WAYLESS is Wide-Area Yielding Low-Energy Surface Stimulation applied to the heart to safely and painlessly terminate ventricular fibrillation.
Ventricular fibrillation (VF) is the most deadly cardiac arrhythmia with a grim survival rate of <5%. VF is the result of unorganized electrical disturbances in the heart's electrical conduction system that leads to sudden cardiac death. VF claims more lives in Europe than common cancers, strokes, and AIDS combined. The ideal therapy for VF is one that quickly terminates its sources and restores the heartbeat back to normal sinus rhythm with minimal side effects. The most effective therapy to date is a far-field electric shock delivered to the patient by an implantable cardioverter defibrillator. Unfortunately, a far-field electric shock only terminates VF when it is strong enough (many Joules) to fully excite all ventricular tissue regions harboring the VF sources. Unsurprisingly, these strong DC electrical shocks delivered to the heart have dangerous side effects that include irreversible tissue damage, severe pain, and increased mortality. The main objective of this research proposal was to rapidly and cost-effectively develop a safer and less painful therapy for terminating lethal ventricular arrhythmias with WAYLESS: Wide-Area Yielding Low-Energy Surface Stimulation.
The basic strategy of WAYLESS is to minimize the energy requirements for terminating VF by using low-energy direct-current stimulation administered via surface electrodes strategically placed over wide areas of the heart. Since applying this strategy directly to humans is unethical due to unknown complications, as well as time consuming and expensive if done solely with animal experimentation, we utilized an innovative multidisciplinary approach to develop WAYLESS. Before costly animal experimentation, an optimal electrode configuration and stimulation protocol for WAYLESS was rapidly and cost-effectively designed in silico using a virtual human heart that simulates realistic lethal cardiac arrhythmia. These results were then tested and validated in situ using a robust optical imaging approach for studying cardiac arrhythmia in large mammalian hearts. To promote the translation of WAYLESS to future clinical trials, its protocol and electrode prototype were designed with compatibility to human patients and modern day implantable cardiac devices. This was the first ever project in France for developing a novel cardiac arrhythmia electrotherapy from in silico to in situ.
Computer simulations with the human ventricles model determined that a single low-energy pulse <0.1 J delivered by parallel line electrodes (widest area with least energy compared to other shapes) on the heart's surfaces optimally terminated VF. Optical imaging of porcine hearts verified that WAYLESS with line electrodes lowered the energy requirements for defibrillation from >20 J to <10 J, but not below the 0.1 J human pain threshold. This was due to surface fat and vasculature unexpectedly hindering WAYLESS efficacy. WAYLESS with alternating current is being explored to improve efficacy.
Project WAYLESS was successful at developing a new approach for defibrillating the ventricles of large mammals with lower energy than overly aggressive strong electric shocks. However, a one-size-fits-all approach for terminating VF below the human pain threshold was not achieved. Additional research is needed to better understand the role of surface fat and vasculature on WAYLESS efficacy, as well as the timing of WAYLESS with respect to VF mechanisms after initiation in order to excite as much tissue as possible. Accordingly, WAYLESS with alternating current timed immediately after VF initiation is being explored to improve efficacy, as well as modifying its electrode configuration and stimulus strength to account for vasculature and fat on the surfaces of large mammalian hearts.
This project produced 8 peer-reviewed journal publications, was presented at 5 international congresses, and generated a new low-energy defibrillation approach for cardiac arrhythmia. It has also shed light onto the elusive mechanisms of arrhythmogenesis in the human ventricles, and led to additional projects that apply WAYLESS to atrial fibrillation, elucidate atrial fibrillation mechanisms, and pioneer the use of conductive stretchable fabrics for cardiac applications in the beating heart.
The beating heart sustains life by pumping oxygen and nutrient rich blood throughout the body. Each heart beat is a mechanical contraction that is triggered and controlled spatially by electrical impulses elicited and propagated by the heart's electrical conduction system. Disturbances to this system are termed cardiac arrhythmia and are lethal if they prevent the heart from contracting effectively. Shockingly, one out of three people who read this proposal will experience a severe cardiac arrhythmia in their lifetime that can result in either ventricular fibrillation or tachycardia. Unless medical attention is received within a few minutes post-arrhythmia induced cardiac arrest or tachycardia, there is a grim 5% chance of survival. Today, the only effective life-saving therapy for terminating deadly cardiac arrhythmia and resetting the heart beat rhythm back to normal is a far-field electric shock.
Outside of the clinic, far-field shock electrotherapy is best and most rapidly delivered by an implantable cardioverter defibrillator, which increases shock strength until the arrhythmia is terminated and sinus rhythm ensues. In order for the shock to be successful with severe cardiac arrhythmia spanning wide-areas of the heart, it has to be strong enough to generate an electric field that fully excites all tissue regions harboring the arrhythmia, which in addition to being extremely painful and triggering phobic anxiety disorders, can significantly damage the heart and increase mortality. As an alternative to defibrillating the heart with overly aggressive far-field shock electrotherapy, the computational-experimental-translational project outlined in this proposal aims to develop a new safer and painless electrotherapy for terminating lethal cardiac arrhythmia with WAYLESS: Wide-Area Yielding Low-Energy Surface Stimulation.
The basic strategy of WAYLESS is to minimize the energy requirements for terminating cardiac arrhythmia by utilizing low-energy direct-current stimulation administered via surface electrodes strategically placed over wide-areas of the heart. To rapidly, cost-effectively, and ethically determine WAYLESS stimulation protocols and electrode configurations that will drastically reduce defibrillation energy requirements below tissue damage and pain thresholds, WAYLESS will first be developed in silico using a virtual human heart that simulates realistic lethal cardiac arrhythmia. After the optimal electrode configurations and stimulation protocols are determined in silico, WAYLESS will be subsequently tested and validated in situ using a robust optical imaging approach for studying cardiac arrhythmia in mammalian tissue preparations and intact hearts. To promote the translation of WAYLESS to future clinical trials, its protocols and electrode prototypes will be designed with compatibility to human patients and modern day implantable cardiac devices. This will be the first ever project in France for developing a novel cardiac arrhythmia electrotherapy from in silico to in situ.
Under the auspices of the proposed ANR funding, the results of this research will generate a new technology for terminating lethal cardiac arrhythmia without the pain and danger associated with modern day far-field shock electrotherapies. In addition, the data resulting from this research will contribute significantly to basic science by bettering our understanding of the mechanisms underlying the initiation, maintenance, and termination of deadly cardiac arrhythmia. Therefore, the outcomes from this proposed research project would have a profound personal (improved quality of life), medical (reduced mortality rates), scientific (elucidation of arrhythmia mechanisms), and economic (rapid cost-effective technology development) impact on mankind.
Monsieur Jason Bayer (Institut de Mathématiques de Bordeaux)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IMB Institut de Mathématiques de Bordeaux
Help of the ANR 261,360 euros
Beginning and duration of the scientific project: November 2016 - 36 Months