Abstract

Aims

To assess the clinical benefit of cardiac resynchronization therapy (CRT) in patients with atrial fibrillation (AF) compared with patients in sinus rhythm (SR), and to evaluate the impact of atrioventricular junction (AVJ) ablation on the outcome of AF patients undergoing CRT.

Methods and results

We conducted a retrospective analysis of 131 consecutive heart failure (HF) patients who underwent CRT implantation. Three groups were considered: SR ( n = 78), AF with AVJ ablation ( n = 26), and AF without AVJ ablation ( n = 27). Patients were evaluated for the occurrence of cardiac death, hospitalization for HF, and responsiveness to CRT (survival with improvement of ≥1 New York Heart Association class at 6 months). The three groups showed a significant improvement in functional class. However, the proportion of responders was significantly lower in AF patients without AVJ ablation (52 vs. 79% in SR and 85% in AF with AVJ ablation, P < 0.008). Atrial fibrillation without AVJ ablation was also independently associated with mortality (HR 5.22, 95% CI: 1.60–17.01, P = 0.006) and hospitalization for HF during the first 12 months (HR 6.23, 95% CI: 2.09–18.54, P = 0.001). The outcomes of AF with AVJ ablation patients were similar to the outcomes of patients in SR.

Conclusion

Sinus rhythm and AF patients display similar survival and clinical improvement after CRT implantation, provided that AVJ ablation is performed in the latter.

Introduction

Congestive heart failure (CHF) and atrial fibrillation (AF) are two increasingly prevalent conditions that predispose to each other and frequently coexist. 1 , 2 Cardiac resynchronization therapy (CRT) is now a well established treatment for patients with drug-refractory end-stage CHF due to systolic dysfunction and cardiac dyssynchrony. 3–5 However, patients with AF are not well represented in the landmark trials that established the clinical benefit of CRT. 6–9 So, it is still unclear if and to what extent CRT provides long-term benefit to patients with AF who otherwise meet the criteria for this therapy. Another unresolved issue is how to achieve the required rate control for CRT to be effective in the setting of AF. Atrioventricular junction (AVJ) ablation has been used in this context to assure rate control and rhythm regularization. 10–13 Whether the potential benefits of this approach outweigh its risks is a matter of ongoing debate. The aims of this study were (i) to assess the long-term clinical benefit of CRT in patients with AF compared with patients in sinus rhythm (SR) and (ii) to evaluate the impact of AVJ ablation on the outcome of AF patients undergoing CRT.

Methods

The study group comprised 131 consecutive patients with CHF who underwent successful CRT implantation in our centre between January 2000 and April 2006. All patients had drug-refractory symptomatic [New York Heart Association (NYHA) functional classes II–IV] CHF due to severe left ventricular (LV) systolic dysfunction (LV ejection fraction ≤ 35%) and QRS duration >120 ms. Patients were identified retrospectively in a registry kept by the electrophysiology and pacing laboratory and divided in two groups (SR and AF), considering whether or not they had at least one episode of previously documented AF at the time of CRT implantation. Patients with AF were further stratified according to whether or not AVJ was performed (independently of the time of AVJ ablation). Therefore, three groups were considered in the analysis: SR, AF with AVJ ablation, and AF without AVJ ablation.

Device implantation and atrioventricular junction ablation

Right ventricular leads were positioned in the apex or the interventricular septum. Left ventricular leads were positioned through the coronary sinus, whenever possible in a lateral or posterolateral cardiac vein, using a coronary sinus venogram for guidance. Active fixation leads were implanted in the right atrial appendage in patients in SR and in patients with paroxysmal/persistent AF. In patients in whom there was little hope of cardioversion to SR (previous failed attempts, >5 years of AF, very large atria), atrial leads were not implanted. In SR patients, devices were programmed in DDD (unless severe sinus node disease was present, in which case devices were programmed in DDD-R); AV interval was set between 100 and 120 ms. Devices with VV offset capabilities were programmed using the narrowest QRS as goal (typically −20 to 0 ms). The mode switch was also set to on. Patients with persistent or permanent AF were programmed in VVI-R (60–130/min). If present, biventricular trigger and ventricular rate regulation algorithms were turned off. One hundred and two subjects (59 in SR and 43 in AF) received a combined cardiac resynchronization and defibrillation device (CRT-D). Three patients had a previously implanted DDD pacemaker for complete AV block and were included in the SR group after upgrade to CRT.

