Asymptomatic brain lesions following laserballoon-based pulmonary vein isolation

Abstract

Aims

Laserballoon-based pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF) has proven safe and effective. Silent brain lesions after AF ablation detected on magnetic resonance imaging (MRI) have been described for several technologies, but its incidence following laserballoon PVI is unknown. The current study sought to assess the incidence of new asymptomatic brain lesions in patients undergoing laserballoon-based PVI.

Methods and results

Patients referred for PVI underwent pre- and post-procedural MRI of the brain. A total of 86 patients were enroled into the study (laserballoon group: 44 patients, 15 female, age 63 ± 9 years, left atrial (LA) diameter 43 ± 5 mm; cryoballoon group: 20 patients, 6 female, age 61 ± 9 years, LA diameter 41 ± 4 mm; and irrigated radiofrequency (RF) group: 22 patients, 11 female, age 64 ± 8 years, LA diameter 43 ± 6 mm). There was no statistically significant difference between the groups with regard to new asymptomatic brain lesions detected on post-procedural MRI: 5 of 44 (11.4%) patients in the laserballoon group, 1 of 20 (5.0%) patients in the cryoballoon group, and 4 of 22 (18.2%) patients in the irrigated RF group, respectively. In the laserballoon group, one additional patient with a new cerebral lesion experienced transient diplopia. In a multivariate regression model the only risk factor for asymptomatic new lesions was the CHA₂DS₂VASc score.

Conclusion

Following laserballoon-based PVI, new asymptomatic brain lesions were detected in 11.4% of patients. A higher CHA₂DS₂VASc score, but not the ablation technology utilized, was the only associated risk factor.

Introduction

Laserballoon-based pulmonary vein isolation (PVI) for the treatment of paroxysmal atrial fibrillation (AF) has demonstrated excellent acute and similar 1-year success rates compared to conventional ablation technologies.^1–3 Among other important complications, several recent studies have reported a significant rate of asymptomatic brain lesions following catheter ablation of AF, visible only on post-procedural magnetic resonance imaging (MRI) of the brain.^4–7 To date, the incidence of silent brain lesions following PVI using the laserballoon is unknown. The current prospective, multicentre study sought to assess the rate and progression of new post-procedural asymptomatic brain lesions after endoscopic laserballoon-based PVI and compare its incidence with a cohort of patients undergoing PVI using the cryoballoon or irrigated radiofrequency (RF) ablation.

Methods

Between March and August 2012 consecutive patients suffering from highly symptomatic, drug-refractory paroxysmal or short-standing persistent AF referred for PVI to two high-volume centres were enroled into one of three study arms (laserballoon group, cryoballoon group, or irrigated RF catheter ablation group). Exclusion criteria were a previous left atrial (LA) ablation procedure, long-standing persistent AF, a LA diameter >60 mm, severe valvular heart disease, and contraindications to post-interventional oral anticoagulation.

All patients underwent pre-procedural transoesophageal echocardiography for assessment of LA diameter and to rule out intracardiac thrombus. All patients gave written informed consent prior to PVI.

Ablation system

The concept of laserballoon-based PVI has been described previously.¹ In brief, the laserballoon-based endoscopic ablation system (HeartLight, CardioFocus) consists of a non-steerable, compliant balloon adjustable in nine sizes from 7 to 35 mm. The balloon is filled and continuously flushed with heavy water and introduced into the LA via a 12F deflectable transseptal sheath (CardioFocus). The catheter shaft contains a 2F fibreoptic endoscope and a second fibre connected to a 980 nm laser diode source for laser energy delivery. Laser energy is applied for 20 or 30 s depending on the preselected power (5.5–12 W). Encircling lesions around individual PVs are deployed in a point-by-point fashion, while a single ablation lesion covers 30° of a circle. Pulmonary vein isolation was confirmed by spiral mapping catheter (Lasso, Biosense Webster) recordings.

In the cryoballoon group, only the 28 mm cryoballoon (Artic Front, Medtronic) was used as detailed previously.⁸ The cryoballoon was advanced into the LA over a guidewire via a 12F steerable transseptal sheath (FlexCath, Medtronic). The cryoballoon was inflated and positioned at the antral aspect of the pulmonary vein (PV). Selective PV occlusion angiography confirmed complete sealing of the balloon-to-LA/PV interface. Cryothermal energy was delivered for 300 s. Following successful PVI, a bonus freeze cycle was applied.

