Interference of Atrial Fibrillation with Cardiac Resynchronization Therapy

Dubravko Petrač; Vjekoslav Radeljić; Diana Delić-Brkljačić; Kristijan Đula

doi:10.15836/ccar2024.303

Back to search

Interference of Atrial Fibrillation with Cardiac Resynchronization Therapy

Review Article

Issue7-8

PublishedJune 2024

Pages303-313

PDF via DOIhttps://doi.org/10.15836/ccar2024.303

interferencija

fibrilacija atrija

resinkronizacijska terapija srca

interference

atrial fibrillation

cardiac resynchronization therapy

Authors

Dubravko Petrač*ORCIDCroatia Poliklinika, Zagreb, Hrvatska

Vjekoslav Radeljić ORCIDKlinički bolnički centar Sestre milosrdnice, Zagreb, Hrvatska

Diana Delić-Brkljačić ORCIDKlinički bolnički centar Sestre milosrdnice, Zagreb, Hrvatska

Kristijan Đula ORCIDKlinički bolnički centar Sestre milosrdnice, Zagreb, Hrvatska

*Correspondence email: d.petrac@inet.hr

Abstract

Cardiac resynchronization therapy (CRT) has become an important treatment option for patients with heart failure (HF) with impaired left ventricular function and ventricular conduction delay. Atrial fibrillation (AF) is the most common arrhythmia in these patients, and its presence may interfere with CRT due to a loss of atrioventricular synchrony and competition between biventricular (BIV) capture and normally conducted beats. This issue is important because the loss of effective BIV pacing is associated with poorer outcomes. Therapeutic options for AF in patients receiving CRT include rate control, with drugs or atrioventricular junction ablation, or rhythm control, with amiodarone or AF ablation, with the main goal of ensuring a high percentage of BIV pacing. In this review, we explain how AF may interfere with CRT, present negative effects of AF in these circumstances, and discuss the therapeutic options for AF in this specific population with HF.

Full Text

Introduction

Cardiac resynchronization therapy (CRT) has become an important treatment option for patients with heart failure (HF) with impaired left ventricular (LV) function and ventricular conduction delay, who are symptomatic despite optimal medical therapy. (1) In such patients, CRT reduces intra- and interventricular conduction delay, can slow disease progression by inducing cardiac reverse remodeling, and improves clinical outcomes, including mortality. (2–5) The current indications for CRT implantation in patients in sinus rhythm (1) are presented in Table 1.

TABLE 1: Recommendations for CRT in patients in sinus rhythm.

LBBB QRS morphology
CRT is recommended for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality (Class I).
CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130-149 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality (Class IIa).
Non-LBBB QRS morphology
CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity (Class IIa).
CRT may be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130-149 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity (Class IIb).
CRT = cardiac resynchronization therapy, LBBB = left bundle branch block, HF = heart failure, SR = sinus rhythm, LVEF = left ventricular ejection fraction, OPT = optimal medical therapy

TABLE 1: Recommendations for CRT in patients in sinus rhythm.

CRT is recommended for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality (Class I).

CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130-149 ms, and LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity and mortality (Class IIa).

Non-LBBB QRS morphology

CRT should be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration ≥150 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity (Class IIa).

CRT may be considered for symptomatic patients with HF in SR with LVEF ≤35%, QRS duration 130-149 ms, and non-LBBB QRS morphology despite OMT, in order to improve symptoms and reduce morbidity (Class IIb).

CRT = cardiac resynchronization therapy, LBBB = left bundle branch block, HF = heart failure, SR = sinus rhythm, LVEF = left ventricular ejection fraction, OPT = optimal medical therapy

Atrial fibrillation (AF) is the most common arrhythmia in patients receiving CRT. According to the report of the last European CRT Survey, 41% of patients receiving CRT had a history of prior AF and 26% of them had AF at the time of implantation. (6) Evaluated by device diagnostics, new-onset AF was found in 20% to 27% of patients with no previous history of AF. (7–9) Apart from worsening the prognosis of HF in general, (10, 11) AF may interfere with CRT delivery due to loss of atrioventricular (AV) synchrony and competition between biventricular (BIV) capture and conducted beats due to AF. This issue is clinically relevant because the loss of effective BIV pacing is associated with a worsening of HF and higher mortality. (12–15) The aim of this review was to explain how AF may interfere with CRT, present the negative effects of AF on survival and CRT delivery, and discuss therapeutic options for AF in this specific group of patients with HF.