Radiofrequency AVJ ablation was performed in 26 AF patients (13 permanent, 6 persistent, and 7 paroxysmal) by standard techniques in the electrophysiology laboratory. Complete AV block was achieved in 100% of the subjects. All patients gave informed written consent to undergo this procedure in the understanding that it would render them pacemaker-dependent. Two patients had undergone previous AVJ ablation for rate control purposes and were already pacemaker-dependent. Nine patients had a history of poor rate control despite adequate pharmacological therapy and underwent ablation at the time of CRT implantation. All other AF patients received negative chronotropic drugs at discharge in order to achieve rate control, thus maximizing biventricular pacing delivery. At the follow-up visits, device interrogation was performed and the percentage of biventricular pacing delivered was recorded. Fifteen AF patients underwent AVJ ablation during follow-up. The reasons for performing AVJ ablation in these patients included poor rate control with a low percentage of biventricular pacing despite adequate pharmacological therapy, and several inappropriate implantable cardioverter defibrillator (ICD) shocks, despite pharmacological and ICD programming efforts. The decision to perform AVJ ablation was left to the clinical judgment of the electrophysiologist and the attending physicians. This study respected the guidelines of good clinical practice and conforms to the principles outlined in the Declaration of Helsinki.

Follow-up and endpoints

All surviving patients were evaluated at 1 and 6 months and at different time intervals thereafter. Responsiveness to CRT was defined as an improvement ≥ 1 NYHA class at 6 months. Subjects who died before 6 months were considered non-responders. Patients were also evaluated for the occurrence of cardiac death and/or hospitalization for decompensated CHF. Cardiac death was defined as death caused by refractory heart failure (HF), cardiac arrhythmias, acute myocardial infarction, or sudden death of unknown cause. Hospitalizations for decompensated CHF comprised any hospital admission with the final main diagnosis of CHF, needing intravenous diuretic and/or inotropic therapy. Dates of events and the most recent event-free follow-up were obtained for all patients by chart review and/or telephonic interview. Patients who underwent cardiac transplantation ( n = 2) were censored at the time of surgery.

Statistical analysis

Normally distributed data are expressed as mean values (±SD). Student’s t -test was used for comparisons of continuous variables and the χ 2 test was used to compare categorical data. Simultaneous comparison of more than two mean values was performed by one-way analysis of variance with Bonferroni’s correction. The Kaplan–Meier survival curves were plotted for each of the rhythm subgroups. The log-rank test was used to evaluate differences between survival functions. Univariate Cox regression analysis was used to assess the prognostic value of clinical variables (age, gender, ischaemic aetiology, NYHA class, use of β-blockers, AF with or without AVJ ablation, and the presence of an ICD) and echocardiographic variables (LV ejection fraction). The multivariate Cox regression was performed in a stepwise forward model with the use of P ≤ 0.10 and P ≤ 0.05 for inclusion or deletion of variables, respectively. Predictors of responsiveness to CRT and hospitalization for decompensated HF during the first 12 months were identified by binary logistic regression. Univariate predictors at a P -value <0.10 were included in the multivariate analysis, except where stated otherwise. All statistics were performed using Statistical Package for the Social Sciences software (SPSS 13.0 Inc., Chicago, IL, USA). Statistical significance was set at P < 0.05 (two-sided).

Results

Patients' characteristics and outcomes

A total of 53 patients had previously documented AF (12 paroxysmal, 16 persistent and 25 permanent). The baseline characteristics of AF and SR patients were not statistically different, except for a higher percentage of men in the AF group ( Table  1 ). After 6 months of CRT, the evaluation of device counters revealed a high biventricular pacing activity in SR patients and in AF patients who underwent AVJ ablation (95 ± 13% and 98 ± 6%, respectively). Biventricular pacing delivery was significantly lower in AF patients without AVJ ablation (87 ± 19%, P = 0.008). At 6 months follow-up, both SR and AF patients showed a significant improvement in the NYHA functional class ( Figure  1 ). Nevertheless, the proportion of responders was significantly lower in AF patients without AVJ ablation when compared with SR and AF with AVJ ablation patients ( Table  2 ). The clinical characteristics of responders and non-responders are shown in Table  3 . Age, pre-CRT NYHA class < III, and AF without AVJ ablation were independent predictors of non-responsiveness to CRT ( Table  4 ).

New York Heart Association functional class before and 6 months after cardiac resynchronization therapy in the three subgroups. Bars represent 95% confidence intervals.
Figure 1

New York Heart Association functional class before and 6 months after cardiac resynchronization therapy in the three subgroups. Bars represent 95% confidence intervals.

