Abstract
Complex spatiotemporal non-linearity as observed during cardiac arrhythmia strongly correlates with vortex-like excitation wavelengths and tissue characteristics. Therefore, the control of arrhythmic patterns requires fundamental understanding of dependencies between onset and perpetuation of arrhythmia and substrate instabilities. Available treatments, such as drug application or high-energy electrical shocks, are discussed for potential side effects resulting in prognosis worsening due to the lack of specificity and spatiotemporal precision. In contrast, cardiac optogenetics relies on light sensitive ion channels stimulated to trigger excitation of cardiomyocytes solely making use of the inner cell mechanisms. This enables low-energy, non-damaging optical control of cardiac excitation with high resolution. Recently, the capability of optogenetic cardioversion was shown in Channelrhodopsin-2 (ChR2) transgenic mice. But these studies used mainly structured and local illumination for cardiac stimulation. In addition, since optogenetic and electrical stimulus work on different principles to control the electrical activity of cardiac tissue, a better understanding of the phenomena behind optogenetic cardioversion is still needed. The present study aims to investigate global illumination with regard to parameter characterization and its potential for cardioversion. Our results show that by tuning the light intensity without exceeding 1.10 mW mm-2, a single pulse in the range of 10–1,000 ms is sufficient to reliably reset the heart into sinus rhythm. The combination of our panoramic low-intensity photostimulation with optical mapping techniques visualized wave collision resulting in annihilation as well as propagation perturbations as mechanisms leading to optogenetic cardioversion, which seem to base on other processes than electrical defibrillation. This study contributes to the understanding of the roles played by epicardial illumination, pulse duration and light intensity in optogenetic cardioversion, which are the main variables influencing cardiac optogenetic control, highlighting the advantages and insights of global stimulation. Therefore, the presented results can be modules in the design of novel illumination technologies with specific energy requirements on the way toward tissue-protective defibrillation techniques.
Highlights
Spatiotemporal dynamics in biological systems, the control of complex excitation patterns, are a fundamental nonlinear problem with extensive potential in medical engineering and therapeutic application
The graph shows that the energy necessary to pace at different intensity and duration combinations remained constant at an average of Egpacing = 98 ± 5 μJ
Lilienkamp et al introduced in silico results similar to our experimental findings, which can give hints that the overall size of an excitable medium has a direct effect on the lifetime of chaotic spatiotemporal dynamics, like the ones seen during arrhythmia (Lilienkamp et al, 2017)
Summary
Spatiotemporal dynamics in biological systems, the control of complex excitation patterns, are a fundamental nonlinear problem with extensive potential in medical engineering and therapeutic application. These, for the patient mostly painful, shocks terminate the chaotic spreading activity almost certainly, but are suspected to worsen the existing tissue conditions mostly due to their potential electroporating effect on cardiomyocytes They serve as trigger for new arrhythmia with increasing probability over time. In order to stimulate at multiple pacing sites either multiple implanted electrodes or specific electrical fields are necessary, which raises obvious translational hurdles All these valuable methods are still based on electrical shock application, which in turn can never be fully acquitted of potential worsening side effects. The evaluation of new cardiac treatments with side effect diminishing properties but fairly high success rates has to be brought into focus At this point patterned light control of optogenetically modified cardiac tissue gives the opportunity to stimulate well-defined tissue regions without critical Faraday reactions. Much effort was put into the characterization of locally applied light intensity and energy (Bruegmann et al, 2010; Zaglia et al, 2015; Diaz-Maue et al, 2018) the underlying dependencies of light intensity, pulse duration and successful cardioversion remains somehow elusive
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