The rapid ventricular rate is the main source of symptoms in this patient group and, if occurring for a prolonged period of time, increases the risk of tachycardia-induced cardiomyopathy, consisting of reversible ventricular dilatation, systolic dysfunction and symptoms of heart failure. The entity may be divided into 2 types: pure (tachycardia being the chief mechanism of LV deterioration); and 2) impure (tachycardia worsens a pre-existing cardiomyopathy of a different cause). Although described in 1913 in a patient with AF, and during the last 3 decades extensively studied in both animal models and in humans, its pathophysiological mechanisms have not been fully elucidated although interplay of several mechanisms clearly exists.3

In animal models sustained atrial or ventricular pacing leads to severe biventricular systolic dysfunction which is characterized by increased ventricular filling pressures, diminished cardiac output and increased systemic vascular resistance.21 At a microscopic level there is myocyte loss, myocyte elongation, effacement of the interface between the basement membrane and sarcolemmal surface, depletion of T-tubules associated with decreased density of L-type calcium channels and beta-adrenergic receptors, resulting in abnormal excitation-contraction coupling which may impair contractile function.22 Diastolic function is impaired by tachycardia with impaired relaxation secondary to a disproportionate increase in sarcoplasmic reticulum calcium content that manifests as diastolic contracture.23 Other mechanisms include exhaustion of high energy stores in the myocardium due to augmented metabolism from the tachycardia, mitral regurgitation secondary to annular dilatation, reduced myocardial blood flow, oxidative stress, and neurohormonal changes.3

Both in animal and human studies, normalization of the rapid heart rates results in recovery of myocardial function with improvements in LV ejection fraction (LVEF) typically observed after 3 to 4 months. In a metaanalysis of 21 studies with a total of 1181 patients with drug refractory AF, an overall improvement in LVEF of 4.4% was observed as well as in a broad range of clinical outcomes including symptoms, number of hospital admissions and New York Heart Association (NYHA) functional class.24

As AVJ ablation became a more widespread therapeutic option for drug refractory fast AF during the 1990s, several studies were published evaluating the potential beneficial aspects of this procedure. Initial uncontrolled studies in highly symptomatic patients with drug refractory permanent AF established that AVJ ablation provides symptom relief25 and improved cardiac function,26,27 the latter attributed to the reversal of tachycardia-induced cardiomyopathy and the favorable hemodynamic effects of regularization of RR intervals.28 For example, The Ablate and Pace Trial,25 a prospective multicenter study including 156 patients with drug refractory fast AF undergoing AVJ ablation and pacemaker implantation, reported after a 12-month follow-up an significant improvement in NYHA class (2.1 to 1.8), quality of life and arrhythmia related symptoms and frequency. The LVEF at 12-month was not different from baseline, however in those with reduced LVEF at baseline a significant improvement was observed (31±2% vs. 41±3%; P=0.0001).

Subsequently, the results of a few randomized trials were reported comparing pharmacological rate control with AVJ ablation in AF patients (Table 1).29-33 Of note, the patient profile was different to the previous uncontrolled studies, in particular since an acceptable pharmacological heart rate control was a pre-requisite. Brignole et al.31 studied 66 patients with AF lasting >6 months, clinically manifest heart failure, evidence of structural heart disease, and heart rate <90 bpm, randomized to AVJ ablation and pacemaker implantation or pharmacological treatment. At 12 month the ablation group showed significantly lower scores in palpitations and exertional dyspnea and a non-significant favorable trend for exercise intolerance, Living with Heart Failure Questionnaire, NYHA class, and Activity Scale when compared with the drug group. No difference in echocardiographic parameters between the 2 groups was observed at the end of the study, perhaps due to the presence of structural heart disease having more of an impact on the depressed cardiac function than tachycardia induced cardiomyopathy. In a similar way, The Australian Intervention Randomized Control of Rate in Atrial Fibrillation Trial (AIRCRAFT)33 compared AVJ ablation and pacemaker implantation with pharmacological rate control in 99 patients with mild to moderately symptomatic permanent AF, normal LVEF, and a ventricular rates that was adequately controlled by medication (<80 bpm and <150 bpm at rest and exercise, respectively). After 12 month of follow-up no difference in echocardiographic parameters or exercise tolerance was observed, however quality of life was significantly improved in the AVJ ablation group. Finally, Ueng et al.32 studied 50 patients with permanent symptomatic AF, reduced LVEF and no evidence of structural heart disease, and normal ventricular rates (60 – 100 bpm). Assignment to AVJ ablation and pacemaker implantation was according to patient preference and after 12 months the ablation group showed significant improvements in quality of life, symptoms and LVEF, the latter likely due to the regularization of R-R intervals when compared to the drug group. A metaanalysis of randomized or prospective trials, including the previously commented studies,31-33 found that AVJ ablation when compared with pharmacotherapy was associated with significant improvement in several symptoms (palpitations, dyspnea) but no significant difference in exercise duration or LVEF.34 In subgroup analysis of patients with reduced LVEF this parameter was significantly improved after AVJ ablation. Importantly, the same metaanalysis reported a low incidence of procedure-related mortality(0.27%) and malignant arrhythmia (0.57%).

