Atrial fibrillation (AF) and its treatment using radiofrequency (RF) and cryoballoon (CB) ablation
AF is the most common arrythmia and is characterized by rapid and irregular beating of the atrial chambers of the heart. This disrupted rhythm occurs because of the irregular and unpredictable conduction of disordered impulses originating in the atria, which cause uncoordinated contractions between the atria and ventricles. The ineffectual contractions result in lower blood output from the atria into the ventricles, and increases the vulnerability to thrombus formation owing to blood pooling in the atria. This thrombus can then travel to the brain and block blood flow to a part of the brain, resulting in a stroke. Indeed, AF is a major risk factor for ischemic stroke and is associated with a 5-fold higher risk of stroke. It is estimated that AF affects more than 3 million people in the US, and more than 33 million people worldwide. The prevalence of AF increases to more than 1 in 10 in the elderly, and the overall prevalence will rise in the near future because of global population aging. The increasing survival rates related to underlying diseases such as hypertension, coronary heart disease, and heart failure are closely associated with rising prevalence of AF.[4,5] Globally, AF treatment constitutes a serious medical burden. It is estimated to amount to 1% of the National Health Service budget in the United Kingdom and $16 to $26 billion of annual US healthcare expenditure. AF is predicted to affect 16 million people in the US and 16 to 17 million people in Europe by 2050.
Thermal ablation of myocardial tissue is currently a major clinical treatment for AF. It involves destroying local myocardial tissue to isolate the faulty electrical signals causing the arrhythmia in the local area. Ablation is usually performed by heating local tissue with RF electrical current, creating conduction-blocking lesions that stop AF. The introduction of RF catheter ablation in the field of cardiac electrophysiology can be traced back to 1987. However, the problems associated with RF ablation (RFA) include: (1) high recurrence rate (as tissue cooling by arterial flow may limit transmural and continuous lesion formation), (2) tissue loss beyond the targeted tissue (non-uniform ablated region), (3) charring that hinders heat conduction, (4) “steam pops” that can cause cardiac perforation, and (5) lengthy ablation procedure. Additionally, there are small risks of certain complications due to the thermal side effects. In a nationwide US study involving 93,801 RFA procedures from 2000 to 2010, the overall incidence of perioperative complications was 6.29%, and in-hospital mortality was 0.46%. The most frequent and severe complications of RFA are: (1) stroke (due to thrombosis formation), (2) pulmonary vein (PV) stenosis, (3) cardiac tamponade, (4) coronary artery injury, (5) phrenic nerve injury, and (6) atrio-esophageal fistula.
CB ablation has emerged as a valid alternative in recent years. In one study, CB ablation reduced the incidence of AF recurrence compared to RFA, and this result was consistent across different study designs and AF types. CB ablation was associated with a significantly higher rate of phrenic nerve palsy, but lower rates of pericardial effusion, cardiac tamponade, and vascular complications than RFA. Therefore, considering its efficacy/safety profile and short procedural time, CB ablation is the preferable procedure for the first AF ablation.
Recently, experts’ opinions and published data have suggested that combination treatment involving surgical and catheter ablation may provide even better results. One of the most invaluable benefits of surgical ablation is the possibility of concomitant occlusion of the left atrial (LA) appendage. The availability of cryosurgical techniques has revolutionized the surgical treatment of AF. By using modern cryosurgical devices and adhering to the technical principles described, surgeons can now perform surgical procedures for AF that are quicker, safer, and as effective as the standard Maze-III/IV procedure.
History of irreversible electroporation (IRE) and its application in cardiology
IRE is a biophysical phenomenon in which the cell membrane permeability to ions and molecules increases significantly in response to an externally applied electric field. The method was termed electroporation which suggests “creating pores electrically”. When the electric field is of relatively strong intensity, it may induce persistent changes in membrane permeability, leading to an irreversible breakdown of membrane structure and function and ultimately to cell death. This process is called IRE and is an emerging non-thermal modality that is approved by the US Food and Drug Administration (FDA) for clinical tumor ablation. Owing to this non-thermal mechanism, IRE ablation has many advantages compared to conventional RFA. A pilot study of IRE ablation during open-chest surgery in pigs by Lavee et al in 2007 found that a bipolar 40-mm parallel clamp led to transmural lesions, with a sharp demarcation between the ablated and normal tissues. In Table 1,[26–37] we detail the significant historical IRE ablation-related events that have made this innovative modality safer and more effective for clinical application, avoiding the multiple severe complications found in RFA. In Figure 1, we summarize these remarkable discoveries from 2007 to 2021.
Table 1 -
Selected historical events involving IRE cardiac ablation
||Experimental model (number)
||Electrode configuration and delivery method
||IRE protocol parameter
||Porcine (n = 5), open chest
||Bipolar 40-mm parallel clamp electrodes, Epi_Delv
||PN = 8, 16, 32,PD = 100 μs,PRI = 200 ms,PA = 1.5∼2 kV
||Transmural lesions (n = 10) with mean 0.9 cm depth, 3.0–3.5 cm length, created in 1–4 s
||First reported successful atrial transmural IRE ablation in vivo, with clear ablated/unablated boundary.
||Ovine (n = 4), open chest
||Bipolar 53-mm linear clamp electrodes, Epi_Delv
||3 or 5 trains of pulses, each train with PN = 10∼40,PD = 100∼400 μs, PRI = 200∼1000 ms, PA = 0.78 kV
||100% transmural lesions in SVC and IVC (n = 14), and high degree of transmural in RAA, LAA, and PVs (n = 19)
||High degree of transmural lesions in different locations in atria. Additionally, esophageal lesions were created showing that IRE ablation is selective (epithelial tissue was kept alive while target muscular tissue was destroyed).
||Porcine (n = 10), closed chest
||Circular 20-mm-diameter with 10-pole 2-mm electrodes, Endo_Delv
||200-J DC pulses, PD = a few ms, DC applied between a skin patch and the multipolar circular electrode
||Sharp lesions (maximum depth = 3.5 mm) created inside PV ostia with reduced PV potentials
||First reported safe and successful low-energy IRE ablation in a sensitive environment (PV ostia). PV angiograms did not show stenosis during the short follow-up.
