Abstract
Background
Some patients fail to respond to persistent atrial fibrillation (PeAF) catheter ablation in spite of multiple procedures and ablation strategies, including low voltage area (LVA)-guided, linear, and complex fractionated atrial electrogram (CFAE)-guided ablation procedures. We hypothesized that LVA extent could predict non-responseto Pe AF catheter ablation in spite of multiple procedures.
Methods
This study included 510 patients undergoing initial ablation procedures for PeAF. LVAs were defined as regions with bipolar peak-to-peak voltages of <0.50 mV after PVI during sinus rhythm. Patients were categorized by LVA size into groups A(0-5 cm2), B (5-20 cm2), and C (over 20 cm2). The primary endpoint was AF-free survival after the last procedure.
Results
During a median follow-up of 25 (17, 36) months, AF recurrence was observed in 101 (20%) patients after 1.4±0.6 ablation procedures (maximum 4). Comparison of clinical outcomes after multiple procedures in the three groups showed that the results depended on the extent of LVA. Multivariate analysis of AF-free survival after the last procedure showed that LVAs > 20 cm2 was an independent factor associated with AF recurrence after the final procedure(Hazard ratio, 7.94; 95% confidence interval, 2.91 to 21.67, P <0.001).
Conclusions
Extensive LVA after initial PVI was associated with poor clinical benefit despite multiple catheter based ablations.
Keywords: Atrial fibrillation, Catheter ablation, Low voltage area, Multiple procedures
Introduction
Although catheter ablation has been established as an important treatment for atrial fibrillation (AF), the outcomes of PVI alone for persistent AF (PeAF) are unsatisfactory.1-3Substrate modification to improve outcomes has been performed, and favorable out comes have been reported for low voltage area (LVA)-guided, linear, and CFAE ablation.4,5Nevertheless, some patients remain as non-responders to PeAF catheter ablation in spite of multiple procedures and various ablation strategies. The prevalence of left atrial low-voltage areas (LVAs) is strongly associated with the recurrence of atrial tachyarrhythmias following catheter ablation.6-11Weconsidered that LVA extent could predict non-responders to PeAF catheter ablation in spite of multiple procedures.
Methods
Study subjects
From October 2014 to December 2018, 518 consecutive patients undergoing initial ablation for persistent AF using Carto 3 (Biosense Webster, Inc., Diamond Bar CA, USA), EnsiteNavX (St. Jude Medical, Inc., St. Paul MN, USA) or Rhythmia (Boston Scientific, Boston MA, USA) at our hospitalwere retrospectively enrolled. Persistent AF was defined as a sustained episode lasting ≥7 days at enrollment. Patients who could not undergo voltage mapping were excluded. Other exclusion criteria were age <20 years, left atrial thrombus, and prior catheter ablation of AF. This study complied with the Declaration of Helsinki. Written informed consent for ablation and the use of data in this study was obtained from all patients, and the protocol was approved by our institutional review board.
Catheter ablation procedure
We discontinued all antiarrhythmic drugs (AADs) ≥ 3 days before ablation, except for amiodarone, which was stopped ≥1 month before. Patients underwent transesophageal echocardiography (TEE) the day before the procedure to exclude the presence of thrombi.
Electrophysiological studies and catheter ablation were performed under intravenous sedation with dexmedetomidine or propofol, with the latter performed by one of four experienced operators (M.M, T.K, A.S, and Y.M). Most of the patients underwent radiofrequency catheter ablation. Cryoballoon ablation was performed for persistent AF of short standing. Patients with common PVs or a large PV diameter underwent radiofrequency catheter ablation.
In cryoballoon ablation, an Arctic Front Advance cryoballoon catheter with a 28-mm balloon size (Medtronic, Inc., Minneapolis MN, USA) was passed into each PV under guidance by fluoroscopy and the 3-D mapping system. After confirming PV occlusion by pulmonary venography, cryoablation commenced and continued for 180 s, during which individual PVs were isolated. If LA–PV conduction persisted after cryoballoon ablation, an additional touch-up ablation was performed using an open-irrigated Thermo cool Smart Touch (Biosense Webster) or Flex Ability (St. Jude Medical) linear ablation catheter with a 3.5-mm tip.
