Coronary Spasm Due to Pulsed Field Ablation: A State‐of‐the‐Art Review

ABSTRACT

With the ever‐growing population of patients undergoing cardiac ablation with pulsed electric fields, there is a need to understand secondary effects from the therapy. Coronary artery spasm is one such effect that has recently emerged as the subject of further investigation in electrophysiology literature. This review aims to elucidate the basic anatomy underlying vascular spasm due to pulsed electric fields and the effects of irreversible electroporation on coronary arteries. This review also aims to gather the current preclinical and clinical data regarding the physiology and function of coronary arteries following electroporation.

Abbreviations

CA

coronary artery

CTGF

connective tissue growth factor

CTI

cavotricuspid isthmus

ECM

extracellular matrix

IRE

irreversible electroporation

MLCP

myosin light chain phosphatase

PFA

pulsed field ablation

RF

radiofrequency

VSM

vascular smooth muscle

1. Introduction

Pulsed field ablation (PFA), also known as irreversible electroporation (IRE), has been rapidly adopted in the treatment for atrial fibrillation (AF) [1, 2]. Recently, commercial use of this technology has been approved in most global markets, and the number of patients treated with PFA increases daily.

The current clinically approved PFA devices are indicated for the treatment of paroxysmal and/or persistent AF [3, 4, 5]. PFA systems approved for use in at least one worldwide geography include the FARAPULSE system with the FARAWAVE pentaspline catheter from Boston Scientific, the PulseSelect system from Medtronic, as well as its Affera system with the Sphere‐9 catheter, the VARIPULSE system from Biosense Webster, and the CENTAURI system from CardioFocus. These systems are a mixture of “single‐shot” devices, where the goal is to achieve pulmonary vein isolation (PVI) (FARAWAVE, PulseSelect, and VARIPULSE catheters), and point‐by‐point ablation (Sphere‐9 and Centauri‐compatible catheters).

As PFA use increases in the treatment of arrhythmias, there has been an expansion of its clinical use beyond PVI, or isolation of the left atrial posterior wall. The treatment of persistent AF as well as additional arrhythmias has resulted in the use of PFA in closer proximity to potentially sensitive structures such as the coronary arteries (CAs) than previously observed. PFA has often been referred to as “tissue selective,” at least from a chronic lesion standpoint, though its effects on the CAs were initially not well understood [6]. In early cardiac PFA clinical trials, there were no significant coronary artery adverse effects reported [7]. The first known human presentation of CA spasm resulting from PFA was reported by Gunawardene et al. [8] during ablation of the mitral isthmus, an off‐label use of the pentaspline catheter (FARAWAVE, Boston Scientific). Since then, other reports have surfaced of CA spasm from predominantly off‐label use of the pentaspline catheter and other catheters, mostly during ablation of the mitral isthmus or cavotricuspid isthmus (CTI). These reports raised interest in whether these coronary spasm events were related to PFA itself [8] or caused by some other mechanism. Later, with other reports of coronary spasm or related symptoms (e.g., ST‐segment elevation) from different PFA systems, it became clear these events were likely a class effect of PFA [9, 10, 11].

This review aims to discuss the potential mechanisms underlying coronary artery spasm with PFA, detail preclinical work evaluating PFA effects on the CAs, and review clinical evidence of the effects of pulsed fields on coronary vessels.

2. Coronary Artery Anatomy and Physiology

CAs are composed of three tissue (tunica) layers: intima, media, and externa [12] (see Figure 1). The tunica intima is the innermost layer where an abundance of extracellular matrix (ECM) and collagen reside, which helps maintain structure and patency of the vessel [13, 14, 15]. The tunica intima also regulates constriction of the arteries based on luminal pressure and metabolic needs [16]. Nitric oxide (NO) is formed in the tunica intima and can diffuse to the tunica media to upregulate vascular relaxation [17]. Nitroglycerin, which metabolizes into NO, is the most commonly used drug for vascular dilatation with a proven medical history [18].