||Porcine (n = 10), open chest
||Circular 20-mm-diameter with 10-pole 2-mm electrodes, and circular 20-mm-diameter single ring electrode, Epi_Delv
||50/100/200-J DC pulse, DC applied between a skin patch and the multipolar circular electrode
||Continuous lesions (n = 5) created with median width (5.3 ± 3.0) mm and median depth (5.2 ± 1.2) mm created by 200 J via devices D which contained 2 mm long electrode
||Proved lesion depth increased with pulse magnitude in a blood-myocardial tissue environment. Continuous and deep lesions for PVI could be created by a single 200-J pulse of a few ms in duration.
||Porcine (n = 5), open chest
||Linear electrode in suction cup, Epi_Delv
||30/100/300-J DC pulses, PD = 6 ms, DC applied between a skin patch and the linear electrode
||Lesions with mean depth of (3.2 ± 0.7), (6.3 ± 1.8), and (8.0 ± 1.5) mm, mean width of (10.1 ± 0.8), (15.1 ± 1.5), and (17.1 ± 1.3) mm, transmural rate was 25%, 100%, and 100% for 30, 100, and 300-J epicardial ablation, respectively
||No permanent coronary artery damage. No arterial luminal narrowing at 3 months.
|van Driel (2015)
||Porcine (n = 20), open and closed chest
||Circular 20-mm-diameter with 8-pole 4-mm electrodes, and circular 18-mm-diameter with 8-pole 2-mm electrodes, Endo_Delv
||200-J DC pulses, DC applied between a skin patch and the multipolar circular electrode
||Transmural lesions after firm contact with the inner superior vena cava wall
||No phrenic nerve damage.
||Rabbit (n = 12), isolated heart
||Parallel penetrating needle electrodes spaced 2–4-mm, Epi_Delv
||PN = 6, 20,PD = 350 ns,PRI = 300 ms, 1 s,PA = 2.3 kV
||Transmural lesions verified based on histological and optical mapping data
||First report of transmural lesions created by nanosecond pulsed electric field.
||Porcine (n = 8), open chest
||Suction cup containing single 35 × 6 mm linear electrode, Epi_Delv
||100/200-J DC pulses, PD = 6 ms, DC applied between a skin patch and the linear electrode
||IRE ablation was tested purposely on anterior esophageal adventitia
||No esophageal ulceration or fistula.
||Human (n = 22), open and closed chest
||Bipolar 12-F over-the-wire catheter with 5 splines each containing 4 separate electrodes for Endo_Delv, and bipolar linear closed ring catheter with multiple electrodes for Epi_Delv
||Mean 78 J per ablation for Endo_Delv and 1146 J per ablation for Epi_Delv, over a few-seconds train of multiple ms pulses, PA = 0.9∼2.5 kV
||15 patients out of 15 are PV isolated with (3.26 ± 0.5) mm lesions from endovascular delivery, and 6 patients out of 7 from epicardial delivery
||First-in-human clinical application of IRE ablation for acute PVI, for both cardiac surgery and catheter-based ablation.
|van Es (2019)
||Porcine (n = 5), open chest
||Suction cup containing single 35 × 6 mm linear electrode, Epi_Delv
||200-J pulses, PN = 10, PD = 2 ms, PRI = 400 ms, frequency = 167 kHz
||Asymmetric HF(aHF) Lesion depth (2.3 ± 1.0) mm, Symmetrical HF (sHF) lesion depth (1.7 ± 0.8) mm.
||aHF IRE ablation avoids skeletal muscle contractions and gas bubble formation.aHF pulses can also create deeper lesions than sHF pulses of the same energy in cardiac tissue.
||Human (n = 81), closed chest
||Bipolar 12-F over-the-wire catheter with 5 splines each containing 4 separate electrodes, Endo_Delv
||Over a few-seconds train of multiple ms pulses, PA = 0.9∼2.0 kV
||All PVs were isolated by monophasic (n = 15) or biphasic (n = 66) approaches. With successive IRE refinement, durability improved from 18% to 100%
||In 81 patients, 100% of all PVs were acutely isolated and no additional primary complications such as stroke, phrenic nerve injury, PV stenosis, or esophageal injury occurred over the 120-day median follow-up.
||Human (n = 121), closed chest
||Bipolar 12-F over-the-wire catheter with 5 splines each containing 4 separate electrodes, Endo_Delv
||Over a few-seconds train of multiple ms pulses, PA = 0.9∼2.0 kV
||All PVs were isolated by monophasic (n = 15) or biphasic (n = 106) approaches. With successive IRE refinement, PVI success 100%
||1-year Kaplan-Meier estimates for freedom from any atrial arrhythmia for the entire cohort and for the optimized biphasic energy PEF ablation waveform cohort were (78.5% ± 3.8%) and (84.5% ± 5.4%), respectively.
DC: Direct current; Endo_Delv: Endovascular IRE delivery; Epi_Delv: Epicardial IRE delivery; IRE: Irreversible electroporation; IVC: Inferior vena cava; LAA: Left atrial appendage; PA: Pulse amplitude; PD: Pulse duration; PEF: Pulsed electric field; PN: Pulse number; PRI: Pulse repetition interval (or pulse cycle length); PV: Pulmonary vein; PVI: Pulmonary vein isolation; RAA: Right atrial appendage; SVC: Superior vena vein.
Depending on the protocol, IRE can be achieved with various modalities: direct current (DC), alternative current (AC), pulsed electric field (PEF), or any combination of these. DC catheter ablation was routinely applied between 1980 and 1990 for the ablation of the bundle of His and ventricular tachycardia. Despite the high success rate, DC ablation was quickly replaced by the more elegant RFA technique that appeared around 1990. The main disadvantages of DC monophasic pulses ablation are that they can lead to potentially painful nerve and muscle capture, arcing, metallic release in solution, and bubble stream formation, also due to electrolysis without arcing, and require complete anesthesia during ablation. In 2011, Wittkampf et al successfully used low-energy DC ablation to create myocardial lesions, avoiding the harmful side effects of standard DC ablation such as sparking and explosions. The DC shocks (pulse duration of a few milliseconds) were applied between a catheter. The electrode was positioned on the target myocardium with an external ground pad.
There are not as many reports of AC ablation as there are of DC or PEF. A pilot study of high-frequency AC ablation by van Es et al in 2019 found that asymmetric high-frequency ablation in pig hearts successfully created myocardial lesions without skeletal muscle contractions or bubble formation. PEF ablation is an adaptation of DC ablation, in that it is a more controlled low-energy form of ablation delivered over a few seconds across multiple electrodes without the use of an external ground pad. PEF consists of multiple short DC pulses with a pulse duration of microseconds or nanoseconds. The local electric field created in a bipolar fashion by PEF leads to the reorganization of the lipid structure of cardiomyocyte membranes, resulting in nanoscale pore formation. These pores increase cell membrane permeability and thus cell leakage, finally leading to cell death. This phenomenon subsequently results in either immediate necrosis or delayed apoptotic cell death.[41–44] Catheter-based pulmonary vein isolation (PVI) with pentaspline PEF ablation catheter creates chronic PV antral isolation areas as encompassing as thermal energy ablation.
