Periodic Reporting for period 1 - TransRhythm (Translational optoelectronic control of cardiac rhythm in atrial fibrillation)
Período documentado: 2023-03-01 hasta 2025-08-31
Cardiac arrhythmias, or heart rhythm disorders, remain a major challenge in medicine in terms of understanding and treatment. Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting 2–3% of the global population, with prevalence increasing with age. AF affects individuals across genders, ethnicities, and geographic origins. Critically, it raises the risk of stroke and heart failure, contributing significantly to morbidity and mortality. As such, it poses a substantial economic burden—over €20 billion are spent annually on AF in the ten largest European countries. Its prevalence is expected to rise sharply due to global aging and improved treatment of chronic diseases. Given the growing personal, societal, and economic impact, extensive research has been conducted over recent decades. Yet, current AF treatments remain limited. Antiarrhythmic drugs are often ineffective and can cause serious side effects, including life-threatening ventricular arrhythmias. Catheter ablation, though helpful for some, carries risks and shows modest long-term success. Consequently, many patients experience recurring, symptomatic, drug-resistant AF, even after multiple ablations. For these patients, high-voltage shocks (electrical cardioversion) under general anesthesia remain the only proven acute intervention, though recurrences are common. Because AF duration inversely affects treatment success, early detection and termination are essential. Trials have shown the benefit of early cardioversion, and implantable atrial cardioverter-defibrillators were developed to enable automated, ambulatory rhythm control. Though effective, they were abandoned due to the pain from repeated shocks. Thus, no therapy currently addresses the urgent need for pain-free ambulatory AF treatment. This project aims to develop acute, shock-free rhythm control by integrating genetic and tissue engineering, computer modeling, and micro-optoelectronics.
Initially, the ERC research team was faced with the usual trial-and-error in setting up certain experiments, but no fundamental issues were encountered that could potentially jeopardize the overall project. The main aim during the first period was to determine and understand the requirements for optoelectronic rhythm control from a clinical translational perspective using a combination of in vitro and in silico modeling to set the stage for future in vivo studies. By performing the experiments as outlined in the proposal, we were able to show how human conditionally immortalized atrial myocytes could be cultured in a way that scalable models of atrial fibrillation (AF) could be produced. Subsequently we show how these cells can be optogenetically modified in order to create models in which shock-free termination of AF can be investigated in a systematic and reproducible manner. By increasing the size of these model to full human atrium-size we revealed new insight into how size affects arrhythmia and termination, which will be instrumental in designing and performing future studies in animals. Moreover, during this first period we developed computational models of these in vitro AF models. This allowed us to perform simulations to better guide the design and execution of corresponding in vitro studies, but also to create additional mechanistic insights beyond the realm of possibilities of wet-lab experiments. Simultaneously computer models were defined and applied to investigate how heart size may affect the realization and effectiveness of optoelectronic rhythm control. In order to realize such optoelectronic rhythm control for shock-free cardioversion in real-life, we had to design and develop high-density multi-LED arrays. Once produced and tested, these arrays were incorporated into an optical mapping system so that electrical wave propagation in optogenetically modified human conditionally immortalized atrial myocytes could not only be monitoring but also modulated via closed-loop activation of the LED array. At the same time we explored how to rapidly and accurately detection AF using electrodes and a customized algorithm. The results of these studies have been published in the journal Advanced Sensor Research, a peer-reviewed open-access journal relevant to the field. In addition, we published a review paper describing the key element of the ERC project concerning optoelectronic rhythm control, such as transgene expression and light delivery. Because of the more translational/clinical focus of the project we published this paper in the Journal of Internal Medicine, which is open-access peer-reviewed journal with a larger clinical readership. Based on prior work of my team, the ongoing ERC project and the fact that Willem Einthoven received his Nobel prize 100 years ago for the invention of how to monitor cardiac bioelectricity, my team was invited to write a perspective paper about the use of optogenetics to control bioelectricity for anti-arrhythmic purposes. Overall, I am pleased we the progress we made during the first period by performing the experiments as detailed in my proposal. Based on what we have learn during this period we will now transition towards in vivo studies to further explore the translational potential of optoelectronic rhythm control and thereby accomplish the remaining objectives to reach the overall aim of the project.
As stated earlier, electrical cardioversion is the most effective method to achieve acute termination of atrial fibrillation (AF) to restore normal rhythm. However, because sedation is required due to the painful electric shocks, this intervention can only be performed in the hospital, thereby delaying treatment and restricting patients’ mobility. The new translational insight from the results so far indicates that optoelectronic rhythm control may enable shock-free conversion of AF, creating the perspective of out-of-hospital acute cardioversion. The use of human conditionally immortalized atrial myocytes to create scalable AF models was crucial in gaining these insights, especially as we could study the impact of size on cardioversion efficiency. Typically, human in vitro AF models use cardiomyocytes derived from induced pluripotent stem cells, which are not only immature but also difficult to expand for large-size studies. We therefore go beyond the state of the art in human in vitro AF modeling by creating full atrium-sized human AF models. This enabled generation of previously unobtainable data on how cardiac tissue size affects AF induction, perpetuation, and termination. As mentioned, we also developed computational models of these in vitro systems, which did not previously exist. These models will be used alongside their in vitro counterparts to advance the field more effectively and are not limited by experimental constraints when exploring mechanisms such as AF termination. In addition, we progressed in arrhythmia monitoring by developing a wearable AF detection system enabling acute detection based on real-time electrogram analysis. Collectively, these results set the stage for future experiments expected to surpass the current state of the art.