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Atrial fibrillation complicating congestive heart failure: Electrophysiological aspects and its deleterious effect on cardiac resynchronization therapy


Atrial fibrillation complicating congestive heart failure: Electrophysiological aspects and its deleterious effect on cardiac resynchronization therapy
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Credits: Osmar Antonio Centurión, MD, PhD, FACC.
Division of Electrophysiology and Arrhythmias. Cardiovascular Institute. Sanatorio Migone-Battilana. Asunción, Paraguay, Departamento de Cardiología. Primera Cátedra de Clínica Médica. Hospital de Clínicas. Universidad Nacional de Asunción.

Running title:Atrial fibrillation and cardiac resynchronization therapy.

Address for correspondence:Prof. Dr. Osmar Antonio Centurión, MD, PhD, FACC. Associate Professor of Medicine. Asunción National University. Chief, Division of Electrophysiology and Arrhythmias. Cardiovascular Institute, Sanatorio Migone-Battilana, Eligio Ayala 1293, Asunción, Paraguay.

ABSTRACT

More successful recognition and treatment of cardiovascular risk factors and diseases continues to decrease mortality and increase the proportion of elderly population. Therefore, there are more people with increased risk of developing heart failure and atrial fibrillation in the course of their lives. Atrial fibrillation (AF) can complicate the course of congestive heart failure (HF) leading to acute pulmonary edema. The prevalence of AF, in patients with heart failure, increases with the severity of the disease, reaching up to 40% in advanced cases. In these HF patients, AF is an independent predictor of morbidity and mortality increasing the risk of death and hospitalization. Despite the excellent results obtained with different drugs, the optimal medical treatment can fail in the intention to improve symptoms and quality of life of patients with severe HF. Thus, the necessity to use cardiac devices emerges facing the failure of optimal medical treatment in order to achieve hemodynamic improvement and correction of the physiopathological alterations. Cardiac resynchronization therapy (CRT) can reduce the interventricular and intraventricular mechanical dissynchrony in HF patients. It has been shown that CRT increases the left ventricular filling time, decreases septal dissynchrony, mitral regurgitation, and left ventricular volumes allowing a hemodynamic improvement. However, the development of AF in this setting can avoid the beneficial effects of CRT. Therefore, this manuscript will review the available data on this topic, the electrophysiological aspects of AF, to determine what can be done in the event of an AF complicating congestive HF in CRT patients.

Key words: Atrial fibrillation. Congestive heart failure. Cardiac resynchronization therapy.  AV node radiofrequency ablation.

INTRODUCTION

Patients with heart failure are at increased risk of developing atrial fibrillation (AF), despite medical improvements made in recent years. AF can complicate the course of heart failure (HF) leading to worsen of HF symptoms and acute pulmonary edema [1-6]. There are several changes that predispose aging patients to develop AF. There is an increasing prevalence of left ventricular wall hypertrophy in aging population [7]. The resulting left ventricular diastolic dysfunction with aging may increase the size of the left atrium through an increase in filling pressures predisposing elderly patients to develop AF. There are also additional changes in the atria which facilitate the development of AF. Some investigators have observed that normal histological changes in the atrial muscle occur with advancing age which may set the milieu for AF to develop in elderly patients [8-14].


Despite the excellent results obtained with different drugs, the optimal medical treatment can fail in the intention to improve symptoms and quality of life of patients with severe HF. Thus, the necessity to use cardiac devices emerges facing the failure of optimal medical treatment in order to achieve hemodynamic improvement and correction of the physiopathological alterations. Cardiac resynchronization therapy (CRT) can reduce the interventricular and intraventricular mechanical dissynchrony in HF patients with left bundle branch block. It has been shown that CRT increases the left ventricular filling time, decreases septal dissynchrony, mitral regurgitation, and left ventricular volumes allowing a hemodynamic improvement. However, AF can avoid these beneficial effects of CRT through the loss of synchronization between fibrillating atria and ventricular contraction, the irregularity of the ventricular rhythm and the frequently rapid ventricular response rate [1-3]. Therefore, this manuscript will review the available data on this topic, the electrophysiological aspects of AF, to determine what can be done in the event of an AF complicating congestive HF in CRT patients.

Atrial fibrillation complicating congestive heart failure

The prevalence of AF, in patients with HF, increases with the severity of the disease, reaching up to 40% in advanced cases. In these HF patients, AF is an independent predictor of morbidity and mortality increasing the risk of death and hospitalization in 76% [4-6]. More successful recognition and treatment of cardiovascular risk factors and diseases continues to decrease mortality and increase the proportion of elderly population. Therefore, there are more people with increased risk of developing HF and AF in the course of their lives.


There are only few studies on the electrophysiological aspects of AF in congestive HF patients. Despite the clinical implications of AF in HF, the reasons for its high prevalence are not clearly understood. Atrial enlargement is recognized to play an important role in the development of AF in HF patients. However, the atrial electrophysiological characteristics that predispose to AF in patients with chronic HF have been scantly determined. Studies of atrial electrical remodeling, that is observed as a result of sustained AF, have provided some insights into the changes in atrial electrophysiology that maintain the arrhythmia [15, 16], however, it does not explain the nature of the underlying substrate that leads to AF in chronic HF. Animal studies of atrial electrical remodeling in chronic HF have demonstrated discrete regions of slow conduction associated with the development of interstitial fibrosis but without apparent change in atrial effective refractory periods [17]. Sanders et al [18] demonstrated by electrophysiological and electroanatomic mapping in patients with congestive HF that they have significant atrial remodelling characterized by anatomic and structural changes. These changes included atrial enlargement, regions of low voltage, and scarring; abnormalities of conduction, including widespread conduction slowing and anatomically determined conduction delay and block. They also observed increased refractoriness; and sinus node dysfunction. These abnormalities encountered in their study were associated with an increased inducibility and sustainability of AF and may be responsible in part for the increased incidence of atrial arrhythmias in patients with congestive HF [18].