IRE protocol parameters
IRE protocols include many parameters that can be modified. These parameters include biphasic or monophasic pulses, voltage amplitude (hundreds to thousands of volts), pulse duration (nanoseconds to milliseconds), pulse repetition interval, interphase interval, number of pulses in the train (single pulse to hundreds), number of trains, and bipolar or unipolar electrode delivery. The characteristics of each pulse that can vary include pulse rise time, pulse fall time, overshoot and ringing, and undershoot. Each of these parameters, combined with others, can significantly influence the efficiency of IRE ablation and result in more/less tissue destruction.
Thermal energies related to high-power, short-duration RFA, RF balloon devices, ultra-low cryoablation, laser, ultrasound, microwave, and X-ray ablate tissues indiscriminately. By contrast, IRE ablation (either DC or PEF), because of its non-thermal ablation nature, can ablate tissues with unique tissue selectivity. This is because the myocardium has a lower threshold (400 V/cm) than the surrounding tissues, therefore IRE will first induce cardiomyocyte necrosis. If IRE protocols are precisely controlled, this can limit collateral damage to periatrial non-target tissues such as the esophagus and phrenic nerves, coronary arteries, and PVs.[29–31,33,34,36] This underlying mechanism of IRE ablation offers a degree of tissue-specific safety: tissues with higher thresholds in an ablative zone can be spared, avoiding clinical complications inherent to RFA (refer to Table 2, which lists all aspects for comparison).
Table 2 -
Comparison of RFA and IRE ablation
| PV stenosis
| Coronary artery damage
| Phrenic nerve injury
| Atrio-esophageal fistula
| Stroke (due to thrombosis)
|Problems associated with thermal effect
| Lengthy procedure
| High recurrence rate
| Tissue loss beyond target tissue
| “Steam pop”
| Tissue-catheter contact force sensing required
||Depends on external factors
||Depends on external factors
| Muscle contractions
||Depends on external factors
| Cardiac fiber orientation dependence
||Depends on external factors
| Areas of reversibility
||Depends on external factors
| Safety and efficacy can be achieved concurrently
∗Based on short-term data (long-term data are not available). In summary, for RFA, there is a zero-sum relationship between safety and efficacy (greater efficacy is achieved with more ablation but at the expense of safety, and vice versa). However, for IRE ablation, the safety and efficacy relationship is a win-win relationship (they can be achieved at the same time). IRE: Irreversible electroporation; PV: Pulmonary vein; RFA: Radiofrequency ablation.
No evidence of PV stenosis
Stenosis of the PV is a serious and potentially life-threatening complication of RFA caused by hyperthermia that induces contraction of the vein wall. The non-thermal mechanism of IRE ablation leads to a much lower propensity for collateral damage compared to procedures using thermal energy sources. In an animal study, the PV diameter was maintained at 3 weeks after IRE DC ablation, while RFA decreased the PV diameter at 3 weeks compared to that in the control group. It was also confirmed in patients that there was no PV stenosis at a 1-month follow-up visit after IRE ablation.
No evidence of coronary artery damage
Thermal ablation induces heat damage to all tissue near the ablation site, including nearby coronary arteries, which can pose a serious risk. The heat may not only coagulate blood inside the vessel, causing thrombus, but also cause intimal hyperplasia and shrinkage of the collagen fibers in the arterial wall that could lead to vessel stenosis and subsequent infarction of the related region. In contrast, IRE ablates the myocardium but selectively spares the arteries themselves entirely. This selective ablation feature can be used in oncological IRE treatment as solid tumors are ablated, while nearby vital structures such as blood vessels and nerves are relatively spared, given that they are relatively resistant to IRE PEF ablation. Neven et al proved that 3 months after epicardial IRE, luminal coronary artery diameter remained unaffected. IRE can create deep lesions and is a safe modality for catheter ablation on or near coronary arteries.
No evidence of phrenic nerve damage
The phrenic nerves are located very close to the superior vena cava, right PVs, and LA appendage. Phrenic nerve palsy is another complication of PVI by using thermal ablation. In 2015, van Driel et al found no evidence of right phrenic nerve damage after intentionally targeted ablation using circular 200-J DC applications with good tissue contact inside the superior vena cava wall. Occasionally, transient nerve palsy was induced, but normal pacing was monitored from the superior vena cava 30 minutes and 3 to 13 weeks after ablation.
No evidence of atrio-esophageal fistula
Atrio-esophageal fistula is another rare but devastating complication of thermal LA ablation. It occurs due to the anatomical location of the LA near the esophagus. Excess heat conduction from the LA to the esophagus can damage esophageal tissue, leading to fistula. IRE ablation involves tissue-specific thresholds, thereby facilitating preferential ablation of only the myocardium, with relative sparing of collateral tissues such as the esophagus. In 2017, Neven et al reported that the architecture of the esophageal tissue remained intact after 2 months after irreversible electroporation. In the novel porcine model of esophageal injury, biphasic PEF ablation induced no chronic histopathologic esophageal changes, while RFA demonstrated a spectrum of esophageal lesions including fistula and deep esophageal ulcers and abscesses.
No evidence of stroke (due to thrombosis)
Thermal ablation carried out in very close proximity to a coronary artery can cause thrombosis and occlusion, as the heat may coagulate blood inside the vessel. Owing to the lack of an obvious temperature increase associated with IRE ablation, the risk of heat-induced thrombus formation is low.
It is time-consuming to use thermal ablation to achieve measurable effects and appropriate temperature gradients. By contrast, IRE is almost instantaneous, occurring in a few seconds [Table 1]. Thus, using IRE ablation dramatically reduces the cumulative time. In 2018, Reddy et al reported that the IRE procedure took (67.0 ± 10.5) minutes (57 PVs in 15 patients). However, in a 2016 study by Boersma et al involving PVI, RFA took (96 ± 36) minutes (61 patients) and using a standard focal irrigated catheter took (166 ± 46) minutes (59 patients).