The mechanisms by which atrial fibrillation interferes with cardiac resynchronization therapy

The basic goal of CRT is to restore intra- and interventricular synchrony when ventricular contractions are dyssynchronous due to intrinsic conduction delay, especially in patients with left bundle branch block. AF interferes with CRT in two ways: 1) by causing the loss of AV synchrony, which happens in every episode of AF, and 2) by causing the competition between BIV capture and conducted beats due to AF, which depends on the speed and irregularity of AF ventricular rate. In sinus rhythm, CRT resynchronizes cardiac contractions by optimizing of AV timing and by BIV pacing. From a clinical point of view, the optimal AV timing should be the AV interval that promotes a maximum contribution of the left atrial contraction to left ventricular (LV) filling, lengthens the filling time, increases the cardiac output, and minimizes mitral regurgitation. (16) Patients with AF do not have AV synchrony and thus no possibility of AV optimization with an appropriately timed AV interval. Therefore, they gain clinical benefit from the CRT only with BIV pacing. In this context, AF may interfere with CRT delivery because conducted beats caused by AF compete with BIV pacing. That happens when the ventricular rate of AF exceeds, interrupts, or disrupts the BIV capture, resulting in spontaneous, fusion, and pseudo-fusion beats. (17, 18) This is further exacerbated in situations of increased myocardial demand, as occurs from increased adrenergic tone during stress or exertion. (19) Fusion and pseudo-fusion beats result from an interaction between AF-conducted and BIV-paced beats (Figure 1). Fusion beats occur when the ventricles are activated at the same time by both the BIV impulse and the normal conducted impulse, producing a variable shape of the QRS complex, which depends on the relative contribution of BIV-paced and intrinsic ventricular activation. Pseudo-fusion beats occur when the BIV impulse is delivered after the ventricles have already been depolarized by normal conducted impulse, and have a QRS shape of the intrinsic beat but with a superimposed BIV spike. All spontaneous, fusion, and pseudo-fusion beats are therapeutically undesirable, because near maximally effective and complete BIV capture is necessary to assure optimal CRT response. (19)

FIGURE 1. Electrocardiogram in patient with cardiac resynchronization therapy (CRT) and atrial fibrillation. Out of 15 recorded cardiac beats, only four were paced appropriately by biventricular pacing (BV). The other beats were pseudofusion (PF) or fusion (F) beats, which markedly reduced effective CRT.

Negative effects of atrial fibrillation in patients with cardiac resynchronization therapy

There is substantial evidence that AF has a negative impact on survival and effective BIV pacing in patients receiving CRT. (12–15, 20, 21) Wilton et al. performed a meta-analysis of 23 observational studies, (12) which compared the outcomes of patients receiving CRT with (n=1912) and those without (n=5583) AF. After a mean follow-up of 33 months, AF was associated with a higher risk of all-cause mortality (10.8% vs 7.1%, p=0.015) and higher risk of nonresponse to CRT (35% vs 27%, p=0.001). The first report of the European CRT Survey has confirmed these results. (20) Among 2438 enrolled patients receiving CRT, those with AF had a poorer 1-year survival than those with sinus rhythm (86% vs 91%, p=0.0038). Cesario et al. (15) examined the impact of AF on survival in >60 000 patients with an implanted CRT-defibrillator followed using a remote monitoring network. They found that patients with an AF burden >0.01% with an AF episode lasting >1 min had decreased survival compared with patients with no AF or AF duration 10% and AF lasting 1 day had the lowest long-term survival rates. A recent meta-analysis of 31 studies with over 80 000 patients has unequivocally demonstrated that patients with AF receiving CRT had significantly higher all-cause and cardiovascular mortality than those with sinus rhythm (both p=0.001). (21)

Koplan et al. were the first (22) who investigated appropriate BIV pacing targets in patients with HF receiving CRT. In their post-hoc analysis of two CRT trials (n=1812), the greatest magnitude of reduction in HF hospitalization and all-cause mortality was observed with a biventricular pacing cutoff of 92%. The patients paced 93% to 100% had a lower risk of death or HF hospitalization compared with patients paced 0% to 92% (p<0.00001). Among patients with BIV pacing <93%, the risk of clinical events was higher in those who developed AF/atrial tachycardia (AT) during follow-up than in those who were without AF/AT (p=0.018).

In a study by Boriani et al., (8) sub-optimal CRT, defined as a percentage of BIV pacing <95%, was significantly associated with the occurrence of persistent or permanent AF (p<0.001) and uncontrolled ventricular rate (p=0.002). When the patients with AF were in sinus rhythm, the percentage of BIV pacing was 98% versus 71% during AF (p<0.01).

The importance of a high percentage of BIV pacing has been demonstrated in a study by Hayes et al. (13), which included >30 000 patients followed in a remote-monitoring network. The mortality was inversely correlated with the percentage of BIV pacing in the presence of sinus rhythm, paced atrial rhythm, and when the atrial rhythm was AF. BIV pacing >98.5% was found to be a cutoff value for significant benefit in survival. Patients with BIV pacing >99.6% experienced a 24% reduction in mortality (p98.5%, patients with AF had a lower survival than those without AF.

In a study by Ousdigian et al. (14) a significant percentage of patients with permanent (69%) and persistent (62%) AF did not achieve high BIV pacing (>98%), and these patients had an increased risk of death. In a multivariable analysis, reduced percentage of BIV pacing (≤98%) was an independent risk factor of higher mortality. Relative to patients with high BIV pacing (>98%), patients with moderate (90-98%) and low (<90%) BIV pacing had an increase in mortality of 20% and 32%, respectively (p<0.001 for both pacing groups). In each of the three BIV pacing groups, all AF groups had increased mortality in comparison with the group with no/little AF (p<0.001). Therefore, in patients with AF receiving CRT, the highest possible percentage of BIV pacing is necessary to achieve maximum benefit from CRT and achieve the therapeutic effect.