In radiofrequency catheter ablation, circumferential ablation around both ipsilateral PVs was performed using an open-irrigated Thermo cool Smart Touch (Biosense Webster) or Flex Ability (St. Jude Medical) linear ablation catheter via an Agilis or Swartz Braided SL0 Transseptal Guiding Introducer Sheath (St. Jude Medical). Radiofrequency energy was applied for 30 s at each site using a maximum temperature of 42°C, maximum power of 35 W, and flow rate of 17 mL/min. PV isolation was considered complete when the 20-pole circular catheter no longer recorded any PV potentials.
We allowed additional ablation procedures in this study at the discretion of the operator, such as focal ablation for reproducible non-PV triggers; ablation of linear lesions, complex fractionated atrial electrograms (CFAE), and LVA homogenization; superior vena cava (SVC) isolation; and cavotricuspid isthmus linear ablation if patients had clinical or induced typical atrial flutter.
The endpoint of the linear ablation was a complete, bidirectional block across the linear lesion. This bidirectional conduction block was rechecked at the end of the procedure or > 20 minutes after the initial success of the conduction block. For the CFAE ablation, CFAE mapping was required during AF. The CFAE sites were identified by validated and automated algorithms of a 3-dimensional mapping system. The endpoint of the CFAE ablation was the elimination of all local CFAE sites or AF termination. AF termination was defined as a direct transition to sinus rhythm or to an organized atrial tachycardia or flutter. LVAs were homogeneously ablated using the open-irrigated radiofrequency catheter with the power set at 30W. The ablation catheter was moved in a point-by-point fashion. The endpoint of each radiofrequency application was an electrogram voltage reduction of > 50%. Isolation of the posterior LVA by PVI, roof, and bottom lines (box isolation) to avoid esophageal injury was permitted. In such cases, both entrance and exit blocks between the posterior wall and other left atrium were confirmed.
Voltage mapping
Following PV isolation, detailed voltage mapping was performed using a bipolar 3.5-mm tip catheter or multi-electrode mapping catheter during sinus rhythm or with pacing from the right atrium. In patients with persisting atrial fibrillation after PVI, voltage mapping was performed after electrical cardioversion. Voltage mapping was not completed due to unstable cardiac rhythm in 8of the total patients. [Figure 1]Mapping points were acquired to fill all color gaps on the voltage map using the electroanatomical mapping system. Respective fill and color interpolation thresholds were 15 mm and 23 mm using Carto 3 (Biosense Webster) and 20 mm and 7 mm using Ensite NavX (St. Jude Medical). Using Rhythmia (Boston Scientific), interpolation threshold was 5 mm.
Figure 1. Patient flow chart.
Among 518 patients in whom voltage mapping was attempted, 374 patients had no LVA (group A). The remaining 136 patients had LVAs after PVI and were allocated to group B orC according to the size of the LVA. Voltage mapping was not completed in 8 patients (group D) due to unstable heart rhythm.
Sites at which LVAs were recorded were then evaluated by high-density mapping to precisely delineate their extent, using the confidence module with the Carto 3 system and Ensite Automap with EnsiteNavX. Adequate endocardial contact was confirmed by distance to the geometry surface and stable electrograms. Each acquired point was classified according to the peak-to-peak electrogram as follows: >0.5 mV, healthy; and <0.5 mV, LVAs, with the band pass filter set at 30 to 500 Hz. The target number of mapping points was ≥100 with the 3.5-mm tip catheter and ≥1000 with the multi-electrode mapping catheter throughout the left atrium. Patients were categorized by LVA size into 3 groups. Patients in Group A had none or small LVAs less than 5cm2; those in Group B had mildly or moderately diseased LA which contained LVAs less than 20 cm2; and those in Group C had severely diseased LA which contained LVAs of more than 20 cm2 [Figure 2].
Figure 2. Example of LVA ablation in addition to PVI.
Patients were categorized by LVA size into 3 groups. Patients in group A had no or small LVAs of less than 5cm2. Patients in group B had mildly or moderately diseased LA which contained LVA of less than 20 cm2. Patients in group C had severely diseased LA which contained LVAsof more than 20 cm2.