AF recurrence after RFA was common in patients with persistent AF in studies by Cappato et al, Callans et al, and Verma et al. This recurrence of PV-LA conduction is associated with the presence of gaps in incomplete lesions, created by RF energy, between the PV and LA. Durable thermal ablation efficacy for AF remains a major challenge in the long term. Depending on the ablation strategy, success rates range from 60% to 80% for paroxysmal AF, and from 50% to 60% for persistent AF. Among the ablation strategies, PVI constitutes the cornerstone of the thermal catheter ablation strategy, by creating a circumferential ring of non-conductive lesions around the individual PV from the LA. The reasons for AF recurrence (ie, recurrence of PV-LA electrical conduction) in the long term after ablation can be classified into 4 possible groups: (1) recovery of PV-LA conduction that was previously ablated, (2) presence of triggers ostial to the PVI site, (3) development of new triggers in non-ablated PVs, or (4) development of new triggers outside the PVs.
Generally, short-term PVI can be achieved even by incomplete lesion formation that causes temporary electric uncoupling but not irreversible cell death (reversible tissue injury) at ≤3.5 mm from the lesion boundary. Ablation involving a gap of ≤1.4 mm can still cause a local conduction block, and the gap can be up to 4 mm in abnormal tissue. These lesions with gaps “mask” the need for permanent complete lesion formation for permanent PVI. Formation of lesion gaps are due to insufficient heat, which is carried away by convective cooling involving nearby arterial blood flow. Over 1 to 4 weeks, the normal conduction of live tissue at the boundary of the transmural lesion recovers, and PV-LA conduction gradually recovers over several weeks or months as the tissue injury heals. Therefore, permanent PVI should be considered as the main goal of AF treatment to avoid AF recurrence. However, the verification of the AF recurrence rate after IRE ablation is still in the early stage, owing to its short history of use. Reddy et al are the pioneers of IRE PEF ablation for treating AF: the rate of durable PVI at 3 months improved from 18% for the initial monophasic waveform to 100% (with all PVs isolated) for the biphasic waveform with successive “waveform refinements”. The details of the successive waveform refinements were not reported, but it appears that bipolar basket electrode configuration without a skin patch is an effective delivery approach for PEF ablation.
In 3 multicenter studies (IMPULSE, PEFCAT, and PEFCAT II), patients with paroxysmal AF underwent PVI using a basket or flower PEF ablation catheter. Invasive remapping was performed at 2 to 3 months, and reconnected PVs were reisolated with PEF ablation (with the optimized biphasic energy PEF ablation waveform) or RFA. Arrhythmia recurrence was assessed over a 1-year follow-up period, and PVI was achieved in 100% of PVs with PEF ablation, with durable PVI in 96.0% of PVs treated with PEF ablation. The 1-year Kaplan-Meier estimate for freedom from any atrial arrhythmia for the optimized biphasic energy PEF ablation waveform cohort was 84.5% ± 5.4%.
Despite this, the complications, which are currently thought to be rare, may actually occur at higher rates than previously thought, as was the case when other new technologies were previously evaluated (eg, cryo, laser, and focused ultrasound).[60–62] Therefore, it is inappropriate to state that each of the risks is definitively lower for IRE ablation than RFA. The true risks are unknown, although the limited preliminary data are promising.
Tissue loss beyond the target tissue
Based on the time-dependent conductive thermal mechanism of RFA, the target zone temperature must involve the following to effectively create transmural lesions: (1) the appropriate peak temperature must be reached at the proximal tissue-electrode interface and (2) the peak temperature must spread from the proximal to distal tissues to destroy the tissue transmurally from the endocardium to the epicardium. In general, the cross-sectional area of lesions is elliptical, that is, it is larger proximally and smaller distally. To ensure sufficient distal damage for a transmural lesion, more proximal tissue has to be sacrificed. Another extra loss of tissue is necessitated because of convective cooling by the arterial blood flow that will carry some heat away, limiting distal lesion formation. To create adequate distal lesions, extra proximal tissue must be sacrificed. In contrast, IRE ablation is not based on a time-dependent thermal mechanism. By selecting the optimized IRE protocol parameters and electrode configuration, a well-controlled ablation region can be expected, with a clear ablated-unablated boundary.
Charring and “steam pop”
During RFA, charring hinders heat conduction, thus affecting the efficacy of lesion formation. Additionally, if tissue temperatures exceed the catheter tip temperature and go beyond 100°C, steam explosions can occur, which are known as “steam pops”. They can cause superficial craters or deep tissue tears, which can lead to cardiac perforation and tamponade. Fortunately, due to the nature of PEF energy, the non-thermal IRE PEF ablation mechanism eliminates high-temperature phenomena that occur during RFA such as catheter tip charring and “steam pops”.[66,67]
Tissue-catheter contact dependence
For RFA, achieving good tissue-catheter contact is critical to produce adequate lesion depth and width. Insufficient contact between the tissue and electrode may lead to shallow and discontinuous lesions that may not be acutely effective. Insufficient contact force (between the electrode tip and the myocardium wall) can result in inadequate lesion formation and higher rates of PV re-connection, but excessive contact force can result in complications such as perforation. Therefore, continuous monitoring of the contact force would be expected to maximize the ablation efficacy of RFA and improve its safety. In contrast, IRE relies on tissue proximity and is not solely contact dependent, because it depends on the lethal electric field strength. Although the relationship between the electric field and the applied external voltage is complicated in the heterogeneous tissue, the local electric field still equals local voltage divided by distance at the specific point. If the local voltage increases and the distance is constant, the local electric field increases. The creation of an electric field, rather than contact-dependent lesions, is an attractive feature of cardiac IRE ablation, which does not require good contact between the tissue and catheter tip, eliminating the need for contact force sensing and the dependence on tissue temperatures that cause cell death.
Limitations associated with IRE ablation
Owing to the short history of development of IRE ablation as an AF treatment, the clinical limitations have not yet been fully explored. However, the following is a list of a few of the most concerning limitations.
Involuntary muscle contractions
Conventional IRE DC ablation, which was routinely applied between 1980 and 1990 for the ablation of the bundle of His and ventricular tachycardia, can lead to significant involuntary skeletal muscle contractions and pain, necessitating the use of complete anesthesia. The DC is delivered in a unipolar fashion, involving an active electrode coupled with a reference dispersal electrode patch on the skin. By contrast, bipolar energy delivered between local electrodes may confine the electric field, resulting in effective local tissue ablation without significant muscle contractions. Depending on the delivered energy, complete anesthesia may or may not be required. In 2019, Reddy et al reported that, in 15 out of 81 patients undergoing monophasic PEF ablation under general anesthesia, skeletal muscle contractions were not observed. In a group of 106 patients undergoing biphasic procedures under conscious sedation, only mild degrees of muscle activation that were well tolerated were observed, and there was occasional transient intra-procedural cough.