AF is a common arrhythmia, and its prevalence in patients with HF increases with aging and the severity of the disease. The process of aging and its effect on the histological appearance of the conduction system of the heart have been scantly described. It was reported that AF in some aged patients was associated with loss of muscle fibers in the sinoatrial node and its approaches without any clear pathological cause [8], while others have shown degenerative changes in the conduction system with age [19]. The increase in prevalence of AF in older persons has been reported to be associated with degeneration of the atrial muscle in pathological studies. It was demonstrated in well designed studies, that there is clear evidence in the human atrial muscle of age-related electrical uncoupling of the side-to-side connections between bundles, related to the proliferation of extensive collagenous tissue septa in intracellular spaces [20, 21].


Electrophysiological aspects of atrial fibrillation: Structural and anatomic abnormalities of the atria were observed in patients with congestive HF and a strong predisposition to develop AF. There is interesting information regarding the electrophysiological and electroanatomic remodeling of the atria in patients with chronic HF [18]. It was demonstrated that patients with chronic HF and no prior atrial arrhythmias have significant atrial remodelling characterized by anatomic and structural changes, abnormalities of conduction, including widespread conduction slowing and anatomically determined conduction delay and block [18]. Despite the fact that the HF patients had no prior atrial arrhythmias in that study, the electrophysiological abnormalities were associated with an increased inducibility and sustainability of AF [18]. Pathological studies of the atria in chronic HF have shown that structural abnormalities such as interstitial fibrosis, cellular hypertrophy, and degeneration are present [17, 22, 23]. Atrial fibrosis has been demonstrated in the atria of patients with chronic HF due to prior myocardial infarction and also from those with idiopathic chronic HF [23]. Atrial arrhythmias themselves may result in structural changes [24]. The substrate for AF in patients with chronic HF may be due to structural abnormalities and conduction delay rather than changes in refractoriness as occurs in remodelling due to rapid atrial rates.


The electrophysiological mechanism of AF is considered to be either a spiral wave with a continuously changing activation wavefront pattern, random multiple independent reentrant wavelets wandering in the atria around arcs of refractory tissue, or accentuation of focal activity originating mainly from the pulmonary veins, superior vena cava, ligament of Marshall, or other sites of the atrium. On the other hand, experimental studies clearly suggest, that overload in ionized calcium in the senescent human atrial myocardial cells may play an important role in arrhythmogenesis [25, 26]. The atrial myocardial cells in the elderly appear to be more susceptible to arrhythmias when calcium homeostasis is disturbed and especially under certain conditions that enhance calcium loading. Strong evidence of abnormalities of the conduction system in an apparently healthy elderly population has been demonstrated. Prolongation of the PR interval, high prevalence of atrioventricular nodal and His-Purkinje disease, and unexplained sinus node abnormalities were consistently found in older apparently healthy individuals [27-30]. Muscle loss with advancing age was found to be accompanied by an increase in fibrous tissue in both the sinoatrial node and the internodal tracts [9-11]. It was strongly suggested that muscle loss and increase of fibrosis in the atria is a slow but continuous process starting around 60 years of age [8]. It was shown that aging has a profound effect on structural changes and electrophysiological properties of the atrium. Fractionated and abnormally prolonged atrial endocardial electrograms were recorded during sinus rhythm in aging patients with paroxysmal AF. These abnormal atrial electrograms may reflect nonsynchronised, delayed local electrical activity through a diseased atrial muscle, which predispose patients to develop AF [12, 31-33]. Indeed, aging has a profound impact on the histological and thus, electrophysiological changes in the human atrial myocardium which contribute to the higher prevalence of AF in the elderly. With a computer model of atrial fibrillation, Moe et al [34] showed that an atrial disease characterized by short and non-homogeneous atrial refractory periods, associated to intra-atrial conduction disturbances, is considered an important factor in the appearance and maintenance of AF. Non-homogeneity of refractory periods of contiguous cells causes a slower conduction velocity of the stimulus that propagates through partially repolarized cells, allowing the genesis of unidirectional blocks and the appearance of multiple reentries [34]. These findings were later corroborated by other investigators [35, 36]. Clinical electrophysiology has identified several atrial features that may lead to the appearance of AF, sometimes with conflicting results. The atrial refractory period and the extent of its dispersion can be determined through the use of programmed atrial stimulation. This method also allows eliciting several abnormal responses of the atrial muscle, such as repetitive atrial firing, fragmented atrial activity, and intra-atrial conduction delay [37-39]. These abnormal responses are considered to indicate the presence of atrial vulnerability and have been found to be related to the initiation and maintenance of AF [40-42]. Therefore, shorter atrial effective refractory periods, greater dispersion of atrial refractoriness, and atrial conduction delays, are of electrophysiological significance in the genesis of AF. The precise electrophysiological and patho-physiological bases for AF initiation and maintenance have not been resolved yet. As newer and more sophisticated technology become available, controversies about AF genesis have reemerged, which tells us that there is still a lot to learn about this arrhythmia. New advances may be relevant to the ultimate understanding of the mechanisms of AF initiation by the interaction of the propagating wavefronts with anatomic or functional obstacles in their paths.