Table 1

Baseline characteristics of sinus rhythm and atrial fibrillation patients with and without atrioventricular junction ablation

Characteristic Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Age (years)66 ± 1067 ± 970 ± 80.178
Male gender (%)58 (74%)24 (92%)26 (96%)0.012
Ischaemic aetiology (%)41 (53%)15 (58%)13 (48%)0.921
NYHA class0.265
 II7 (9%)2 (8%)4 (15%)
 III61 (78%)20 (77%)22 (81%)
 IV10 (13%)4 (15%)1 (4%)
LVEF (%)26 ± 924 ± 926 ± 90.590
Medication before CRT implantation
 β-blockers (%)48 (62%)13 (50%)18 (67%)0.436
 ACEi and/or ARB (%)76 (97%)25 (96%)27 (100%)0.877
 Diuretics (%)76 (97%)26 (100%)27 (100%)0.502
 Spironolactone (%)32 (41%)12 (46%)8 (30%)0.555
 Amiodarone (%)46 (59%)14 (54%)9 (33%)0.098
 Digoxin (%)31 (40%)14 (54%)17 (63%)0.067
CRT-D (%)59 (76%)20 (77%)23 (85%)0.343
Characteristic Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Age (years)66 ± 1067 ± 970 ± 80.178
Male gender (%)58 (74%)24 (92%)26 (96%)0.012
Ischaemic aetiology (%)41 (53%)15 (58%)13 (48%)0.921
NYHA class0.265
 II7 (9%)2 (8%)4 (15%)
 III61 (78%)20 (77%)22 (81%)
 IV10 (13%)4 (15%)1 (4%)
LVEF (%)26 ± 924 ± 926 ± 90.590
Medication before CRT implantation
 β-blockers (%)48 (62%)13 (50%)18 (67%)0.436
 ACEi and/or ARB (%)76 (97%)25 (96%)27 (100%)0.877
 Diuretics (%)76 (97%)26 (100%)27 (100%)0.502
 Spironolactone (%)32 (41%)12 (46%)8 (30%)0.555
 Amiodarone (%)46 (59%)14 (54%)9 (33%)0.098
 Digoxin (%)31 (40%)14 (54%)17 (63%)0.067
CRT-D (%)59 (76%)20 (77%)23 (85%)0.343

Values are means ± SDs or number of patients (percentages). NYHA, New York Heart Association functional class; LVEF, left ventricular ejection fraction; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; and CRT-D, combined cardiac resynchronization therapy with defibrillator device.

Table 1

Baseline characteristics of sinus rhythm and atrial fibrillation patients with and without atrioventricular junction ablation

Characteristic Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Age (years)66 ± 1067 ± 970 ± 80.178
Male gender (%)58 (74%)24 (92%)26 (96%)0.012
Ischaemic aetiology (%)41 (53%)15 (58%)13 (48%)0.921
NYHA class0.265
 II7 (9%)2 (8%)4 (15%)
 III61 (78%)20 (77%)22 (81%)
 IV10 (13%)4 (15%)1 (4%)
LVEF (%)26 ± 924 ± 926 ± 90.590
Medication before CRT implantation
 β-blockers (%)48 (62%)13 (50%)18 (67%)0.436
 ACEi and/or ARB (%)76 (97%)25 (96%)27 (100%)0.877
 Diuretics (%)76 (97%)26 (100%)27 (100%)0.502
 Spironolactone (%)32 (41%)12 (46%)8 (30%)0.555
 Amiodarone (%)46 (59%)14 (54%)9 (33%)0.098
 Digoxin (%)31 (40%)14 (54%)17 (63%)0.067
CRT-D (%)59 (76%)20 (77%)23 (85%)0.343
Characteristic Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Age (years)66 ± 1067 ± 970 ± 80.178
Male gender (%)58 (74%)24 (92%)26 (96%)0.012
Ischaemic aetiology (%)41 (53%)15 (58%)13 (48%)0.921
NYHA class0.265
 II7 (9%)2 (8%)4 (15%)
 III61 (78%)20 (77%)22 (81%)
 IV10 (13%)4 (15%)1 (4%)
LVEF (%)26 ± 924 ± 926 ± 90.590
Medication before CRT implantation
 β-blockers (%)48 (62%)13 (50%)18 (67%)0.436
 ACEi and/or ARB (%)76 (97%)25 (96%)27 (100%)0.877
 Diuretics (%)76 (97%)26 (100%)27 (100%)0.502
 Spironolactone (%)32 (41%)12 (46%)8 (30%)0.555
 Amiodarone (%)46 (59%)14 (54%)9 (33%)0.098
 Digoxin (%)31 (40%)14 (54%)17 (63%)0.067
CRT-D (%)59 (76%)20 (77%)23 (85%)0.343

Values are means ± SDs or number of patients (percentages). NYHA, New York Heart Association functional class; LVEF, left ventricular ejection fraction; ACEi, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; and CRT-D, combined cardiac resynchronization therapy with defibrillator device.