Therapeutic options for atrial fibrillation in patients receiving cardiac resynchronization therapy

As for other patients with AF, therapeutic options for patients receiving CRT include rate or rhythm control. The choice of these options depends on the type of AF (Figure 2), and their main goal is to ensure a high percentage of BIV pacing (>98%). (23)

FIGURE 2. Therapeutic options for atrial fibrillation (AF) in patients with cardiac resynchonization therapy (CRT) regarding to type of AF. BVP = biventricular pacing, AVJA = atrioventricular junction ablation

Rate control refers to therapeutic options which effectively reduce and regularize heart rate in patients receiving CRT who have permanent or persistent AF that cannot be readily cardioverted to sinus rhythm. (23) Pharmacological rate control is an initial therapeutic option, (24, 25) but the drugs are rarely adequate in ensuring a high percentage of BIV pacing without fusion beats. (18, 26) In one prospective study, as many as 71% of patients with permanent AF could not achieve satisfactory rate control with drugs. (27) Beta-blockers are usually used as first-line therapy to control ventricular rate because of their established safety and effectiveness during physical exertion and high sympathetic tone. (24, 28) Digoxin or digitoxin come into play when ventricular rate remains high despite beta-blockers or when beta-blockers are not tolerated or contraindicated. (24, 29)

In contrast to drug therapy, atrioventricular junction (AVJ) ablation completely eliminates AV conduction and ensures almost 100% BIV pacing, (30) but with consequent permanent pacemaker dependency. Several observational studies showed a significant benefit of AVJ ablation versus rate control drugs in patients receiving CRT with permanent or longstanding persistent AF in improving LVEF, reversing the remodeling effect, and improving exercise tolerance and survival. (27, 31, 32) In systematic review of 768 patients receiving CRT with AF, (33) patients with additional AVJ ablation had a substantial reduction of all-cause mortality and cardiovascular mortality compared with those treated with rate control drugs. These results have been confirmed in the CERTIFY (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry) study, (34) which compared the clinical outcomes in three groups of patients receiving CRT: those with sinus rhythm (n=6046), those with permanent AF and AVJ ablation (n=895), and those with permanent AF and rate control drugs (n=895). At a mean follow-up of 37 months, total mortality (6.8% vs 6.1%) and cardiac mortality (4.2% vs 4.0%) were similar for patients with AF with AVJ ablation and patients in sinus rhythm. In contrast, patients with AF receiving rate control drugs had a significantly higher total and cardiac mortality than both the patients sinus with and the patients with AF with AVJ ablation (both p<0.001). Furthermore, the improvement in left ventricular ejection fraction (LVEF) and LV end-systolic volume in patients with AF with AVJ ablation was comparable to that observed in patients with sinus rhythm, and significantly higher than that observed in patients with AF receiving rate control drugs (both p<0.001).

The first randomized study (35) that compared AVJ ablation with optimal medical therapy in patients with permanent AF receiving CRT did not find that AVJ ablation improved echocardiographic or clinical outcomes. However, the study included too small a number of patients (12 in each randomized group) to allow relevant clinical suggestions or conclusions.

In conclusion, prospective observational studies have consistently shown that AVJ ablation was superior to rate control drugs in achieving adequate BIV pacing and reducing long-term mortality, as well as in improving LVEF, functional capacity, and reversing ventricular remodeling. For these reasons, AVJ ablation should be performed in most, if not all, patients with permanent AF receiving CRT, and in those with frequent and prolonged episodes of persistent AF that are unresponsive or intolerant to drug therapy. (23)

Rhythm control refers to therapeutic options that can restore and maintain sinus rhythm. In patients with AF receiving CRT, the restoration of sinus rhythm can be achieved with electrical or pharmacological cardioversion. When pharmacological cardioversion is preferred, amiodarone is the drug of choice (36, 37) because other antiarrhythmic drugs are associated with a negative impact on survival. (38–40) Amiodarone is the only drug suitable for rhythm control in patients receiving CRT, (41, 42) but its success rate in the maintenance of sinus rhythm is modest and no higher than 34% after 24 months of follow-up. (42)

