*Article* **Long-Term Outcomes of Transvenous Lead Extraction: A Comparison in Patients with or without Infection from the Italian Region with the Oldest Population**

**Luca Barca 1, Giuseppe Mascia 2,\*, Paolo Di Donna 2, Paolo Sartori 2, Daniele Bianco 2, Roberta Della Bona 2, Stefano Benenati 1, Andrea Carlo Merlo 1, Antonia Luisa Buongiorno 1, Niki Kaufman 1, Antonio Vena 3, Matteo Bassetti <sup>3</sup> and Italo Porto 1,2**


**Abstract:** Background: The gold standard for the treatment of cardiac implantable electronic devices (CIEDs)-related infection and lead malfunction is transvenous lead extraction (TLE). To date, the risk of mortality directly related to TLE procedures is relatively low, but data on post-procedural and long-term mortality are limited, even more in the aging population. Methods: Consecutive patients with CIEDs who underwent TLE were retrospectively studied. The primary outcome was the endpoint of death, considering independent predictors of long-term clinical outcomes in the TLE aging population comparing patients with and without infection. Results: One hundred nineteen patients (male 77%; median age 76 years) were included in the analysis. Eighty-two patients (69%) documented infection, and thirty-seven (31%) were extracted for a different reason. Infected patients were older (80 vs. 68 years, *p*-value > 0.001) with more implanted catheters (*p*-value < 0.001). At the last follow-up (FU) available (median FU 4.1 years), mortality reached 37% of the patient population, showing a statistically significant difference between infected versus non-infected groups. At univariable analysis, age at TLE, atrial fibrillation, and anemia remained significant correlates of mortality; at multivariable analysis, only patients with anemia and atrial fibrillation have a 2.3-fold (HR 2.34; CI 1.16–4.75) and a 2.5-fold (HR 2.46; CI 1.33–4.54) increased rate of death, respectively. Conclusion: Our long-term data showed that aging patients who underwent TLE for CIED-related infection exhibit a high mortality risk during a long-term follow-up, potentially leading to a rapid and effective procedural approach in this patient population.

**Keywords:** lead extraction; device infection; lead malfunction; aging population

#### **1. Introduction**

The implant rate of cardiac implantable electronic devices (CIEDs) has increased progressively due to increasing life expectancy [1–8], and, more commonly today, CIEDs are implanted in older patients with many comorbidities [7–9]. Advanced age is related to multiple comorbidities and frailty, potentially increasing the probability of complications during invasive procedures [9,10]. Although infrequent, CIED-related infections, as well as lead malfunction, represent a serious complication after cardiac device implantation [5], with several data showing device complications associated with significant mortality and morbidity [7–9]. Transvenous lead extraction (TLE) represents the gold standard for

**Citation:** Barca, L.; Mascia, G.; Di Donna, P.; Sartori, P.; Bianco, D.; Della Bona, R.; Benenati, S.; Merlo, A.C.; Buongiorno, A.L.; Kaufman, N.; et al. Long-Term Outcomes of Transvenous Lead Extraction: A Comparison in Patients with or without Infection from the Italian Region with the Oldest Population. *J. Clin. Med.* **2023**, *12*, 4543. https:// doi.org/10.3390/jcm12134543

Academic Editor: Andrea Di Cori

Received: 28 May 2023 Revised: 28 June 2023 Accepted: 3 July 2023 Published: 7 July 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

the treatment of CIED-related infection and lead malfunction [8]. To date, the mortality risk directly related to TLE procedures is relatively low [6–8], while data regarding postprocedural and long-term mortality are limited [8,9,11]. Considering the aging population, TLE will play an increasing role in the future management of these subjects. Therefore, in our study, we analyze independent predictors of long-term clinical outcomes of patients undergoing TLE, assessing the prognostic role of an infective indication on long-term survival in the aging population.

#### **2. Methods**

We identified a cohort of 119 consecutive patients undergoing TLE at our institution in the Liguria region. Liguria is an Italian region located in the northwest part of Italy, and it is currently the oldest Italian Region [12]. We retrospectively analyzed patient characteristics, procedural indications, and clinical outcomes. For the purpose of the study, the patient population was categorized as infected and non-infected, following the Heart Rhythm Society (HRS) consensus document on TLE [10] and European Heart Rhythm Association (EHRA) expert consensus statement on lead extraction [13]. An infective indication included a systemic (bacteremia and/or endocarditis) or local (pocket infection or erosion) infection, while a non-infective indication included lead malfunction and venous thrombosis. The primary endpoint of the study was a comparison of long-term mortality between patients with or without infection after hospital discharge. Secondary endpoints included complete procedural success, procedural failure, and the occurrence of complications defined by the HRS and EHRA consensus [10,13]. For the aim of the study, we considered complications as only the adverse events occurring before hospital discharge. In particular: death, cardiac tamponade, cardiac/vascular avulsion or tear, respiratory arrest, pulmonary embolism, and stroke were regarded as major complications, whereas complications that did not meet the major criteria were considered minor complications.

#### *2.1. Extraction Techniques*

After obtaining written informed consent, invasive hemodynamic monitoring through an arterial line was placed. Procedures were performed under general anesthesia and cardiac surgical backup. Device removal and disconnection of the lead(s) were performed through an infraclavicular incision. The lead(s) were extracted through a subclavian approach. Lead removal with simple traction was attempted as the first step. If lead removal proved unsuccessful, the lead was cut; a locking stylet (Liberator Cook Medical) was introduced, and traction was reattempted. If this still proved unsuccessful at the "first step", a mechanical sheath was used, eventually considering a powered sheath (Evolution Cook Medical) when necessary. Laser-assisted lead extraction was never performed in our center. Complete procedural success was achieved if all targeted leads/lead material were removed from the vascular space, while clinical success was achieved if all targeted leads/lead material were removed with retention of a small lead portion (<5 cm), with no impact on the outcome goals. In cases of infection, complete removal of both foreign material and infected tissue was mandatorily performed. Failure was considered if neither complete procedural success nor clinical procedural success was achieved.

#### *2.2. Antibiotic Therapy*

In patients with device infection, an empiric antibiotic therapy such as daptomycin (i.v. 8–10 mg/kg every 24 h) or vancomycin (i.v. 30–60 mg/kg/day) until a potential microbiological identification was performed according to the clinical scenarios. Cefepime (i.v. 2 g every 8 h) or ceftriaxone (i.v. 2 g every 24 h) or gentamycin (i.v. 5–7 mg/kg every 24 h) were only considered in case of systemic symptoms [14]. In patients with systemic infection, once the pathogen was identified (usually within 3 days), the antibiotic treatment was tailored to the antimicrobial susceptibility pattern. In this scenario, the collaboration between cardiologists and infectious disease specialists with expertise in the field of CIEDrelated infection was of primary importance. The duration of therapy could depend on the

presence or lack thereof of concomitant systemic infection and could vary from 2 weeks in case of isolated pocket infection to typically 4–6 weeks in case of positive blood cultures and or vegetations. In particular, all patients with systemic infection underwent appropriate antibiotic treatment after removal according to antibiograms of positive bacteria cultures and current guidelines [14].

#### *2.3. Statistical Analysis*

Continuous variables were expressed as mean ± standard deviation or median (interquartile range) and compared with the Student T test or Mann–Whitney test, as appropriate. Categorical variables were expressed as frequencies and percentages and compared with the Chi-square or Fisher exact test, as appropriate. Time-to-event curves were built, and survival was compared between infected and non-infected patients using the log-rank test. Univariable and multivariable Cox analyses were carried out to explore the predictors of survival, deriving hazard ratios (HR), and associated 95% confidence intervals. Candidate variables were entered in the multivariate analysis when proven to be significant univariate predictors. All tests were 2-tailed, and *p* < 0.05 was considered significant. Statistical analysis was performed using "R" software (the R foundation for statistical computing version 3.6.2. using the "meta" package).