In patients assigned to RF-based PVI, ablation within the LA was aided by use of an electroanatomical mapping system (CARTO, Biosense Webster). Ablation was performed using a 3.5 mm irrigated tip catheter (Thermocool Navistar, Biosense Webster). Radiofrequency current was delivered at a target temperature of 43°C using a power limit of 30 W and an infusion rate of 17 mL/min along the superior, posterior, and inferior portions of the PVs, and a power limit of 40 W and an infusion rate of 25 mL/min along the anterior aspect of the PV. Successful PVI was verified by recordings from a spiral mapping catheter positioned within the PV.

Intraprocedural management

Any attempt was made to complete PVI using the assigned ablation technology. Ablation was performed during conscious sedation using intravenous midazolam, sulfentanyl, and a continuous infusion of propofol. A diagnostic mapping catheter was placed within the coronary sinus. Prior to transseptal puncture a bolus of heparin was administered (100 IU/kg). Single or double transseptal puncture using an 8.5F transseptal sheath (SL1, St Jude Medical) and the modified Brockenbrough technique was performed under fluoroscopic or echocardiographic guidance. The transseptal sheaths were continuously flushed with normal saline at a rate of 10 mL/h (irrigated RF group) or 20 mL/h (laserballoon and cryoballoon group, respectively). Upon insertion or withdrawal of the ablation catheter the transseptal sheath and catheter were flushed simultaneously. The activated clotting time (ACT) was measured every 30 min and a bolus of heparin administered targeting an ACT > 300 s.

Magnetic resonance imaging

A pre- and post-procedural MRI scan of the brain was performed in all patients to detect the true incidence of new asymptomatic brain lesions. The radiologists interpreting the MRI were blinded to the ablation technology used. A new lesion on post-procedural MRI was defined as a focal hyperintense signal on T2 diffusion-weight imaging (DWI). Lesions detected on MRI were analysed with respect to their number, location, and size. Patients with new embolic lesions on post-procedural MRI were encouraged to undergo a follow-up MRI to assess lesion progression. T2 diffusion-weight imaging, T1-weighted and T2*-weighted gradient echo images, and FLAIR imaging were performed in all patients before and after the intervention. Depending on the MRI scanner used, the following parameters were applied to perform individual sequences:

3.0 T MRI (Achieva TX, Philips Healthcare): DWI: b 1000, TR 3770 ms, TE 85 ms, thickness 5 mm, gap 1.0 mm; FLAIR: 11000 ms, TE 125 ms, TI 2800 ms, thickness 5 mm, gap 1.0 mm; T1: TR 300 ms, TE 4.6 ms, thickness 4 mm, gap 0.4 mm; T2* TR 837 ms, TE 16 ms, thickness 5 mm, gap 0.4 mm.

1.5 T MRI (Avanto, Siemens AG): DWI: b 1000, TR 3400 ms, TE 102 ms, thickness 5 mm, gap 0.5 mm; FLAIR: TR 9000 ms, TE 114 ms, TI 2500 ms, thickness 4 mm, gap 0.6 mm; T1: TR 577 ms, TE 11 ms, thickness 4 mm, gap 0.4 mm; T2* TR 859 ms, TE 20.4 ms, thickness 5 mm, gap 0.7 mm.

1.5 T MRI (Symphony, Siemens AG): DWI: b 1000, TR 4200 ms, TE 139 ms, thickness 5 mm, gap 0.5 mm; FLAIR: TR 9000 ms, TE 114 ms, TI 2500 ms, thickness 5 mm, gap 0.5 mm; T1: TR 697 ms, TE 14 ms, thickness 4 mm, gap 0.4 mm; T2* TR 830 ms, TE 25 ms, thickness 5 mm, gap 0 mm.

1.5 T MRI (GE SignaHDxt): DWI: b 1000, TR 8625 ms, TE 98 ms, thickness 5 mm, gap 0.5 mm; FLAIR: TR 8002 ms, TE 125.8 ms, TI 2000 ms, thickness 5 mm, gap 0.6 mm; T1: TR 577 ms, TE 11 ms, thickness 4 mm, gap 0.4 mm; T2* TR 859 ms, TE 20.4 ms, thickness 5 mm, gap 0.5 mm.

