Periodic Reporting for period 1 - TACAIRE (Tools for Ablation of Cardiac Arrhythmias by IRreversible Electroporation)
Reporting period: 2021-06-14 to 2023-06-13
Cardiac arrhythmias, a group of conditions in which the heartbeat is abnormal, are among the most recurrent cardiovascular diseases with an important impact in the quality of life of patients (atrial fibrillation is predicted to affect 17.9 million patients in Europe by 2060). When drug therapy fails in the correct management of these diseases, ablation, the selective damage of small regions of the cardiac tissue, is used instead. Current ablation techniques use thermal energy to destroy the target areas with success rates up to 70 %. However, there are complications, such as severe oesophageal or phrenic nerve injury or vascular stenosis, that current thermal treatments cannot overcome.
The TACAIRE proposal is focused on the development of new technological tools and methods for the non-thermal ablation of cardiac arrhythmias. In particular, the explored technique is Irreversible Electroporation (IRE), commonly known as Pulsed Field Ablation (PFA) which consists in the application of short and high intensity electric field pulses to kill the cells of the target tissue region.
The goal of TACAIRE is to study the mechanisms of the technique and propose technological improvements to overcome some identified limitations of PFA that could prevent this technique from being definitively established in the routine clinical practice for cardiac ablation. In particular, some of these limitations are related to the induction of strong muscle contractions during PFA application with monopolar catheters. Another challenge deals with increasing lesion depth for ablation of ventricular tissue in a safe manner.
The project involved a host team of biomedical/electronic engineers and a secondment partner of cardiologists. This structure was perfectly aligned with the multidisciplinary nature of the proposal and provided all the necessary resources to correctly develop the action and the career prospects of the fellow.
This project demonstrated the effects of different energy application parameters, specifically the frequency of the waveform applied on the induction of muscle contractions and efficacy of the treatment. It also developed a numerical modelling framework to compare the classical ablation technology (radiofrequency) with the new technology studied. During the project a proof of concept of a novel catheter and therapeutic strategy was validated what could open the door for future medical devices and therapies.
The TACAIRE proposal is focused on the development of new technological tools and methods for the non-thermal ablation of cardiac arrhythmias. In particular, the explored technique is Irreversible Electroporation (IRE), commonly known as Pulsed Field Ablation (PFA) which consists in the application of short and high intensity electric field pulses to kill the cells of the target tissue region.
The goal of TACAIRE is to study the mechanisms of the technique and propose technological improvements to overcome some identified limitations of PFA that could prevent this technique from being definitively established in the routine clinical practice for cardiac ablation. In particular, some of these limitations are related to the induction of strong muscle contractions during PFA application with monopolar catheters. Another challenge deals with increasing lesion depth for ablation of ventricular tissue in a safe manner.
The project involved a host team of biomedical/electronic engineers and a secondment partner of cardiologists. This structure was perfectly aligned with the multidisciplinary nature of the proposal and provided all the necessary resources to correctly develop the action and the career prospects of the fellow.
This project demonstrated the effects of different energy application parameters, specifically the frequency of the waveform applied on the induction of muscle contractions and efficacy of the treatment. It also developed a numerical modelling framework to compare the classical ablation technology (radiofrequency) with the new technology studied. During the project a proof of concept of a novel catheter and therapeutic strategy was validated what could open the door for future medical devices and therapies.
This project included a completely multidisciplinary approach to give response to the different scientific questions presented in the proposal of the project.
During the project, purely engineering tasks were developed. An equipment for performing experiments was an electric field generator with a high flexibility for delivering arbitrary and high-frequency electric field waveforms was developed. As the equipment needed to be robust and safe for performing the subsequent experiments in proper safety conditions, the generator was developed with an external company expert in power electronics design. Additional to the electric field delivery system, an impedance sensing system was developed to be used in synchronization with the generator. Also, proper electrical isolation was provided to the system. A high speed temperature measuring system based on optical fibers was also integrated in the experimental setup to enable temperature recordings during electric field delivery.
Another important aspect covered during this project, was the development of numerical models for finite element simulations. These models enable to calculate the electric field distribution in the target tissue for any catheter topology and predict the shape and size of the lesion area created by Pulsed Field Ablation (PFA) therapies. Additionally, the models enabled to estimate the temperature gradients during treatments. The models were also used to compare PFA to the standard radiofrequency ablation technique. The numerical comparison of both techniques was published in a journal article (https://www.nature.com/articles/s41598-022-20212-9(opens in new window)) and presented in international conferences. Also, in the framework of a collaboration with cardiologists from the Mayo Clinic in United States, numerical models based on MRI reconstructions of real animal cases were used to estimate the electric field lethal thresholds necessary to create damage to cardiac tissue. This was presented in a high-impact international medical conference (https://doi.org/10.1093/eurheartj/ehac544.475(opens in new window)).