#### **3. Results**

Between January 2014 and April 2020, 119 patients (224 leads) underwent TLE, out of which 82 patients (69%) had an infection diagnosis (181 leads). Males represented 77% of patients, and the median age at the TLE procedure was 76 (67–82) years. Table 1 shows the baseline characteristics of the patient population. Infected patients were older (80 vs. 68 years, *p*-value > 0.001), with more implanted catheters (*p*-value < 0.001) despite a lower incidence of heart failure (43.4% versus 65.7%, *p*-value = 0.03), whereas other comorbidities were balanced compared to non-infected patients. The median time from first device implantation to TLE was longer in the infected population (109 months versus 66 months, *p* = 0.03) compared to non-infected patients. Table 2 shows a comparison between infected and non-infected patients. In the infection-related group (82 patients), pathogenic organisms were identified in 18% of cases: positive microbiologic culture results showed Gram-positive in 15% of cases, and *Staphylococcus aureus* was the most commonly detected bacterium, as shown in Figure 1. Moreover, we compared the characteristics of patients with local infection versus systemic infection, documenting no significant difference among baseline characteristics (See Table S1 from Supplementary Materials). Among TLE procedures, a total of 224 leads were extracted, with a mean of 1.9 ± 0.9 lead per procedure. The mean procedural time was 129 ± 50.2 min; the oldest lead was in place for 396 months. Complete procedural success was achieved in 84.9% of patients, with a 91.6% clinical success rate. In total, 194 leads (81.1%) were removed completely, 16 leads (6.7%) were removed with retention of a small portion of lead without negatively affecting outcome goals and therefore leading to clinical success, one lead (0.42%) was submitted to surgical lead extraction, and one lead (0.42%) was considered as failure. Procedural characteristics are reported in Table 3.


**Table 1.** Overall study population characteristics.


**Table 1.** *Cont.*

**Figure 1.** Microbiology of transvenous lead extraction from 82 patients with infection. MSSA = Meticillin-Sensitive *Staphylococcus aureus*, MRSA *=* Methicillin-resistant *Staphylococcus aureus*.


**Table 2.** Study population stratified by diagnosis of infection.


**Table 3.** Procedural Characteristics stratified by diagnosis of infection.

#### *3.1. Procedural Complications*

A single case (0.84%) of death was documented in the subject with an indication of lead malfunction due to cardiac avulsion during the procedure. Surgical extraction was required in three cases after cardiac tamponade. In a fourth case, initially performed for lead malfunction, the procedure failed because of a lead fracture at the level of the left subclavian. A total of seven intraprocedural complications occurred, including two strokes.

#### *3.2. Short-Term Outcome*

Ten patients (8.4%) died at the hospital (25-days average after TLE), six of whom individuals had infectious indications for TLE (three local and three systemic). The three patients with systemic infection died of multiorgan failure secondary to sepsis due to methicillin-resistant *Staphylococcus aureus*, *P. aeruginosa* or *K. pneumoniae*. Four patients with no infection died at short-term follow-up: two patients died in the hospital due to progressive heart failure 15 days after TLE, one patient died of a complication of a renal biopsy performed during hospitalization (exsanguinating retroperitoneal hemorrhage), last patient at 85 years old died due to spontaneous cerebral hemorrhage 1 week after TLE.

#### *3.3. Long-Term Outcome*

At the last follow-up available (median observation time 49 months, range: 1–93 months), mortality reached 37% of the patient population, including only patients after hospital discharge. The mortality analysis ended on January 2023: reasons for death during longterm outcomes were not available for most patients. Kaplan Meier curves describing mortality after hospital discharge of the TLE population showed a statistically significant difference between infected versus non-infected groups (Figure 2).

**Figure 2.** Kaplan Meier analysis of all-cause death after hospital discharge.

#### *3.4. Predictors of Mortality*

Univariable and multivariable analyses by Cox regression identified several correlates of mortality (Table 4). At univariable analysis, age at TLE, atrial fibrillation, and anemia remained significant correlates of mortality. In particular, the instantaneous mortality rate increases by 3% per year of patient age (HR 1.03; CI 1.01–1.06). At multivariable analysis, patients with anemia and atrial fibrillation have a 2.3-fold (HR 2.34; CI 1.16–4.75) and a 2.5-fold (HR 2.46; CI 1.33–4.54) increased rate of death, respectively.

**Table 4.** Univariate and multivariate Cox regression for all-cause death.


#### **4. Discussion**

This study analyzes long-term mortality in TLE procedures from a medium-volume single center in the oldest Italian Region: not by chance, the patients are older compared to other large studies such as LExlCon [15], ELECTRa [16], and PROMET [17] (mean age 76 versus 63–65 years, respectively), while the proportion of males is comparable to the aforementioned studies (79.3%) [15–17]. In the results, long-term mortality is significantly higher in the older median-age CIED-infected population when compared to the noninfected population; actually, infection-related indications were different when compared to larger studies (68.9% in our study versus 46–57%) [15–17]. This finding may be because of the lower threshold for performing TLE in non-infected CIEDs, due to a potentially higher procedural risk in the older population since octogenarians are deemed as high-risk candidates for TLE; despite in previous little populations, the old age could not influence TLE effectiveness, being successfully performed [18,19].

The procedural success rate was achieved in 91.6%, a slightly lower percentage than the studies mentioned above (94.3–98.7%) [15–17] without any significant difference when comparing CIED-infected and non-infected populations. Intraprocedural mortality was low (0.84%) and comparable to large series: the ELECTRa registry [16] showed a procedural mortality of 0.5%, while Wazni O et al. [15] showed a procedural mortality of 0.28%. On the other hand, in-hospital mortality was 8.4%: older age and overlapping comorbidities could increase the risk in patients requiring TLE. According to a prospective multicenter study [16], age over 68 years is a predictor of increased all-cause mortality during hospitalization. Finally, the results show that long-term mortality is significantly higher in the older median-age CIED population, documenting an all-cause mortality rate of 37% during the entire follow-up period. Long-term mortality after TLE is significantly higher in patients with infection; notably, the survival curves of patients undergoing TLE for infection diverge from those of patients undergoing TLE for lead malfunction or other indications from the first few months after hospital discharge. These findings are consistent with a recent report from Arabia et al. [20], documenting that patients who perform TLE for CIEDrelated infection may exhibit a 30% mortality rate during a 6.5 median follow-up. Migliore et al. [18] recently described long-term mortality in elderly patients undergoing TLE: the main indication for TLE was an infection in 84.3% of cases with an overall mortality rate of 29% during a mean follow-up of ≈2 years. Finally, Henrikson et al. [21] described midterm mortality in a small population undergoing TLE for infectious indications, documenting a 30% mortality rate during the follow-up.

In our results, anemia and atrial fibrillation were the strongest correlates of mortality in multivariable analysis, and age at the extraction reached statistical significance. Therefore, in an older population undergoing TLE, more effort should be dedicated to the preoperative e postoperative treatment of comorbidities such as severe anemia and poorly managed atrial fibrillation. Moreover, considering that survival continues to be burdened by the progression of multiple chronic diseases beyond the clinical resolution of the infection, old patients who undergo successful TLE (especially for an infectious cause) remain at high risk of death at a median follow-up of 49 months. Also, infection prevention may have a significant impact on long-term mortality reduction. In particular, a preoperative antibiotic strategy combined with an early procedural approach is extremely important in order to have the best clinical condition at baseline and potentially a more favorable prognosis, also in older populations. Not by chance, today's recommendations suggest complete device and lead removal for all patients with CIED infection [10].

#### **5. Limitations**

In terms of limitations, this study is a retrospective analysis and thus is subject to bias. The main limitation is the small number of patients (n: 119), which limits data analysis. The cohort was limited to a single, medium-volume academic center, and the experience may differ at other types of institutions. In addition, the details regarding the mode of death are not available.

#### **6. Conclusions**

This study evaluates the long-term outcomes of TLE in elderly patients with or without infection from a single-center experience. Our data show that patients undergoing TLE for CIED-related infection have a high risk of mortality during a long-term follow-up, potentially leading to a rapid and effective procedural approach in this patient population.