Post-procedural management

All patients underwent transthoracic echocardiography and thoracic fluoroscopy the day after ablation to rule out a pericardial effusion or pneumothorax. Proton-pump inhibitors were given for 6 weeks following ablation. If PVI was performed on a therapeutic international normalized ratio (INR, 2–3), warfarin was continued uninterrupted for at least 3 months following the ablation procedure. In patients with subtherapeutic INR prior to PVI, low-molecular-weight heparin was administered beginning 6 h after the procedure until a therapeutic INR of 2–3 was achieved. Warfarin was continued for at least 3 months after the procedure. Previously ineffective antiarrhythmic drug therapy was continued for 3 months.

Statistical analysis

Continuous data were described as means and standard deviations, if the variables were normally distributed, or as median, minima, first and third quartiles, and maxima if they were not. Differences of metric variables between the two groups were analysed using the t-test, if data were normally distributed, and with the Wilcoxon–Mann–Whitney test otherwise. Differences between three groups were analysed by analysis of variance for normally distributed data and by the Kruskal–Wallis test otherwise. Categorical data were described with absolute and relative frequencies. Differences between categorical variables were evaluated with the χ² test or with Fisher's exact test in case of smaller expected cell frequencies. If tests for group effects were significant, two group comparisons were performed using the multiple comparison adjustment of Bonferroni. Univariate logistic regression models were used to identify variables that are related with the occurrence of lesions. Baseline, procedural, and echocardiographic data were associated with the outcome. Variables with a univariate P value <0.2 were included in a multiple logistic regression model. Stepwise selection procedures were used to determine the final model. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) as well as the P values of the final model are presented. Odds ratios and their CIs are specified for the explanatory variables. All P values are two-sided. For all tests, a P≤ 0.05 was considered significant and for multiple comparisons and subgroup analyses Bonferroni adjusted significance levels were used. All calculations were performed with the statistical analysis software SAS (SAS Institute Inc., version 9.2).

Results

A total of 86 patients were enroled; 44 patients in the laserballoon group, 20 patients in the cryoballoon group, and 22 patients in the irrigated RF ablation group. The patients' baseline characteristics are detailed in Table 1.

Baseline characteristics

Compared with the cryoballoon group (100%), fewer patients in the laserballoon (68%, P = 0.003) and irrigated RF ablation group (73%, P = 0.0216) suffered from paroxysmal AF. All other patient baseline characteristics including the CHADS₂ and CHA₂DS₂VASc score were similar between groups.

Intraprocedural parameters

Intraprocedural parameters are depicted in Table 2. Acute PVI using the pre-specified ablation technology was achieved in 41 of 44 (93.2%) patients in the laserballoon group and in all patients in the cryoballoon and irrigated RF group. Procedure duration, defined from time of vascular access to removal of vascular sheaths was significantly shorter in the cryoballoon group (164 ± 29 min) compared with the laserballoon (195 ± 48 min, P = 0.0021) and irrigated RF ablation group (208 ± 69 min, P = 0.0111). Intraprocedural electrical cardioversion was performed in a total of 24 of 86 (28%) patients without a significant difference between groups. Sixty-six of 86 (77%) patients had at least one ACT value <300 s and 27 of 86 (31%) patients an ACT < 250 s throughout the duration of LA access. One of 44 (2.3%) patients in the laserballoon group experienced right phrenic nerve palsy during the first laser application along the posterior aspect of the right superior PV with clinical improvement at 6-month follow-up. In addition, 2 of 44 (4.5%) patients in the laserballoon group required a single RF application along the anterior ridge of the left PVs to achieve PVI.

Findings on magnetic resonance imaging

On pre-procedural MRI of the brain, 49 of 86 (57%) patients demonstrated abnormal findings ranging from microangiopathical changes to old ischaemic lesions. The number of patients with abnormal pre-procedural MRI findings was not statistically different between the groups. The number of days between the ablation procedure and the post-procedural MRI ranged from 1 to 5 days.