Bubble formation and arcing
Standard DC causes electrolysis on the metal electrode surfaces in the blood pool, thus producing micro bubbles containing the gaseous products of electrolysis. Arcing is another phenomenon that occurs when a critical electric current density between the electrode and surrounding blood is reached; the resulting flash or arc leads to a transient temperature rise up to a thousand within the bubble. In 2011, Wittkampf et al explored low-energy DC with a modified electrode configuration and reported the creation of myocardial lesions without arcing and only small gas bubbles that adhered to the metal electrode surface and disappeared within a few seconds. Furthermore, using a low-energy PEF protocol, in 2019, Reddy et al reported no arcing or significant visible bubble formation.
Cardiac fiber orientation dependence
The local electric field distribution (electric current density divided by conductivity tensor) determines the effective ablated cardiac tissue region. Due to the anisotropic orientation of cardiac fibers, a lethal electric field cannot create consistent lesions, according to a numerical model reported by Xie and Zemlin in 2016. In addition, the existence of fibrosis and blood vessels can make the myocardium conductivity even more heterogeneous. Moreover, the electrical conductivity of infarcted myocardial tissue is higher than that of healthy myocardial tissue. Therefore, IRE protocols must be tailored according to the target cardiac tissue, to make the ablation lesion more consistent. Unfortunately, due to the complicated geometry of the heart, there are very few studies to investigate how varying conductivity and protocol modifications affect heterogeneous ablation lesions.
Areas of reversibility
RFA-induced non-conductive lesions (including complete and incomplete) originate from the combination of irreversible and reversible atrial thermal injury. An incomplete lesion involving reversible damage can cause temporary electric uncoupling but not complete cell death at ≤3.5 mm from the lesion boundary (dependent on tissue temperature and tissue geometry), which increases the risk of long-term AF recurrence. Owing to the short history of use of IRE ablation, there is a lack of evidence on whether it can cause irreversible injury, and it is not clear how far away from the lesion boundary temporary non-conductivity can occur.
Conclusion and future perspectives
IRE ablation has significant potential to become an important ablation modality in both invasive and interventional cardiology. In the field of AF treatment, the unique ability of IRE to induce a tissue-selective and well-controlled ablation zone with no thermal damage offers important advantages, as its non-thermal nature reduces the risk of complications, such as PV stenosis, coronary artery damage, phrenic nerve injury, and atrio-esophageal fistula. The absence of a large thermal effect also decreases the ablation procedure duration, lowers the recurrence rate, avoids charring, and may allow direct treatment of vessels, where the muscular cell layer is destroyed but the structural integrity of the vessel is preserved, as has been demonstrated in previous studies.[64,73] A high level of safety has been demonstrated due to IRE's tissue selectivity, which spares nerves, coronary arteries, esophageal muscle, phrenic nerves, and PVs, while destroying the myocardium. However, the mechanism underlying the lower IRE electric field strength threshold of cardiac tissue compared to surrounding tissues is not completely clear. It may be related to cell size, cardiac fiber orientation, membrane characteristics, and sensitivity to non-specific cation entry. With axons connected, only parts of nearby collateral membranes are exposed to the IRE electric field, but these parts may be too small for the effects to be lethal. It has been confirmed in animal and human studies that IRE ablation does not have many of the short-term complications of RFA.[74,75] However, long-term follow-up (using computed tomography/magnetic resonance imaging) to assess long-term complications such as PV stenosis, coronary artery damage, phrenic nerve injury, and atrio-esophageal fistula is required before IRE ablation technology is applied clinically.
In terms of efficacy, efforts should be made to develop IRE ablation strategies that achieve more durable lesions. Ablation strategies to ensure permanent PVI (to prevent recurrent PV-LA conduction) may have the greatest impact on reducing AF recurrence. Although Reddy et al reported that IRE PEF ablation with waveform refinement improved the PVI durability at 3 months from 18% to 100%, provocative testing with adenosine or isoproterenol was not performed, and longer-term research needs to be conducted to ensure that the number of patients with permanent PVI is increased, which will result in a lower AF recurrence rate. Until recently, IRE ablation catheters have been used for PV ablation, but new IRE ablation catheters can be used for non-PV ablation, including posterior wall isolation and lines of conduction block; moreover, a study found that Purkinje tissue can be ablated using IRE without any evidence of underlying myocardial damage.
Although pre-clinical studies indicate excellent efficacy and safety profiles for IRE ablation, it has several disadvantages, such as the need for general anesthesia and neuromuscular paralysis to avoid skeletal muscle contractions; furthermore, arcing and bubble formation need to be avoided. Thus, an optimized IRE ablation protocol that avoids muscle contraction, pain, arcing, and bubble formation is highly desired. Additionally, the features of cardiac fiber orientation dependence and areas of reversibility need to be investigated, to fully understand the whole picture of how to exploit this promising technique that may replace conventional RFA.
IRE PEF ablation is a new technique for treating AF. Animal and clinical studies have confirmed its feasibility and safety.[64,73] The limited preliminary data are promising. The technique has strong tissue specificity and a short ablation time, which can effectively reduce perioperative complications and shorten the operation time. The limited data currently available indicate that the injury caused by IRE PEF ablation is tissue specific, and the risks of complications such as PV stenosis, nerve injury, and atrial esophageal fistula are low. However, at present, clinical research on this technique is rare, the sample sizes are small, the follow-up periods are short, and it is necessary to carry out surgery under general anesthesia, which currently limits its extensive clinical use. There is still a lack of robust data on the efficacy of IRE ablation for AF compared to conventional RFA/CB ablation, which needs to be further investigated using randomized controlled trials.
This work was supported by National S&T Major Project (2018ZX10301201), Chinese Natural Science Foundation Grants (82027803), Science and Technology Development Special Fund of Shanghai Health and Family Planning Commission (ZK2019B25), Plateau Discipline Construction Fund of Pudong New Area Health and Family Planning Commission (PWYgy2018-03), Chinese Academy of Engineering (2019-ZD-6-01), and Zhejiang University Education Foundation (2020XGZX063).