**Supplementary Materials:** The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/jcm12134543/s1, Table S1 Study population characteristics stratified by diagnosis of local versus systemic infection.

**Author Contributions:** Methodology, L.B., G.M., P.D.D. and A.C.M.; Software, D.B. and A.V.; Validation, P.S.; Investigation, R.D.B.; Resources, N.K.; Data curation, S.B. and A.L.B.; Writing—original draft, M.B.; Writing—review & editing, I.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** This retrospective study did not require ethical approval.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data presented in the study are available on request from the corresponding author.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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## *Article* **Electroanatomical Conduction Characteristics of Pig Myocardial Tissue Derived from High-Density Mapping**

**Theresa Isabelle Wilhelm 1,2,†, Thorsten Lewalter 1,†, Johannes Fischer 3, Judith Reiser 3, Julia Werner 3, Christine Baumgartner 3, Lukas Gleirscher 1, Petra Hoppmann 4, Christian Kupatt 4, Klaus Tiemann 1,4 and Clemens Jilek 1,4,\***


**Abstract:** Background: Ultra-high-density mapping systems allow more precise measurement of the heart chambers at corresponding conduction velocities (CVs) and voltage amplitudes (VAs). Our aim for this study was to define and compare a basic value set for unipolar CV and VA in all four heart chambers and their separate walls in healthy, juvenile porcine hearts using ultra-high-density mapping. Methods: We used the Rhythmia Mapping System to create electroanatomical maps of four pig hearts in sinus rhythm. CVs and VAs were calculated for chambers and wall segments with overlapping circular areas (radius of 5 mm). Results: We analysed 21 maps with a resolution of 1.4 points/mm2. CVs were highest in the left atrium (LA), followed by the left ventricle (LV), right ventricle (RV), and right atrium (RA). As for VA, LV was highest, followed by RV, LA, and RA. The left chambers had a higher overall CV and VA than the right. Within the chambers, CV varied more in the right than in the left chambers, and VA varied in the ventricles but not in the atria. There was a slightly positive correlation between CVs and VAs at velocity values of <1.5 m/s. Conclusions: In healthy porcine hearts, the left chambers showed higher VAs and CVs than the right. CV differs mainly within the right chambers and VA differs only within the ventricles. A slightly positive linear correlation was found between slow CVs and low VAs.

**Keywords:** conduction velocity; voltage; ultra-high-density mapping; heart; pig

#### **1. Introduction**

Cardiac arrhythmias are a disruption of the normal cardiac rhythm and can range from simple changes in heart rate to complex fibrillation events. They may result in various clinical symptoms, from reduced physical resilience to sudden cardiac arrests [1]. Atrial fibrillation is the most common sustained arrhythmia, affecting 0.51% of the world's population. Its worldwide prevalence has increased by 33% over the past 20 years and is expected to rise by >60% in the coming 30 years [2].

Re-entry mechanisms cause many cardiac arrhythmias. The zones of slow conduction play a key role in developing and maintaining reentrant tachycardias [1,3–5]. Therefore, treatment by catheter ablation involves the ablation of slow conduction or low voltage zones [6] that can be identified with ultra-high-density mapping systems [7].

Until recently, there have been few, mostly incomplete data on conduction velocities in healthy hearts.

**Citation:** Wilhelm, T.I.; Lewalter, T.; Fischer, J.; Reiser, J.; Werner, J.; Baumgartner, C.; Gleirscher, L.; Hoppmann, P.; Kupatt, C.; Tiemann, K.; et al. Electroanatomical Conduction Characteristics of Pig Myocardial Tissue Derived from High-Density Mapping. *J. Clin. Med.* **2023**, *12*, 5598. https://doi.org/ 10.3390/jcm12175598

Academic Editors: Gianfranco Mitacchione, Antonio Curnis, Giovanni Battista Forleo and Jeffrey L. Anderson

Received: 25 May 2023 Revised: 19 August 2023 Accepted: 22 August 2023 Published: 28 August 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Hansson et al. collected data from the right atrial wall with an epicardial electrode array [8]. Martin et al. measured conduction velocities and electrogram amplitudes in different sections of re-entry circuits, mainly among patients with ischemic cardiomyopathy [5]. Kléber et al. observed the time course of left ventricular conduction velocity changes during induced ischemia in isolated porcine hearts [9].

None of these studies provided an overall approach with reference values or comparisons between physiological conduction velocity and voltage amplitude in all four heart chambers. Characterizing normal heart electrical physiology is crucial to distinguish between physiological and diseased patterns.

In this study, we aimed to define and compare a basic value set for unipolar conduction velocities and voltage amplitudes in all four heart chambers and their separate walls in healthy, in vivo porcine hearts using ultra-high-density mapping. In addition, we analysed whether conduction velocity and voltage amplitude are correlated in healthy hearts. Our velocity calculations for the three-dimensional myocardial surface were based on overlapping circular areas.

#### **2. Materials and Methods**

Experimental data were collected from four juvenile healthy swine (German Landrace x Pietrain; 31–41 kg (mean 36 kg), 3–4 months old), two of which were female (pigs 3 and 4). The study was approved by the government of Bavaria (ROB-55.2-2532.Vet\_02-1 7-174).

#### *2.1. Electroanatomical Mapping*

Electrophysiological studies were performed in vivo under general anaesthesia and mechanical ventilation during intrinsic sinus rhythm. Sedation was administered intramuscularly with ketamine (10–15 mg/kg), azaperone (2 mg/kg), and atropine (1 mg). Anaesthesia was introduced with 1% and maintenance with 2% propofol i.v. We administered acetylsalicylic acid (250 mg i.v.) and heparin (150 IE/kg i.v. as a bolus and 200 IU/mL i.v. as continuous drip infusion depending on activated clotting time) for intraoperative anticoagulation after the sheath was placed. Intraoperative analgesia was provided by fentanyl boluses (0.015 mg/kg i.v.) every 20–30 min, and metamizole (40–50 mg/kg i.v.) was administered before the first incision. Transvenous catheters were inserted under fluoroscopic guidance. Access to the left heart was gained via a transseptal approach. Electroanatomical mapping was performed during sinus rhythm using Rhythmia, an ultrahigh-density mapping system (Boston Scientific Corp., Marlborough, MA, USA), and its proprietary, 64-lead, multi-electrode basket mapping catheter Intellamap Orion (Boston Scientific Corp., USA). The sedation dosage was constant throughout the whole period of mapping to ensure comparable conditions between the different maps. The catheter is bidirectionally steerable and consists of eight splines, each containing eight electrodes spaced 2.5 mm apart [10].

#### *2.2. Post-Processing in Rhythmia*

After completing the electrophysiological studies, the annotated beats were manually checked for plausibility and, if necessary, reannotated in Rhythmia to specifically ensure that no His–Purkinje-system signals were falsely annotated. Transitions to other cardiac chambers, arteries, and veins were identified based on the morphology and amplitude of electrograms and marked as cutouts (blue in Figure 1). The mean heart rate was calculated for each mapping procedure.

#### *2.3. Calculation of Local Conduction Velocity and Voltage Amplitude*

To compute local conduction velocities and voltage amplitudes from the measured activation times while considering the variability of wavefront directions, we defined circular areas with an approximately 5 mm radius on the map surfaces and left out the cutouts. We used spherical filters from ParaView (v.5.8.0 and 5.10.0, Kitware Inc., New York, NY, USA) to create circular areas on the curved heart surface [11,12], as shown in Figure 1. Additional simulations were created for each heart chamber, where the circles only cover the septal, lateral, posterior, or anterior region in the case of ventricles plus the superior of the atria, respectively.

**Figure 1.** Example of a right atrium showing circular areas for calculating local conduction velocities and voltage amplitudes in ParaView. The blue colour indicates transitions to the venae cavae and right ventricle, where no circles are placed.