In the absence of randomized studies on AF ablation in patients receiving CRT, its benefit in these patients can be assumed based on randomized studies on AF ablation in patients with HF with LVEF less than 40% (Table 2). The PABA-CHF (Pulmonary Vein Antrum Isolation versus AV Node Ablation with Bi-Ventricular Pacing for Treatment of Atrial Fibrillation in Patients with Congestive Heart Failure) study (43) compared AF ablation with a combination of AVJ ablation and BIV pacing in 81 patients with LVEF <40%, NYHA class II or III HF, and paroxysmal or persistent AF. At six-month follow-up, the patients randomized to AF ablation had a greater improvement in primary end points comprising LVEF, 6-minute walk distance (6-MWD), and Minnesota Living with Heart Failure (MLWHF) score than those randomized to a combination of AVJ ablation and BIV pacing (35% vs 28%, p<0.001), and 71% of patients in the ablation group were AF-free with no antiarrhythmic medication. In two subsequent studies, (44, 45) patients with symptomatic HF, LVEF<40%, and persistent AF were randomized to AF ablation or rate control drugs. In the study by MacDonald et al., (44) AF ablation did not improve LVEF, level of N-terminal pro brain natriuretic peptide (BNP), 6-MWD, and quality of life (QoL) compared with rate-control drugs, and only 50% of patients who underwent AF ablation were in sinus rhythm at 6 months. In contrast, Jones et al. (45) reported a significant benefit of AF ablation versus rate control drugs in improving peak oxygen consumption, BNP level, and MLWHF score, and 88% of patients in the ablation group were able to maintain sinus rhythm at 12 months.

TABLE 2: Randomized clinical studies on ablation in patients with atrial fibrillation, heart failure, and left ventricular ejection fraction <40%.

Study (year)	Inclusion criteria	Randomized treatment groups	F/U (months)	Outcomes regarding the primary end point	AF ablation procedural success
PABA-CHF (42) (2008)	Paroxysmal or persistent AF NYHA II-III HF LVEF <40%	AF ablation (n=41) AVJA + CRT (n=40)	6	Significant improvement in LVEF, 6-MWD, and MLWHF in the ablation group	88.0%
MacDonald et al. (43) (2011)	Persistent AF NYHA II-IV HF LVEF ≤35%	AF ablation (n=22) Rate control drugs (n=10)	6	No difference in LVEF between the groups	50.0%
Jones et al. (44) (2013)	Persistent AF NYHA II-III HF LVEF ≤35%	AF ablation (n=25) Rate control drugs (n=26)	12	Significant improvement in PO2 in the ablation group	88.0%
AATAC (41) (2017)	Persistent AF NYHA II-III HF LVEF <40%	AF ablation (n=102) Amiodarone (n=101)	36	Significant improvement in freedom from AF in the ablation group	70.0%
CASTLE-AF (45) (2018)	Paroxysmal or persistent AF NYHA II-IV HF LVEF ≤35%	AF ablation (n=179) Rate/rhythm control drugs (n=184)	60	Significant improvement in mortality or HFH in the ablation group	63.1%
AMICA (46) (2019)	Persistent AF NYHA II-IV HF LVEF ≤35%	AF ablation (n=68) Best medical therapy (n=72)	12	No difference in LVEF between the groups	73.5%

F/U = follow up, AF = atrial fibrillation, NYHA = New York Heart Association, LVEF = left ventricular ejection fraction, AVJA = atrioventricular junction ablation, 6-MWD = six-minute walking distance, MLWHF = Minessota Living with Heart Failure, PVO2 = peak oxygen consumption, HFH = hospitalization for heart failure

TABLE 2: Randomized clinical studies on ablation in patients with atrial fibrillation, heart failure, and left ventricular ejection fraction <40%.

PABA-CHF (42) (2008)

Inclusion criteria: Paroxysmal or persistent AF NYHA II-III HF LVEF <40%
Randomized treatment groups: AF ablation (n=41) AVJA + CRT (n=40)
F/U (months): 6
Outcomes regarding the primary end point: Significant improvement in LVEF, 6-MWD, and MLWHF in the ablation group
AF ablation procedural success: 88.0%

MacDonald et al. (43) (2011)

Inclusion criteria: Persistent AF NYHA II-IV HF LVEF ≤35%
Randomized treatment groups: AF ablation (n=22) Rate control drugs (n=10)
F/U (months): 6
Outcomes regarding the primary end point: No difference in LVEF between the groups
AF ablation procedural success: 50.0%

Jones et al. (44) (2013)

Inclusion criteria: Persistent AF NYHA II-III HF LVEF ≤35%
Randomized treatment groups: AF ablation (n=25) Rate control drugs (n=26)
F/U (months): 12
Outcomes regarding the primary end point: Significant improvement in PO2 in the ablation group
AF ablation procedural success: 88.0%

AATAC (41) (2017)

Inclusion criteria: Persistent AF NYHA II-III HF LVEF <40%
Randomized treatment groups: AF ablation (n=102) Amiodarone (n=101)
F/U (months): 36
Outcomes regarding the primary end point: Significant improvement in freedom from AF in the ablation group
AF ablation procedural success: 70.0%

CASTLE-AF (45) (2018)

Inclusion criteria: Paroxysmal or persistent AF NYHA II-IV HF LVEF ≤35%
Randomized treatment groups: AF ablation (n=179) Rate/rhythm control drugs (n=184)
F/U (months): 60
Outcomes regarding the primary end point: Significant improvement in mortality or HFH in the ablation group
AF ablation procedural success: 63.1%

AMICA (46) (2019)

