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.

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 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)

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 <1 min (p<0.001). The patients with an AF burden >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 (p<0.001), while those with BIV% pacing <94.8% had a 19% increase in mortality. Importantly, at the same percentage of BIV pacing, including BIV pacing >98.5%, 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.

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)

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.

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.

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.

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.