The mean voltage amplitude and conduction velocity of the covered map surface were calculated for each sphere. We divided the theoretical circle diameter, determined from the actual circular surface area, by the time difference between the first and last activations in each area to calculate conduction velocity, as seen in (1).

$$\text{Amuction velocity} = \frac{2 \times \sqrt{\frac{area}{\pi}}}{\Delta \, activation} \tag{1}$$

All values and metadata were calculated and exported from ParaView using a customwritten Python script.

#### *2.4. Statistical Analysis*

Statistical analysis was performed using the statistical programming language R, v4.1.2 [13].

The relationship between conduction velocity and voltage amplitude, respectively, with the two factors mapping location and heart rate, was investigated by means of linear mixed effects analysis using lme4 [14,15] since repeated measurements, and a varying number of observations were obtained from four individuals. Mapping location and heart rate were used as fixed effects (with no interaction term). As a random effect, we used random intercepts for the pigs to account for inter-individual variation. The velocity was log-transformed in the linear model to obtain a normal distribution.

We used the lmerTest [16,17] and emmeans [18] packages for post hoc tests and comparisons, i.e., to compare the estimated mean values of the response variables for all levels of the explanatory variable under consideration. Tukey's HSD was used for all pairwise comparisons and Sidak for targeted comparisons to adjust for multiple comparisons.

Post hoc test results are reported on the original scale. All estimated values are provided for a heart rate of 90 bpm. Estimates are reported in the format (estimate ± standard error, *p*-value). Correlations were tested via Pearson's correlation coefficient, reported in the format (r (degrees of freedom) = r-statistic, *p* = *p*-value). Velocity values of >6 m/s were defined as outliers and ignored in the calculations. The *p*-values of <0.05 were considered significant. Measured amplitude values are reported as unipolar signals.

#### **3. Results**

A total of 21 maps were analysed, each consisting of 5632 ± 295 measurement points. The map surfaces had 131 ± 8 spheres, each covering an area of 77.8 mm<sup>2</sup> ± 0.05, including <sup>105</sup> ± 0.19 measurement points. Therefore, the mapping resolution was 1.4 points/mm2. The volumes in Table 1 correspond to three-dimensional electroanatomic maps. Since these measurements also include transitions to the other chambers and adjacent parts of the vessels (excluded in the further calculations), the calculated volumes overestimate the actual size of the chambers, especially for the right atria.

**Table 1.** Overview of the recorded maps, the mean heart rate during the procedure, the number of recorded measurement points, map volume, and the number of circles in whole maps and regions of each map.


#### *3.1. No Influence of Sex on Conduction Velocity and Voltage Amplitude*

Since the study was performed on two male and two female pigs, we performed a linear mixed-effects analysis to test whether sex affected conduction velocity and voltage amplitude. In our study, sex had no influence on conduction velocity (*p* = 0.50) or voltage amplitude (*p* = 0.30).

#### *3.2. Mean Velocity and Voltage of Heart Chambers during Sinus Rhythm*

The overall unipolar conduction velocity at a heart rate of 90 bpm is highest in the left atrium (LA) (0.79 ± 0.05 m/s), followed by the left ventricle (LV) (0.59 ± 0.04 m/s), the right ventricle (RV) (0.54 ± 0.03 m/s), and the right atrium (RA) (0.50 ± 0.03 m/s).

The overall unipolar voltage amplitude at a heart rate of 90 bpm is highest in the LV (10.98 ± 0.34 mV), followed by the RV (7.83 ± 0.32 mV), LA (4.81 ± 0.35 mV), and RA (3.35 ± 0.31 mV) (Figure 2).

**Figure 2.** Comparison of estimated unipolar conduction velocities and voltage amplitudes during sinus rhythm across the cardiac chambers (RA, LA, RV, and LV) normalized to 90 bpm. The left graph displays mean conduction velocities (m/s), and the right graph shows mean voltage amplitudes (mV) with 95% confidence intervals. Brackets denote selected pairwise comparisons between chambers, with *p*-values testing if the ratio of mean velocities equals 1 or the difference in mean voltages equals 0 mV. The data were obtained using linear mixed-effects models and analysed using estimated marginal means. For velocity, we analysed the data on the log scale and then back-transformed the results for interpretation.

#### *3.3. Velocity and Voltage Differences between Chambers* 3.3.1. Inter-Atrial and Inter-Ventricular Comparison

We compared conduction velocities and voltage amplitudes between the atria and between the ventricles. The RA conducts significantly slower (×0.64 ± 0.03, *p* < 0.001) and has a lower voltage amplitude (−1.46 mV ± 0.19, *p* < 0.001) than the LA. By contrast, the voltage amplitude is higher in the LV than in the RV (−3.16 mV ± 0.21, *p* < 0.001), and no significant difference in conduction velocity was observed between the ventricles (Figure 2).

#### 3.3.2. Comparison between Atria and Ventricles of the Left and Right Heart

We then compared the conduction velocity and voltage amplitude between the atrium and ventricle of the same half of the heart. In the left chamber of the heart, the conduction velocity was higher in the atrium than in the ventricle (×0.748 ± 0.041, *p* < 0.001). We found no significant difference in conduction velocity between RA and RV. Voltage amplitudes were generally lower in the atria than in the ventricles (*p* < 0.001) (Figure 2).

#### *3.4. Regional Velocity and Voltage Characteristics within Each Chamber*

Each heart chamber was divided into subregions representing different walls. The following conduction velocity and voltage amplitude estimates are normalized to a heart rate of 90 bpm.

#### 3.4.1. Conduction Velocity

In the RA, the conduction velocity was highest in the posterior wall (0.61 ± 0.04 m/s), compared to the superior (0.42 ± 0.04 m/s, *p* < 0.044), lateral (0.44 ± 0.03 m/s, *p* < 0.001), and septal walls (0.48 ± 0.03 m/s, *p* = 0.009). In the RV, the anterior wall (0.44 ± 0.04 m/s) showed the lowest conduction velocity and was significantly different from the posterior (0.83 ± 0.08 m/s, *p* < 0.001), lateral (0.69 ± 0.07 m/s, *p* < 0.001), and septal walls (0.63 ± 0.06 m/s, *p* = 0.008). All other walls within these right heart chambers did not differ significantly.

Within the LA, the superior wall had the highest conduction velocity (1.09 ± 0.12 m/s) and was significantly faster than the anterior wall, which had the slowest conduction velocity (0.72 ± 0.09, *p* = 0.043). We did not find any significant difference in conduction velocity between any other regions of the LA and LV (Figure 3).

**Figure 3.** Visualization of estimated mean unipolar conduction velocities (m/s) during sinus rhythm, normalized to 90 bpm, across distinct regions of each cardiac chamber and their pairwise comparisons. The figure shows four subplots, each representing a cardiac chamber (right atrium, left atrium, right ventricle, and left ventricle), with potential mapping regions (anterior, posterior, lateral, septal, and superior). The 95% confidence interval is given for each mean velocity. Brackets highlight significant contrast ratios (*p* < 0.05) between the regions within the corresponding chamber, indicating divergence from a ratio of 1. The data were obtained using linear mixed-effects models and estimated marginal means. We conducted tests on the log scale and subsequently back-transformed the results for interpretation.

#### 3.4.2. Voltage Amplitude

The atria showed no voltage differences between different walls.

The RV had high voltage amplitudes at the posterior (9.59 ± 0.52 mV) and septal walls (10.64 ± 0.52 mV), which were significantly higher than at the anterior (5.95 ± 0.52 mV) and lateral (6.73 ± 0.54 mV) walls (*p* < 0.001).

Within the LV, the posterior wall (8.89 ± 0.52 mV) had the lowest voltage amplitude and was significantly different from any other (*p* < 0.001). The lateral wall (13.48 ± 0.61 mV) had the highest voltage amplitude (anterior vs. lateral *p* = 0.041; posterior vs. lateral *p* < 0.001; septal vs. lateral *p* < 0.001) (Figure 4).

