Nanosecond PFA5
In recent years, PFA has rapidly transformed the technological landscape of atrial fibrillation ablation. Its widespread attention stems not only from its speed and non-thermal nature, but more importantly, from its pioneering move from laboratory concepts to clinical application. Currently, clinically used PFA almost exclusively relies on microsecond-level pulses. This means the electric field application time is typically in the range of 10–100 microseconds. These pulses have been proven to create relatively clear and stable ablation foci in the myocardium, achieving a degree of selective myocardial ablation.
In recent years, however, a new direction has begun to attract attention: nanosecond pulsed electric fields (nsPEF). Compared to microsecond PFAs, nanosecond pulses typically last only 10–300 nanoseconds, a reduction of about three orders of magnitude. It seems to simply be a matter of “shorter pulses.” But from a biophysical perspective, things are far more complex. Because when the timescale changes, the object of the electric field may also change. In other words, nanosecond PFAs may not just be “shorter PFAs,” but rather a different biological model of electric fields.
I. The cell membrane is not a "thin film", but a capacitor.
Structurally, the cell membrane consists of a lipid bilayer, only about 5 nanometers thick. However, from an electrical perspective, the cell membrane is more like a capacitor. When an external electric field is applied to the cell surface, the charges on both sides of the membrane do not rearrange instantaneously, but rather undergo a gradual accumulation process to eventually form a transmembrane potential. A key parameter in this process is the membrane charging time constant. For most cells, this time constant is typically on the order of tens to hundreds of nanoseconds. This means that the cell membrane does not immediately “respond” to an electric current; it needs time to establish a stable transmembrane potential. This is precisely the starting point for the differentiation between microsecond PFAs and nanosecond PFAs.
II. Microsecond PFA: Primarily acts on the cell membrane
In microsecond PFA, the pulse duration is significantly longer than the charging time constant of the cell membrane. Therefore, the cell membrane has sufficient time to complete charging and establish a significant transmembrane potential. When the transmembrane potential rises to approximately 0.5–1 V, nanopores begin to form on the membrane. Subsequently, if the electric field dose continues to accumulate, these pores will continue to expand, eventually leading to irreversible damage, also known as irreversible electroporation (IRE). This process can be roughly summarized as follows:
1. • Charge accumulates across the membrane
2. • Transmembrane potential increases
3. • Nanopore formation
4. • Pore enlargement
5. • Cell membrane structural instability or even rupture
III. Why does microsecond PFA sometimes "successfully isolate but recover later"?
This is an issue that is receiving increasing attention in clinical practice. After electroporation, cells are not always “certainly dead.” If the electric field strength is insufficient or the number of pulses is inadequate, the pores in the membrane have a chance to repair themselves.
In this case, the cell has only undergone reversible electroporation, not irreversible electroporation. This also partially explains why, in some PFA procedures, although acute pulmonary vein isolation is successful intraoperatively, conduction may resume after a period of time.
This is because in some areas, only “temporary inactivation” is achieved, not “permanent damage.” Only when the electric field dose exceeds a certain critical threshold will the cell membrane completely lose its repair capacity, forming a truly stable ablation lesion.
IV. The difference of nanosecond PFA: The pulse ends before the electric field can "fill" the membrane.
The duration of a nanosecond pulse is typically 10–300 nanoseconds. This timescale is quite unique because it is close to, or even shorter than, the charging time constant of the cell membrane. This means that in a nanosecond PFA, the pulse may end before the cell membrane has fully established its transmembrane potential. This leads to an important phenomenon: the electric field no longer remains only on the cell membrane surface but can potentially “penetrate” the cell membrane and enter the cell interior. This is the most significant aspect of nanosecond PFA. Its target may no longer be limited to the cell membrane but extends further to multiple substructures within the cell. Therefore, nanosecond PFA is not simply “shortening the microsecond.”
V. Which organelles might be damaged by a nanosecond electric field?
If an electric field can penetrate the cell interior, it affects more than just the membrane itself. Current research suggests that nanosecond electric fields may act on several key organelles.