FIGURE 1.

Gross anatomy and cross section of a coronary artery. The smooth muscle cells are mainly located in the tunica media of the artery. Note the direction of the actin‐myosin crisscrossing within the cell. Activation of contractility does not take orientation in its regard. [Colour figure can be viewed at wileyonlinelibrary.com]

The tunica media is where the vascular smooth muscle (VSM) resides along with collagen and elastin. VSM regulates arterial tone and blood flow by contracting to narrow or relaxing to expand the luminal space in response to external or internal stimuli on the arterial vessel [19]. The mechanism of contraction is through the cross‐binding of actin‐myosin bridges; however, unlike skeletal muscle, the actin‐myosin complexes are not uniformly aligned but instead arranged like a mesh [20]. This mesh‐like structure allows the smooth muscle cell to contract in all directions. The activation of the actin‐myosin bridges is through calcium binding. Intracellular calcium concentration mediates the strength of contraction by causing conformational changes immediately after binding [21]. Relaxation is mediated by myosin light chain phosphatase (MLCP). Activation of the MLCP complex is through a series of biochemical signaling cascades that start with an influx of NO into the cell [17]. Relaxation is a calcium‐independent process; therefore, even if calcium is lost from the intracellular space, the speed of relaxation is unchanged. This leads to prolonged contraction even after the calcium gradient has been depleted [22].

The tunica media is of special interest in cardiac health since it is where neointima formation (the generation of new intimal cells) takes place. This occurs when VSM cells migrate from the tunica media into the tunica intima, disrupting size, tonicity, and structural integrity [23]. Neointima formation is clinically relevant as a main cause of coronary narrowing (restenosis) following stent placement. Restenosis can have a major impact on patient health and may require clinical intervention. The mechanism of lesion formation is due to overstress of the intima during stent deployment, causing disruption of the structural components of the arterial wall [24]. Radiofrequency (RF) ablation has also been known to cause neointima formation due to collagen denaturation resulting from excessive heat [25]. The tunica externa is mostly comprised of fibroblasts that respond to stimuli and can initiate fibrotic changes [26]. These elements of the tunica externa do not take part in the mechanisms of vascular contraction and relaxation and have not been shown to be affected by electrical fields.

3. Electric Fields Effects on CAs

VSM cells, much like skeletal muscle cells, can be electrically induced to contract [27]. Electrical currents passing through arterial vascular tissue can evoke either action potentials in nerves, or a direct muscle activation, both of which result in a contraction. The main difference between induction of contraction via an action potential or direct muscle activation is the timing of the electrical pulse. The chronaxie, or minimum time required for activation, for nervous stimulation is around 0.1 ms, while the chronaxie for direct muscle activation is around 5 ms [28]. This large difference can be attributed to fast sodium channels that are present in nerves as opposed to activation mediated by calcium in the muscles [22].

Once the muscle cells have contracted, they remain in this state for a much longer time than the activation signal. That is, the action potential generated by electrical currents that causes the rise and fall of calcium in the cell is much shorter than the active contraction time. This contraction time is also resistant to external stimuli and certain pharmacological agents since the VSM relaxation is mediated by multiple biochemical cascades and intracellular calcium concentration. Neurotransmitters, ATP‐blockers, and adrenoreceptor antagonists have been shown to be ineffective at reducing or preventing electrically induced VSM contraction [29]. Electrical currents have also not been shown to alter the naturally occurring wave propagation of extracellular calcium [30]. These extracellular calcium waves are responsible for voltage‐gated calcium channel activation that increases intracellular calcium concentration, leading to contraction. In contrast, electrical currents have been shown to alter only intracellular calcium concentration, and this excess of calcium can only be cleared by intracellular mechanisms. Thus, the result is the aforementioned prolonged contraction [31]. The fact that extracellular calcium propagation remains largely unchanged by electrical stimulation, and that relaxation is resistant to neurotransmitter blockers points to direct muscle stimulation, not a nervous response, as the driver of contraction due to electrical stimulation. This contraction is characterized by a slow mechanism of relaxation via the MLCP process [29].