Patient follow-up
If their clinical status was stable, patients were discharged two days after ablation. After a 3-month blanking period, they attended outpatient clinic visits and underwent 12-lead ECG monitoring at 1, 3, 6 and 12 months, and 24 h-Holter ECG monitoring every 6 months. Additional Holter monitoring was performed if arrhythmic symptoms occurred.
Repeat ablation was allowed for patients with recurrence of AF but was avoided during the blanking period. Repeat ablation during this period was counted as a recurrence just after the blanking period. Use of anti-arrhythmic drugs during the blanking period was allowed, but discontinuation after the blanking period was strongly recommended.
Study endpoints
The primary endpoint was AF-free survival after the last procedure without antiarrhythmic drugs. Either of two events was considered an AF/AT recurrence: (1) atrial tachyarrhythmia recorded on routine or symptom-triggered ECG during an outpatient visit, or (2) at least 30 s of atrial tachyarrhythmia during ambulatory ECG monitoring.
Statistical Analysis
Categorical variables are expressed as counts (percentages) and compared with the chi-squared test or Fisher’s exact test. Continuous variables are expressed as mean (standard deviation) or median [interquartile range] and compared using Student’s t-test and Mann–Whitney U test, respectively. Event-free survival rates were estimated by the Kaplan–Meier method. Univariate and multivariate logistic regression analyses were used to determine clinical factors associated with AF recurrence after the final procedure and extent of LVAs, wherein variables with a P value < 0.05 in the univariate models were included in the multivariate analysis. All analyses were performed using SPSS 26.0 (IBM Corporation, Armonk, NY). P values of less than 0.05 were considered statistically significant.
Results
Study subjects
This study enrolled 518 patients. After excluding 8 patient whose voltage mapping was not completed due to unstable cardiac rhythm, a total of 510 patients were stratified according to LVA area into 3 groups. 374 patients had no LVA (group A). The remaining 136 patients had LVAs after PVI and were allocated to groups B (n=96) and C (n=40) according to the size of their LVAs [Figure 1]. Patient characteristics are shown in [Table 1].Patients in group B and C were older than those in groups A, more female, had lower BMI, more diabetes, higher CHA2DS2VASc scores, higher BNP or NT-BNP levels, lower eGFR, larger left atrial diameter (LAD), and higher E/e'. On comparison of groups B and C, patients in group C had a significantly lower BMI and a larger LAD.
Table 1. Patient characteristics.
Abbreviations: NT-proBNP, N-terminal pro-brain natriuretic peptide; eGFR, estimated glomerular filtration rate; E, diastolic early transmitral flow velocity; e’, diastolic early mitral annular velocity
| Group A (0-5 cm2) n=374 | Group B (5-20 cm2) n=96 | Group C (>20 cm2) n=40 | P value A vs. B and C | P value B vs. C | |
|---|---|---|---|---|---|
| Age, years | 65±10 | 72±8 | 71±8 | <0.001 | 0.479 |
| Female, n (%) | 67 (18) | 47 (49) | 21 (53) | <0.001 | 0.707 |
| Body mass index, kg/m2 | 24.7±3.8 | 24.1±4.6 | 22.4±3.4 | 0.009 | 0.039 |
| AF duration, months | 4 (2, 11) | 6 (3, 11) | 4 (2, 17) | 0.709 | 0.978 |
| Hypertension, n (%) | 207 (56) | 47 (49) | 24 (60) | 0.494 | 0.240 |
| Diabetes mellitus, n (%) | 57 (15) | 24 (25) | 10 (25) | 0.011 | 1.000 |
| Heart failure, n (%) | 92 (25) | 31 (32) | 10 (25) | 0.207 | 0.398 |
| CHA2DS2-VASc score | 2.2±1.4 | 3.1±1.3 | 3.4±1.7 | <0.001 | 0.301 |
| BNP ≥ 100 pg/ml or NT-proBNP ≥ 400 pg/ml, n (%) | 297 (79) | 88 (92) | 36 (90) | 0.001 | 0.562 |
| eGFR, ml/min | 63±17 | 55±17 | 55±22 | <0.001 | 0.887 |
| Echocardiographic parameters | |||||
| Left atrial diameter, mm | 43±6 | 43±6 | 47±7 | 0.006 | 0.010 |
| Ejection fraction, % | 58±13 | 57±13 | 60±14 | 0.734 | 9.448 |
| Left ventricular mass, g | 194±57 | 184±66 | 194±69 | 0.254 | 0.278 |
| E/e’ | 10.4±3.8 | 12.4±6.5 | 12.4±5.6 | 0.001 | 0.985 |
Ablation procedure
PVI was successfully completed in all patients, using Carto 3 in 479 (94%), Rhythmia in 20 (4%) and Ensite NavX in 11 (2%).The majority of cases underwent radiofrequency catheter ablation. Cryoballoon ablation was performed in 23 cases (5%).