1. Mitochondria
Mitochondria are central to cellular energy metabolism. A nanosecond electric field may induce: altered mitochondrial membrane potential, cytochrome C release, and initiation of the apoptosis pathway.
In other words, it may more directly trigger programmed cell death.
2. Endoplasmic Reticulum (ER)
The ER is involved in protein folding, calcium ion storage, and stress responses.
A nanosecond electric field may lead to: ER stress, calcium ion release, and disruption of cellular signaling networks.
3. Nucleus
Some studies also suggest that nanosecond electric fields may further affect: nuclear membrane permeability and DNA structural stability.
VI. Will nanosecond PFA change the way cells die?
This is a very interesting question. Cell death induced by traditional microsecond PFA (Programmable Acid Activation) is usually a mixed pattern of necrosis and apoptosis.
However, nanosecond electric fields, because they can potentially act directly on organelles such as mitochondria and endoplasmic reticulum, are theoretically more likely to trigger programmed cell death (Apoptosis). This means that the tissue response induced by nanosecond PFA may differ from that of traditional microsecond PFA. Theoretically, it could lead to: less inflammation, smoother tissue boundaries, and a “cleaner” tissue remodeling process.
Of course, this is currently still at the theoretical and experimental research level and is far from clinical confirmation.
VII. It also has a potential advantage: reducing muscle and nerve stimulation.
In the early stages of PFA development, a very real problem was that muscle capture could be triggered by electrical field stimulation of nerves or muscles, potentially leading to significant contractions. This is why some PFA procedures still present challenges in anesthesia management. The response time of nerves and muscles to electrical stimulation is typically in the microsecond to millisecond range. Nanosecond pulses are extremely short, theoretically potentially below their effective stimulation time window.
Therefore, theoretically, nanosecond PFA holds the promise of significantly reducing muscle capture and non-target stimulation. This has already been observed to some extent in tumor electroporation research. If validated in future cardiac applications, it will be a very important systemic advantage.
VIII. Will nanosecond PFA further improve tissue selectivity?
One of the key reasons PFA is so fascinating is its tissue selectivity. Different tissues have varying sensitivities to electroporation: myocardium: lower threshold; nerves: moderate; blood vessels: higher. This allows PFA to preferentially damage myocardium while minimizing damage to vascular and neural structures. Nanosecond PFA may further amplify this difference. This is because different cells not only have different membrane thresholds, but also differ in organelle structure, stress response, and repair capabilities. Therefore, nanosecond electric fields may produce more complex and nuanced effects on cell type differences.
IX. The real challenge of nanosecond PFA lies in the engineering aspects.
Conceptually, nanosecond PFA is fascinating. However, its engineering implementation is far from simple. To truly enter clinical practice, at least several core questions need to be answered: 1. What are the optimal pulse parameters? How can voltage, pulse width, pulse number, and frequency be combined optimally? 2. How is the electric field distributed? Is the propagation behavior of the nanosecond electric field in complex left atrial anatomy controllable? 3. How should the catheter be designed? Nanosecond pulses place higher demands on insulation, electrode structure, and connection systems. 4. Is myocardial selectivity sufficiently stable? More systematic data are needed to understand the actual differences in responses of different tissues at the nanosecond scale. 5. Is long-term lesion durable? Acute injury does not equate to long-term isolation; ultimately, durability is paramount. Therefore, nanosecond PFA currently resembles a direction that is very exciting in its mechanism but still requires long-term validation in engineering.
Conclusion
Microsecond PFA has already brought electroporation technology into clinical practice. It showed us for the first time that atrial fibrillation ablation doesn’t necessarily have to rely on heat. Nanosecond PFA may push this approach even further. If the main target of microsecond PFA is the cell membrane, then the target of nanosecond PFA may be the entire cellular system. The future competition in atrial fibrillation ablation technology may no longer be about who has higher voltage or faster surgery, but rather about who can more precisely control the space, depth, and biological consequences of the electric field on a shorter timescale. In this sense, nanosecond PFA is not just “another parameter,” but more likely represents the next paradigm shift in electric field ablation technology after PFA.