Inclusion criteria: Persistent AF NYHA II-IV HF LVEF ≤35%
Randomized treatment groups: AF ablation (n=68) Best medical therapy (n=72)
F/U (months): 12
Outcomes regarding the primary end point: No difference in LVEF between the groups
AF ablation procedural success: 73.5%

The AATAC (Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients with Congestive Heart Failure and an Implanted Device) study (42) enrolled 203 patients with HF and LVEF <40%, persistent AF, and an implanted dual chamber cardioverter-defibrillator or CRT-defibrillator, who were randomly assigned to AF ablation or amiodarone. Over the 2-year follow-up, AF ablation was superior to amiodarone in achieving freedom from AF (70% vs 34%, p<0.001) and reducing unplanned HF hospitalization (31% vs 38%, p<0.001) and mortality (8% vs 18%, p=0.037), as well as in improving LVEF (p=0.02), 6-MWD (p=0.02), and MLFHQ scores (p=0.04).

The CASTLE-AF (Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation) study (46) included 363 patients with symptomatic paroxysmal or persistent AF, NYHA class II-IV HF, LVEF ≤35%, and an implanted cardioverter-defibrillator (n=263) or CRT-defibrillator (n=100), who were randomized to either AF ablation or medical therapy (rate or rhythm control). After a median follow-up of 37.8 months, the use of AF ablation was associated with a significantly lower rate of a composite end point of death from any cause or HF hospitalization than medical therapy (51 vs 82, p=0.007). There was also significant benefit in all-cause mortality alone, which was driven by a significantly lower rate of cardiovascular death in the ablation group (Table 3). Importantly, the mortality benefit of ablation did not emerge until after 3 years. Furthermore, AF ablation improved LVEF (p=0.005 vs the medical group), increased 6-MWD, and 63% of patients treated with ablation were free of AF after 60 months of follow-up. The limitations of the CASTLE-AF study were extended enrollment period of highly-selected population (only 12% of 3013 recruited patients during 8 years) and lack of blinding with respect to randomization and treatment.

TABLE 3: Secondary end points in the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation Study.

End point	AF ablation (n = 179)	Medical therapy (n = 184)	p Value
	Number (%)	Number (%)	Cox regression
Death from any cause	24 (13.4)	46 (25.0)	0.009
HF hospitalization	37 (20.7)	66 (35.9)	0.004
CV death	20 (11.2)	41 (22.3)	0.008
CV hospitalization	64 (35.8)	89 (48.4)	0.04
Hospitalization for any cause	114 (63.7)	122 (66.3)	0.96
Cerebrovascular accident	5 (2.8)	11 (6.0)	0.14

AF = atrial fibrillation, HF = heart failure, CV = cardiovascular

TABLE 3: Secondary end points in the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation Study.

Row 1

AF ablation (n = 179): Number (%)
Medical therapy (n = 184): Number (%)
p Value: Cox regression

Death from any cause

AF ablation (n = 179): 24 (13.4)
Medical therapy (n = 184): 46 (25.0)
p Value: 0.009

HF hospitalization

AF ablation (n = 179): 37 (20.7)
Medical therapy (n = 184): 66 (35.9)
p Value: 0.004

CV death

AF ablation (n = 179): 20 (11.2)
Medical therapy (n = 184): 41 (22.3)
p Value: 0.008

CV hospitalization

AF ablation (n = 179): 64 (35.8)
Medical therapy (n = 184): 89 (48.4)
p Value: 0.04

Hospitalization for any cause

AF ablation (n = 179): 114 (63.7)
Medical therapy (n = 184): 122 (66.3)
p Value: 0.96

Cerebrovascular accident

AF ablation (n = 179): 5 (2.8)
Medical therapy (n = 184): 11 (6.0)
p Value: 0.14

AF = atrial fibrillation, HF = heart failure, CV = cardiovascular

The AMICA study included 140 patients with persistent or longstanding persistent AF and LVEF ≤35%, who were randomly allocated to AF ablation or best medical therapy. (47) Terminated earlier due to futility, the study did not find statistically significant differences between treatment groups in LVEF, 6-MWD, MLWHF score, BNP level, and restoration of sinus rhythm. The different results in the AMICA and CASTLE-AF studies might be explained by the fact that AMICA enrolled a patient population with more advanced HF and AF, who were less suitable for ablation. Indeed, a direct comparison of patients receiving ablation in these two studies shows that patients in the AMICA study had a lower mean LVEF (27.6% vs 32.5%), higher prevalence of persistent AF (100% vs 70%), and more prevalent NYHA class III or IV (60% vs 31%) at baseline evaluation. (47)

A recent analysis from the CABANA study examined 778 patients with stable HF and paroxysmal or persistent AF, who were assigned to AF ablation (n=378) or drug therapy (n=400). (48) After 48.5 months of follow-up, there was a significant reduction in a composite end point of death, stroke, serious bleeding, or cardiac arrest (9% versus 12.3%, HR: 0.64) and mortality (6.1 vs 9.3%, HR: 0.57) in the ablation group. However, it should be noted that these results were obtained in patients with HF of whom only 9.3% had LVEF<40%.