Pharmacological measures in atrial fibrillation: Considering the high prevalence of AF in the elderly and its deleterious effect on HF patients, it is very important to maintain sinus rhythm in these already compromised patients. It has been shown by several studies that pharmacological agents are effective in the treatment of AF complicating HF. The angiotensine converting enzyme (ACE) inhibitors produce a decrease in atrial pressure and in left ventricular end diastolic pressure in patients with HF [43]. Therefore, it is possible that these agents could decrease the susceptibility to develop AF simply by decreasing atrial pressure and atrial wall stress and consequently by attenuation of atrial enlargement. However, a decrease in atrial fibrosis was also demonstrated experimentally only with ACE inhibitors despite similar decrease in atrial pressure obtained with hidralazine [43]. Among other potentially beneficial mechanisms of ACE inhibition, a direct antiarrhythmic effect can not be excluded. Even in the absence of HF, it seems that angiotensine II directly contributes to atrial electrical remodelling. The shortening of the atrial refractoriness during rapid atrial pacing is more pronounced in the presence of angiotensine II. However, this electrical change was prevented with a previous treatment with candesartan or captopril [44]. There was a beneficial effect on AF recurrence with irbesartan in patients with persistant AF who underwent electrical cardioversion [45]. When the drug was administered 3 weeks before cardioversion combined with amiodarone, there was a significant decrease in recurrent episodes of AF. The greater benefit of blocking angiotensine II type I receptors occurred during the first 2 months after electrical cardioversion, suggesting an important role of irbesartan in atrial electrical remodelling after cardioversion. It is very interesting to note that the ACE inhibitor is apparently more effective in patients with lesser symptoms [46]. This is probably due to potentially reversible milder structural changes in patients with lesser symptoms. Therefore, irbesartan demonstrated an additional positive effect to amiodarone, which is a class III, multichannel ion blocker that significantly prolongs the atrial effective refractory period.


The safety and efficacy of amiodarone was tested in HF patients in the CHF-STAT trial and SCD-HeFT trial [47, 48]. The first trial demonstrated the safety profile of amiodarone in HF patients, with a trend to better survival in non-ischemic cardiomyopathy [47]. The latter trial also showed that amiodarone did not influence significantly overall mortality, however, a subgroup analysis showed an increased mortality in NYHA class III HF patients [48]. Amiodarone is a potent atrial antifibrillatory agent, that together with sotalol, quinidine, and verapamil [47-54] were individually found to significantly maintain sinus rhythm compared to placebo, reduce the incidence of the first AF recurrence, and significantly reduce the ventricular rate. However, amiodarone was found to be more effective than sotalol in prolonging time to the first recurrence after DC cardioversion in patients with persistent AF [47]. Although amiodarone was not directly compared to dronedarone yet, relatively similar findings were observed with dronedarone in maintaining sinus rhythm and in reducing ventricular rate during arrhythmia recurrence [55]. Dronedarone, a benzofuran derivative with electro-pharmacologic profile closely resembling that of amiodarone but without its adverse effects is a new, promising class III drug for the treatment of AF [55]. The SAFE-T investigators have demonstrated that amiodarone is superior to sotalol for maintaining sinus rhythm. However, both drugs have similar efficacy in patients with ischemic heart disease [49]. These class III antiarrhythmic drugs seem to exert their beneficial anti-fibrillatory action by active blocking of potassium channels in patients with structural heart disease. Dofetilide and azimilide, newer class III antiarrhythmic drugs, were also tested to convert atrial fibrillation and maintain sinus rhythm [56-60]. Although the anti-arrhythmic efficacy of azimilide was superior to placebo, it was significantly inferior to sotalol in patients with persistent AF and structural heart disease. This modest antiarrhythmic efficacy, in addition to, the high rate of torsade des pointes and marked QTc prolongation, limit azimilide utilization for the therapeutic management of AF [56]. Class IA and IC drugs may cause lethal ventricular arrhythmias, and especially the latter drugs are generally precluded in ischemic and structural heart disease. 


Wachtell et al [61] demostrated that losartan, an angiotensine receptor blocker (ARB), reduced the incidence of new-onset AF in 33% compared to atenolol despite a similar blood pressure control in both treated groups. In addition, the clinical relevance of preventing new onset AF was clearly demonstrated, since AF was associated with a 2 to 5 fold greater cardiovascular morbidity and mortality, cerebrovascular accidents and hospitalization due to HF. New onset AF was reduced 45% with trandolapril in the TRACE study [62]. A sub-analysis of the SOLVD study showed a 78% reduction of new onset AF with enalapril [46]. It is important to note that both were placebo controlled studies, therefore, it is probable that the antihypertensive effect of the ACE inhibitor contributed to the less incidence of AF decreasing atrial pressure and left ventricular end diastolic pressure. In this regard, the LIFE study showed that high systolic pressure is an independent predictor of the development of new onset AF [61]. The LIFE study showed that patients with AF history had a reduction of 42% in combined end point and cardiovascular morbidity and mortality, with a 45% reduction in the risk of cerebrovascular accidents [63]. A probable explanation of the benefit obtained with losartan, could be the regression of atrial hypertrophy. Ventricular hypertrophy is an important predictor of the development of new onset AF. Patients with left ventricular hypertrophy have atrial enlargement, which is associated with an increased risk of cerebrovascular accidents [64-67].