Table 2

Baseline and follow-up data

Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Follow-up duration (months)29 ± 1834 ± 1924 ± 180.145
NYHA class
 Baseline3.0 ± 0.43.1 ± 0.52.9 ± 0.40.332
 At 6 months2.0 ± 0.52.1 ± 0.52.2 ± 0.70.303
 End follow-up2.1 ± 0.62.2 ± 0.72.5 ± 0.90.071
Percentage of biventricular pacing (at 6 months)95 ± 1398 ± 687 ± 190.008
Responders (%)62 (79%)22 (85%)14 (52%)0.008
Cardiac death (%)2 (3%)3 (12%)7 (26%)0.001
Hospitalization for CHF at 12 months (%)6 (8%)4 (15%)11 (41%)<0.001
Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Follow-up duration (months)29 ± 1834 ± 1924 ± 180.145
NYHA class
 Baseline3.0 ± 0.43.1 ± 0.52.9 ± 0.40.332
 At 6 months2.0 ± 0.52.1 ± 0.52.2 ± 0.70.303
 End follow-up2.1 ± 0.62.2 ± 0.72.5 ± 0.90.071
Percentage of biventricular pacing (at 6 months)95 ± 1398 ± 687 ± 190.008
Responders (%)62 (79%)22 (85%)14 (52%)0.008
Cardiac death (%)2 (3%)3 (12%)7 (26%)0.001
Hospitalization for CHF at 12 months (%)6 (8%)4 (15%)11 (41%)<0.001

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 2

Baseline and follow-up data

Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Follow-up duration (months)29 ± 1834 ± 1924 ± 180.145
NYHA class
 Baseline3.0 ± 0.43.1 ± 0.52.9 ± 0.40.332
 At 6 months2.0 ± 0.52.1 ± 0.52.2 ± 0.70.303
 End follow-up2.1 ± 0.62.2 ± 0.72.5 ± 0.90.071
Percentage of biventricular pacing (at 6 months)95 ± 1398 ± 687 ± 190.008
Responders (%)62 (79%)22 (85%)14 (52%)0.008
Cardiac death (%)2 (3%)3 (12%)7 (26%)0.001
Hospitalization for CHF at 12 months (%)6 (8%)4 (15%)11 (41%)<0.001
Sinus rhythm ( n = 78) AF + AVJ ablation ( n = 26) AF without AVJ ablation ( n = 27) P -value
Follow-up duration (months)29 ± 1834 ± 1924 ± 180.145
NYHA class
 Baseline3.0 ± 0.43.1 ± 0.52.9 ± 0.40.332
 At 6 months2.0 ± 0.52.1 ± 0.52.2 ± 0.70.303
 End follow-up2.1 ± 0.62.2 ± 0.72.5 ± 0.90.071
Percentage of biventricular pacing (at 6 months)95 ± 1398 ± 687 ± 190.008
Responders (%)62 (79%)22 (85%)14 (52%)0.008
Cardiac death (%)2 (3%)3 (12%)7 (26%)0.001
Hospitalization for CHF at 12 months (%)6 (8%)4 (15%)11 (41%)<0.001

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 3

Clinical characteristics of responders and non-responders to cardiac resynchronization therapy

Variable Responders ( n = 98) Non-responders ( n = 33) P -value
Age (years)66 ± 1069 ± 80.072
Male gender (%)81 (83%)27 (82%)1.000
Ischaemic aetiology (%)56 (57%)13 (39%)0.106
NYHA ≥ III pre-CRT95 (97%)23 (70%)<0.001
LVEF (%)26 ± 928 ± 90.283
β-blockers pre-CRT(%)56 (57%)23 (70%)0.224
CRT-D (%)75 (77%)27 (82%)0.632
AF pre-CRT (%)36 (37%)17 (52%)0.154
AF without AVJ ablation (%)14 (14%)13 (39%)0.005
Percentage of biventricular pacing at 6 months95 ± 1393 ± 160.612
Variable Responders ( n = 98) Non-responders ( n = 33) P -value
Age (years)66 ± 1069 ± 80.072
Male gender (%)81 (83%)27 (82%)1.000
Ischaemic aetiology (%)56 (57%)13 (39%)0.106
NYHA ≥ III pre-CRT95 (97%)23 (70%)<0.001
LVEF (%)26 ± 928 ± 90.283
β-blockers pre-CRT(%)56 (57%)23 (70%)0.224
CRT-D (%)75 (77%)27 (82%)0.632
AF pre-CRT (%)36 (37%)17 (52%)0.154
AF without AVJ ablation (%)14 (14%)13 (39%)0.005
Percentage of biventricular pacing at 6 months95 ± 1393 ± 160.612