Regarding the biological experimentation performed along the project, different levels of complexity were implemented. First, in vitro experiments with cells in culture were used to establish the basic dependencies of different electric field waveform parameters (amplitude, frequency, number of applications) on efficacy. Subsequently, a complete study was performed in small animals (rats) with the goal of performing a first in vivo validation and optimization of the therapy previous to transferring the experiments to bigger animals. These studies demonstrated the strong dependency of PFA efficacy with the frequency of the applied waveform. The main results were published in a journal article in a relevant electrophysiology journal (https://doi.org/10.1161/CIRCEP.122.010992(opens in new window)). At the final stage of the project, preclinical studies were performed in swine. The first study consisted in the validation of the PFA efficacy on the ventricular epicardium and a detailed characterization of the changes in the local electrograms produced as a consequence of the therapy both in reversible and irreversible electroporation areas. The results of this study could have important implications in the routine practice of the electrophysiologists using this ablation modality. The main results were published in a relevant electrophysiology journal (https://doi.org/10.1161/CIRCEP.123.011914(opens in new window)). The second study consisted in a proof of concept of a novel idea which would use a new catheter design capable of injecting substances to cardiac tissue and applying PFA at the same time. The results of this proof of concept are being prepared for publication.
During the project, purely engineering tasks were developed. An equipment for performing experiments was an electric field generator with a high flexibility for delivering arbitrary and high-frequency electric field waveforms was developed. As the equipment needed to be robust and safe for performing the subsequent experiments in proper safety conditions, the generator was developed with an external company expert in power electronics design. Additional to the electric field delivery system, an impedance sensing system was developed to be used in synchronization with the generator. Also, proper electrical isolation was provided to the system. A high speed temperature measuring system based on optical fibers was also integrated in the experimental setup to enable temperature recordings during electric field delivery.
Another important aspect covered during this project, was the development of numerical models for finite element simulations. These models enable to calculate the electric field distribution in the target tissue for any catheter topology and predict the shape and size of the lesion area created by Pulsed Field Ablation (PFA) therapies. Additionally, the models enabled to estimate the temperature gradients during treatments. The models were also used to compare PFA to the standard radiofrequency ablation technique. The numerical comparison of both techniques was published in a journal article (https://www.nature.com/articles/s41598-022-20212-9(opens in new window)) and presented in international conferences. Also, in the framework of a collaboration with cardiologists from the Mayo Clinic in United States, numerical models based on MRI reconstructions of real animal cases were used to estimate the electric field lethal thresholds necessary to create damage to cardiac tissue. This was presented in a high-impact international medical conference (https://doi.org/10.1093/eurheartj/ehac544.475(opens in new window)).
Regarding the biological experimentation performed along the project, different levels of complexity were implemented. First, in vitro experiments with cells in culture were used to establish the basic dependencies of different electric field waveform parameters (amplitude, frequency, number of applications) on efficacy. Subsequently, a complete study was performed in small animals (rats) with the goal of performing a first in vivo validation and optimization of the therapy previous to transferring the experiments to bigger animals. These studies demonstrated the strong dependency of PFA efficacy with the frequency of the applied waveform. The main results were published in a journal article in a relevant electrophysiology journal (https://doi.org/10.1161/CIRCEP.122.010992(opens in new window)). At the final stage of the project, preclinical studies were performed in swine. The first study consisted in the validation of the PFA efficacy on the ventricular epicardium and a detailed characterization of the changes in the local electrograms produced as a consequence of the therapy both in reversible and irreversible electroporation areas. The results of this study could have important implications in the routine practice of the electrophysiologists using this ablation modality. The main results were published in a relevant electrophysiology journal (https://doi.org/10.1161/CIRCEP.123.011914(opens in new window)). The second study consisted in a proof of concept of a novel idea which would use a new catheter design capable of injecting substances to cardiac tissue and applying PFA at the same time. The results of this proof of concept are being prepared for publication.
This project will deeply study the effects of waveform in PFA efficacy and collateral effects. Specifically, the project will try to find the limits of using high-frequency waveforms to avoid muscle contractions while preserving ablation efficacy. The multidisciplinary approach proposed will provide data from numerical computational models, in vitro experiments on cells and small and big animals. It will also develop technological tools to apply this novel ablation technique in different conditions. During the project, other current scientific gaps will be covered, specifically dealing with the changes of myocardial tissue during PFA (electrical activity or dielectric properties).
The project will provide basic scientific knowledge to the scientific community, practical knowledge applicable by electrophysiologists and also will develop technologies that could attract the interest of private companies.
The project will provide basic scientific knowledge to the scientific community, practical knowledge applicable by electrophysiologists and also will develop technologies that could attract the interest of private companies.