Pulse Field Ablation of Atrial Fibrillation and Hemolysis—Red Blood Cells Also Demand Our Attention

In this issue of the journal of cardiovascular electrophysiology, Stojadinović et al. [1] try to further characterize pulse field ablation (PFA) associated hemolysis. In a series of 60 patients with atrial fibrillation (AF), treated with PFA using the pentaspline catheter for pulmonary vein isolation (PVI) and additional posterior wall (65%), as well as cavotricuspid and mitral isthmus ablation. They found a strong correlation between the amount of PFA applications and evidence of hemolysis as determined by fHb, lacate dehydrogenase (LDH), and billirubin. Based on these data, they created a threshold for induction of major hemolysis. This in turn could imply risk for the occurrence of significant clinical complications of hemolysis such as renal failure. PFA is an emerging non-thermal energy source in cardiac electrophysiology for ablation of cardiac tissue. Here, intermittent, high-intensity electrical fields are applied for extremely short periods of time (micro- or nanoseconds), and in turn result in cellular and tissue pore formation that is reversible or irreversible (depending on settings and pulse field properties), ultimately leading to cell death [2, 3]. PFA has been found to destroy tissue in a more selective way than established thermal modalities, which has fueled the hope for development of a truly cardiomyocyte-selective ablation approach. The hope is that this would subsequently eliminate devastating complications such as, atrial-esophageal fistula, pulmonary vein stenosis, and phrenic nerve palsy. Most recent study and registry data for this appears quite promising regarding outcomes, but particularly the safety of PFA [4, 5]. As it has been proven many times in the past, real world safety data oftentimes challenges our initial data, deriving from limited amounts of patients. Recent data from the largest PFA safety registry, discovered the relatively unexpected complication of hemolysis-related renal failure [4]. Osmancik et al. [6] further characterized PFA-related hemolysis in a focused study where they compared patients who underwent radiofrequency catheter ablation (RFA) to PFA. In a total number of 70 patients they found a dose-related effect of hemolysis markers to the number of PFA applications [6]. In turn, effects were more pronounced in patients who underwent additional ablation compared to PVI only. Several other groups have provided similar data supporting these findings [7]. The data from Stojadinović et al. [1] confirms this association between PFA applications and the occurrence of hemolysis in a relatively linear relationship. However, one has to be careful in interpreting the proposed “optimal cut-off” of 74 applications, a statistical term, which means the value that gives equal weight to sensitivity and specificity while maximizing prediction accuracy. The “optimal clinical cut-off” is the maximum number of applications that can safely be applied without incurring any hemolytic adverse event and that number appears to be somewhere around 66 based on the linear relationship in these data. A useful contribution to the clinical literature will be to know how many PFA applications can be done without incurring any hemolysis in the form of a risk stratification table that gives the probability of hemolysis with the number of PFA applications. Mechanistically, it will be important to understand what the determinants of hemolysis with PFA are and how these are impacted by the catheter design and the ablation/PFA settings. In the data provided so far, it appears that patients who undergo PVI as well as additional lines develop a larger amount of hemolysis. Is this simply due the additional applications of PFA or even enhanced by the design of the pentaspline catheter that is not optimized for linear ablation? For example, this catheter has a relatively large surface area that gets in contact with the blood volume when ablation of the mitral isthmus and other linear locations is performed and poles from which PFA is delivered cannot be turned off. While the dose-relationship between the occurrence of hemolysis and the amount of PFA used has now been relatively well described, these data derive from a very limited number of patients. How clinically meaningful is the determination of a threshold to avoid the occurrence of major hemolysis when the amount of hemolysis created has very different clinical implications for each patient depending on e.g. the baseline kidney function. While it is oftentimes difficult to go beyond surrogates as endpoints in our field, development of an accurate risk prediction model for hemolysis as well as its clinical complications will be an important contribution for the future. Nevertheless, Stojadinović et al. [1] are to be congratulated to provide us with further data regarding the occurrence of hemolysis in patients undergoing AF ablation using the Pentaspline catheter. Some of the longstanding challenges in our field includes additional ablation beyond PVI for persistent AF and making deeper lesions for ventricular arrhythmias. For persistent AF many strategies beyond PVI have been proposed, but they all have had limited success. There is even evidence to suggest that repeat ablation is helpful in preserving the atrial mechanical function [8]. Hence, there is a need for developing newer strategies based on a combination of the mechanism underlying the arrhythmia as well as optimizing ablation strategies. One strategy beyond PVI has been to target other areas based on different metrics like drivers of AF but they might be ephemeral making a case for other strategies [9]. One proposed approach has been to make use of the refractory period of the cardiac tissue and minimize the contiguous area available for fibrillatory waves to sustain themselves [10, 11]. PFA provides distinct advantages given the better complication profile as regards to esophageal and phrenic nerve injury making it possible to pursue these ablation approaches that could not be done earlier due to concerns like esophageal injury. Nonetheless, one must balance that optimism with the risk of dose-dependent hemolysis as outlined by Stojadinović et al. [1]. PFA represents a significant advancement in the treatment of cardiac arrhythmias, including increased tissue specificity and reduced complications. Hemolysis is a complication that is unique to PFA and potentially leads to renal failure and liver injury. Ongoing research to determine and fully understand the association of PFA and hemolysis and prevention of adverse outcomes remains essential, particularly as other PFA catheters and systems will start to be clinically used. This will ensure that we harness the benefits of this technology while safeguarding patient health. Ravi Ranjan is a consultant to Abbott and is PI on research grants from Biosense Webster to the University of Utah. He is also supported by NIH R01HL142913 and R01HL162353. The authors have nothing to report.