Use of light to defibrillate cardioarrhythmic events in humans could offer a gentler alternative to shocking the heart back to normal rhythm through a generalized electrical discharge. With the introduction of Channelrhodopsin (ChR) as a tool to control cardiac activity, optogenetics-based approaches to treating arrhythmias are being more actively investigated as a potential alternative to electrical stimulation. While these approaches would still employ an implanted defibrillator (ICD) to dispense therapy, the ICD would be used to deliver less energy, in a more focused way. Researchers at the European Laboratory for Non-Linear Spectroscopy (LENS) and National Institute of Optics (INO-CNR) in collaboration with University of Florence, University of Connecticut Health Center and University of Glasgow are developing a method to defibrillate arrhythmias using light in combination with the photosensitive channeldropsin2 (ChR2). The team has demonstrated that defibrillation energies received by the body can be reduced 25-fold by applying light therapy in discrete stimulation patterns. “Reducing the amount of energy required to administer therapy could be a huge improvement for patients’ quality of life,” said researcher Leonardo Sacconi. The research team developed an ultrafast wide-field macroscope, able to operate at 2,000 frames per second, to simultaneously map and control the electrical activity of whole mouse hearts at sub-millisecond temporal resolution. An ultra-fast laser scanning system was used to design arbitrarily-chosen stimulation patterns across the whole heart. The platform was then used to characterize arrhythmias and to efficiently restore the cardiac sinus rhythm by intervening with customized ChR2 stimulation patterns, designed by the team based on the features of the arrhythmias that they observed. Optical manipulation of the cardiac conduction pathway. Three patterns of optogenetic stimulation: single-point; single-barrier; and triple-barrier, designed as reported by the blue traits on the fluorescence image of the heart. Courtesy of Leonardo Sacconi. The researchers compared the activation features of a point source stimulation induced with an electrode with stimulation induced with the ChR2 photo-activation. Electrical and optical point stimulation evoked similar isochronal maps, suggesting that the ChR2 activation could represent an effective alternative to electrical stimulation. The team further found that use of red-shifted voltage-sensitive dye with an excitation wavelength of 640 nm prevented unwanted ChR2 activation. To activate ChR2, the team used blue light excited at 473 nm — far from the 640 nm range used for the voltage-sensitive dye. “Use of the voltage-sensitive dye enabled us to observe arrhythmic events and manipulate the electrical activity in a fully optical manner,” said researcher Claudia Crocini. “For clinical application, voltage-sensitive dyes would not represent a real opportunity. However, the sensing could be performed by an array of microelectrode placed on the heart.” The team’s novel approach has enabled them to cardiovert a ventricular tachycardia with high efficiency, using a total energy output of 2mJ. Typical output from an ICD delivering therapy is between 25-40J. “We were able to optimize patterns capable of successfully interrupting arrhythmias using 25-fold less irradiation energy than a whole heart intervention,” said Crocini. The team believes that the combination of light microscopy with functional reporters and optogenetics has the potential to ultimately control heart activity and monitor functional responses in a non-invasive manner. The findings of the research could be used in current electrical therapies for technologically-improved defibrillators. The work also provides novel insights that could be exploited for the realization of a light-driven cardioversion (that would nevertheless require the implantation of a light source close to the heart). “We strongly believe that the development of this methodology will provide fundamental insights into cardiac disease, boosting new therapeutic strategies and, more generally, will represent a whole new approach for the investigation of the physiology of the heart, opening promising perspectives for the clinical development of minimally invasive optical pacemaker-defibrillators,” said Sacconi. “Light provides the versatility required to develop and test customized stimulation patterns capable of successfully interrupting arrhythmias at much lower energy,” he added. “We were able to exploit recent advancements in optogenetics and imaging techniques to develop a novel optical platform that is capable of characterizing arrhythmias, and that can efficiently restore the cardiac sinus rhythm by delivering an intervention based on the pattern of the arrhythmia.” The team’s next steps will be focused on translating the same experimental rationale in whole live mammals. For this purpose, the team could implement a fully-integrated array of blue OLEDs and co-localized microelectrodes cast in a 3D conformable substrate, shaped to wrap the heart pericardium, to allow a multipoint detection and control of electrical activity in vivo. Once the methodology is set up, the multipurpose implantable device could be tested in healthy animals to trigger arrhythmogenic settings and in animal models of cardiac diseases to stop arrhythmias and improve ventricular synchrony. The research was published in Scientific Reports (doi: 10.1038/srep35628).