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 3

Clinical characteristics of responders and non-responders to cardiac resynchronization therapy

Variable Responders ( n = 98) Non-responders ( n = 33) P -value
Age (years)66 ± 1069 ± 80.072
Male gender (%)81 (83%)27 (82%)1.000
Ischaemic aetiology (%)56 (57%)13 (39%)0.106
NYHA ≥ III pre-CRT95 (97%)23 (70%)<0.001
LVEF (%)26 ± 928 ± 90.283
β-blockers pre-CRT(%)56 (57%)23 (70%)0.224
CRT-D (%)75 (77%)27 (82%)0.632
AF pre-CRT (%)36 (37%)17 (52%)0.154
AF without AVJ ablation (%)14 (14%)13 (39%)0.005
Percentage of biventricular pacing at 6 months95 ± 1393 ± 160.612
Variable Responders ( n = 98) Non-responders ( n = 33) P -value
Age (years)66 ± 1069 ± 80.072
Male gender (%)81 (83%)27 (82%)1.000
Ischaemic aetiology (%)56 (57%)13 (39%)0.106
NYHA ≥ III pre-CRT95 (97%)23 (70%)<0.001
LVEF (%)26 ± 928 ± 90.283
β-blockers pre-CRT(%)56 (57%)23 (70%)0.224
CRT-D (%)75 (77%)27 (82%)0.632
AF pre-CRT (%)36 (37%)17 (52%)0.154
AF without AVJ ablation (%)14 (14%)13 (39%)0.005
Percentage of biventricular pacing at 6 months95 ± 1393 ± 160.612

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 4

Univariate and multivariate predictors of non-responsiveness to cardiac resynchronization therapy

Variable χ 2HR95% CIP -value
Univariate
 Age2.871.040.91–1.090.090
 Ischaemic aetiology3.060.490.22–1.090.080
 NYHA < III pre-CRT14.1113.773.51–54.09<0.001
 without AVJ ablation8.813.851.59–10.000.003
Multivariate
 Age5.331.081.01–1.150.021
 NYHA < III pre-CRT14.9524.334.82–122.74<0.001
 AF without AVJ ablation5.663.331.23–9.090.017
Variable χ 2HR95% CIP -value
Univariate
 Age2.871.040.91–1.090.090
 Ischaemic aetiology3.060.490.22–1.090.080
 NYHA < III pre-CRT14.1113.773.51–54.09<0.001
 without AVJ ablation8.813.851.59–10.000.003
Multivariate
 Age5.331.081.01–1.150.021
 NYHA < III pre-CRT14.9524.334.82–122.74<0.001
 AF without AVJ ablation5.663.331.23–9.090.017

HR, hazard ratio; CI, confidence interval, AF, atrial fibrillation; CRT, cardiac resynchronization therapy; AVJ, atrioventricular junction.

Table 4

Univariate and multivariate predictors of non-responsiveness to cardiac resynchronization therapy

Variable χ 2HR95% CIP -value
Univariate
 Age2.871.040.91–1.090.090
 Ischaemic aetiology3.060.490.22–1.090.080
 NYHA < III pre-CRT14.1113.773.51–54.09<0.001
 without AVJ ablation8.813.851.59–10.000.003
Multivariate
 Age5.331.081.01–1.150.021
 NYHA < III pre-CRT14.9524.334.82–122.74<0.001
 AF without AVJ ablation5.663.331.23–9.090.017
Variable χ 2HR95% CIP -value
Univariate
 Age2.871.040.91–1.090.090
 Ischaemic aetiology3.060.490.22–1.090.080
 NYHA < III pre-CRT14.1113.773.51–54.09<0.001
 without AVJ ablation8.813.851.59–10.000.003
Multivariate
 Age5.331.081.01–1.150.021
 NYHA < III pre-CRT14.9524.334.82–122.74<0.001
 AF without AVJ ablation5.663.331.23–9.090.017

HR, hazard ratio; CI, confidence interval, AF, atrial fibrillation; CRT, cardiac resynchronization therapy; AVJ, atrioventricular junction.