In conclusion, randomized studies on AF ablation in patients with HF with reduced LVEF (<40%) have demonstrated that AF ablation was superior to rate and rhythm control drugs in improving QoL, LVEF, BNP levels, functional capacity, and freedom from AF during follow-up. The results on HF hospitalization and mortality were obtained with a relatively small number of events, which does not allow for definitive conclusions. Current guidelines recommend AF ablation in patients with reduced LVEF who remain symptomatic after rate control therapy. Accordingly, AF ablation should be considered in patients receiving CRT with paroxysmal or persistent AF, who are symptomatic and have reduced CRT delivery (≤98) despite optimal medical therapy.

From a clinical point of view, AF ablation may have an advantage over AVJ ablation in patients receiving CRT because simultaneously restores AV synchrony and provides a high percentage of CRT delivery. New data on this topic will be provided by the prospective RHYTHMIC (Rate or Rhythm Control in CRT) study, (49) which will investigate whether the restoration of AV synchrony with AF ablation will lead to better LV reverse remodeling compared to AV node ablation in CRT patients with suboptimal (<95%) BIV pacing caused by AF.

Conclusion

AF interferes with CRT delivery due to the loss of AV synchrony and competition between BIV capture and conducted beats due to AF, which in turn results in a reducing of effective BIV pacing and poorer outcomes. Therapeutic options for patients with AF receiving CRT comprise rate or rhythm control strategies, with the main goal of ensuring a high percentage of BIV pacing (>98%) and thus better prognosis. Pharmacological rate or rhythm control can be used, but their efficacy in achieving sufficient BIV pacing is modest. AVJ ablation eliminates interference with normally conducted beats, provides complete BIV capture, and improves outcomes, including survival. For these reasons, AVJ ablation should be used as the first-line therapeutic option in the majority of CRT patients with permanent AF, and also in patients with persistent AF in whom drug therapy has failed. AF ablation should be considered in CRT patients who have paroxysmal or persistent AF, when these arrhythmias are symptomatic and reduce effective BIV pacing despite medical therapy. Randomized studies on AF ablation in patients receiving CRT are needed in order to assess whether it can be the first-line therapeutic option for rhythm control in these patients.