The pharmacological treatment of AF still remains a clinical challenge. The ACE inhibitors and ARB agents have demonstrated a significant efficacy in reducing the incidence of AF in HF and hypertensive patients. The relative efficacy and safety of antiarrhythmic drugs over long periods of time limits their usefulness in patients with congestive HF. Advance HF patients with AF may be treated with amiodarone or dofetilide, but most other antiarrhythmic drugs are unsuitable. The class III multichannel blockers appear to exert a better performance in AF patients than other antiarrhythmic classes, and dronedarone seems promising. The relatively high incidence of ventricular arrhythmias and marked QT interval prolongation with some “pure” class III antiarrhythmic agents limit their utilization for the therapeutic management of AF. Therefore, the pharmacological treatment of AF still remains uncertain, and requires careful and detailed evaluation from a safety perspective.

Cardiac resynchronization therapy in congestive heart failure

Despite the good results obtained with different drugs in the treatment of HF, the optimal medical treatment can fail in the intention to improve symptoms and quality of life of patients with severe HF. Thus, the necessity to use cardiac devices emerges facing the failure of optimal medical treatment in order to achieve hemodynamic improvement and correction of the physio-pathological alterations. Patients with HF and complete left bundle branch block (LBBB) commonly have an abnormal movement of the interventricular septum that is related with interventricular dissynchrony and the resultant abnormal pressure gradient between the two ventricles [68-70]. Due to this abnormal septal movement, there is an increase in the end systolic diameter of the left ventricle and a decrease in regional septal ejection fraction. Patients with LBBB with or without cardiac disease may show a decrease global left ventricular ejection fraction, a decrease in cardiac output, and dP/dt [70, 71]. In addition, in cases of ventricular dissynchrony, the closure of the mitral valve may be incomplete because atrial contraction is not followed by a time-adecuate ventricular systole. If this delay is sufficiently long, a ventriculo-atrial pressure gradient is generated which promotes mitral regurgitation in the early phase of diastole. It is easy to imagine that ventricular dissynchrony in HF patients puts the failing heart in additional mechanical disadvantage. By placing pacing electrodes in the coronary sinus, the right ventricular apex, and in the right atrial appendage (Figure 1), CRT can deliver simultaneous electrical stimulation of both ventricles which results in a significant hemodynamic improvement restoring a more homogeneous contraction pattern. Furthermore CRT can adjust bi-ventricular stimulation (simultaneous, anticipated, or delayed) to better synchronization. CRT can reduce the interventricular and intraventricular mechanical dissynchrony produced by LBBB. It has been shown that CRT increases the left ventricular filling time (Figure 2), decreases septal dissynchrony and mitral regurgitation (Figure 3), allowing a hemodynamic improvement [72-74]. These beneficial hemodynamic changes are already seen in a few days and are followed by chronic adaptations that allow long term benefits. Several longitudinal clinical studies demonstrated beneficial effects of CRT in left ventricular remodeling [75-78]. There was a structural and functional ventricular improvement during CRT. At 3 months, there was a significant improvement in left ventricular ejection fraction, and a significant decrease in end systolic and end diastolic volumes [75-78]. These beneficial effects are, apparently dependent on continuous bi-ventricular stimulation since interruption of electric stimulation produce a progressive but not immediate loss of effect. Therefore, CRT reverts the ventricular reverse remodeling produced by chronic heart failure, and it is suggested that improvement in mechanical synchrony is the predominant mechanism. There are significant hemodynamic beneficial changes produced by CRT that are clearly seen at the clinical level and outcome.

Figure 1: Catheter electrodes position during CRT. By placing pacing electrodes in the coronary sinus, the right ventricular apex, and in the right atrial appendage, CRT can deliver simultaneous electrical stimulation of both ventricles which results in a significant hemodynamic improvement restoring a more homogeneous contraction pattern.

Figure 2: Transmitral Pulse Wave Doppler Echocardiography. With the CRT device on, there is an increase and improvement in the left ventricular filling time.

Figure 3: Transmitral Color Doppler Echocardiography. With the CRT device on, there is a decrease in mitral regurgitation.

Atrial fibrillation and cardiac resynchronization therapy

Various studies have shown that CRT is beneficial to patients with HF in sinus rhythm [79-81]. However, CRT is interrupted in over one-third after successful implantation of a CRT device, and the most common reasons for interruption of CRT are the development of AF (18%) and loss of left ventricular capture (10%) [82]. However, CRT can be re-instituted in a high proportion of patients so that only 5% of patients who successfully undergo implantation of a CRT device permanently lose adequate CRT. About one third of patients do not respond to CRT for varying reasons, these are the so called “non-responders”. Some have a complex coronary sinus anatomy that does not allow adequate positioning of the electrode catheter. Others have myocardial scars that do not respond to stimulation. Some other reasons are related to the device itself [82-85].


