Leadership in MedTech: Marlou Janssen talks PFA, how it offers new method to revolutionize Afib treatment and improve patients outcomes.

Stan: What is Pulsed Field Ablation (PFA), and how does it differ from traditional ablation techniques used in the treatment of Afib?

Marlou: Pulsed Field Ablation (PFA is a novel technique used in treatment of atrial fibrillation). Unlike traditional ablation techniques, whereby hot or cold energy are applied to create therapeutic scars or destroy abnormal heart tissue causing abnormal heart rhythms like tachycardia, PFA employs strong but very brief electrical pulses to create irreversible damage to the targeted tissue.

The impact of different ablation energies on safety and success can be significant. When a traditional thermal energy like radio frequency (RF) electrocautery is used, heating destroys all tissues in the target volume including extracellular structural proteins, blood vessels, nerve fibers, endocardium et cetera. The physics of heat transfer are complex and unpredictable eventually leading to collateral damage and unpredictable treatment volumes.

This is different with PFA, whereby a series of low energy but very short and extremely high voltage electric pulses are delivered to the tissue. These low energy pulses disrupt cell structures responsible for compartmentalization ultimately impacting metabolic function. If the right combination of PFA pulses are delivered it is possible to ablate the target cardiac tissue selectively and leave bystander tissues and extracellular matrix intact. So the PFA approach is designed to provide a non-thermal and non-cryogenic alternative to existing ablation methods with some significant advantages.

Stan: What are the advantages of PFA technology over other treatment modalities for Afib?

Marlou: Compared to traditional ablation techniques, PFA offers several potential advantages. Firstly, PFA has the potential to be significantly faster, allowing for shorter procedures times. Secondly, PFA may reduce some risk of complications associated with thermal based ablation methods, specifically pulmonary vein stenosis, phrenic nerve palsy, and esophageal injury. One, less serious but underappreciated example of collateral injury in patients treated with Cryo and especially with RF occurs in the post procedure recovery. Sometimes patients feel a burning sensation in the chest after undergoing AF ablation which is called thermal pericarditis. With PFA this burning sensation seems to be absent and is therefore providing much less chest discomfort to patients during the recovery period.

This is likely explained by the growing body of research that shows PFA can be tissue selective and remarkably predictable when it comes to titrating ablation lesion volume. The predictability can reduce risk of collateral damage to surrounding structures as physicians can potentially tailor treatment to individualize patient care.

A third potential advantage is that PFA may improve efficacy in procedures where the physics of thermodynamics have interfered with our ability to ablate the target tissue. Although PFA is a relatively new technology, and long-term studies evaluating its efficacy and safety are still ongoing early results look very promising.

Stan: How does it improve patient outcomes?

Marlou: PFA technology has the potential to improve patient outcomes by reducing key procedural risks, providing similar or superior efficacy, and most importantly increasing access to care by dramatically improving procedural workflow.

As I pointed out above, PFA may offer improved safety in AF ablation compared to conventional thermal ablation methods. In a recently published randomized study comparing PFA to thermal ablation (Advent Trial) there was no significant difference between the control and PFA groups.

However, if you look at types of complications that occurred in the two groups you can see some important difference in serious or long-lasting events occurring between PFA and thermal ablation arms. With thermal ablation there was one stroke and two cases of persistent phrenic nerve paralysis. With PFA pericardial effusion occurred in two patients. These serious complications that occurred in the thermal arm were likely related to the ablation itself. Whereas with PFA the complications were not related to ablation energy but could potentially be caused to manipulation of large catheters within the heart. The MANAFEST-AF registry supported the observation that PFA likely reduces risk in energy-related complications like esophageal fistula, phrenic paralysis, pulmonary vein stenosis but technical challenges more related to large bore catheter manipulation such as vascular access and cardiac perforation remain a concern.

I find this extremely encouraging because these types of problems can be solved with iteration. After all this is the first generation of this technology to make it to the market. I fully expect future generation PFA catheters will address the mechanical or delivery system related challenges by integrating well established safety features ubiquitous in current technologies, things like contact force, magnetic localization, and size reduction of the devices.

Procedural outcomes in AF ablation are largely linked to our ability to effectively isolate electrically active tissues in the pulmonary veins from the rest of the atria. This is why AF ablation is often called pulmonary vein isolation (PVI). Long term outcomes for AF ablation are therefore agnostic to the energy that is used to achieve isolation. What may give PFA a leg up is the predictable lesion characteristics it promises. Data from a 1758 patient post market registry (MANAFEST-PF) evaluating the first commercially available system in Europe are encouraging, showing 81% success at one year. However, when effective PVI using PFA is compared directly to thermal ablation in the ADVENT trial the differences were not significant with both approaches showing success in the low 70% range. This is still encouraging because in the ADVENT trial there were very few individual physicians that performed more than 5 cases. The real-world results from the MANAFEST registry suggest that superior efficacy may depend on learning curve. Regardless it is impressive to see any first generation technology perform so well when put head to head against tools that the physicians are true experts at using. I have high expectations that over the next ten years we will see significant transformation in the field.

One decade ago AF ablation procedures took over 4 hours to complete. Incremental improvements over the intervening years brought the duration closer to 2 hours. Now the average procedure time is likely to drop below an hour with PFA. My understanding is that in experienced hands it is possible to complete PVI from access to removal of the catheters in less than 30 minuets. The impact on the procedural workflow efficiency has big implications; There are a limited number of labs in the world and it takes enormous time & resources to train physicians. If we want to treat tens-of-millions of patients reducing the procedure time can greatly expand access to care.