Literature

1.
Glikson M, Nielsen JC, Kronborg MD, Michowitz Y, Auricchio A, Barbash IM, et al. ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Developed by the Task Force on cardiac pacing and cardiac resynchronization therapy of the European Society of Cardiology (ESC) with the special contribution of the European Heart Rhythm Association (EHRA). Eur Heart J. 2021 September 14;42(35):3427–520.DOI
2.
Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004 May 20;350(21):2140–50.DOI
3.
Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005 April 14;352(15):1539–49.DOI
4.
Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med. 2009 October 1;361(14):1329–38.DOI
5.
Ypenburg C, van Bommel RJ, Borleffs CJ, Bleeker GB, Boersma E, Schalij MJ, et al. Long-term prognosis after cardiac resynchronization therapy is related to the extent of left ventricular reverse remodeling at midterm follow-up. J Am Coll Cardiol. 2009 February 10;53(6):483–90.DOI
6.
Dickstein K, Normand C, Auricchio A, Bogale N, Cleland JG, Gitt AK, et al. CRT Survey II: a European Society of Cardiology survey of cardiac resynchronisation therapy in 11 088 patients-who is doing what to whom and how? Eur J Heart Fail. 2018 June;20(6):1039–51.DOI
7.
Santini M, Gasparini M, Landolina M, Lunati M, Proclemer A, Padeletti L, et al. cardiological centers participating in ClinicalService Project. Device-detected atrial tachyarrhythmias predict adverse outcome in real-world patients with implantable biventricular defibrillators. J Am Coll Cardiol. 2011 January 11;57(2):167–72.DOI
8.
Boriani G, Gasparini M, Landolina M, Lunati M, Proclemer A, Lonardi G, et al. ClinicalService cardiac centres. Incidence and clinical relevance of uncontrolled ventricular rate during atrial fibrillation in heart failure patients treated with cardiac resynchronization therapy. Eur J Heart Fail. 2011 August;13(8):868–76.DOI
9.
Sade LE, Atar I, Özin B, Yüce D, Müderrisoğlu H. Determinants of New-Onset Atrial Fibrillation in Patients Receiving CRT: Mechanistic Insights From Speckle Tracking Imaging. JACC Cardiovasc Imaging. 2016 February;9(2):99–111.DOI
10.
Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, Wolf PA, et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation. 2003 June 17;107(23):2920–5.DOI
11.
Mamas MA, Caldwell JC, Chacko S, Garratt CJ, Fath-Ordoubadi F, Neyses L. A meta-analysis of the prognostic significance of atrial fibrillation in chronic heart failure. Eur J Heart Fail. 2009 July;11(7):676–83.DOI
12.
Wilton SB, Leung AA, Ghali WA, Faris P, Exner DV. Outcomes of cardiac resynchronization therapy in patients with versus those without atrial fibrillation: a systematic review and meta-analysis. Heart Rhythm. 2011 July;8(7):1088–94.DOI
13.
Hayes DL, Boehmer JP, Day JD, Gilliam FR, Heidenreich PA, Seth M, et al. Cardiac resynchronization therapy and the relationship of percent biventricular pacing to symptoms and survival. Heart Rhythm. 2011 September;8(9):1469–75.DOI
14.
Ousdigian KT, Borek PP, Koehler JL, Heywood JT, Ziegler PD, Wilkoff BL. The epidemic of inadequate biventricular pacing in patients with persistent or permanent atrial fibrillation and its association with mortality. Circ Arrhythm Electrophysiol. 2014 June;7(3):370–6.DOI
15.
Cesario D, Powell BD, Gilliam R, Day J, Hayes D, Jones P, et al. The role of atrial fibrillation in CRT-D patients: The ALTITUDE Study Group. J Innov Card Rhythm Manag. 2015;6:1873–80.Link
16.
Barold SS, Ilercil A, Herweg B. Echocardiographic optimization of the atrioventricular and interventricular intervals during cardiac resynchronization. Europace. 2008 November;10 Suppl 3:iii88–95.DOI
17.
Gasparini M, Regoli F, Galimberti P, Ceriotti C, Cappelleri A. Cardiac resynchronization therapy in heart failure patients with atrial fibrillation. Europace. 2009 Nov;11 Suppl 5(Suppl 5):v82-6.DOI
18.
Kamath GS, Cotiga D, Koneru JN, Arshad A, Pierce W, Aziz EF, et al. The utility of 12-lead Holter monitoring in patients with permanent atrial fibrillation for the identification of nonresponders after cardiac resynchronization therapy. J Am Coll Cardiol. 2009 March 24;53(12):1050–5.DOI
19.
Upadhyay GA, Steinberg JS. Managing atrial fibrillation in the CRT patient: controversy or consensus? Heart Rhythm. 2012 August;9(8) Suppl:S51–9.DOI
20.
Bogale N, Priori S, Cleland JG, Brugada J, Linde C, Auricchio A, et al. The European CRT Survey: 1 year (9-15 months) follow-up results. Eur J Heart Fail. 2012 January;14(1):61–73.DOI
21.
Mustafa U, Atkins J, Mina G, Dawson D, Vanchiere C, Duddyala N, et al. Outcomes of cardiac resynchronisation therapy in patients with heart failure with atrial fibrillation: a systematic review and meta-analysis of observational studies. Open Heart. 2019 March 19;6(1):e000937.DOI
22.
Koplan BA, Kaplan AJ, Weiner S, Jones PW, Seth M, Christman SA. Heart failure decompensation and all-cause mortality in relation to percent biventricular pacing in patients with heart failure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol. 2009 January 27;53(4):355–60.DOI
23.
Petrač D. Atrial Fibrillation in Patients with Cardiac Resynchronization Therapy: Therapeutic Options. Cardiol Croat. 2017;12(5-6):254–63.DOI
24.
Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 February 1;42(5):373–498.DOI
25.
McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021 September 21;42(36):3599–726.DOI
26.
Healey JS, Hohnloser SH, Exner DV, Birnie DH, Parkash R, Connolly SJ, et al. RAFT Investigators. Cardiac resynchronization therapy in patients with permanent atrial fibrillation: results from the Resynchronization for Ambulatory Heart Failure Trial (RAFT). Circ Heart Fail. 2012 September 1;5(5):566–70.DOI
27.
Gasparini M, Auricchio A, Regoli F, Fantoni C, Kawabata M, Galimberti P, et al. Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation. J Am Coll Cardiol. 2006 August 15;48(4):734–43.DOI
28.