Our group aimed to determine the change in LVEF after AVJ ablation and RV apical pacing and the clinical predictors of LVEF deterioration in a sample of 104 consecutives patients referred for AVJ ablation.35 After 2 years of follow up there was a decrease in the rate of hospital admission (from 0.9 admission/year to 0.35, P<0.001), an increase in the functional status in at least one NYHA class in 58 patients, and an increase in the global LVEF (from 48.9% to 54,1%; P<0.001). Valvular replacement and LVEF <50% were independently associated with a decrease in the LVEF. Therefore, we hypothesized that the mechanical ventricular dyssynchrony induced by long-term RVA apical pacing may have more impact in patients with mitral disease, which as is known, plays an important role in the cardiac mechanics. Scarce information in this subgroup is currently available and it is our belief that it warrants further investigations

RVA pacing produces electrical and mechanical ventricular dyssynchrony, similar to left bundle branch block, with subsequent detrimental effects on cardiac structure and function.36 During the last 2 decades the clinical relevance of the negative effects of longterm RVA pacing has gained recognition following the publication of large pacemaker and implantable cardiac defibrillator (ICD) trials where a high amount of chronic RVA pacing was associated with increased risk of AF, HF and death.36-38 Subanalyses from these trials suggest that patients with reduced LVEF subject to >40-50% of RVA pacing are at high risk.39,40 Such findings are also relevant for patients who undergo AVJ ablation and conventional pacemaker implantation since they will receive near 100% of pacing for the rest of their life. Importantly, the vast majority of patients studied (including all studies commented in the previous section) received an RVA pacing system (typically VVIR), and it is therefore likely that some of the benefits associated with the AVJ ablation procedure were offset by the detrimental effects of chronic RVA pacing, especially after years of chronic pacing. This was observed by Tops et al41 who retrospectively evaluated 55 patients with medically refractory AF and preserved LVEF who had undergone AVJ ablation. After a relatively long follow-up of 3.8±1.7 years, 49% had developed LV dyssynchrony and in this subgroup LVEF was significantly worsened (from 48±7% to 43±7%; P<0.05) as well as NYHA class (from 1.8±0.6 to 2.2±0.7; P<0.05). On the contrary, a retrospective study42 of 286 patients with baseline LVEF of 48±18% with a shorter follow-up (1.7±1.6 years) than the Tops et al.41 who had undergone AVJ ablation showed short-term improvement in mean LVEF with no significant change compared to baseline at the end of the study follow-up. Differences in the prevalence of patients with tachycardia-induced cardiomyopathy, duration of exposure to RVA pacing (i.e. study follow-up), and baseline LV dysfunction are possible explanations for the contradictory study results.

During the 2010s several studies compared RVA pacing with cardiac CRT in patients undergoing AVJ ablation for AF (Table 2). This was first studied in the randomized controlled trial Post AV Nodal ablation Evaluation (PAVE) study43 where 184 patients with drug refractory AF and baseline LVEF of 46±18%, who had undergone AVJ ablation were randomized to CRT or RVA pacing. At 6 months postablation, the LVEF remained stable in the CRT group but had deteriorated by 3.1% at 6 weeks and 3.7% at 6 months in the RVA pacing group. Similar results were reported in the more recent Ablate and Pace in Atrial Fibrillation (APAF)44 randomized controlled trial, which included 186 patients with impaired cardiac function (mean LVEF 37.5±14%) and AVJ ablation for symptomatic AF. After a mean follow-up of 20 months, the primary composite endpoint of death from HF, hospitalization due to HF, or worsened HF occurred more frequently in the RVA pacing group than the CRT group (26% vs. 11%; P=0.005), principally driven by the latter 2 endpoints (Figure 3). Of note, 50% of the patients had a QRS duration ≥120ms, however patients benefited equally from CRT independent of QRS duration. A meta-analysis of 5 RCTs43-47 that compared RVA pacing with CRT following AVJ ablation in patients with drug refractory fast AF and at least mildly depressed LVEF (<45%) found a significant reduction in hospitalization for HF and increase in LVEF but no effect on exercise capacity, quality of life or mortality.5 Taken together, in patients with reduced LVEF and drug refractory fast AF who undergo AVJ ablation, RVA pacing is associated with deterioration of LV function and increase risk for hospitalization for HF and in this cohort CRT confers significant clinical and cardiac functional benefits. Given the lack of clinical studies, there is currently no evidence to support CRT after AVJ ablation for AF when LV function is normal.