Excitation due to electroporation could further exacerbate the prolonged duration of contraction of VSM cells. The large electric fields create pores that would further disrupt calcium intake into the cells, as well as activate voltage‐gated calcium channels and promote calcium‐dependent calcium release from the sarcoplasmic reticulum [20]. Electroporation has also been shown to increase the intracellular calcium levels by expanding pore size due to calcium‐mediated stabilization of the pores [32]. The concentration of intracellular calcium is then increased by several magnitudes, while the permeabilization of the cell membrane disrupts active membrane processes that would normally regulate calcium to normal levels [32]. This leads to unregulated activation of actin‐myosin bridges and to a vascular spasm that can last for minutes [33].

NO can help ameliorate the spasm resulting from electroporation induced VSM contraction. The relaxation of VSM cells is a slow process compared to the excitation caused by the additional intracellular calcium, which could explain the long spasm times observed following electroporation [34]. The concentration of MLCP is magnitudes lower than calcium that has entered the cell due to nondiscriminatory pores caused by electroporation. While clinical reports, further described later, delineate resolution of spasm in the time course of minutes, it is not fully understood whether the applied electric field results in IRE of VSM cells (versus a reversible, transient effect), and how the vascular physiology changes as a result.

For successful ablation of cardiac tissue at a therapeutic depth, the applied electric fields near the surface of catheter electrodes are much higher than the minimum IRE threshold for cardiomyocytes. These higher electric field levels mean that CAs, if they are close enough to the catheter electrodes, could experience IRE even though vascular tissue has a higher minimum IRE threshold than myocardial tissue. It is important to understand the effects of IRE on the arterial wall and the effects of VSM cell death.

If the CA wall were to be fully and irreversibly electroporated, a total loss of VSM would eventually occur in the tunica media of the arterial walls (as can be seen in Figure 2), though the structural elements would still be intact. That is, the extracellular matrix, collagen lattice, and all connective tissue would remain mostly unaffected by the large electric fields [34, 35]. The nature of intact structural components maintains the integrity of the arterial wall and promotes VSM cell proliferation in the tunica media, thus minimizing the risk for neointima hyperplasia [34, 36]. This contrasts damage to the CA structure by thermal mechanisms, such as RF ablation, where the disruption to collagen and extracellular matrix can lead to significant neointima hyperplasia [37].

FIGURE 2.

Control (left), Day 7 (middle), and Day 35 (right). Top row shows the absence of VSM cells in the PFA‐treated arteries when compared with the control. Tunica media at Day 7 is marked with asterisks, and regenerated cellular components at Day 35 are marked with an arrow. The middle row shows the absence of multiplying cells at 7 days (asterisks) and a relatively active process at 35 days, with some cells staining positive (arrow). Lower row shows that the endothelial layer at 35 days is regenerated and regular in shape, with the endothelial cells producing the vWF molecule (arrow). Reproduced from Maor et al., “Vascular smooth muscle cells ablation with endovascular nonthermal IRE,” Journal of Vascular and Interventional Radiology 21, no. 11 (2010): 1708–1715, with permission from Elsevier. SMA = smooth muscle actin, vWF = Von Willebrand factor. [Colour figure can be viewed at wileyonlinelibrary.com]

From an understanding of the basic anatomy and mechanisms of vascular contraction, it is evident that injection of current, from PFA or other mechanisms, can evoke CA spasm. In the context of PFA, the current can be directly generated by the applied voltage or by the ion (i.e., calcium) imbalance caused by the electroporation. Since VSM has a complex‐mediated relaxation mechanism via the MLCP, electrically evoked vascular spasms tend to last longer than the stimulus signal and persist even after calcium has returned to normal levels [29]. How does this present in a clinical setting? The following sections explore the translational data from preclinical studies where coronary artery spasm was studied and a review of the clinical evidence of arterial spasm due to pulsed electric fields.