Recent studies have also focused on the benefit of CRT to HF patients with chronic AF, since these patients have substantially increased morbidity and mortality [83]. These studies showed that patients with AF may benefit from CRT as well [79-81, 84]. In this regard, Leon et al [84] reported improved clinical parameters in 20 patients with chronic AF. In particular the NYHA functional class improved by 29%, the quality of life by 33%, and the LV ejection fraction by 44%. Leclercq et al [81] reported a 10% improvement in six minute walk distance in a substudy of the MUSTIC trial, which is a randomized trial evaluating patients with AF. Kíes et al [85] obtained similar results by showing significant improvements in NYHA class, quality of life score, and six minute walk test after six months of CRT. However, on an individual basis, 22% of their patients did not respond to CRT, in line with studies of patients with sinus rhythm [85]. A significantly greater benefit was observed among patients who had an AV node ablation. This may be explained by the fact that AV node ablation ensures 100% ventricular capture, whereas 100% capture and rate control are difficult to achieve with medical treatment [84, 86]. Even with optimized rate control in the non-ablated patients, an average of only 81% ventricular pacing during CRT was obtained, which is not good enough to deliver optimal CRT.


Almost one fifth of patients who undergo successful implantation of a defibrillator capable of delivering CRT experience an AF with a rapid ventricular response, which at least temporarily results in the inability to deliver adequate CRT. Predictors of interruption of CRT as the result of the development of AF in the HF population include a previous history of AF, a relatively slow resting heart rate, and the absence of therapy with both beta-blockers and ACE inhibitors [83]. These findings are consistent with a recent analysis of the SOLVD study which found that treatment with enalapril markedly reduces the risk of development of AF in patients with left ventricular dysfunction [78]. Therefore, although it is not clear whether the use of both beta-blockers and ACE inhibitors directly influence the effectiveness of CRT, their use appears to improve the ability to deliver CRT.


Implantable atrial pacemakers and defibrillators can significantly decrease the incidence of AF and also improve quality of life. These implantable devices have an important role in the treatment of AF, particularly in association with other treatments [87]. It is clear to see that prevention of AF will improve the ability to deliver CRT, and these implantable devices play an important role to achieve this goal. In this regard, it is useful the atrial fibrillation suppression algorhythm (AFSA) in dual-chamber permanent pacemakers [88]. It was stated that the AFSA is a stimulation parameter designed specifically to suppress AF. It eliminates the unnecessary rapid stimulation produced by the pacemaker associated to the fixed overdrive stimulation when the patient is at rest. AFSA even performs the overdrive stimulation when the intrinsic atrial rate of the patient increases in response to physical activity (Table 1).  It is a valuable tool to apply to paroxysmal and persistent AF in selected patients that need a permanent pacemaker [88].

Table 1: The benefits of the atrial fibrillation suppression algorithm

AV node ablation in AF and cardiac resynchronization therapy

Patients in AF do not have AV synchrony, thus it is not possible to perform a synchronized pacing with adequately programmed AV intervals [88-91]. Therefore, the efficacy of CRT is compromised since adequate capture of biventricular pacing can not be guaranteed. In addition, since AF patients usually have a consistent or intermittent rapid ventricular rate, they require higher pacing rates. Higher pacing rates are not constantly effective because of fused or pseudo-fused ventricular complexes making the percentage of capture inexact, which leads to overestimation of effective CRT capture. It is required an almost maximal and complete biventricular capture to assure an optimal CRT response [81]. The exact treatment of patients with AF undergoing CRT is unclear; concomitant AV node ablation has been proposed to avoid non-capture of pacing during AF. AV node ablation in this setting may be an interesting way of controlling the cardiac rate and reliably delivering CRT (Table 2). On the other hand, it has been suggested that patients may return to sinus rhythm after a certain period of time with CRT, making AV node ablation unnecessary. However, it is unclear whether patients with chronic AF will revert to sinus rhythm after CRT. In this regard, Kíes et al [85] found in patients with severe HF and chronic AF that CRT improved symptoms, exercise capacity, systolic LV function, and LV reverse remodeling. In addition, left atrial reverse remodeling was observed in this patient population. However, these beneficial atrial changes did not restore sinus rhythm in patients with HF with concomitant AF. These findings suggest that AV node ablation should be considered for patients with chronic AF undergoing CRT. There should be a strong effort to prevent AF, since it would significantly improve the ability to deliver CRT in patients with HF. Because patients with slower heart rates are more likely to develop AF, a dual-chamber rate-modulated pacing mode (DDDR) may reduce interruptions of CRT. On the other hand, the search for better pharmacological maneuvers to maintain sinus rhythm should continue to provide the help needed to cardiac devices. The incorporation of the AF suppression algorhythm to CRT devices may be very useful in eliminating AF, allowing a better performance of the CRT device without interruption [86].