During a mean follow-up period of 29 ± 18 months, there were 12 cardiac deaths (10 for refractory CHF and 2 sudden). One of the sudden cardiac deaths occurred in a patient with a CRT-D who had undergone AVJ ablation at the time of device implantation, 32 months before the event. Unfortunately, his device was not interrogated post-mortem. The survival curves of the three subgroups are shown in Figure  2 . Mean survival was significantly lower in AF patients without AVJ ablation when compared with patients in SR (log rank P < 0.001). The difference in survival between subjects in SR vs. AF + AVJ ablation was not significant (log rank P = 0.120). The difference in survival functions between AF + AVJ ablation vs. AF without AVJ ablation had a borderline significance (log rank P = 0.070). The proportion of patients with AF (with or without AVJ ablation) was significantly higher in non-survivors. Patients who suffered cardiac death were also older and had a lower percentage of biventricular pacing at 6 months ( Table  5 ). Age and AF without AVJ ablation were the only independent predictors of cardiac mortality in multivariate analysis ( Table  6 ).

Kaplan–Meier curves depicting survival after cardiac resynchronization therapy implantation in the three subgroups.
Figure 2

Kaplan–Meier curves depicting survival after cardiac resynchronization therapy implantation in the three subgroups.

Table 5

Clinical characteristics of survivors and non-survivors

Variable Survivors ( n = 119) Non-survivors ( n = 12) P -value
Age (years)66 ± 974 ± 50.010
Male gender (%)96 (81%)12 (100%)0.125
Ischaemic aetiology (%)61 (51%)8 (67%)0.373
NYHA ≥ III pre-CRT106 (89%)12 (100%)0.608
LVEF (%)26 ± 927 ± 80.895
β-blockers pre-CRT (%)74 (62%)5 (42%)0.218
CRT-D (%)91 (77%)11 (92%)0.299
AF pre-CRT (%)43 (36%)10 (83%)0.003
AF without AVJ ablation (%)20 (17%)7 (58%)0.003
Percentage of biventricular pacing at 6 months95 ± 1285 ± 220.007
Variable Survivors ( n = 119) Non-survivors ( n = 12) P -value
Age (years)66 ± 974 ± 50.010
Male gender (%)96 (81%)12 (100%)0.125
Ischaemic aetiology (%)61 (51%)8 (67%)0.373
NYHA ≥ III pre-CRT106 (89%)12 (100%)0.608
LVEF (%)26 ± 927 ± 80.895
β-blockers pre-CRT (%)74 (62%)5 (42%)0.218
CRT-D (%)91 (77%)11 (92%)0.299
AF pre-CRT (%)43 (36%)10 (83%)0.003
AF without AVJ ablation (%)20 (17%)7 (58%)0.003
Percentage of biventricular pacing at 6 months95 ± 1285 ± 220.007

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 5

Clinical characteristics of survivors and non-survivors

Variable Survivors ( n = 119) Non-survivors ( n = 12) P -value
Age (years)66 ± 974 ± 50.010
Male gender (%)96 (81%)12 (100%)0.125
Ischaemic aetiology (%)61 (51%)8 (67%)0.373
NYHA ≥ III pre-CRT106 (89%)12 (100%)0.608
LVEF (%)26 ± 927 ± 80.895
β-blockers pre-CRT (%)74 (62%)5 (42%)0.218
CRT-D (%)91 (77%)11 (92%)0.299
AF pre-CRT (%)43 (36%)10 (83%)0.003
AF without AVJ ablation (%)20 (17%)7 (58%)0.003
Percentage of biventricular pacing at 6 months95 ± 1285 ± 220.007
Variable Survivors ( n = 119) Non-survivors ( n = 12) P -value
Age (years)66 ± 974 ± 50.010
Male gender (%)96 (81%)12 (100%)0.125
Ischaemic aetiology (%)61 (51%)8 (67%)0.373
NYHA ≥ III pre-CRT106 (89%)12 (100%)0.608
LVEF (%)26 ± 927 ± 80.895
β-blockers pre-CRT (%)74 (62%)5 (42%)0.218
CRT-D (%)91 (77%)11 (92%)0.299
AF pre-CRT (%)43 (36%)10 (83%)0.003
AF without AVJ ablation (%)20 (17%)7 (58%)0.003
Percentage of biventricular pacing at 6 months95 ± 1285 ± 220.007

Values are means ± SDs or number of patients (percentages). Abbreviations as in Table  1 .

