History Of PFA Starting with Electroporation
Use in the Life Science world for delivery of DNA
Electroporation, a process where strong electrical fields temporarily or permanently increase the permeability of cell membranes, has extensive applications across various fields, including medicine. Originally well-known in industries such as food processing and pharmaceuticals, its medical implementation began in 1982 when researchers used pulsed electric fields to facilitate the delivery of foreign DNA into cells. This paved the way for several clinical applications aimed at cancer treatment, such as electrochemotherapy, which involves using electric pulses to enhance the uptake of chemotherapeutics by tumor cells, and gene electrotransfer, which delivers DNA or RNA to cells to stimulate an anti-cancer response. Additionally, irreversible electroporation (IRE) has been developed to ablate solid tumors, showcasing the versatile and impactful role of electroporation in contemporary medical therapies.
The journey of electroporation in cardiac electrophysiology began in 1982 when researchers first explored its potential by applying high-amplitude, single monophasic shocks (direct current, DC) for atrioventricular nodal ablation. This method aimed to treat supraventricular arrhythmias and presented a non-surgical alternative to open-chest procedures. Despite its innovative approach, controlling the extent of tissue ablation proved challenging, and the technique exposed patients to risks such as barotrauma and arcing. As a result, during the 1990s, this method was largely superseded by radiofrequency (RF) ablation, which offered more precision and safety.
Biophysics: An Overview
Every biological cell is encased in a bilayer lipid plasma membrane. This membrane features various proteins that function as ion pumps or channels, facilitating the transport of specific molecules in and out of the cell. Additionally, the membrane acts as a biological barrier, shielding the cell from external elements. The membrane's lipids are comprised of hydrophilic (polar) and hydrophobic (non-polar) parts. These components, along with the ion pumps and channels, help maintain an electric potential difference across the membrane. Typically, this resting transmembrane voltage in eukaryotic cells ranges between −40 to −70 mV.
When cell membranes are subjected to an electric field that surpasses the transmembrane voltage, the electrical conductivity can increase and the permeability of the membrane may rise, allowing the formation of aqueous pores. These pores enable the transport of molecules that are usually impermeable, potentially altering the cell’s integrity. Depending on the intensity of the electric field, the effects on cell integrity can either be transient—where the cell may regain its structural and electrical integrity—or irreversible, leading to cell death.
Cell death post-electric field exposure can manifest primarily as necrosis or through various apoptotic pathways, such as necroptosis and pyroptosis. These processes, particularly under different pulsed electric field protocols, are complex and not fully understood, which can affect treatment outcomes and the comparability of protocols.
For cardiac arrhythmia treatments, the goal is to achieve irreversible electroporation (IRE). The success of IRE depends on several factors, most critically the electric field strength required, which varies by cell type. Consequently, electroporation protocols must be customized to specific target tissues and cannot simply be adapted from other applications.
Enter AC and Pulses
Today, advancements in the control and quality of pulsed electric fields have led to a resurgence in the use of electroporation for cardiac ablation. Modern protocols now precisely define voltage amplitude, pulse width, and repetition frequency, making electroporation a promising and sophisticated option for cardiac procedures once again.
A notable secondary effect of electric currents in tissues is Joule heating, which is directly proportional to the square of the current and the duration of its application. This can lead to unintended tissue heating in cardiac electroporation procedures, thus necessitating careful protocol design to ensure effective ablation without significant thermal impact.
Additionally, electroporation can result in the formation of gaseous microbubbles due to electrolysis, particularly with monophasic pulse applications, which could lead to thromboembolic complications. However, studies using cerebral MRIs and histology in dogs showed no cerebral events after such applications. Biphasic pulses and shorter pulse durations have been associated with fewer or no gas bubble formations.
Historically, monophasic direct current (DC) was commonly used for electroporation but was linked to issues like painful nerve and muscle capture or arcing. These side effects are mitigated by using biphasic or alternating current (AC), as demonstrated in feasibility and safety studies involving AC-PFA in swine myocardium and reduced muscle contractions and pain in human muscles.
Electroporation protocol variables include voltage, number of pulses, pulse width, shape, delay, and frequency. These parameters and the local tissue properties, such as cell size, geometry, and orientation relative to the electric field vector—as well as catheter shape and electrode arrangement—are crucial in achieving successful IRE.
PFA ablation timing and ECG Waveform
The timing of the pulsed field ablation (PFA) cycle during the ST wave in electrocardiogram (ECG) recordings is strategically chosen to minimize cardiac risks, particularly arrhythmias. Here's why this timing is critical:
Vulnerable Period Avoidance: The ST segment in an ECG represents the period just after the ventricles have depolarized and before they repolarize. This is considered a relatively stable cardiac phase, unlike the T wave, which represents ventricular repolarization and is a more vulnerable period for inducing arrhythmias. By timing the PFA cycle to the ST wave, the risk of triggering dangerous arrhythmias like ventricular tachycardia or fibrillation is minimized.
Cardiac Cycle Synchronization: The ST segment offers a predictable and consistent window in the cardiac cycle across different heart rates and conditions. This synchronization ensures that the energy delivery is timed precisely when the cardiac tissue is less reactive to electrical disturbances, thereby increasing the efficacy of ablation and reducing complications.
Energy Delivery Optimization: PFA works by creating strong electric fields that disrupt cellular membranes leading to cell death, primarily affecting cardiac tissue where ablation is targeted. Timing the delivery during the ST segment ensures that the surrounding tissues are in a refractory state, thus focusing the ablation effect on the intended areas without collateral damage.
By carefully selecting the ST segment for the ablation cycle, PFA can achieve effective results while enhancing safety profiles. This approach leverages the inherent properties of the cardiac cycle to optimize therapeutic outcomes.
DESRES PROTOYPE PFA CONTROLLER
NPULSE Nano Pulse Width
Biphasic and Monophasic
Hardware Redundant Systems
ECG Sync incorporated
Local WIFI AES encrypted protocol to Fluid Management System
PFA Design and Development