Details of the initial and additional procedures are listed in [Table 2]. In the initial procedure, BOX isolation and LVA ablation were more frequently performed in group B and C. At the additional catheter ablation procedures, a higher percentage of PVI was completed in group C and there was more LVA ablation in groupsB and C. In group A, SVC isolation was performed more frequently. There was no difference in the number of times ABL was performed among the three groups.
Table 2. Procedural background.
Abbreviations: PV, pulmonary vein; PVI, pulmonary vein isolation; CFAE, complex fractionated atrial electrogram; LVA, low voltage area; SVC, superior vena cava; CTI, cavo tricuspid isthmus
| Group A (0-5 cm2) n=374 | Group B (5-20 cm2) n=96 | Group C(>20 cm2) n=40 | P value A vs. B and C | P value B vs. C | |
|---|---|---|---|---|---|
| Number of procedures | 1.4±0.3 | 1.4±0.6 | 1.6±0.3 | 0.304 | 0.116 |
| Initial procedure | n=374 | n=96 | n=40 | ||
| PVI, n (%) | 374 (100) | 96 (100) | 40 (100) | 1.000 | 1.000 |
| Mitral isthmus, n (%) | 31 (8) | 12 (13) | 3 (8) | 0.339 | 0.396 |
| BOX isolation, n (%) | 4 (1) | 2 (2) | 3 (8) | 0.048 | 0.126 |
| Roof line, n (%) | 34 (10) | 11 (11) | 3 (8) | 0.361 | 0.823 |
| CFAE, n (%) | 20 (5) | 0 (0) | 2 (5) | 0.155 | 0.027 |
| LVA ablation, n (%) | 12 (3) | 31 (32) | 10 (25) | <0.001 | 0.398 |
| Non PV foci, n (%) | 2 (1) | 1 (1) | 2 (5) | 0.090 | 0.152 |
| SVC isolation, n (%) | 2 (1) | 0 (0) | 1 (3) | 0.793 | 0.120 |
| CTI, n (%) | 65 (17) | 13 (14) | 10 (25) | 0.255 | 0.120 |
| Additional procedure | n=102 | n=35 | n=23 | ||
| Redo PVI, n (%) | 66 (65) | 25 (71) | 7 (30) | 0.234 | 0.002 |
| Mitral isthmus, n (%) | 8 (8) | 6 (17) | 3 (13) | 0.048 | 0.920 |
| BOX isolation, n (%) | 5 (5) | 2 (6) | 5 (22) | 0.756 | 0.011 |
| Roof line, n (%) | 10 (10) | 5 (14) | 3 (13) | 0.195 | 0.546 |
| CFAE, n (%) | 7 (7) | 1 (3) | 1 (4) | 0.142 | 0.761 |
| LVA ablation, n (%) | 15 (15) | 25 (71) | 20 (87) | <0.001 | 0.035 |
| Non PV foci, n (%) | 31 (30) | 15 (43) | 8 (35) | 0.215 | 0.689 |
| SVC isolation, n (%) | 27 (26) | 1 (3) | 1 (4) | 0.002 | 0.326 |
| CTI, n (%) | 39 (38) | 8 (23) | 7 (30) | 0.351 | 0.176 |
Ablation outcomes
AF recurrence was observed in 101 (20%) patients after 1.4±0.6 ablation procedures (maximum 4). Group A had 1.4±0.7 times, group B had 1.4±0.6 times, and group C had 1.6±0.6 times, with no significant difference between the groups (P=0.20). On analysis of AF recurrence at 1 year after the first ablation [Figure 3A], group Aperformed significantly better than the other groups, but there was no difference between groups B and C. Comparison of clinical outcomes after multiple procedures in the three groups showed that the results depended on the extent of LVA [Figure 3B]. Namely, the group without LVA (group A) had an extremely high success rate despite persistent AF. In contrast, more than half of the patients with extensive LVAs (group C) developed recurrence within a few years, even after multiple treatments. The poor prognosis of patients with extensive LVAs was also seen in the analysis of patients who were retreated [Figure 3C].