New lesions on post-procedural MRI were found in 11 of 86 (12.8%) patients without a statistically significant difference between the groups: 6 of 44 (13.6%), 1 of 20 (5.0%), and 4 of 22 (18.2%) patients in the laserballoon, cryoballoon, and irrigated RF ablation group, respectively (P = 0.4870, Table 3). One patient in the laserballoon group experienced diplopia, which correlated with a small acute ischaemic lesion in the region of the right mesencephalon. Upon hospital discharge on Day 5, all symptoms had resolved. No overt neurological deficits were detected in the remaining patients following the procedure.

New asymptomatic embolic brain lesions were found in 10 of 86 (11.6%) patients. There was no statistically significant difference between the groups: 5 of 44 (11.4%) patients in the laserballoon group, 1 of 20 (5.0%) in the cryoballoon group, and 4 of 22 (18.2%) patients in the irrigated RF group, respectively (P = 0.4148). In two of five patients in the laserballoon group RF touch-up was necessary to achieve PVI. The location, size, and number of lesions per group are detailed in Table 3. The number of lesions per patient ranged between 1 and 4 with a maximum size of 8 mm. The lesion location was not confined to a specific anatomical region. The baseline characteristics of those patients with asymptomatic embolic lesions are depicted in Table 4. Patients with new asymptomatic lesions on MRI were older (68 ± 4 vs. 62 ± 9 years, P = 0.037) and all had abnormal findings on pre-procedural MRI. In addition, the CHA₂DS₂VASc score was significantly higher in patients with new asymptomatic lesions (3.0 ± 1.3 vs. 1.8 ± 1.4, P = 0.0108). No other parameters were statistically different between patients with and without new findings on post-procedural MRI.

Eight of 10 patients with silent cerebral lesions agreed to undergo a follow-up MRI (laserballoon group: four of five patients, cryoballoon group: one of one patients, and irrigated RF group: three of four patients). In three patients the previously noted lesion disappeared, in two patients the lesion remained unchanged, in two patients one lesion disappeared and one was still visible, and in one patient, while the previous asymptomatic lesion had disappeared, a new silent lesion could be detected.

Univariate and multivariate regression model

Variables included in the univariate regression model are depicted in Table 5. In a multivariate regression model only a higher CHA₂DS₂VASc score (Table 6) was a significant predictor for the occurrence of new asymptomatic lesions on post-procedural MRI (OR, 1.664; 95% CI, 1.018–2.721).

Discussion

This is one of the first studies to report on the rate of asymptomatic brain lesions following laserballoon-based PVI. The major findings are (i) that 11.4% of patients undergoing laserballoon-based PVI had newly visible asymptomatic embolic brain lesions on post-procedural MRI, that (ii) this rate is comparable with established ablation technologies such as irrigated RF or cryoenergy, and that (iii) the only predictor for silent cerebral embolism in the present study was the CHA₂DS₂VASc score.

The incidence of symptomatic cerebral thrombo-embolic events in patients undergoing catheter ablation for AF is estimated from 0.8 to 0.94%.^9,10 Recently, Lickfett et al.¹¹ reported a significantly higher rate (10%) of asymptomatic embolic brain lesions on post-procedural MRI in patients that underwent PVI using irrigated RF ablation. In a different study the incidence of silent cerebral lesions following irrigated RF PVI was 14%.⁴ Herrera Siklody et al. detected asymptomatic brain lesions in 37.5% of patients undergoing PVI using the multielectrode duty-cycled ablation system [pulmonary vein ablation catheter (PVAC)]. The only risk factor for silent cerebral lesions in the latter study was the use of PVAC as an ablation tool, which highlights the need to carefully scrutinize new ablation technologies with regard to their safety aspect.⁵ In this context, the current study was designed to investigate the incidence of asymptomatic embolic brain lesions using the laserballoon. While the efficacy, durability, and safety profile of laserballoon PVI has been proven, the current two-centre study is the first to prospectively assess the rate of silent embolic brain lesions comparing the laserballoon technology with irrigated RF and cryoballoon-based PVI.^1,12

In the present study, the study protocol included the routine use of pre-procedural MRI to minimize false-positive findings on post-procedural imaging of the brain. The rate of asymptomatic embolic lesions was not statistically different between study groups; in fact, the incidence reported for the laserballoon group is similar to that reported in the study by Gaita et al.⁴ using irrigated RF energy. In contrast to the latter study, the current study, in a multivariate regression model, failed to establish an ACT level <250 as a predictor for silent embolic lesions on post-procedural MRI. In the presence of a low ACT, thrombus may form along the sheath, spiral mapping catheter, or at the site of ablation. Although the study protocol targeted an ACT > 300 s, at least once during the procedure, 77% of patients remained below this cut-off value, while 31% patients had an ACT level below 250 s.