**Figure 4.** Visualization of estimated mean unipolar voltage amplitudes (mV) during sinus rhythm, normalized to 90 bpm, across distinct regions of each cardiac chamber and their pairwise comparisons. The figure shows four subplots, each representing a cardiac chamber (right atrium, left atrium, right ventricle, and left ventricle), with potential mapping regions (anterior, posterior, lateral, septal, and superior). The 95% confidence interval is given for each mean voltage. Brackets highlight significant voltage mean differences (Δ > 0 mV; *p* < 0.05) between the regions within the corresponding chamber. Data were derived from linear mixed-effects models with estimated marginal means.

#### *3.5. Correlation of Velocity and Voltage*

No general linear correlation between voltage amplitude and conduction velocity (r(2736) = 0.05, *p* = 0.008) was observed (|r| < 0.2).

Separated by mapping location, we found a low positive linear correlation between voltage amplitude and conduction velocity (r(408) = 0.30, *p* < 0.001) for the LA. In the other heart chambers, no linear correlation was observed (RA r(1252) = 0.11, *p* < 0.001; LV r(496) = 0.09, *p* = 0.053; RV r(574) = −0.07, *p* = 0.114) (Figure 5).

**Figure 5.** Relationship between unipolar voltage amplitude and unipolar conduction velocity for right (blue) and left (red) atria, and right (purple) and left (green) ventricles during sinus rhythm. Pearson's correlation coefficients and their *p*-values for each heart chamber are provided.

At velocities of <1.5 m/s, a low positive linear correlation between voltage amplitude and conduction velocity was observed in the LA (r(310) = 0.47, *p* < 0.001), LV (r(424) = 0.23, *p* < 0.001), and RA (r(1105) = 0.25, *p* < 0.001). No correlation was found in the RV (r(496) = −0.09, *p* = 0.05).

#### **4. Discussion**

To our knowledge, the current study is the first to use an ultra-high-density mapping system to systematically analyse intrinsic conduction velocities and voltage amplitudes in healthy pig hearts.

Our first key finding was that the highest conduction velocity of the heart chambers was found in the LA, whereas the highest amplitudes were measured in the LV. The left heart chambers showed higher voltage amplitudes and conduction velocities than their right counterparts. One explanation might be that a high conduction velocity in the left heart chambers is crucial to ensuring a synchronized electrical excitation of the chambers because of their larger size and greater myocardial mass [19]. As gap junctions seem to be the main determinant of conduction velocity in healthy myocardium [1], our observation may lead to the hypothesis that gap junction coupling might be higher in left-sided myocardium than right-sided myocardium.

Our second key finding was that within one heart chamber, conduction velocity varied more in the right heart chamber than in the left. In the RA, the posterior wall showed higher conduction velocities than the septal, lateral, and superior wall segments. In the RV, the anterior wall showed lower conduction velocities than the lateral, posterior, and septal wall segments. Within the LA, only the superior and anterior walls differed significantly, with the superior wall conducting the fastest. We interpret this finding as a measurement of the fast-conducting Bachmann bundle, which confirms the validity of our data [20,21]. The LV did not show any significant differences in conduction velocities between different segments.

Our third key finding was that there was no significant difference in voltage amplitude within the atria, except for one within the ventricles. In the RV, the posterior and septal walls showed higher voltage amplitudes than the anterior and lateral walls. In the LV, the lateral wall showed the highest voltage amplitude, whereas the posterior wall showed the lowest. The amplitudes in all segments of the ventricles were in the high range of >5 mV. In other words, no relevant low-voltage areas could be identified in absolute numbers. Further investigations should reveal whether differences in this high-amplitude range correspond to physiological structures.

Our fourth key finding was that in healthy, juvenile pig hearts, there was a slightly positive correlation between conduction velocity and voltage amplitude at velocities <1.5 m/s in all chambers except the RV. This finding might be due to the correlation between slow conduction zones and low-voltage areas in partially scarred myocardium [22,23].

The mapping resolution was very high compared to the published data. On average, the maps in our analysis showed a mapping resolution of 1.4 points/mm2 compared to the resolutions of 0.2 points/mm2 in another work characterizing left atrial slow conduction zones among patients with atrial fibrillation [24]. The number of mapping points is crucial to identifying critical ablation targets [7].

Our data are comparable to published human data on conduction velocities derived from electrodes with small surfaces and small inter-electrode distances. Martin et al. measured the conduction velocities among patients with ischemic cardiomyopathy [5]. Kléber et al. observed that myocardial tissue showed an ischemia-induced slowing of conduction velocity [9]. In contrast, Sanders et al. compared a prolonged conduction velocity in the right lateral atrium of patients with sinus node diseases to a matching group of patients with normal sinus node function. They conducted a second comparative analysis among patients with congestive heart failure and another matching group. The conduction velocities were 10 times higher than the pigs' velocities in our study. The reason for this may

lie in the mapping technique used by Sanders at the time, which was a non-high-density 3D mapping system [25,26] with a very rough analysis of conduction velocity.

In our analysis, we used unipolar signals, not bipolar signals, to calculate ultra-highdensity 3D voltage maps. Moreover, unipolar mapping has been useful for identifying alterations in voltage amplitude, reflecting histologically proven viable myocardium in the scar areas of ischemic origin [27], as well as low-voltage areas in the LA.

#### *Limitations*

Our data are derived from healthy porcine hearts, and their validity might be limited when transferred to human hearts. Healthy human heart measurements and outside interventions for all four heart chambers remain scarce for ethical reasons. Studies describing models to estimate local atrial conduction velocities [28] may develop and verify their models with the help of porcine heart data. Since pigs' cardiovascular system, heart size, and body weight are similar to those of humans, we used a pig model as a valuable preclinical model [29]. The volumes in our study are smaller than in adult human hearts (RA 100 mL [30], LA 129 ± 44 mL [31], RV 44–101 mL [32], LV 58–120 mL [33]), possibly due to the juvenile age of the pigs (31–41 kg, 3–4 months old).

The porcine hearts were healthy and juvenile. Correlations between conduction velocities and voltage amplitudes that are presumed and observed in diseased hearts may be absent in healthy hearts. Therefore, conclusions regarding diseased and aged hearts can be misleading.

The sample size was limited to four pigs due to animal welfare. Despite using the random effect 'heart', we cannot rule out the possibility that strong inter-individual differences interfered with our statistical model.

The signals were recorded with one ultra-high-density mapping system and one distinct mapping catheter. There are several mapping systems on the market with different mapping catheter designs. As there are no head-to-head comparisons between different ultra-high-density mapping systems, limitations or advantages are unknown with regard to signal quality.

Since the velocity was calculated using time differences between the first and last excitations in the circle, colliding wavefronts might be misinterpreted. The probability of colliding wavefronts in healthy hearts should be low. The small radius of the circles prevents disturbances in analysing velocities due to colliding wavefronts.

The heart chambers and different segments of each heart chamber were mapped consecutively. Therefore, an overtime effect on velocities or voltages cannot be fully excluded. We tried to keep the influence of time low by adhering to strict timelines for mapping. Furthermore, we did not administer any anti-arrhythmic drugs that could influence cardiac electrophysiology.

Heart rate was estimated over a recording period of approximately 5 min, which may cause inaccuracies in the heart rate analysis. To allow a better interpretation of results, we assumed a linear relation in our mixed-effects model, which provided a good approximation of higher-dimensional interactions.

Anaesthesia has been shown to influence cardiac electrophysiology [34–37]. The pigs were mapped under stable sedation to ensure comparability with the electrophysiological baseline circumstances. Specifically, we cannot rule out systematic bias in the absolute values of conduction velocity.

#### **5. Conclusions**

In healthy porcine hearts, conduction velocities and voltage amplitudes differ between the left and right heart chambers. Within each heart chamber, voltage amplitude differs only in the ventricles and conduction velocity differs more in the right than in the left chambers.

There is a slightly positive correlation between conduction velocity and voltage amplitude at velocities of <1.5 m/s in the atria and LV of healthy porcine hearts.

A comprehensive characterization of the conduction velocities and voltage amplitudes of all heart chambers could facilitate future computations for human heart models.