Table 6

Univariate and multivariate predictors of cardiac mortality

Variable χ 2HR95% CIP -value
Univariate
 Age7.641.151.04–1.270.006
 AF pre-CRT6.717.441.63–33.990.010
 AF without AVJ ablation10.896.952.20–22.000.001
 Percentage of biventricular pacing at 6 months3.910.970.94–1.000.048
Multivariate
 Age5.921.121.02–1.230.015
 AF without AVJ ablation7.515.221.60–17.010.006
Variable χ 2HR95% CIP -value
Univariate
 Age7.641.151.04–1.270.006
 AF pre-CRT6.717.441.63–33.990.010
 AF without AVJ ablation10.896.952.20–22.000.001
 Percentage of biventricular pacing at 6 months3.910.970.94–1.000.048
Multivariate
 Age5.921.121.02–1.230.015
 AF without AVJ ablation7.515.221.60–17.010.006

HR, hazard ratio; CI, confidence interval; AF, atrial fibrillation; CRT, cardiac resynchronization therapy; AVJ, atrioventricular junction.

Table 6

Univariate and multivariate predictors of cardiac mortality

Variable χ 2HR95% CIP -value
Univariate
 Age7.641.151.04–1.270.006
 AF pre-CRT6.717.441.63–33.990.010
 AF without AVJ ablation10.896.952.20–22.000.001
 Percentage of biventricular pacing at 6 months3.910.970.94–1.000.048
Multivariate
 Age5.921.121.02–1.230.015
 AF without AVJ ablation7.515.221.60–17.010.006
Variable χ 2HR95% CIP -value
Univariate
 Age7.641.151.04–1.270.006
 AF pre-CRT6.717.441.63–33.990.010
 AF without AVJ ablation10.896.952.20–22.000.001
 Percentage of biventricular pacing at 6 months3.910.970.94–1.000.048
Multivariate
 Age5.921.121.02–1.230.015
 AF without AVJ ablation7.515.221.60–17.010.006

HR, hazard ratio; CI, confidence interval; AF, atrial fibrillation; CRT, cardiac resynchronization therapy; AVJ, atrioventricular junction.

There were 21 hospitalizations for decompensated HF during the first 12 months after CRT implantation (6 in SR, 4 in the AF with AVJ ablation group, and 11 in the AF without AVJ ablation group) ( Figure  3 ). The difference in hospital admissions between AF with vs. without AVJ ablation was of borderline significance ( P = 0.066). Atrial fibrillation without AVJ ablation was the only univariate predictor of admission for decompensated CHF during this period (HR 6.46, 95% CI: 2.36–17.69, P < 0.001). Even after forcing age, NYHA class, LV ejection fraction, and β-blocker use into the model, AF without AVJ ablation remained independently associated with the admission for CHF (HR 6.23, 95% CI: 2.09–18.54, P = 0.001).

Incidence of hospitalization for decompensated heart failure during the first 12 months after cardiac resynchronization therapy implantation.
Figure 3

Incidence of hospitalization for decompensated heart failure during the first 12 months after cardiac resynchronization therapy implantation.

Three patients without a previous history of AF developed arrhythmia during follow-up, requiring electrical cardioversion. Sinus rhythm was not restored in any of the patients with previous permanent AF.

Discussion

The main findings of this study include the following: (i) survival, hospitalization rate and responsiveness to CRT were relatively similar among patients in SR and patients with AF who underwent AVJ ablation; (ii) AF without AVJ ablation was an independent predictor of cardiac mortality, hospital admissions and non-responsiveness to CRT.

Several studies have demonstrated that CRT reduces symptoms, decreases neurohormonal activation and improves exercise capacity, LV function, and prognosis in patients with moderate to severe HF due to systolic dysfunction and cardiac dyssynchrony. 6–9 , 14 , 15 Whether this benefit could also be extended to patients with AF was the rationale for a number of recent studies. The limited available evidence suggests a favourable effect of cardiac resynchronization in this setting. Initial work showed a beneficial acute effect of CRT on haemodynamic parameters, 16–18 whereas studies looking at the long-term effects of CRT in patients with AF demonstrated improvements in NYHA functional class, exercise capacity, LV ejection fraction, and quality of life. 10 , 12 , 13 , 19 , 20 The MUSTIC AF trial 21 studied 59 patients with end-stage CHF and permanent AF in a cross-over design of conventional RV pacing vs. CRT. In patients with effective therapy (arbitrarily defined as ≥85% of biventricular capture), significant functional improvement and LV reverse remodelling were observed, as well as a reduction in hospitalization rate. Two further studies prospectively compared RV pacing with LV and/or biventricular pacing in patients undergoing AVJ ablation for the management of AF with rapid ventricular rates. 22 , 23 In the PAVE trial, 23 patients with biventricular pacing had a significant improvement in 6 min walking distance and ejection fraction when compared with patients receiving RV pacing, whereas in the OPSITE trial, 22 only a modest or no favourable effect on functional status was provided by biventricular pacing. Both studies had relatively small observation periods.