4. Preclinical Studies

There are few studies that explore the lethal thresholds from electroporation in VSM. Due to this, the approximate electric field threshold for IRE of VSM is not well established. In one such study, Maor et al. electroporated rat carotid vessels at different energy and waveform levels, finding that, for the electrode geometry and dosing utilized, a minimum electric field of 1750 V/cm was necessary to achieve irreversible vascular ablation [34]. Though IRE thresholds are affected by electrode geometry and dosing, compared to cardiac muscle electroporation thresholds [38, 39], this early study demonstrated a higher threshold for VSM and thus gave promise for relative VSM safety for future cardiac PFA therapies [40, 41, 42, 43, 44, 45, 46].

Indeed, early preclinical studies in swine showed promising safety outcomes. In a 3‐week survival swine study, PFA was performed directly over CAs with epicardial access. Three different catheter forms were assessed, two circular and one large linear electrode. The energy was delivered in monophasic fashion with an external defibrillator, with a range from 30 to 360 J. Pathology showed that 5/56 arteries directly in the ablation zone had some level of intimal hyperplasia, and 0% stenosis on the LAD as measured by angiography [47]. The study also looked at levels of connective tissue growth factor (CTGF) to observe fibrotic reconstruction. At the 3‐week termination of the animals, the pattern of CTGF within the medial and intimal layers of affected vessels was congruent with those of the controls. This study was early in the field for PFA and provided an optimistic outlook, but waveforms and energy amplitudes have evolved. As clinical waveforms and energies were developing, so was the understanding of their effects on coronary anatomy.

Recent preclinical work on large animals has elucidated further the extent of coronary spasm and damage resulting from exposure to pulsed electric fields. Koruth et al. performed a direct epicardial ablation approach similar to that of Maor et al. Three swine, one healthy and two infarcted, were ablated with a focal catheter using clinically relevant PFA energies. Acutely, coronary spasm was observed in all three animals that resolved within 50 min. In the healthy swine, there was one mild ST‐segment elevation. Nitroglycerin was administered, but it did not immediately resolve the spasm. In the infarcted swine models, the LAD did not exhibit narrowing of the coronary lumen, but the right coronary artery (RCA) did show acute transient spasm response and minimal vascular damage at the 7‐day time point. Histology, as shown in Figure 3, showed minimal intimal hyperplasia and medial fibrosis [48].

FIGURE 3.

(A) The focal pulsed field ablation (PFA) catheter. (B) Angiography before, spasm (arrowheads) after, and resolution at 50 min. (C) Right coronary artery (RCA) spasm (arrowheads) following endocardial PFA. (D) Histology at the site of the spasm reveals a preserved lumen and a shallow myocardial lesion (double‐headed arrow). (Inset) Left anterior descending coronary artery (LAD) demonstrating tunica media fibrosis (TMF), intimal hyperplasia (IH), epicardial lymphocytic inflammation (EI), and epicardial fibrosis (EF). (E) Histology through the lateral right atrium: RCA is seen with preserved lumen, adjacent to the myocardial lesion (double‐headed arrow). (Inset) RCA demonstrates TMF, IH, EI, and EF. Reproduced from Koruth et al., “Coronary Arterial Spasm and Pulsed Field Ablation: Preclinical Insights,” Clinical Electrophysiology 8, no. 12 (2022): 1579–1580, with permission from Elsevier. [Colour figure can be viewed at wileyonlinelibrary.com]