**Author Contributions:** T.I.W.: animal work, data collection, data analysis/interpretation, drafting article, revision of article, and statistics; T.L.: Concept/design, data analysis/interpretation, drafting article, revision of article, statistics, and funding; J.F., J.R., J.W. and C.B.: Concept/design, animal work, data collection, data analysis/interpretation, and drafting article; L.G., P.H., C.K. and K.T.: animal work, data collection, data analysis/interpretation, drafting article, and statistics; C.J.: Concept/design, animal work, data collection, data analysis/interpretation, drafting article, revision of article, approval of article, statistics, and funding. All authors have read and agreed to the published version of the manuscript.

**Funding:** The animal research was funded by Boston Scientific (Marlborough, MA, USA).

**Institutional Review Board Statement:** Government of Bavaria: ROB-55.2-2532.Vet\_02-1 7-174.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** The data presented in this study are available on request from the corresponding author.

**Conflicts of Interest:** T.L. and C.J. received lecture honoraria, educational grants, and/or research grants from Boston Scientific, Abbott, Biotronik, and Medtronic. PH and CK received research support from Boston Scientific. All other authors have no conflicts of interest.

#### **References**


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## *Article* **Antiplatelet and Anti-Coagulation Therapy for Left-Sided Catheter Ablations: What Is beyond Atrial Fibrillation?**

**Martina Nesti 1, Fabiana Lucà 2,\*, David Duncker 3, Francesco De Sensi 4, Katarzyna Malaczynska-Rajpold 5, Jonathan M. Behar 6, Victor Waldmann 6, Ahmed Ammar 7,8, Gianluca Mirizzi 1, Rodrigue Garcia 9,10, Ahran Arnold 11, Evgeny N. Mikhaylov 12, Jedrzej Kosiuk <sup>13</sup> and Luigi Sciarra <sup>14</sup>**


**Abstract: Aim:** International guidelines on the use of anti-thrombotic therapies in left-sided ablations other than atrial fibrillation (AF) are lacking. The data regarding antiplatelet or anticoagulation strategies after catheter ablation (CA) procedures mainly derive from AF, whereas for the other arrhythmic substrates, the anti-thrombotic approach remains unclear. This survey aims to explore the current practices regarding antithrombotic management before, during, and after left-sided endocardial ablation, not including atrial fibrillation (AF), in patients without other indications for anti-thrombotic therapy. **Material and Methods:** Electrophysiologists were asked to answer a questionnaire containing questions on antiplatelet (APT) and anticoagulation therapy for the following left-sided procedures: accessory pathway (AP), atrial (AT), and ventricular tachycardia (VT) with and without structural heart disease (SHD). **Results:** We obtained 41 answers from 41 centers in 15 countries. For AP, before ablation, only four respondents (9.7%) used antiplatelets and two (4.9%) used anticoagulants. At discharge, APT therapy was prescribed by 22 respondents (53.7%), and oral anticoagulant therapy (OAC) only by one (2.4%). In patients with atrial tachycardia (AT), before ablation, APT prophylaxis was prescribed by only four respondents (9.7%) and OAC by eleven (26.8%). At discharge, APT was recommended by 12 respondents (29.3%) and OAC by 24 (58.5%). For VT without SHD, before CA, only six respondents (14.6%) suggested APT and three (7.3%) suggested OAC prophylaxis. At discharge, APT was recommended by fifteen respondents (36.6%) and OAC by five (12.2%). Regarding VT in SHD, before the procedure, eight respondents (19.5%) prescribed APT and five (12.2%) prescribed OAC prophylaxis. At discharge, the administration of anti-thrombotic therapy depended on the LV ejection fraction for eleven respondents (26.8%), on the procedure time for ten (24.4%), and on the radiofrequency time for four (9.8%), with a cut-off value from 1 to 30 min. **Conclusions:** Our survey indicates that the management of anti-thrombotic therapy surrounding left-sided endocardial ablation of patients without other indications for anti-thrombotic therapy is highly variable. Further studies are necessary to evaluate the safest approach to these procedures.

**Citation:** Nesti, M.; Lucà, F.; Duncker, D.; De Sensi, F.; Malaczynska-Rajpold, K.; Behar, J.M.; Waldmann, V.; Ammar, A.; Mirizzi, G.; Garcia, R.; et al. Antiplatelet and Anti-Coagulation Therapy for Left-Sided Catheter Ablations: What Is beyond Atrial Fibrillation? *J. Clin. Med.* **2023**, *12*, 6183. https://doi.org/10.3390/ jcm12196183

Academic Editors: Daniele Masarone and Francesco Pelliccia

Received: 30 June 2023 Revised: 9 August 2023 Accepted: 7 September 2023 Published: 25 September 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

**Keywords:** left-sided ablations; anticoagulation therapy; ventricular tachycardia; atrial tachycardia

#### **1. Introduction**

Catheter ablation (CA) procedures are associated with a potential threat of thromboembolic complications in patients without other indications for anti-thrombotic therapy. Catheter instrumentation activates the clotting cascade and, consequently, increases the risk of thrombus formation [1,2], particularly in the case of procedures performed on the left side of the heart. Most of the available data are focused on periprocedural anticoagulation regimens and describe CA procedures for atrial fibrillation (AF) [3–5]. However, the anticoagulation protocols during other left-sided ablation procedures are not well assessed, particularly in complex ablations with extensive radiofrequency applications. The purpose of our survey was to address the contemporary clinical practices of electrophysiologists in antiplatelet (APT) and anticoagulation therapy (OAC) for left-sided endocardial CA, other than AF, in patients without other indications for antithrombotic therapy.

#### **2. Methods**

An online questionnaire consisting of multiple-choice questions was prepared and sent via SurveyMonkey to centers among electrophysiologists' scientific network that performed left-sided ablation. The responses were collected from 1 February 2019 to 15 March 2019. This study complied with the European General Data Protection Regulation law. All centers that took the survey agreed to participate in the study.

#### *2.1. Data Collected*

The questionnaire collected information on antithrombotic management before, during, and after left-sided endocardial CA procedures, except for AF, in patients without other indications for anti-thrombotic therapy. Left-sided ablation for atypical atrial flutter was also excluded. The left-sided endocardial CA procedures that were evaluated included CA of an accessory pathway (AP), atrial tachycardia (AT), ventricular tachycardia (VT) without known structural heart disease (SHD), and VT in SHD. Antithrombotic therapy included all pharmacological agents used to treat or avoid thromboembolism, including vitamin K antagonists (VKA), novel oral anticoagulants (NOAC) as well as APTs such as aspirin and P2Y12 inhibitors.

The questionnaire also collected information about the type of center (academic vs. public vs. private), the country of location, the number of procedures/year, the number of left-sided ablation procedures/year, and the number of electrophysiologists working in the EP lab.

The complete questionnaire is provided in Appendix A.

#### *2.2. Statistical Analysis*

Categorical data were reported as numbers and percentages. The mean (standard deviation [SD]) and the median (interquartile range [IQR]) have been used for the description of normally and non-normally distributed data, respectively. All data were analyzed using SPSS v 20.0 (SPSS Inc., Chicago, IL, USA). The authors had full access to the data and take full responsibility for its integrity. All authors have read and agreed to the manuscript as written.

#### **3. Results**

The centers were contacted to participate to the survey through EHRA database. Fortyone centers from 15 countries responded (63.4% university hospitals, 24.4% public hospitals, and 12.2% private hospitals) (Table 1).



The median number of EP procedures per center was in the range of 503 to 441 per year. The number of left-sided procedures per year was in the range of 37 to 21 (not including AF CA).

#### *3.1. Accessory Pathway*

Before CA, the majority of respondents (35, or 85%) did not use antithrombotic therapy. Only four respondents (9.7%) administered APT and two (4.9%) administered OAC (Figure 1). During CA, heparin was used by 85.4% (Figure 2) to maintain the ACT target of 300–350 s in 36.6% of cases (Figure 3). Heparin was used to irrigate the sheaths by 22 respondents (53.7%). After CA, APT was prescribed by twenty-two respondents (53.7%) and OAC only by one (2.4%) (Figure 4).