Conflicts of Interest
. Son MK, Lim NK, Kim HW, et al. Risk of ischemic stroke after atrial fibrillation diagnosis: a national sample cohort. PLoS One 2017;12(6):e0179687. doi: 10.1371/journal.pone.0179687.
. Chyou JY, Hunter TD, Mollenkopf SA, et al. Individual and combined risk factors for incident atrial fibrillation and incident stroke: an analysis of 3 million at-risk US patients. J Am Heart Assoc 2015;4(7):e001723. doi: 10.1161/JAHA.114.001723.
. Chung MK, Eckhardt LL, Chen LY, et al. Lifestyle and risk factor modification for reduction of atrial fibrillation: a scientific statement from the American Heart Association. Circulation 2020;141(16):e750–e772. doi: 10.1161/CIR.0000000000000748.
. Chen Q, Yi Z, Cheng J. Atrial fibrillation in aging population. Aging Med (Milton) 2018;1(1):67–74. doi: 10.1002/agm2.12015.
. Morillo CA, Banerjee A, Perel P, et al. Atrial fibrillation: the current epidemic. J Geriatr Cardiol 2017;14(3):195–203. doi: 10.11909/j.issn.1671-5411.2017.03.011.
. Stewart S, Murphy NF, Walker A, et al. Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart 2004;90(3):286–292. doi: 10.1136/hrt.2002.008748.
. Munir MB, Khan MZ, Darden D, et al. Pericardial effusion requiring intervention in patients undergoing percutaneous left atrial appendage occlusion: prevalence, predictors, and associated in-hospital adverse events from 17,700 procedures in the United States. Heart Rhythm 2021;18(9):1508–1515. doi: 10.1016/j.hrthm.2021.05.017.
. Kornej J, Börschel CS, Benjamin EJ, et al. Epidemiology of atrial fibrillation in the 21st century: novel methods and new insights. Circ Res 2020;127(1):4–20. doi: 10.1161/CIRCRESAHA.120.316340.
. du Pré BC, van Driel VJ, van Wessel H, et al. Minimal coronary artery damage by myocardial electroporation ablation
. Europace 2013;15(1):144–149. doi: 10.1093/europace/eus171.
. Thiagalingam A, Campbell CR, Boyd A, et al. Catheter intramural needle radiofrequency ablation
creates deeper lesions than irrigated tip catheter ablation
. Pacing Clin Electrophysiol 2003;26(11):2146–2150. doi: 10.1046/j.1460-9592.2003.00334.x.
. Di Biase L, Fahmy TS, Patel D, et al. Remote magnetic navigation: human experience in pulmonary vein ablation
. J Am Coll Cardiol 2007;50(9):868–874. doi: 10.1016/j.jacc.2007.05.023.
. Cochet H, Sacher F, Chaumeil A, et al. Steam pop during radiofrequency ablation
: imaging features on magnetic resonance imaging and multidetector computed tomography. Circ Arrhythm Electrophysiol 2014;7(3):559–560. doi: 10.1161/CIRCEP.113.001418.
. Haghshenas H, Mansoori P, Najafi S, et al. The effect of changes in patients’ body position on the back pain intensity and hemodynamic status during and after radiofrequency catheter ablation
of cardiac dysrhythmias. Iran J Nurs Midwifery Res 2013;18(2):89–93.
. Deshmukh A, Patel NJ, Pant S, et al. In-hospital complications associated with catheter ablation
of atrial fibrillation in the United States between 2000 and 2010: analysis of 93 801 procedures. Circulation 2013;128(19):2104–2112. doi: 10.1161/CIRCULATIONAHA.113.003862.
. Yokoyama K, Nakagawa H, Wittkampf FH, et al. Comparison of electrode cooling between internal and open irrigation in radiofrequency ablation
lesion depth and incidence of thrombus and steam pop. Circulation 2006;113(1):11–19. doi: 10.1161/CIRCULATIONAHA.105.540062.
. Ueda M, Tada H, Kurosaki K, et al. Pulmonary vein morphology before and after segmental isolation in patients with atrial fibrillation. Pacing Clin Electrophysiol 2005;28(9):944–953. doi: 10.1111/j.1540-8159.2005.00214.x.
. Loh KB, Bux SI, Abdullah BJ, et al. Hemorrhagic cardiac tamponade: rare complication of radiofrequency ablation
of hepatocellular carcinoma. Korean J Radiol 2012;13(5):643–647. doi: 10.3348/kjr.2012.13.5.643.
. Bhaskaran A, Chik W, Thomas S, et al. A review of the safety aspects of radio frequency ablation
. Int J Cardiol Heart Vasc 2015;8:147–153. doi: 10.1016/j.ijcha.2015.04.011.
. Mears JA, Lachman N, Christensen K, et al. The phrenic nerve and atrial fibrillation ablation
procedures. J Atr Fibrillation 2009;2(1):176. doi: 10.4022/jafib.176.
. Zhang P, Zhang YY, Ye Q, et al. Characteristics of atrial fibrillation patients suffering esophageal injury caused by ablation
for atrial fibrillation. Sci Rep 2020;10(1):2751. doi: 10.1038/s41598-020-59539-6.
. Andrade JG. Cryoballoon ablation
for pulmonary vein isolation. J Cardiovasc Electrophysiol 2020;31(8):2128–2135. doi: 10.1111/jce.14459.
. Fortuni F, Casula M, Sanzo A, et al. Meta-analysis comparing cryoballoon versus radiofrequency as first ablation
procedure for atrial fibrillation. Am J Cardiol 2020;125(8):1170–1179. doi: 10.1016/j.amjcard.2020.01.016.
. Witkowska A, Suwalski P. Insights from advancements and pathbreaking research on the minimally invasive treatment of atrial fibrillation. J Thorac Dis 2021;13(3):2000–2009. doi: 10.21037/jtd-20-1876.
. Cox JL, Malaisrie SC, Churyla A, et al. Cryosurgery for atrial fibrillation: physiologic basis for creating optimal cryolesions. Ann Thorac Surg 2021;112(2):354–362. doi: 10.1016/j.athoracsur.2020.08.114.
. Chang DC, Reese TS. Changes in membrane structure induced by electroporation as revealed by rapid-freezing electron microscopy. Biophys J 1990;58(1):1–12. doi: 10.1016/S0006-3495(90)82348-1.
. Lavee J, Onik G, Mikus P, et al. A novel nonthermal energy source for surgical epicardial atrial ablation
: irreversible electroporation. Heart Surg Forum 2007;10(2):E162–E167. doi: 10.1532/HSF98.20061202.