Table 2: Benefits of AV nodal ablation in CRT for HF and atrial fibrillation

The MUSTIC AF trial [81], the OPSITE trial [92], and the PAVE trial [93] are the only randomized CRT trials that permitted enrollment of AF patients who underwent AV nodal ablation. The MUSTIC AF trial enrolled patients with persistent AF of at least 3 months duration with spontaneous or induced slow ventricular rate [81]. Most of the patients had slow ventricular rates induced by AV node ablation. These AF patients with slow ventricular rate have a higher grade of ventricular capture and CRT efficacy. The “intention-to-treat” analysis did not find a significant difference in the primary end point: 6 min walking test. This is probably due to the small sample size, and to the fact that only 39 out of 64 patients completed the cross over phase. Nevertheless, this trial demonstrated a positive trend in the secondary end points, namely, NYHA functional class, quality of life, hospitalization for worsening HF, and oxygen consumption. However, this positive trend became statistical significant when only patients with 85% or more biventricular stimulation percentage was included. These patients had significantly left ventricular reverse remodeling. The OPSITE trial [92] had a heterogeneous population, and was also strongly limited by a high percentage of drop-out (32%). Therefore, it only showed a modest effect on quality of life and exercise capacity in patients with CRT and AV node ablation. The PAVE trial demonstrated at 6 months of follow-up that patients with CRT and AV node ablation had significantly increased exercise capacity, quality of life, and left ventricular ejection fraction [93]. A recent observational study [94] with 673 consecutive patients treated with CRT enrolled 114 AF patients. Only 42% of these AF patients had an adequate biventricular capture despite optimal medical treatment and optimal pacing programming. Therefore, these patients underwent AV node ablation. The final results showed that only the patients with AV node ablation had evidence of reverse remodeling, increased ejection fraction, decreased left ventricular volumes, and improved clinical functional status. In an extension of this study, a much larger multi-center, observational study [95], Gasparini et al demonstrated in HF patients with permanent AF, that AV node ablation, in addition to CRT, improves long-term overall mortality primarily by reducing HF deaths. Although promising and inspiring, this result comes from a non-randomized study, therefore, well designed and controlled prospective randomized trials are necessary to further confirm these findings.

Conclusion

The results of several randomized trials demonstrated that CRT devices improve HF symptoms and decrease mortality when the optimal medical treatment fails in severe HF patients. It was demonstrated in patients with permanent AF and CRT that AV node ablation permitted an effective biventricular capture allowing the beneficial effect of CRT. The AV node ablation turns the patient pacemaker-dependent, and allows a complete and consistent CRT without fusion or pseudo-fusion, with a regular cardiac rhythm. AV node ablation, in addition to CRT, improves long-term overall mortality primarily by reducing HF deaths in patients with severe congestive HF and chronic AF. Although promising and inspiring, this result comes from a non-randomized study, therefore, well designed and controlled prospective randomized trials are necessary to further confirm these findings. In the meanwhile, detailed individual evaluation of our HF patients based on scientific evidence will provide us with the best therapeutic decision making for each particular case.