Figure 3. AF recurrence-free survival rates.
Kaplan-Meier curves for AF-recurrence-free survival are shown. Figure3A shows the analysis of AF recurrence at 1 year after the first ablation. Figure 3B indicates that clinical outcomes after multiple procedures depended on the extent of LVAs. Figure 3C shows the results of the post-re intervention analysis by extracting the re intervention group only.
Blue line, patients in group A); red line, patients allocated to group B; green line, patients allocated to group C. In Figures 3B and 3C, patients in group A demonstrated excellent rhythm outcomes. In contrast, those with extensive LVAs (group C) had a significantly lower AF-recurrence-free survival rate.
Multivariate analysis of AF-free survival after the last procedure showed thatLVAs> 20cm2 and longer AF duration were independent factors associated with AF recurrence [Table 3].
Table 3. Factors associated with AF recurrence after the final procedure.
Factors with p <0.05 in the univariate analysis were incorporated in the multivariate analysis.
HR, hazard ratio; CI, confidence interval, AF, atrial fibrillation; GFR, glomerular filtration rate; LVA, low-voltage area.
| Recurrence | Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|---|
| With n = 101 | Without n =409 | HR | 95% CI | P value | HR | 95% CI | P value | |
| Age, years | 68±9 | 67±10 | 1.02 | 0.999-1.05 | 0.055 | |||
| Female, n (%) | 26 (26) | 109 (27) | 1.38 | 0.86-2.22 | 0.186 | |||
| Body mass index | 24.6±5.0 | 24.4±3.8 | 0.99 | 0.94-1.05 | 0.825 | |||
| AF period, months | 5 (2, 37) | 4 (2, 10) | 1.007 | 1.001-1.01 | 0.026 | 1.01 | 1.001-1.014 | 0.024 |
| Heart failure, n (%) | 19 (19) | 114 (28) | 0.92 | 0.56-1.52 | 0.917 | |||
| CHA2DS2-VASc score | 2.6±1.6 | 2.4±1.5 | 1.15 | 0.998-1.33 | 0.054 | |||
| Estimated GFR, pg/ml | 59±17 | 61±18 | 0.99 | 0.98-1.006 | 0.993 | |||
| Left atrial diameter, mm | 44.5±6.7 | 42.8±6.1 | 1.04 | 1.01-1.08 | 0.027 | 1.02 | 0.978-1.068 | 0.324 |
| Ejection fraction, % | 58.0±14.4 | 58.0±12.5 | 1.001 | 0.98-1.02 | 0.872 | |||
| LVAs > 20 cm2, n (%) | 16 (16) | 24 (6) | 5.39 | 2.77-10.48 | <0.001 | 8.82 | 3.32-23.45 | <0.001 |
The percentage of patients taking anti arrhythmic medication at the last follow-up was 9% in group A, 17% in group B, and 10% in group C, with no significant difference between groups (P=0.12).
Predictors of extensive LVAs
Because the extent of LVA after initial PVI might contribute significantly to clinical outcomes, we performed additional analyses of factors that predict extensive LVAs. Univariate analysis revealed that advanced age, female, lower BMI, longer AF duration, higher CHA2DS2-VASC score, lower renal function, and large LAD were significant predictors for extensive LVAs[Table 4]. After multivariate analysis, female, low BMI, and large LAD were considered to be independent factors associated with extensive LVAs[Table 4].
Table 4. Factors associated with extensive LVAs (>20 cm2).
Factors with p <0.05 in the univariate analysis were incorporated in the multivariate analysis.