In a more comprehensive study by Higuchi et al., epicardial ablations performed with a focal catheter, employing clinically relevant PFA energies, were evaluated using angiograms and histology [33]. The animals survived for 4 and 8 weeks postprocedure and a final angiogram was performed at this time point. The study observed a median 47% luminal narrowing acutely without any meaningful clinical presentation (e.g., unstable hemodynamics or EKG changes indicating ventricular arrhythmias). The luminal narrowing also normalized to baseline levels within 30 min. After 4 and 8 weeks, angiography revealed no stenosis at ablation sites. Histology of the lesion area showed the typical PFA lesion on the myocardium with homogenized fibrosis, with depths extending beyond the coronary lumen. On the CAs, 87.5% had some level of neointimal hyperplasia and tunica media fibrosis. The level of injury was minimal and did not have a significant effect on blood flow. On the other hand, 12.5% of the CAs within ablation sites had no level of injury. The study concludes that there are two possible mechanisms for coronary spasm: VSM contraction due to the electric field, or the release of mediators due to electroporation, which initiate a cascade of signaling leading to vasoconstriction.

As has been observed in animal studies, the lesion formation in VSM differs between PFA, RF ablation, and cryoablation. While the conservation of the intima lamina morphology and its structural components can be observed as a result of PFA [49], the same cannot be said about the damage caused by RF ablation. RF energies are known to cause significant intimal hyperplasia and disruption of the internal elastica lamina, as well as thickening of the tunica media from an increase in the extracellular matrix [37]. Cryoablation, much like PFA has demonstrated in animal studies that it conserves the structural elements of CAs and has low instances of intimal hyperplasia or thickening of the tunica media [50, 51].

5. Clinical Evidence

Evidence of coronary spasm in human clinical use of PFA has been sparse but growing with the numbers of patients treated. In early PFA clinical trials and first‐in‐human studies, the incidence of coronary spasm or symptoms was below one percent [3, 5, 52–54]. The lack of significant early evidence of coronary spasm was likely due to PVI and posterior wall isolation (PWI) workflows, where application of pulsed electric fields is distant from the CAs. For use of PFA in closer proximity to CAs, lack of a concurrent angiogram makes ascertaining the incidence of vasospasm caused by PFA challenging without clinically relevant effects (such as ST‐segment elevation). The first human study to evaluate PFA for creating a line of block across the CTI did not report any evidence of coronary spasm or damage, despite the close proximity of the RCA to the CTI. This first‐in‐human trial investigated a wide focal PFA catheter in conjunction with a pentaspline catheter for the treatment of persistent AF. This study used the pentaspline catheter to achieve PVI and PWI, whereas the wide focal PFA catheter was used to ablate the CTI [55]. The size of the patient cohort was small, with only 25 patients, but invasive remapping was performed at approximately 75 days. No clinical evidence of coronary spasm was reported at chronic time points. In one of the largest PFA studies to date comparing PFA to thermal ablation modalities for PVI, there were also no coronary spasm‐related events reported [56].

As the usage of PFA expanded, so did the possibilities for therapeutic uses and anatomical targets utilizing currently approved PVI‐only catheters to ablate novel targets. It was in one such study where one of the first reported cases of clinically relevant coronary spasm was observed [8]. A 77‐year‐old patient with history of arterial hypertension and coronary artery disease underwent PFA ablation for persistent AF. A pentaspline catheter was used to deliver PFA for PVI and used off‐label for PWI and mitral isthmus ablation. Immediately after all the ablations were delivered, there was ST‐segment elevation in leads II, III, aVF, V5, and V6. ST‐segment elevation persisted after the ablation catheter was withdrawn. An angiogram was performed, and occlusion of the left circumflex artery was observed. Intracoronary nitroglycerin was administered, and the spasm resolved. At 16 min, ST segment elevation had resolved. The patient returned 2 days later, and a repeat angiogram revealed no occlusion, and hemodynamics were normal.

In a more recent clinical trial [4], investigators performed additional non‐PV lesions sets, including mitral and CTI lines, which are more likely to result in significant catheter manipulation and the application of energy in potential proximity to the CAs. No clinical evidence of coronary spasm, such as ST‐segment elevation, was reported. However, angiograms, which may have identified subclinical spasm, were not performed [56].