**Figure 1.** Anti-thrombotic management before ablation. SHD: structural heart disease.

**Figure 2.** Use of heparin during ablation. AP: accessory pathway, AT: focal atrial tachycardia, VT: ventricular tachycardia, SHD: structural heart disease.

**Figure 3.** Heparin dosage during ablation. AP: accessory pathway, AT: atrial tachycardia, VT: ventricular tachycardia, SHD: structural heart disease, ACT: activated clotting time.

**Figure 4.** Anti-thrombotic management at discharge. SHD: structural heart disease.

#### *3.2. Atrial Tachycardia*

Before CA, APT prophylaxis was recommended by only four respondents (9.7%) and OAC by eleven (26.8%) (Figure 1). During the procedure, almost all respondents (40, or 97.6%) used heparin (Figure 2), and an ACT target of 300–350 s was adopted in 58.5% of cases (Figure 3). The sheaths were routinely irrigated with continuous intravenous heparin by 25 respondents (61%). After CA, APT was recommended by 12 respondents (29.3%) and OAC by 24 (58.5%) (Figure 4).

#### *3.3. Ventricular Tachycardia in Patients without Structural Heart Disease*

Before CA, only six respondents (14.6%) suggested antiplatelets and three (7.3%) suggested anticoagulation prophylaxis (Figure 1). During ablation, almost all respondents (40, or 97.6%) used heparin (Figure 2), maintaining an ACT target of 300–350 s in 46.3% of cases (Figure 3). Continuous intravenous heparin was used by 22 respondents (53.7%) to irrigate the sheaths. After CA, APT was recommended by fifteen (36.6%) and OAC by five respondents (12.2%) (Figure 4).

#### *3.4. Ventricular Tachycardia in Patients with Structural Heart Disease*

APT and OAC prophylaxis before CA were prescribed by eight (19.5%) and five (12.2%) respondents, respectively (Figure 1). Conversely, the intraprocedural use of heparin was adopted by all respondents (Figure 2), maintaining an ACT target of 300–350 s in 58% of cases (Figure 3). The sheaths were routinely irrigated with continuous intravenous heparin by 26 respondents (63.4%). After CA, the choice of administering APT was based on the left ventricular ejection fraction (LVEF), the procedure time, and the radiofrequency time, with a cut-off value ranging from 1 to 30 min for eleven (26.8%), ten (24.4%), and four (9.8%) respondents, respectively. (Figure 1). During CA, all respondents used heparin (Figure 2), maintaining an ACT target of 300–350 s in 58% of cases (Figure 3). The sheaths were routinely irrigated with continuous intravenous heparin by 26 respondents (63.4%). After CA, the administration of APT depended on the left ventricular ejection fraction (LVEF) for eleven respondents (26.8%), on the procedure time for ten (24.4%), and on the radiofrequency time for four (9.8%), with a cut-off value ranging from 1 to 30 min.

#### **4. Discussion**

Nowadays, CA is considered the strategy of choice for a wide range of arrhythmias in light of its high percentage of success and its low rate of complications [6]. With regard to thromboembolic complications, it is worth mentioning that manipulating catheters and simultaneously performing lesions during procedures may increase thrombotic risk, particularly in left heart procedures [7–10].

An incidence of cerebral embolism (CE) and peripheral arterial embolism of 0.46–0.06% in left-sided CS has been reported by Hindricks [8].

In the MERFS registry [8], which analyzed 1715 subjects who underwent right-sided ablation (AV node re-entrant tachycardia or AV junction ablation), the rates of CE, pulmonary embolism (PE), and venous thrombosis (VTE) were 0.06%, 0.23%, and 1.04%, respectively. On the other hand, the percentages of pericardial tamponade (PT), pericardial effusion (PEff), and major bleeding (MB)/hematoma have been reported as 0.17%, 0.41%, and 0.11%, respectively.

In the NASPE registry [11], among 2142 adults who underwent right-sided ablation, the rates of thrombo-embolism, PT, and MB/hematoma have been shown to be 0.14%, 0.09%, and 0.28%, respectively. In contrast, no embolic events have been reported after the CA of left free-wall accessory pathways in 418 adults.

In Atakr Multicenter's registry [12], it has been observed that thromboembolic events occurred in 0.7% and 1.1% of patients who underwent right-sided and left-sided CA, respectively, in the absence of other risk factors for systemic embolization.

In comparison, rates of PT, PEff, and MB/hematoma of 0.6%, 1.9%, and 3.5%, respectively, were described [12].

Furthermore, embolic complications after CA procedures in patients with VT seem to be lower in the absence of SHD compared to patients with structural abnormalities.

However, an anticoagulation strategy is usually used during CA procedures, consisting of administering a venous bolus of heparin (50–100 U/kg) followed by a heparin infusion with the aim of maintaining an ACT above 300 s [13–15].

Nevertheless, the intraprocedural risk of a systemic thromboembolic event is significantly lowered by the intravenous administration of heparin or bivalirudin [16]. Despite this, the post-procedural risk remains considerable, and it should be accurately evaluated [16]. Indeed, it has been shown that cerebral events, including subclinical ones, cause long-term neurocognitive impairment [17].

However, data regarding either the APT or the OAC approach after CA are limited.

Our survey sheds light on the fact that considerable variation exists in the management of OAC and APT surrounding left-sided non-AF endocardial CA in patients without other indications for anti-thrombotic therapy.

However, it should be highlighted that for some indications, the respondents largely agreed not to use antithrombotic medication, whereas the indications varied considerably for other procedures. During left-sided electrophysiological procedures, due to an increase in the thrombophilic state, a three-fold increase in the incidence of thromboembolic complications (1.8–2%) was observed, compared with an overall rate of only 0.6% when all CA procedures are considered [18]. Despite this important data that differs from AF indications [4], no guidelines indicate the correct choices in this setting. The only indication was given by the consensus document published in 2015 [18] and by a recent consensus on ventricular arrhythmias [19].

A previous survey about the prevention of VTE after EP procedures was conducted; however, it described only right-sided ablation [20]. To our knowledge, this is the first survey about left-sided ablations.

#### *4.1. Accessory Pathway*

Patients undergoing accessory pathway (AP) CA are more likely to be young, without risk factors for thromboembolic events, or those who are at low risk. Only a single catheter in the left atrium (LA) or left ventricle (LV) is commonly used; moreover, the ablation (CA) is usually focal, resulting in much shorter total CA times and less time spent in the left atrium. For this reason, Sticherling et al. [18] recommend neither anti-thrombotic prophylaxis before AP ablation, nor the post-interventional use of OAC or APT.

Moreover, previous studies reported an incidence of 0.46–2% [8,16] of thromboembolic events related to AP ablation and, recently, Głowniak et al. documented the presence of silent cerebral infarcts after AP ablation [21]. Thakur et al. [22] reported that 2% of embolic events were late incidences in left-sided accessory pathways CA, in spite of the intraprocedural administration of heparin followed by APT for 3 months after CA.

For this reason, continuous flushing of the sheaths and antithrombotic therapy (with 5000–15,000 U or 90–200 U/kg of intravenous sodium heparin followed by 1000 U/h) are advised during the procedure to avoid thrombus formation [18].

Our survey showed a different scenario: 15% of surveyed participants used antithrombotic prophylaxis before CA of the accessory pathway and 50% used it after CA. On the other hand, the heparin dose was mainly driven by the activated clotting time (ACT) value, and only half of the participants irrigated the sheaths during procedures.

#### *4.2. Atrial Tachycardia*

In contrast to patients with atrial flutter, who are thought to have the same risk of thromboembolism as patients with AF [23], there is no clear data regarding thromboembolic risk in patients with FAT. In our survey, only about a quarter of respondents used OAC in patients with FAT prior to the procedure, and about one-fifth recommended APT. During CA procedures, almost all the participants were heparinized. The respondents administered heparin to their patients based on ACT control, and over half of them also used heparin in side flushes. Heparinization with ACT > 300 s is a standard of care in left-sided CA procedures according to the most recent European guidelines for AF management [24]; however, it was not specified whether the continuous irrigation of the sheaths further reduced the risk of thromboembolic complications.