In the absence of robust randomized clinical trials in this setting, several groups tried to ascertain the usefulness of CRT in AF patients by comparing the benefit of CRT in patients with AF vs. patients with SR. 10–13 Together, these studies included 730 patients in SR and 303 patients with permanent or persistent AF, 168 of whom (55%) underwent AVJ ablation. All found a similar clinical benefit of CRT among patients with AF and SR patients in terms of improvement in functional class, exercise capacity, and LV ejection fraction. Our results add to the growing amount of evidence showing a similar clinical benefit of CRT among SR and AF patients and support the use of AVJ ablation in the latter group to assure almost complete biventricular capture. Our findings suggesting an important role for AVJ ablation in patients with AF are in accordance with the ones reported by Gasparini et al . 11 The reasons that may account for the better outcome of ablated patients include complete rhythm regularization by optimizing the alternation of systolic and diastolic phases of the cardiac cycle, 24–26 lower mean heart rates that are beneficial to diastolic performance, 26 and the almost complete biventricular capture that is considered essential to assure optimal CRT response. The main arguments against AVJ ablation include lifelong pacemaker dependency and the possible restoration of SR with prolonged CRT. It is possible that in near future, catheter ablation of AF may be used in combination with CRT, as an alternative to AVJ ablation. 27

The sudden death of a CRT-D patient who had been submitted to AVJ ablation is noteworthy. Even though the temporal relationship between the procedure and the event suggests another cause, this death should be considered likely or possibly related to the ablative procedure. A recent meta-analysis of 1181 AF patients who underwent radiofrequency AVJ ablation reported a sudden mortality rate of 2.0%/year (range 0–9% in studies with ≥1 year follow-up). 28 Even though sudden death possibly caused by the ablative procedure remains a matter of concern, the better survival of AF patients who underwent AVJ ablation compared with those who did not suggests a favourable risk–benefit relationship of ablative therapy in AF patients undergoing CRT.

The percentage of responders in both SR and AF was similar to previously reported data, 6 , 12 , 29 , 30 although the definition of response to CRT differs widely in the literature. 31 Not surprisingly, most of the 13 patients in NYHA class II at the time of CRT implantation did not experience a significant change in functional class and were classified as non-responders. The purpose of CRT in these subjects (all of whom had previous admissions for decompensated HF) was to prevent further LV remodelling and clinical deterioration and, in some cases, to avoid the deleterious effects of right ventricular pacing in patients requiring a pacemaker for other reasons. Although two studies suggest a beneficial effect on LV remodelling and heart rate variability, 9 , 32 the value of CRT in NYHA class II HF remains unproven and is still under evaluation. 33

Besides AF without AVJ ablation, age was the only independent predictor of both mortality and non-responsiveness to CRT. This should be taken into account when selecting patients for resynchronization therapy.

The differences between the three groups in terms of hospitalization for decompensated HF during the first 12 months are also noteworthy. Atrial fibrillation without AVJ ablation was independently associated with a higher incidence of hospital admissions during the first year, again suggesting a beneficial role for AVJ ablation in AF patients. To the best of our knowledge, this is the first study to suggest that AVJ ablation may influence survival and hospitalization rates in AF patients undergoing CRT.

Limitations of the study

Several limitations of this observational study must be acknowledged. Systematic objective measurements of changes in LV ejection fraction, functional capacity, quality of life, or neurohormonal activation were not performed. The endpoint symptomatic improvement is to some extent subjective and sometimes difficult to ascertain. As AVJ ablation was not randomly allocated, differences in outcome between AF patients with and without AVJ ablation may reflect selection bias or the effect of confounding variables that were not consistently measured in this study, rather than the real effect of ablative therapy on survival and responsiveness to CRT. Also, the relative contributions of better rate control and CRT in the ablated group cannot be discerned. The percentage of effective biventricular pacing may be overestimated by device interrogation due to the fusion or pseudo-fusion of ventricular complexes. Finally, the CHF hospitalization rate and exact duration of AF before implantation are unknown in most cases, and data about the number of AF episodes and burden are lacking.

Conclusions

Clinical improvement and survival after CRT in patients with AF are similar to that in patients with SR. Performing AVJ ablation in AF patients undergoing CRT seems crucial to attain maximal clinical benefit. Well-designed and powered clinical trials assessing these issues are needed.

Funding

The present work was not supported by any grant.

Acknowledgements

The authors thank Dr Filipe Seixo for his help in data collection. This work is original and has not been proposed to publication to other journals. All coauthors have agreed with the content of the proposed manuscript.

Conflict of interest: none declared.

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