HR, hazard ratio; CI, confidence interval, AF, atrial fibrillation; GFR, glomerular filtration rate; LVA, low-voltage area
BNP, Brain natriuretic peptide; NT-proBNP, N-terminal pro-brain natriuretic peptide
| Extensive LVAs (> 20 cm2) | Univariate | Multivariate | ||||||
|---|---|---|---|---|---|---|---|---|
| With (n = 40) | Without (n = 470) | HR | 95% CI | P value | HR | 95% CI | P value | |
| Age, years | 71±8 | 67±10 | 1.06 | 1.02-1.10 | 0.004 | 1.04 | 0.97-1.12 | 0.275 |
| Female, n (%) | 21 (53) | 114 (24) | 3.45 | 1.79-6.65 | <0.001 | 3.86 | 1.40-10.64 | 0.009 |
| Body mass index | 22.4±3.4 | 24.6±4.0 | 0.84 | 0.76-0.93 | 0.001 | 0.82 | 0.70-0.95 | 0.010 |
| AF period, months | 4 (2,17) | 4 (2,11) | 1.007 | 1.001-1.01 | 0.026 | 1.004 | 0.99-1.02 | 0.498 |
| Heart failure, n (%) | 10 (25) | 122 (26) | 0.94 | 0.45-1.98 | 0.871 | |||
| CHA2DS2-VASc score | 3.4±1.7 | 2.3±1.4 | 1.59 | 1.28-1.97 | <0.001 | |||
| Estimated GFR, pg/ml | 55.2±21.8 | 61.2±17.0 | 0.98 | 0.97-0.999 | 0.037 | 0.99 | 0.96-1.01 | 0.355 |
| BNP ≥ 100 pg/ml or NT-proBNP ≥ 400 pg/ml, n (%) | 36 (90) | 385 (82) | 1.85 | 0.64-5.35 | 0.257 | |||
| Left atrial diameter, mm | 47±6 | 43±6 | 1.10 | 1.04-1.15 | <0.001 | 1.09 | 1.01-1.18 | 0.020 |
| Ejection fraction, % | 60±14 | 58±13 | 1.01 | 0.99-1.04 | 0.383 | |||
| E/e’ | 11.6±4.7 | 10.8±4.6 | 1.06 | 0.996-1.13 | 0.065 |
Discussion
In this study, we found that the extent of LVAs was an independent predictor for recurrence even after multiple procedures. The efficacy of catheter ablation was limited in patients with extensive LVAs.In patients with extensive LVAs, the indications and strategies for additional treatment should be carefully considered. In addition, female sex, lower BMI, and larger LAD were shown to be predictors of extensive LVAs. These findings suggest that the results of voltage mapping after initial PVI can help predict procedural success of subsequent catheter ablation.
Efficacy of AF ablation in patients with no or limited LVAs
In this study, group A patients without LVA had a good prognosis up to the late phase after multiple procedures. This result is consistent with previous studies of LVA-guided therapy12-14. Considering the implications of LVAs on AF development, LVAs reflect atrial fibrosis15,16and fibrotic remodeling tissue leads to slow conduction and short action potential duration, which facilitates reentry17,18. In group A patients who did not have these arrhythmic substrates, many non-PV procedures such as SVC isolation were performed at the time of additional procedures, suggesting that if the AF initiator could be treated, the results might be comparable to those of paroxysmal patients.
Efficacy of ablation in patients with LVAs
As described above, clinical outcomes were worse in patients with LVAs after initial PVI than in the group without LVA after multiple procedures, when patients with LVAs were compared with each other, a significant difference in clinical outcomes was seen after additional procedures, depending on the extent of the LVA.
Although PV reconnection is still considered a major cause of AF recurrence after initial ABL19, this factor seems to have diminished in terms of post-retreatment outcomes. At repeat procedures, the operator used his or her own discretion to determine treatment strategy for non-pulmonary veins, and most of the ablation targeted the LVA. This result suggests that LVA ablation, linear ablation, and CFAE can be effective adjunctive ablation with concomitant PVI. 4,5
It has been reported that LVA is associated with fibrosis of the left atrium. Extensive LVAs were associated with more residual fibrosis.20 Development and progression of atrial fibrosis, which plays an important role in AF maintenance, is the hallmark of structural remodeling in AF. The presence of extensive LVAs can lead to multiple or complex areas of arrhythmogenicity. Extensive LVAs could have increased the area that could not be treated by ablation therapy, which might have resulted in poor clinical outcomes.