Van Gelder IC, Rienstra M, Crijns HJ, Olshansky B. Rate control in atrial fibrillation. Lancet. 2016 August 20;388(10046):818–28.DOI
29.
Khand AU, Rankin AC, Martin W, Taylor J, Gemmell I, Cleland JG. Carvedilol alone or in combination with digoxin for the management of atrial fibrillation in patients with heart failure? J Am Coll Cardiol. 2003 December 3;42(11):1944–51.DOI
30.
Gasparini M, Galimberti P, Ceriotti C. The importance of increased percentage of biventricular pacing to improve clinical outcomes in patients receiving cardiac resynchronization therapy. Curr Opin Cardiol. 2013 January;28(1):50–4.DOI
31.
Gasparini M, Auricchio A, Metra M, Regoli F, Fantoni C, Lamp B, et al. Long-term survival in patients undergoing cardiac resynchronization therapy: the importance of performing atrio-ventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J. 2008 July;29(13):1644–52.DOI
32.
Dong K, Shen WK, Powell BD, Dong YX, Rea RF, Friedman PA, et al. Atrioventricular nodal ablation predicts survival benefit in patients with atrial fibrillation receiving cardiac resynchronization therapy. Heart Rhythm. 2010 September;7(9):1240–5.DOI
33.
Ganesan AN, Brooks AG, Roberts-Thomson KC, Lau DH, Kalman JM, Sanders P. Role of AV nodal ablation in cardiac resynchronization in patients with coexistent atrial fibrillation and heart failure a systematic review. J Am Coll Cardiol. 2012 February 21;59(8):719–26.DOI
34.
Gasparini M, Leclercq C, Lunati M, Landolina M, Auricchio A, Santini M, et al. Cardiac resynchronization therapy in patients with atrial fibrillation: the CERTIFY study (Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry). JACC Heart Fail. 2013 December;1(6):500–7.DOI
35.
Steinberg JS, Gorcsan J, Mazur A, Jain SK, Rashtian M, Greer GS, et al. Junctional AV ablation in patients with atrial fibrillation undergoing cardiac resynchronization therapy (JAVA-CRT): results of a multicenter randomized clinical trial pilot program. J Interv Card Electrophysiol. 2022 August;64(2):519–30.DOI
36.
Deedwania PC, Singh BN, Ellenbogen K, Fisher S, Fletcher R, Singh SN. Spontaneous conversion and maintenance of sinus rhythm by amiodarone in patients with heart failure and atrial fibrillation: observations from the veterans affairs congestive heart failure survival trial of antiarrhythmic therapy (CHF-STAT). The Department of Veterans Affairs CHF-STAT Investigators. Circulation. 1998 December 8;98(23):2574–9.DOI
37.
Butter C, Winbeck G, Schlegl M, Seifert M, Wagner A, Wellnhofer E, et al. Management of atrial fibrillation in cardiac resynchronization therapy clinical practice of CRT: How to improve the success rate. Eur Heart J Suppl. 2004;6 Suppl D:D106–11.DOI
38.
Lafuente-Lafuente C, Valembois L, Bergmann JF, Belmin J. Antiarrhythmics for maintaining sinus rhythm after cardioversion of atrial fibrillation. Cochrane Database Syst Rev. 2015 March 28; (3):CD005049.DOI
39.
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 March 21;324(12):781–8.DOI
40.
Køber L, Torp-Pedersen C, McMurray JJ, Gøtzsche O, Lévy S, Crijns H, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008 June 19;358(25):2678–87.DOI
41.
Ciszewski JB, Tajstra M, Gadula-Gacek E, Kowalik I, Maciag A, Chwyczko T, et al. Rhythm or rate control strategy in CRT recipients with long-standing persistent atrial fibrillation - preliminary results of the PilotCRAfT study. EP Europace. 2021;23(Suppl 3):euab116.466.DOI
42.
Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, et al. Ablation Versus Amiodarone for Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Multicenter Randomized Trial. Circulation. 2016 April 26;133(17):1637–44.DOI
43.
Khan MN, Jaïs P, Cummings J, Di Biase L, Sanders P, Martin DO, et al. PABA-CHF Investigators. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med. 2008 October 23;359(17):1778–85.DOI
44.
MacDonald MR, Connelly DT, Hawkins NM, Steedman T, Payne J, Shaw M, et al. Radiofrequency ablation for persistent atrial fibrillation in patients with advanced heart failure and severe left ventricular systolic dysfunction: a randomised controlled trial. Heart. 2011 May;97(9):740–7.DOI
45.
Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol. 2013 May 7;61(18):1894–903.DOI
46.
Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. CASTLE-AF Investigators. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018 February 1;378(5):417–27.DOI
47.
Kuck KH, Merkely B, Zahn R, Arentz T, Seidl K, Schlüter M, et al. Catheter Ablation Versus Best Medical Therapy in Patients With Persistent Atrial Fibrillation and Congestive Heart Failure: The Randomized AMICA Trial. Circ Arrhythm Electrophysiol. 2019 December;12(12):e007731.DOI
48.
Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, et al. CABANA Investigators. Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial. Circulation. 2021 April 6;143(14):1377–90.DOI
49.
Elliott MK, de Vere F, Mehta VS, Wijesuriya N, Strocchi M, Rajani R, et al. Rate or Rhythm Control in CRT (RHYTHMIC): Study rationale and protocol. Heart Rhythm O2. 2022 September 13;3 6Part A:681–7.DOI

Authors

Abstract

Keywords

DOI

Full Text

Literature

Interference of Atrial Fibrillation with Cardiac Resynchronization Therapy

Authors

Abstract

Full Text

Introduction

TABLE 1: Recommendations for CRT in patients in sinus rhythm.

The mechanisms by which atrial fibrillation interferes with cardiac resynchronization therapy

Negative effects of atrial fibrillation in patients with cardiac resynchronization therapy

Therapeutic options for atrial fibrillation in patients receiving cardiac resynchronization therapy

TABLE 2: Randomized clinical studies on ablation in patients with atrial fibrillation, heart failure, and left ventricular ejection fraction <40%.

TABLE 3: Secondary end points in the Catheter Ablation versus Standard Conventional Therapy in Patients with Left Ventricular Dysfunction and Atrial Fibrillation Study.

Conclusion

Literature