In addition, this study failed to detect a significant correlation between intraprocedural cardioversion and the rate of silent embolic lesions. This is in line with the study by Herrera Siklody et al. including a similar number of patients (N = 74) than the current study and contrasts findings by Gaita et al., in which cardioversion at time of ablation was a significant risk factor for asymptomatic brain lesions.^4,5 This difference, however, may simply be explained on the basis of a larger patient cohort enroled in the study by Gaita et al. (N = 232).

The CHADS₂ and CHA₂DS₂VASc score are used to estimate the risk of overt embolic stroke in patients with AF. Interestingly, in the present study a higher CHA₂DS₂VASc score was associated with an increased risk of silent cerebral embolism, while the CHADS₂ score failed to show a significant correlation. Two parameters, female sex and age between 65 and 74 years, resulted in a higher CHA₂DS₂VASc score in the current patient cohort.

The present study was not designed to elucidate the underlying pathophysiology of silent embolic brain lesions detected on MRI following PVI. Since no statistically significant higher rate was found for one particular patient group, other yet unknown factors besides the particular ablation technology utilized must predispose certain patients for silent emboli. The detrimental effects of asymptomatic cerebral lesions on cognitive function and their role in the development of dementia are well known.¹³ Nevertheless, additional research is indicated to further our understanding of the pathophysiological mechanism and to develop preventive measures during catheter ablation of AF.

Based on preliminary results from the Evaluation of Reduction of Asymptomatic Cerebral Embolism (ERACE) study and observations from the current study, a number of procedural interventions may reduce the risk for new brain lesions.¹⁴ The target ACT should be >300 s, while sheaths should be flushed continuously throughout the procedure. During insertion or withdrawal of the catheter, sheath and catheter should be flushed simultaneously. Immersion of the catheter tip under water prior to insertion may prevent air trapping.

Limitations

The current study was non-randomized including a limited number of patients. Enrolling 44 patients in the laserballoon group was considered sufficient, since a prior study reporting on a smaller number of patients detected a significant correlation between the occurrence of new asymptomatic embolic cerebral lesions and the use of the PVAC catheter.⁵ Indeed, the rate of asymptomatic brain lesions was less in the laserballoon group (11.4%) compared with the RF ablation group (18.2%). To prove in a future trial that use of the laserballoon results in a statistically significant lower rate of asymptomatic brain lesions compared with RF ablation, based on the current results, 424 patients would need to be enroled in each treatment arm.

The present study protocol did not incorporate a detailed neurological examination; therefore, discrete neurological deficits may have been missed on gross neurological examination. Finally, two patients with asymptomatic brain lesions refused a follow-up MRI.

Conclusions

The incidence of asymptomatic thrombo-embolic events detected on post-procedural MRI of the brain following laserballoon-based PVI is 11.4%, which is comparable with more established technologies such as irrigated RF or cryoballoon-based PVI. A higher CHA₂DS₂VASc score, but not the ablation technology utilized, was the only risk factor associated with the occurrence of new asymptomatic brain lesions.

Supplementary material

Supplementary material is available at Europace online.

Conflict of interest: E.W., A.M., P.N., V.Y.R., and K.-H.K. have received speaker's honoraria from Cardiofocus, Biosense Webster, and Medtronic. R.R.T. received speaker's honoraria from Biosense Webster. F.O. received speaker's honoraria from Biosense Webster and Medtronic. E.W. is a consultant to Biosense Webster and Medtronic. P.N., V.Y.R., and K.-H.K. are consultants to Cardiofocus, Biosense Webster, and Medtronic.

Funding

This work was supported by an unrestricted grant from CardioFocus, Marlborough, MA, USA.

References

Author notes