On the other hand, it must also be considered that fibrosis may simply be the final step of a remodeling cascade which includesmyocyte architectural changes, ion channel dysfunction, connexin disarray and disruption of fiber orientation, all of which might precede scarring but not be seen on voltage mapping or imaging.20Based on this concept, the extent of an LVA might indicate the progression of fibrosis throughout the atrium. This might in turn suggest that patients with extensive LVAs are more likely to develop new arrhythmogenic features in the future.
The results of our study suggest that the benefit of beyond PVI therapy applies to patients with moderately advanced remodeling, such as those in group B. [Table 2] and [Figure 3] show that group C, with extensive LVAs, had a high recurrence rate even when PVI was complete. This suggests that clinical outcomes in patients with extensive LVA sarenot yet sufficient, even with additional treatment of PVIs with high durability. Ablation therapy can also create new iatrogenic LVAs, which may limit the effectiveness of treatment in cases that already have extensive LVAs. These cases may require concomitantuse of appropriate anti-arrhythmic drugs, in addition to ablation therapy.
Clinical factors associated with extensive LVAs
Although several methods for preoperative prediction of the presence of LVAs have been reported21-23, the present study showed that widespread LVAs worsen the clinical prognosis. We identified the following as independent predictors of extensive LVAs: female, low BMI, and large LAD [Table 4]. These factors have been reported to be related to LVAs in the past, and we discuss them here with reference to these reports.
These previous reports identified mechanisms underlying the sex differences in atrial fibrosis.24 On histological analysis of atrial tissue, females showed stronger expression of CX40 than males, which indicates remodeling-induced change in connexins.25 In addition, fibrosis-related genes were up regulated in post-menopausal woman with AF.26 Clinically, females reportedly experience AF recurrence more frequently than males during long-term follow-up after AF ablation, likely due to non-PV arrhythmogenicity.27
The reason why low BMI and large LAD are associated with extensive LVAs may be that they both reflect wall stress on the LA. As reported previously, LVA is are sult of the progression of remodeling.LA remodeling in AF patients is suggested to be associated with continuous internally generated stretch and wall stress.9,28-30Anatomical contact with external structures surrounding the LA provokes the perpetuation of AF by arrhythmogenic substrates in patients with persistent AF.31,32 In patients with low BMI, the distance between the LA and external structures such as the vertebral bodies may be close enough to trigger the development of LVA.
Clinical implications
It has become widely known that LVA predicts the outcome of the first treatment.10,12,21,33 Our presentresults indicate that evaluating the extent of LVA can predict the clinical course of the second and subsequent treatments.
Limitations
Several limitations of our study warrant mention. The main limitation is the study’s retrospective design, which meant that procedures were not standardized but rather at the discretion of the operator. Although prospective studies are necessary to solve these problems, standardization of procedures and long-term observation in an era of constantly improving strategies is not easy. Second, our follow up did not include routine continuous monitoring with implanted devices or transtelephonic electrocardiographic monitoring, and our AF-recurrence-free rate might therefore be underestimated. Third, since we performed voltage mapping using either bipolar 3.5-mm tip catheters or multi-electrode mapping catheters, the distribution of LVAs might have changed, given that multielectrode catheters produce smaller LVA measurements than ablation catheters.34 Fourth, our conduct of voltage mapping after the completion of PV isolation and in the left atrium only might have influenced the prevalence of LVAs. Fifth, patients with the worst prognosis, namely those in whom a voltage map could not be obtained after the first PVI, were excluded. Sixth, the cut-off values (5 cm2 and 20 cm2) used for grouping were arbitrary. Finally, statistical analyses were limited by the relatively small size of the study population.
Conclusions
Extensive LVA after initial PVI was associated with no significant clinical benefit despite multiple catheter ablation procedures. Predictors of extensive LVAs included female sex, lower BMI and large LAD.
References
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