Following the growth of patients treated with PFA, there has been more potential for observation of PFA‐induced coronary spasm. In one case, a 67‐year‐old patient undergoing PVI ablation manifested ST segment elevation indicative of a left anterior descending (LAD) artery occlusion. Three milligrams of nitroglycerin were administered intravenously, and the ST segment elevation resolved in seconds [57]. Notably, delivery of PFA therapy immediately prior to the ST segment elevation was at the right inferior pulmonary vein. Angiography revealed that the location of the catheter was remote from the LAD, but the responsiveness to nitroglycerin was consistent with spasm following PFA delivery. The location of suspected spasm, the LAD artery, and the location of PFA delivery, the RIPV, may also point to a case of Prinzmetal angina‐like generalized coronary spasm [58]. In the largest PFA registry to date, although the majority of coronary spasm events were proximity‐related, there was also evidence of generalized spasm, albeit to a lesser extent, with three reported cases and a rate of 0.02% [59].

Most of the reported clinical cases have been procedures using a pentaspline [8, 57, 60] catheter. This is due to the widespread use and number of patients treated. However, there are reports of CA spasm with different PFA systems [9, 10, 11]. In a study of 20 patients undergoing CTI ablation, 10 with angiograms (e.g., in Figure 4), coronary spasm was observed [10] in 33% of patients that did not have a nitroglycerin pretreatment protocol. CA spasm was prevented in all patients that were pretreated with a nitroglycerin dosage of 3 mg intravenous initial bolus followed by 2 mg at 2 min, delivered directly in the right atrium via a femoral venous sheath. This study was performed with a deflectable Lasso catheter, which points to the observed preclinical findings that vascular spasm is a PFA class effect. In all these clinical reports, the administration of nitroglycerin postspasm alleviated signs and symptoms.

FIGURE 4.

Shown is the preablation baseline coronary angiography (A) to (C), and postablation angiography (D) to (F). The arrows indicate areas of vasospasm. Reproduced from Malyshev et al., “Nitroglycerin to Ameliorate Coronary Artery Spasm During Focal Pulsed‐Field Ablation for Atrial Fibrillation,” JACC: Clinical Electrophysiology 10, no. 5 (2024): 885–896, with permission from Elsevier. [Colour figure can be viewed at wileyonlinelibrary.com]

6. Nitrates to Ameliorate PFA Spasm

Further studies into the effects of nitroglycerin have been published [61, 62]. In an initial study by Reddy et al., vascular spasm was assessed peri‐procedurally during PFA ablation of PVs, PWI, and CTI [63]. The investigators found that left atrial ablations, specifically PVI and PWI, did not provoke coronary spasm. However, CTI ablations had a 100% rate of coronary spasm, albeit to varying degrees, if not pretreated with nitroglycerin. The spasm was almost exclusively detected by angiography, as there was only one patient who did not receive nitroglycerin prophylaxis and developed mild EKG changes; none of the patients in the entire cohort (with or without nitroglycerin administration) experienced ST segment elevation or hemodynamic compromise. All patients saw a recovery with nitroglycerin administration, 1 mg intracoronary, as it has been shown in previous studies. In patients undergoing CTI ablation and who received intracoronary nitroglycerin pretreatment, there was a reduction of spasm, with only one out of five patients developing mild spasm (< 50%) and no cases of severe coronary spasm (> 90%). Nitroglycerin was also administered intravenously, from the femoral vein, 2 mg 2 min prior to CTI ablation. This cohort of patients experienced only mild spasm in 2 out of 10 patients, and the spasm resolved within 2 min.