After the CA procedure, slightly more than half of the participants recommended OAC, and a quarter preferred to give antiplatelet agents. The rationale for using OAC after AF ablation included the risk of arrhythmia in the blanking period and the phenomenon of atrial stunning following sinus rhythm restoration [25]. Again, there is no data on the prevalence of LA appendage thrombus after left-sided FAT CA. More data is needed to understand if the risk of thromboembolic events in FAT is similar to that in AF, and hence if respective antithrombotic therapy should be warranted.

#### *4.3. Ventricular Tachycardia in Patients without Structural Heart Disease*

VT can also occur in a structurally normal heart [26]. Idiopathic VTs (the most common type) are typically monomorphic because they originate from a single focus, and can be ablated by the limited delivery of radiofrequency energy to the site of origin of the arrhythmia [15]. Probably due to the limited area of CA, the risk of thromboembolism in patients without SHD undergoing VT ablation is lower than in patients with SHD [27], but data about the correct management of antithrombotic therapy in these procedures are not available, and there is a large variability among participants.

In a survey regarding intraprocedural anticoagulation among the writing committee members of the EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias [28], for idiopathic VA, 48% of the respondents used ACT levels longer than 250 s, 39% longer than 300 s, and 13% longer than 350 s. However, a clear distinction was not made between VT with and without SHD regarding antithrombotic therapy after CA. Our data confirmed the use of heparin during ablation. However, a difference in terms of ACT targets has been reported. Indeed, the data from our survey indicated that the achieved ACT values were higher, ranging from 300 to 350 s (Figure 2).

#### *4.4. Ventricular Tachycardia in Patients with Structural Heart Disease (SHD)*

Our results showed that anti-thrombotic therapy was variable in patients undergoing LV substrate ablation.

According to the 2019 HRS/EHRA/APHRS/LAHRS Consensus [19], antithrombotic therapy should not be adopted before CA; however, this point is not generally agreed upon.

Regarding anticoagulation during the CA procedure, previous authors have suggested different protocols: a bolus of at least 5000 U after the insertion of sheaths followed by a 1000 U/h heparin infusion without intra-procedural ACT monitoring [29], or strict ACT monitoring with the target values of 200–250 s [30]. In contrast, according to the consensus document, after sheath insertion, the administration of a bolus of intravenous heparin (bolus dose empirically 5000–10,000 U or 50–100 U/kg) should be followed by a continuous infusion of 1000–1500 U/h in order to maintain an ACT level of 300 s. Our data are not consistent with these indications. Indeed, the ACT target is higher (300–350).

Regarding post-procedural anticoagulation management, in our survey, APT was prescribed after CA by 53.6% of respondents and OAC by 31.7%.

However, there are no conclusive data in this sense [31,32], and the choice of APT after CA depends on the physician [7] (Table 2).

Another important part of the data to consider is the role of OAC with warfarin or NOACs for patients who received extensive areas of CA, or those who are at increased risk of thromboembolism. In a paper by Reddy et al. [33], and in the Multicenter Thermocool Ventricular Tachycardia Ablation Trial [34], the choice between VKA or aspirin after a VT ablation depended on the extension of the CA area (Table 2). In the SMASH VT study [33], OAC was continued for 4 to 6 weeks (providing that they had more than five CA lesions). In the Multicenter Thermocool Ventricular Tachycardia Ablation Trial [34] patients received OAC for 3 months in cases in which CA was performed on over 3 cm of the lesion area.


**Table 2.** Antithrombotic management after ablation of ventricular tachycardia in structural heart disease.

VKA: vitamin K antagonist; OAC: oral anticoagulant therapy.

The EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias [35], published in 2009, recommended 6–12 weeks of warfarin after CA over large endocardial areas. However, the latest version [19] suggested that anticoagulation is reasonable after less extensive endocardial VT ablation, or with OAC after extensive endocardial VT ablation (classes of recommendation IIa and IIb, and level of evidence C, respectively) even without a specific indication regarding the timing.

More recently, according to Shivkumar et al., it should be advisable to continue OAC after VT CA for at least 4 weeks in these patients and this indication should be extended to all cases of extensive ablation. With regard to long-term OAC, the choice should be based on whether preexisting indications exist or not [15]. Despite this evidence, in our survey, only four respondents followed this indication. More respondents decided to prescribe OAC or APT therapy according to the LV ejection fraction (26.8%).

#### **5. Limitations**

This study has several limitations. These data represent the most current practices among some electrophysiologists, which may not represent the standards of practitioners in other countries, or those in other settings. Moreover, voluntary participation can represent a selection bias. It should be noted that this may be exacerbated by the fact that the centers and not the individual doctors received the survey. The use of anti-thrombotic therapy depends on the radiofrequency time and the LV ejection fraction, but no data are available on the drugs used. Moreover, the choice of treatment in clinical practice is likely to be influenced by diverse clinical factors.

#### **6. Conclusions**

Our survey showed that there is considerable variation in the management of antithrombotic therapy surrounding left-sided non-AF endocardial CA in patients without other indications for anti-thrombotic therapy. Further studies are necessary to evaluate the optimal approach to these procedures.

**Author Contributions:** Conceptualization, M.N., D.D., L.S. and J.K.; methodology, M.N., F.D.S., F.L., K.M.-R. and J.M.B.; software, V.W.; validation, V.W. and A.A. (Ahmed Ammar); formal analysis, M.N., G.M. and F.L.; investigation, G.M. and R.G.; resources, G.M. and A.A. (Ahmed Ammar); data curation, M.N. and A.A. (Ahran Arnold); writing—original draft preparation, M.N., D.D. and F.D.S.; writing—review and editing, M.N., F.L., J.K. and E.N.M.; visualization, M.N.; supervision, M.N., E.N.M., J.K. and L.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Ethical review and approval were waived for this study due to the fact that it was a survey.

**Informed Consent Statement:** Patient consent was waived because it was a survey.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** Evgeny N. Mikhaylov is a consultant for Biosense Webster and Boehringer Ingelheim and received speaker honoraria from Biosense Webster, Boehringer Ingelheim, Pfizer, Medtronic, and Boston Scientific. The other authors have nothing to declare.

#### **Appendix A**

Questionnaire:

	- a. Type of institution (University Hospital, Public Hospital, Private Hospital)
	- b. Country
	- c. Number of procedures/year
	- d. Number of left-sided ablation procedures/year (accessory pathway, atrial tachycardia, ventricular tachycardia)
	- a. Do you use antiplatelet prophylaxis in:
		- the accessory pathway? yes/no
		- atrial tachycardia? yes/no
		- ventricular tachycardia with structural heart disease? yes/no
		- ventricular tachycardia without structural heart disease? yes/no
	- b. Do you use anticoagulation prophylaxis in:
		- the accessory pathway? yes/no
		- atrial tachycardia? yes/no
		- ventricular tachycardia with structural heart disease? yes/no
		- ventricular tachycardia without structural heart disease? yes/no
	- a. Do you use heparin in:
		- the accessory pathway? yes/no
		- atrial tachycardia? yes/no
		- ventricular tachycardia with structural heart disease? yes/no
		- ventricular tachycardia without structural heart disease? yes/no
	- b. Do you use heparin to irrigate the sheath introducers? yes/no
	- c. For the heparin dose do you
		- i. maintain ACT target 300–350 s
		- ii. maintain ACT target >350 s
		- iii. use a weight-based protocol
		- iv. use a fixed dose < 3000 Units
		- v. use a fixed dose > 3000 Units
	- a. Do you prescribe antiplatelet therapy after the ablation of
		- the accessory pathway? yes/no
		- atrial tachycardia? yes/no
		- ventricular tachycardia with structural heart disease? yes/no
		- ventricular tachycardia without structural heart disease? yes/no

#### **References**


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