Shedding Light on the Heart – Optogenetic Control of Cardiac Arrhythmias

Background: The control of spatiotemporal dynamics underlying life-threatening cardiac arrhythmias is extremely challenging due to the interaction of vortex-like rotating excitation waves with the heterogeneous anatomical substrate. For a lack of a better strategy, high-energy electric shocks are used to terminate cardiac fibrillation. However, these shocks may have severe side effects including tissue damage and intolerable pain. We have shown that low-energy anti-fibrillation pacing (LEAP) terminates cardiac fibrillation with 80-90% less energy compared to conventional defibrillation. We have provided experimental evidence that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and termination of arrhythmia. However, further development and optimization of LEAP towards clinical application requires improved understanding of the dynamical and molecular mechanisms underlying the onset, perpetuation, and control of cardiac arrhythmias. Here we demonstrate successful termination of cardiac arrhythmias using optogenetic photostimulation and structured illumination. We will discuss the potential of this versatile approach to investigate and optimize the dynamics and mechanisms underlying multisite pacing strategies including LEAP. Methods: Intact, Langendorff-perfused hearts of transgenic channelrhodopsin-2 mice were stained with potentiometric and calcium dyes to measure the spatiotemporal dynamics of membrane voltage and intracellular calcium. Structured illumination (λ = 470 ± 10 nm) permits spatiotemporal photostimulation. Rapid optical pacing is used to induce cardiac arrhythmias. Results: Depending on the spontaneous beating frequency of the heart, we succeeded to stimulate the right ventricle at frequencies of 10 Hz with 1:1 coupling percentage of 97.1 ± 5.3 %. Rapid pacing induced dysrhythmias showed tachycardia-like ECG patterns, sustaining for at least 12 sec before anti-arrhythmic photostimulation was applied. Using this approach, polymorphic cardiac arrhythmias are induced and terminated ex-vivo. Conclusion: Our results demonstrate control of vortex dynamics during cardiac arrhythmias using optogenetic photostimulation, suggesting that this experimental approach will enable the development, validation, and optimization of methods to control cardiac arrhythmias.