. Hong J, Stewart MT, Cheek DS, et al. Cardiac ablation
via electroporation. Annu Int Conf IEEE Eng Med Biol Soc 2009;2009:3381–3384. doi: 10.1109/IEMBS.2009.5332816.
. Wittkampf FH, van Driel VJ, van Wessel H, et al. Feasibility of electroporation for the creation of pulmonary vein ostial lesions. J Cardiovasc Electrophysiol 2011;22(3):302–309. doi: 10.1111/j.1540-8167.2010.01863.x.
. Wittkampf FH, van Driel VJ, van Wessel H, et al. Myocardial lesion depth with circular electroporation ablation
. Circ Arrhythm Electrophysiol 2012;5(3):581–586. doi: 10.1161/CIRCEP.111.970079.
. Neven K, van Driel V, van Wessel H, et al. Epicardial linear electroporation ablation
and lesion size. Heart Rhythm 2014;11(8):1465–1470. doi: 10.1016/j.hrthm.2014.04.031.
. van Driel VJ, Neven K, van Wessel H, et al. Low vulnerability of the right phrenic nerve to electroporation ablation
. Heart Rhythm 2015;12(8):1838–1844. doi: 10.1016/j.hrthm.2015.05.012.
. Xie F, Varghese F, Pakhomov AG, et al. Ablation
of myocardial tissue with nanosecond pulsed electric fields. PLoS One 2015;10(12):e0144833. doi: 10.1371/journal.pone.0144833.
. Neven K, van Es R, van Driel V, et al. Acute and long-term effects of full-power electroporation ablation
directly on the porcine esophagus. Circ Arrhythm Electrophysiol 2017;10(5):e004672. doi: 10.1161/CIRCEP.116.004672.
. Reddy VY, Koruth J, Jais P, et al. Ablation
of atrial fibrillation with pulsed electric fields: an ultra-rapid, tissue-selective modality for cardiac ablation
. JACC Clin Electrophysiol 2018;4(8):987–995. doi: 10.1016/j.jacep.2018.04.005.
. van Es R, Konings MK, Du Pré BC, et al. High-frequency irreversible electroporation for cardiac ablation
using an asymmetrical waveform. Biomed Eng Online 2019;18(1):75. doi: 10.1186/s12938-019-0693-7.
. Reddy VY, Neuzil P, Koruth JS, et al. Pulsed field ablation
for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2019;74(3):315–326. doi: 10.1016/j.jacc.2019.04.021.
. Reddy VY, Dukkipati SR, Neuzil P, et al. Pulsed field ablation
of paroxysmal atrial fibrillation: 1-year outcomes of IMPULSE, PEFCAT, and PEFCAT II. JACC Clin Electrophysiol 2021;7(5):614–627. doi: 10.1016/j.jacep.2021.02.014.
. Wittkampf FHM, van Es R, Neven K. Electroporation and its relevance for cardiac catheter ablation
. JACC Clin Electrophysiol 2018;4(8):977–986. doi: 10.1016/j.jacep.2018.06.005.
. Gallagher JJ, Svenson RH, Kasell JH, et al. Catheter technique for closed-chest ablation
of the atrioventricular conduction system. N Engl J Med 1982;306(4):194–200. doi: 10.1056/NEJM198201283060402.
. Caluori G, Odehnalova E, Jadczyk T, et al. AC pulsed field ablation
is feasible and safe in atrial and ventricular settings: a proof-of-concept chronic animal study. Front Bioeng Biotechnol 2020;8:552357. doi: 10.3389/fbioe.2020.552357.
. Kotnik T, Kramar P, Pucihar G, et al. Cell membrane electroporation-Part 1: the phenomenon. IEEE Electr Insul Mag 2012;28(5):14–23. doi: 10.1109/Mei.2012.6268438.
. Davalos RV, Mir IL, Rubinsky B. Tissue ablation
with irreversible electroporation. Ann Biomed Eng 2005;33(2):223–231. doi: 10.1007/s10439-005-8981-8.
. Rubinsky B, Onik G, Mikus P. Irreversible electroporation: a new ablation
modality—clinical implications. Technol Cancer Res Treat 2007;6(1):37–48. doi: 10.1177/153303460700600106.
. Edd JF, Horowitz L, Davalos RV, et al. In vivo results of a new focal tissue ablation
technique: irreversible electroporation. IEEE Trans Biomed Eng 2006;53(7):1409–1415. doi: 10.1109/TBME.2006.873745.
. Kawamura I, Neuzil P, Shivamurthy P, et al. How does the level of pulmonary venous isolation compare between pulsed field ablation
and thermal energy ablation
(radiofrequency, cryo, or laser). Europace 2021;23(11):1757–1766. doi: 10.1093/europace/euab150.
. Anic A, Breskovic T, Sikiric I. Pulsed field ablation
: a promise that came true. Curr Opin Cardiol 2021;36(1):5–9. doi: 10.1097/HCO.0000000000000810.
. Verma MS, Terricabras M, Verma A. The cutting edge of atrial fibrillation ablation
. Arrhythm Electrophysiol Rev 2021;10(2):101–107. doi: 10.15420/aer.2020.40.
. Howard B, Haines DE, Verma A, et al. Reduction in pulmonary vein stenosis and collateral damage with pulsed field ablation
compared with radiofrequency ablation
in a canine model. Circ Arrhythm Electrophysiol 2020;13(9):e008337. doi: 10.1161/CIRCEP.120.008337.
. Neven K, van Driel V, van Wessel H, et al. Safety and feasibility of closed chest epicardial catheter ablation
using electroporation. Circ Arrhythm Electrophysiol 2014;7(5):913–919. doi: 10.1161/CIRCEP.114.001607.
. Koruth JS, Kuroki K, Kawamura I, et al. Pulsed field ablation
versus radiofrequency ablation
: esophageal injury in a novel porcine model. Circ Arrhythm Electrophysiol 2020;13(3):e008303. doi: 10.1161/CIRCEP.119.008303.
. Boersma LV, van der Voort P, Debruyne P, et al. Multielectrode pulmonary vein isolation versus single tip wide area catheter ablation
for paroxysmal atrial fibrillation: a multinational multicenter randomized clinical trial. Circ Arrhythm Electrophysiol 2016;9(4):e003151. doi: 10.1161/CIRCEP.115.003151.
. Cappato R, Negroni S, Pecora D, et al. Prospective assessment of late conduction recurrence across radiofrequency lesions producing electrical disconnection at the pulmonary vein ostium in patients with atrial fibrillation. Circulation 2003;108(13):1599–1604. doi: 10.1161/01.CIR.0000091081.19465.F1.