In a more recent study of CTI ablation with a focal PFA catheter, different nitroglycerin dosing strategies were assessed with similar results [64]. In the cohort without pretreatment, there was subclinical moderate to severe spasm, assessed via angiography, in 80% of patients. They observed that intracoronary administration had better results at preventing spasm than intravenous delivery over several doses. They also administered nitroglycerin through the deflectable sheath directly into the right atrium; the dosing strategy comprised of a 3 mg bolus prior to PFA, followed by 2 mg every 2 min. Patients also received 320 ± 155 µg of phenylephrine at three different time points: pre‐, intra‐, and postablation. The most favorable outcomes were with this latter strategy, with 0% of patients developing severe coronary spasm. Moreover, there was no evidence of ST segment changes.

Alternative strategies to prevent coronary spasm have incorporated the use of different nitrates. A study by Mene et al. looked at the efficacy of isosorbide dinitrate (ISDN) administered intravenously [65]. ISDN was chosen because of its longer half‐life, and it may confer a longer protective treatment when compared to nitroglycerin. Two minutes prior to mitral line ablation, 1–2 mg of ISDN was administered. Following the application of PFA, any ST‐segment changes that resolved after administration of nitrates or spontaneously after 5 min were classified as evidence of clinical level of coronary spasm. The study observed that only the cohort without nitrate pretreatment, 10/103 patients, had a presentation of spasm. Patients pretreated with ISDN had 0% incidence of clinical spasm.

Though luminal narrowing is the primary physiological effect observed from PFA‐induced coronary spasm, the question remains whether there is a chronic effect as well. A recent study presented the results of angiograms of 30 patients who had confirmed coronary spasm with PFA and returned 1‐year later for repeat angiography [66]. Although all patients experienced coronary spasm in the index study, angiography revealed no irregularities at follow‐up.

7. Conclusion

In the largest registry for PFA outcomes, with over 17,000 patients, the rate of coronary spasm reported is 0.14% [59, 67]. Most of those cases (88%) come from off‐label use of the pentaspline catheter, specifically with ablation of CTI and mitral lines. This correlation between the incidence of spasm and the ablation of particular anatomic sites in proximity to CAs supports a direct pulsed electric field effect. Coronary spasm has been triggered by a variety of catheter and waveform types in both preclinical [33, 41, 47–49], and clinical settings [8, 57, 63]. This could be due to currents stimulating innervated sites, or VSM voltage gated calcium channels, or due to calcium influx into the cell from the poration effect. There are also naturally occurring calcium waves along the arterial wall that can become trapped after loss of cell function due to electroporation [30]. This spasm from any electrical input classifies PFA‐induced spasm as a class effect. However, this spasm effect appears to be mitigated using nitrates prior to ablation. The specific dosage and administration protocols are still being evaluated and will require investigation with each PFA system and waveform configuration.

In comparison with radiofrequency ablation (RFA) [68], and cryo‐thermal ablation [69], PFA has demonstrated to be capable of yielding positive clinical outcomes with a reduction in collateral damage. Coronary spasm with PFA presents most often subclinically [3, 4, 5, 54, 56, 67], and while coronary spasm due to RFA does not seem to present spasm as frequently, there are reports of acute spasm with RFA [70]. RF ablation has also been shown to damage connective tissues, lead to collagen shrinkage, and cause collagen denaturation [25, 71]. The damage to these structural elements has also demonstrated susceptibility of the arterial vessel to neointima formation and vessel narrowing [72, 73, 74]. In comparative studies, PFA versus thermal ablation modalities did not reveal any statistical difference in coronary safety outcomes [56, 75, 76, 77]. This could be due to the preservation of extracellular matrix and collagen, allowing VSM to repopulate the tunica media without encroaching into the intima layer [36, 49].

Overall, coronary spasm resulting from pulsed fields is a class effect that has been observed to be managed with the prophylactic use of nitrates. Current and future investigations will allow for the continued delivery of safe, tailored PFA therapy.

Conflicts of Interest

All authors are employees of Boston Scientific Corporation.

Data Availability Statement

Data sharing is not applicable to this article, as no new data were created or analyzed in this study.