Catheter ablation is the most effective therapy for atrial fibrillation and improving access improves patient outcomes overall. Additionally, shorter procedure times can minimize patient discomfort, anesthesia exposure and the risk of complications associated with longer interventions.

Stan: Can you discuss any recent advancements or innovations in PFA technology that have the potential to revolutionize Afib treatment?

Marlou: Pulsed Field Ablation (PFA) is a relatively new technology in the field of atrial fibrillation (Afib) treatment and it is a fast evolving field of innovation. I can certainly discuss some general advancements and potential areas of innovation that could impact PFA and Afib treatment.

1. Catheter Designs: Advancements in catheter technology can enhance the effectiveness and precision of PFA. Innovations may include improved electrode designs, such as multielectrode arrays or optimized shapes, to deliver pulses more efficiently and achieve better lesion formation.

One of the best-in-class examples of such improved catheter design is the new Catheter design of Field Medical Inc. This catheter is clearly build for purpose of specifically delivering PFA energy. Moreover Field Medical has been able to create a proprietary catheter design whereby a second electrode is inside the catheter and the catheter has a ceramic tip. This particular catheter design allows for Field Bending which controls the shape of the electric field around the catheter with the objective of better tolerability and a larger range. This catheter is also designed to address the technical challenges of treating deadly arrhythmias like ventricular tachycardia (VT). A market that has not been fully addressed today as tool kits for VT ablation are still suboptimal today. That could potentially change with this specific new catheter design. Early animal studies show histology and pathology data with very large and deep footprints in the Ventricle.

2. Energy Delivery Optimization: Research is ongoing to optimize the parameters of pulsed energy delivery in PFA. This includes determining the ideal pulse duration, frequency, amplitude, and waveform characteristics to maximize lesion formation while minimizing potential complications. Refinements in energy delivery could enhance the efficacy and safety of PFA procedures. Coming back to the Field Medical technology they have

developed the concept of bending of PFA energy which I believe will hold the promise for another great wave of innovations in this field.

3. Imaging and Navigation Integration: Integration of advanced imaging techniques, such as intracardiac echocardiography (ICE) or three-dimensional mapping systems, can aid in guiding catheter placement and assessing lesion formation during PFA. Real-time imaging combined with precise navigation could improve the accuracy and outcomes of the procedure.

4. Mapping of patient specific AF drivers: coming back to the results of the Advent I think I would like to point out that in this study (and other PFA studies), PFA was used to perform standard anatomically-guided pulmonary vein isolation and thus did not address patient-specific drivers outside of the pulmonary veins that could be the actual cause of that patient's AF. These non-pulmonary vein AF drivers are currently difficult to map using standard catheters and so typically are not targeted in most ablation procedures. I am aware of a new AI-powered 12-lead ECG based mapping system – the Vektor Medical vMap? system – that can identify patient-specific AF drivers and could easily be incorporated into a workflow with PFA to safely eliminate them.

This novel approach would be an enormous paradigm shift in the treatment of AF, and would allow a truly patient-centric approach to AF ablation. In any case newly developed AI based Software to aid PFA treatment is definitely a trend to watch in the coming years.

5. Hybrid Approaches: Hybrid ablation combines different treatment modalities, such as PFA and traditional thermal ablation, to achieve more comprehensive lesion sets. This approach may be beneficial for complex cases or when targeting specific areas that may be better addressed with a combination of techniques. Hybrid approaches have the potential to provide tailored treatment options for individual patients, improving success rates. A great example of such a hybrid approach is PFCA a combination of PFA with Cryo. Lets briefly discuss the advantages of such hybrid approach. As I said at the beginning of the interview, PFA employs electrical field as ablation energy. As we may remember from Ohm’s law in our high school curriculum, the electrical field (V/cm) comes from multiplying resistance with current. The problem is that since the tissue and the blood are good conductors, the resistance (impedance) is very low. Therefore, a very high current is required to achieve a sufficient electrical field in plain PFA. Products on the market today require at least 15 amp to achieve a minimum electrical field, causing unwanted side effects like bubbles (silent emboli), coronary artery spasm, skeleton contractions and even heat. In comparison, the Adagio PFCA catheter uses less than 1 amp to achieve an even higher electrical field than PFA. The secret to this is that the law of nature causes the tissue resistance (impedance) to increase by orders of magnitude when tissue is frozen below 0 degrees C, which makes the tissue a prefect substrate to deliver PFA a high electrical field and achieve a durable, contiguous transmural lesion.

Stan: Looking ahead, what does the future hold for PFA technology and its role in the management of Afib?

Marlou: Looking at the many advantages of PFA as outlined above many medical device companies have made PFA development a major priority for their R&D and Clinical Research program. PFA is believed to truly cause a paradigm shift in the management of Afib but also holds a lot of promise for other types of arrhythmias such as VT, which today are more difficult to treat with conventional ablation therapy. Some market research projections foresee that by 2030 more than 50% of all WW ablation procedures will be performed using PFA energy. It is obvious that such a paradigm shift is fueling innovations, inspires new perspectives to be taken by physicians and medical device companies and could encourage collaborations on many fronts. Most importantly it will lead to better treatment options for patients if today’s promise of PFA holds up in long term clinical research.

Stan: Thank you Marlou Janssen for your insights on PFA and technology advancements, its perspective and impact.

Stan Kalinin draws on an extensive track record of more than 14 years of search and executive team-building expertise. He is the host of MedTech Opinion Leader supporting growth of MedTech industry and creating insightful stories with key market executives forging alternative narrative about the sector current and future trends.