. Callans DJ, Gerstenfeld EP, Dixit S, et al. Efficacy of repeat pulmonary vein isolation procedures in patients with recurrent atrial fibrillation. J Cardiovasc Electrophysiol 2004;15(9):1050–1055. doi: 10.1046/j.1540-8167.2004.04052.x.
. Verma A, Kilicaslan F, Pisano E, et al. Response of atrial fibrillation to pulmonary vein antrum isolation is directly related to resumption and delay of pulmonary vein conduction. Circulation 2005;112(5):627–635. doi: 10.1161/CIRCULATIONAHA.104.533190.
. Sultan A, Lüker J, Andresen D, et al. Predictors of atrial fibrillation recurrence after catheter ablation
: data from the German Ablation
Registry. Sci Rep 2017;7(1):16678. doi: 10.1038/s41598-017-16938-6.
. Kumar S, Michaud GF. Unipolar electrogram morphology to assess lesion formation during catheter ablation
of atrial fibrillation: successful translation into clinical practice. Circ Arrhythm Electrophysiol 2013;6(6):1050–1052. doi: 10.1161/CIRCEP.113.001145.
. Gerstenfeld EP, Callans DJ, Dixit S, et al. Incidence and location of focal atrial fibrillation triggers in patients undergoing repeat pulmonary vein isolation: implications for ablation
strategies. J Cardiovasc Electrophysiol 2003;14(7):685–690. doi: 10.1046/j.1540-8167.2003.03013.x.
. Wood MA, Fuller IA. Acute and chronic electrophysiologic changes surrounding radiofrequency lesions. J Cardiovasc Electrophysiol 2002;13(1):56–61. doi: 10.1046/j.1540-8167.2002.00056.x.
. Ranjan R, Kato R, Zviman MM, et al. Gaps in the ablation
line as a potential cause of recovery from electrical isolation and their visualization using MRI. Circ Arrhythm Electrophysiol 2011;4(3):279–286. doi: 10.1161/CIRCEP.110.960567.
. Ramirez FD, Reddy VY, Viswanathan R, et al. Emerging technologies for pulmonary vein isolation. Circ Res 2020;127(1):170–183. doi: 10.1161/CIRCRESAHA.120.316402.
. Schmidt B, Neuzil P, Luik A, et al. Laser balloon or wide-area circumferential irrigated radiofrequency ablation
for persistent atrial fibrillation: a multicenter prospective randomized study. Circ Arrhythm Electrophysiol 2017;10(12):e005767. doi: 10.1161/CIRCEP.117.005767.
. Bachu VS, Kedda J, Suk I, et al. High-intensity focused ultrasound: a review of mechanisms and clinical applications. Ann Biomed Eng 2021;49(9):1975–1991. doi: 10.1007/s10439-021-02833-9.
. Ishidoya Y, Ranjan R. Novel energy source for ablating the pulmonary veins; is pulsed field ablation
the new ablation
modality. J Cardiovasc Electrophysiol 2021;32(4):970–972. doi: 10.1111/jce.14982.
. Stewart MT, Haines DE, Miklavčič D, et al. Safety and chronic lesion characterization of pulsed field ablation
in a porcine model. J Cardiovasc Electrophysiol 2021;32(4):958–969. doi: 10.1111/jce.14980.
. Seiler J, Roberts-Thomson KC, Raymond JM, et al. Steam pops during irrigated radiofrequency ablation
: feasibility of impedance monitoring for prevention. Heart Rhythm 2008;5(10):1411–1416. doi: 10.1016/j.hrthm.2008.07.011.
. Neven K, Füting A, Byrd I, et al. Absence of (sub-)acute cerebral events or lesions after electroporation ablation
in the left-sided canine heart. Heart Rhythm 2021;18(6):1004–1011. doi: 10.1016/j.hrthm.2021.02.015.
. Groen MHA, van Es R, van Klarenbosch BR, et al. In vivo analysis of the origin and characteristics of gaseous microemboli during catheter-mediated irreversible electroporation. Europace 2021;23(1):139–146. doi: 10.1093/europace/euaa243.
. Barnett AS, Bahnson TD, Piccini JP. Recent advances in lesion formation for catheter ablation
of atrial fibrillation. Circ Arrhythm Electrophysiol 2016;9(5):10. doi: 10.1161/CIRCEP.115.003299.
. Bardy GH, Sawyer PL. Biophysical and anatomical considerations for safe and efficacious catheter ablation
of arrhythmias. Clin Cardiol 1990;13(6):425–433. doi: 10.1002/clc.4960130611.
. Xie F, Zemlin CW. Effect of twisted fiber anisotropy in cardiac tissue on ablation
with pulsed electric fields. PLoS One 2016;11(4):e0152262. doi: 10.1371/journal.pone.0152262.
. Miklavčič D. Cardiac ablation
by electroporation. JACC Clin Electrophysiol 2018;4(11):1481–1482. doi: 10.1016/j.jacep.2018.09.014.
. Zager Y, Kain D, Landa N, et al. Optimization of irreversible electroporation protocols for in-vivo myocardial decellularization. PLoS One 2016;11(11):e0165475. doi: 10.1371/journal.pone.0165475.
. Yavin H, Brem E, Zilberman I, et al. Circular multielectrode pulsed field ablation
catheter lasso pulsed field ablation
: lesion characteristics, durability, and effect on neighboring structures. Circ Arrhythm Electrophysiol 2021;14(2):e009229. doi: 10.1161/CIRCEP.120.009229.
. Nakatani Y, Sridi-Cheniti S, Cheniti G, et al. Pulsed field ablation
prevents chronic atrial fibrotic changes and restrictive mechanics after catheter ablation
for atrial fibrillation. Europace 2021;23(11):1767–1776. doi: 10.1093/europace/euab155.
. Koruth JS, Kuroki K, Kawamura I, et al. Focal pulsed field ablation
for pulmonary vein isolation and linear atrial lesions: a preclinical assessment of safety and durability. Circ Arrhythm Electrophysiol 2020;13(6):e008716. doi: 10.1161/CIRCEP.120.008716.
. Livia C, Sugrue A, Witt T, et al. Elimination of Purkinje fibers by electroporation reduces ventricular fibrillation vulnerability. J Am Heart Assoc 2018;7(15):e009070. doi: 10.1161/JAHA.118.009070.