Both the North American and the European AF clinical practice guidelines recommend AVJ ablation followed by permanent pacemaker implantation in patients with AF when rate is not controlled pharmacologically and rhythm control is not achievable (when antiarrhythmic therapy is ineffective or associated with intolerable side effects and direct catheter-based or surgical ablation of AF is not indicated, has failed or is rejected) (recommendation Class IIa; Level B).1,2 When it comes to device selection the European clinical practice guidelines on cardiac pacing recommends CRT in those with reduced LVEF (without a specific cutoff value) (recommendation Class IIa; Level B)48 and the North American clinical practice guidelines recommends CRT when LVEF is ≤35% but state that it should also be considered for patients with less severe dysfunction.2

Although there is no randomized controlled trial data available, most observational studies indicate that AVJ ablation is associated with significant clinical benefits when compared with medical rate control in patients with AF who undergo CRT implantation (Table 3). A metaanalysis published in 2012 that included 768 CRT patients with AF, from 4 retrospective and 2 prospective cohort studies, reported that AVJ ablation in CRT-AF patients was associated with significant risk reduction in all-cause mortality (risk ratio 0.42; 95% confidence interval [CI]: 0.26 to 0.68; P<0.001), cardiovascular mortality (risk ratio 0.44; 95% CI: 0.24 to 0.81; P=0.008), and improvement NYHA class (mean difference -0.34; 95% CI: -0.56 to -0.13; P=0.002) (Figure 4).8 Of the studies included, 3 consisted solely of permanent AF patients, 1 of persistent AF lasting >3 months and 1 did not report data on AF subtype. One year later the results from the prospective, multicenter, international, observational Cardiac Resynchronization Therapy in Atrial Fibrillation Patients Multinational Registry (CERTIFY) study were published.53 The study reported the clinical outcome of CRT patients with permanent AF undergoing CRT implantation followed by AVJ ablation (n=443) or pharmacological rate control (n=895) compared with patients in SR (n=6046). After a median follow-up of 37 months total mortality (6.8 vs. 6.1 per 100 patient-years) and cardiac mortality (4.2 vs. 4.0) were similar for those with AF+AVJ ablation. On the contrary, the AF+drug group had a significantly higher total and cardiac mortality than the sinus rhythm (SR) group (11.3 and 8.1 respectively; P<0.001). The biventricular pacing capture (by means of device counters) in the AF + AVJ ablation group was significantly higher than the AF+drug group (96±6% vs. 87±14%; P<0.001), reinforcing the importance of achieving a high percentage of biventricular capture, particularly in AF patients (the SR group presented 92±13% biventricular pacing). Interestingly, in the same year a single-center prospective observational study,54 including 155 patients with permanent AF treated with CRT, found that AVJ block (either spontaneous or ablation induced) did not improve survival at a mean follow-up of 30 months. The contradictory results could be explained insufficient statistical power with a study population of only 155 patients and a lower baseline LVEF.55 Future randomized controlled trials, comparing the 2 rate-control strategies, are in great need and if such trials would prove AVJ ablation superior to medical rate-control we might see an ablate and CRT pace strategy becoming increasingly prevalent for HF patients with concomitant AF and CRT indication. Finally, it should also be noted that rhythm control through direct catheter ablation might be an option in selected HF patients with paroxysmal/persistent AF receiving CRT, although there is currently no data available to supports this strategy.

Both the North American and European clinical practice guidelines underline the importance of ensuring a near 100% biventricular pacing in patients with AF undergoing CRT implantation.48,50 The European guidelines further states that, since most studies favor AVJ ablation over pharmacological rate control in most AF patients, this should be considered in most patients always taking into account the risks associated with creating pacing dependency.

Figure 1.

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