlier reports have shown that sustained illumination with ChR2(H134R) can enhance the vulnerability to spontaneous ventricular extrabeats but cannot suppress the activity due to lower sensitivity and poor penetration of blue light (Bruegmann et al., 2010).…”

“…To date, various excitatory opsins, including ChR2, ChR2(H134R), CatCh and ReaChR, and inhibitory opsins, including NpHR and ArchT, have been used in cardiac optogenetics (Bingen et al., 2014; Bruegmann et al., 2010; Nussinovitch et al., 2014; Nyns et al., 2014; Park et al., 2014; Williams & Entcheva, 2015; Williams et al., 2013). ChR2(H134R), which generates large photocurrent, is one of the most used optogenetic actuators (Karathanos, Boyle et al., 2016; Williams & Entcheva, 2015; Williams et al., 2013).…”

Optical control of cardiac rhythm byin vivophotoactivation of an ERG channel peptide inhibitor

“…By allowing a spatio-temporal control of ion channel activity by light, both optogenetics and photopharmacology appear as promising approaches to equally solve the selectivity and temporal issues in treating arrhythmias. Impressive and convincing reports have illustrated the blooming power of optogenetics for the treatment of arrhythmias [8][9][10][11][12] .…”

“…By allowing a spatio-temporal control of ion channel activity by light, both optogenetics and photopharmacology appear as promising approaches to equally solve the selectivity and temporal issues in treating arrhythmias. Impressive and convincing reports have illustrated the blooming power of optogenetics for the treatment of arrhythmias 8–12 . Nevertheless, while this approach is powerful, it suffers from one major drawback which is the need to genetically modify the heart in order to express photosensitive ion channels, which is irreconcilable so far with clinical applications.…”