References

  1. Carson PE, Johnson GR, Dunkman WB, et al. The influence of atrial fibrillation on prognosis in mild to moderate heart failure: The V-HeFT studies. Circulation 1993;87: 102VI-110VI.
  2. Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advance heart failure: A study of 390 patients. Circulation 1991;84:40-48.
  3. Pozzoli M, Cioffi G, Traversi E, et al. Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: A prospective study in 344 patients with baseline sinus rhythm. J Am Coll Cardiol 1998;32:197-204. CrossRef  PubMed
  4. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: A retrospective analysis of the SOLVD trials. J Am Coll Cardiol 1998;32:695-703. CrossRef  PubMed
  5. Bourassa MG, Gurné O, Bangdiwala SI, et al. Natural history and patterns of current practice in heart failure. J Am Coll Cardiol 1993;22:14A-19A.
  6. Mathew J, Hunsberger S, Fleg J, et al. Incidence, predictive factors, and prognostic significance of supraventricular tachyarrhythmias in congestive heart failure. CHEST 2000;118:914-922. CrossRef  PubMed
  7. Kannek WB, Abbot RD, Savage DD, et al. Epidemiologic features of chronic atrial fibrillation: The Framingham study. N Engl J Med 1982;306:1018-1022.
  8. Davies M.J., Pomerance A. Pathology of atrial fibrillation in man. Br Heart J 1972; 34:520-25. CrossRef
  9. Lev M. Aging changes in the human sinoatrial node. J Geront 1954; 9:1.
  10. Davies M.J., Pomerance A. Quantitative study of aging changes in the human sinoatrial node and internodal tracts. Br Heart J 1972; 34:150-152. CrossRef
  11. Hudson REB. The human pacemarker and its pathology. Br Heart J 1960; 22: 153. CrossRef
  12. Centurion O.A., Fukatani M., Konoe A., Tanigawa M., Shimizu A., Isomoto S., Kaibara M., Hashiba K. Different distribution of abnormal endocardial electrograms within the right atrium in patients with sick sinus syndrome. Br Heart J 1992; 68: 596-600. CrossRef
  13. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ. Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs. Circ Res 1988;62:395-410.
  14. Wiener N, Rosenblueth A. The mathematical formation of the problem of conduction of impluses in a network of connected excitable elements, specifically in cardiac muscle. Arch Inst Cardiol Mex 1946;16:205-265.
  15. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation 1995;92:1954 –1968.
  16. Gaspo R, Bosch RF, Talajic M, et al. Functional mechanisms underlying tachycardia-induced sustained atrial fibrillation in a chronic dog model. Circulation 1997;96:4027– 4035.
  17. Li D, Fareh S, Leung TK, et al. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 1999;100:87–95.
  18. Sanders P, Morton JB, Davidson NC, et al. Electrical remodeling of the atria in congestive heart failure: Electrophysiological and electroanatomic mapping in humans. Circulation 2003;108:1461-1468. CrossRef  PubMed
  19. Erickson E.E., Lev M. Aging changes in the human AV node, bundle and bundle branches. J Gerontol 1952; 7: 1.
  20. Spach M. S., Dober P. C. Anderson P. A. W. Multiple regional differences in cellular properties that regulate repolarization and contraction in the right atrium of adult and newborn dogs. Circ Res 1989; 65: 1594-1611.
  21. Spach M. S., Dober P. C. Relating extracellular potentials and their derivatives to anisotropic propagation at microscopic level in human cardiac muscle. Evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986; 58: 356-371.
  22. Escande D, Coulombe A, Faibre JF, et al. Two types of transient outward currents in adult human atrial cells. Am J Physiol 1987;252:142H-148H.
  23. Ohtani K, Yutani C, Nagata S, et al. High prevalence of atrial fibrosis in patients with dilated cardiomyopathy. J Am Coll Cardiol 1995;25:1162–1169. CrossRef  PubMed
  24. Ausma J, Wijffels M, Thone F, et al. Structural changes of atrial myocardium due to sustained atrial fibrillation in the goat. Circulation 1997;96:3157–3163.
  25. Van wagoner DR, Pond AL, McCarthy PM, et al. Outward K+ current densities and Kv 1.5 expression are reduced in chronic human atrial fibrillation. Circ Res 1997;80:772-781.
  26. Fleg JL, Dhirenda ND, Lakatta EG. Right bundle branch block: Long term prognosis in apparently healthy men. J Am Coll Cardiol 1983;1:887-892.
  27. Fleg JL, Kennedy HL. Cardiac arrhythmias in a healthy elderly population. CHEST 1982;81:302-307. CrossRef  PubMed
  28. Tresh DD, Fleg JL. Unexplained sinus bradycardia: Clinical significance and long-term prognosis in apparently healthy persons older than 40 years. Am J Cardiol 1986;58:1009-1013. CrossRef  PubMed
  29. Maurer MS, Shefrin EA, Fleg JL. Prevalence and prognostic significance of exercise induced supraventricular tachycardia in apparently healthy volunteers. Am J Cardiol 1995;75:788-792. CrossRef  PubMed
  30. Centurion OA, Isomoto S, Shimizu A, Konoe A, Kaibara M, Hirata T, Hano O, Sakamoto R, Hayano M, Yano K. The effects of aging on atrial endocardial electrograms in patients with paroxysmal atrial fibrillation. Clin Cardiol 2003;26:435-438. CrossRef  PubMed
  31. Centurión OA, Shimizu A, Isomoto S, et al. Influence of advancing age on fractionated right atrial endocardial electrograms. Am J Cardiol 2005; 96:239-242. CrossRef  PubMed
  32. Shimizu A, Centurión OA. Electrophysiological properties of the human atrium in atrial fibrillation. Cardiovasc Res 2002;54:302-314. CrossRef  PubMed
  33. Centurión OA, Shimizu A, Isomoto S, Konoe A. Mechanisms for the genesis of paroxysmal atrial fibrillation in the Wolff-Parkinson-White syndrome: Intrinsic atrial muscle vulnerability vs. electrophysiological properties of the accessory pathway. Europace 2008;10:294-302. CrossRef  PubMed
  34. Moe GK, Rheinbolt WC, Abildskov IA. A computer model of atrial fibrillation. Am Heart J 1964;67:200-220. CrossRef  PubMed
  35. Alessie MA, Lammers WJEP, Bonke FIM. Experimental evaluation of Moe’s multiple wavelet hypothesis of atrial fibrillation. In DP Zipes, J Jalife (eds): Cardiac electrophysiology and arrythmias. Orlando, FL, Grune & Stratton, 1985, pp 265-275.
  36. Tsuji H, Fujiki A, Tani M, et al. Quantitative relationship between atrial refractoriness and the dispersion of refractoriness in atrial vulnerability. PACE 1992;15:403-410. CrossRef  PubMed
  37. Hashiba K, Centurión OA, Shimizu A: Electrophysiologic Properties of the human atrial muscle in paroxysmal atrial fibrillation. Am Heart J 1996;131:778-789. CrossRef  PubMed
  38. Centurión OA, Isomoto S, Fukatani M, Shimizu A, Hirata T, Hano O, Konoe A, Tanigawa M, Kaibara M, Sakamoto R, Yano K: Relationship between atrial conduction defects and fractionated atrial endocardial electrograms in patients with sick sinus syndrome. PACE 1993; 16:2022-2033. CrossRef  PubMed
  39. Centurión OA, Shimizu A, Isomoto S, Konoe A, Hirata T, Kaibara M, Yano K: Repetitive atrial firing and fragmented atrial activity elicited by extrastimuli in the sick sinus syndrome with and without abnormal atrial electrograms. Am J Med Sciences 1994; 307(4):247-254.
  40. Centurión OA, Isomoto S, Shimizu A, Konoe A, Hirata T, Kaibara M, Hano O, Yano K: Supernormal atrial conduction and its relation to atrial vulnerability and atrial fibrillation in patients with sick sinus syndrome and paroxysmal atrial fibrillation. Am Heart J 1994; 128:88-95. CrossRef  PubMed
  41. Centurión OA, Shimizu A, Isomoto S, Konoe A. Mechanisms for the genesis of paroxysmal atrial fibrillation in the Wolff-Parkinson-White syndrome: Intrinsic atrial muscle vulnerability vs. electrophysiological properties of the accessory pathway. Europace 2008;10:294-302. CrossRef  PubMed
  42. Centurión OA, Konoe A, Isomoto S, Hayano M, Yano K: Possible role of Supernormal atrial conduction in the genesis of atrial fibrillation in patients with idiopathic paroxysmal atrial fibrillation. CHEST 1994; 106:842-847. CrossRef  PubMed
  43. Li D, Shinagawa K, Pang L, et al. Effects of angiotensin converting enzime inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure. Circulation 2001;104:2608-2614. CrossRef  PubMed
  44. Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation 2000;101:2612-17.
  45. Madrid AH, Bueno MG, Rebollo MG, et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation. Circulation 2002;106:331-336. CrossRef  PubMed
  46. Goette A, Arndt M, Rocken C, et al. Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans. Circulation 2000;101:2678-2681.
  47. Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD, Deedwania PC, Massie BM, Colling C, Lazzeri D. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival trial of antiarrhythmic therapy in congestive heart failure. N Engl J Med 1995; 333: 77-82. CrossRef  PubMed
  48. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, Domanski M, Troutman C, Anderson J, Johnson G, McNulty SE, Clapp-Channing N, Davidson- Ray LD, Fraulo ES, Fishbein DP, Luceri RM, Ip JH, Sudden Cardiac Death in Heart Failure Trial (SCDHeFT) Investigators. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005; 352: 225-237. CrossRef  PubMed
  49. Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, Fletcher RD, Sharma SC, Atwood JE, Jacobson AK, Lewis HD Jr, Raisch DW, Ezekowitz MD; Sotalol Amiodarone Atrial Fibrillation Eficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:1861–1872. CrossRef  PubMed
  50. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, KusT, Lambert J, Dubuc M, Gagne P, Nattel S, Thibault B, for the Canadian Trial of Atrial Fibrillation Investigators. Amiodarone to prevent recurrence of atrial fibrillation. N Engl J Med 2000;342:913–920. CrossRef  PubMed
  51. Zehender M, Hohnloser S, Mu¨ller B, Meinertz T, Just H. Effects of amiodarone versus quinidine and verapamil in patients with chronic atrial fibrillation: results of a comparative study and a 2-year follow-up. J Am Coll Cardiol 1992;19:1054–1059.
  52. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 1990;82:1932–1939.
  53. Benditt DG, Williams JH, Jin J, Deering TF, Zucker R, Browne K, Chang-Sing P, Singh BN, for the D,L-Sotalol Atrial Fibrillation/Flutter Study Group. Maintenance of sinus rhythm with oral D,L-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. Am J Cardiol 1999;84:270–277. CrossRef  PubMed
  54. Singh S, Saini RK, DiMarco JP, Kluger J, Gold R, Chen YW. Efficacy and safety of sotalol in digitalized patients with chronic atrial fibrillation. The Sotalol Study Group. Am J Cardiol 1991;68:1227–30. CrossRef  PubMed
  55. Singh BN, Connolly SJ, Crijns HJM, Roy D, Kowey PR, Capucci A, Radzik D, Aliot, EM Hohnloser SH, for the EURIDIS and ADONIS Investigators. Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter. N Engl J Med 2007;357:987-99. CrossRef  PubMed
  56. Lombardi F, Borggrefe M, Ruzyllo W, and Lu¨deritz B for the A-COMET-II Investigators Azimilide vs. placebo and sotalol for persistent atrial fibrillation: the A-COMET-II (Azimilide-Cardioversion Maintenance Trial-II) trial. Eur Heart J 2006;27:2224–2231. CrossRef  PubMed
  57. Torp-Pedersen C, Moller M, Bloch-Thomsen PE, Kober L, Sandoe E, Egstrup K, Agner E, Carlsen J, Videbae J, Marchant B, Camm AJ. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999;341:857–865. CrossRef  PubMed
  58. Singh S, Zoble RG, Yellen L, Brodsky MA, Feld GK, Berk M, Billing CB Jr. Eficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation 2000;102:2385–2390.
  59. Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, Karam R, Sonnenblick EH, Brum JM; Azimilide post infarct survival evaluation (ALIVE) Investigators. Mortality in patients after a recent myocardial infarction: a randomized, placebo-controlled trial of azimilide using heart rate variability for risk stratification. Circulation 2004;109:990–996. CrossRef  PubMed
  60. Singer I, Al-Khalidi H, Niazi I, Tchou P, Simmons T, Henthorn R, Holroyde M, Brum J. Azimilide decreases recurrent ventricular tachyarrhythmias in patients with implantable cardioverter defibrillators. J Am Coll Cardiol 2004;43:39–42. CrossRef  PubMed
  61. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The losartan intervention for end point reduction in hypertension (LIFE) study. J Am Coll Cardiol 2005;45:712-719. CrossRef  PubMed
  62. Pedersen OD, Bagger H, Kober L, et al. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation 1999;100:376-80.
  63. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The losartan intervention for end point reduction in hypertension (LIFE) study. J Am Coll Cardiol 2005;45:705-711. CrossRef  PubMed
  64. Gerdts E, Oikarinen L, Palmieri V, et al. Correlates of left atrial size in hypertensive patients with left ventricular hypertrophy: The losartan intervention for end point reduction in hypertension (LIFE) study. Hypertension 2002;39:739-43. CrossRef  PubMed
  65. Fuster V, Ryden LE, Asinger RW, et al. ACA/AHA/ESC guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2001;38:1231-66. CrossRef  PubMed
  66. Benjamin EJ, D’Agostino RB, Belanger AJ, et al. Left atrial size and the risk of stroke and death. The framingham heart study. Circulation 1995;92:835-41.
  67. Gottdiener JS, Reda DJ, Williams DW, et al. Effect od single-drug therapy on reduction of left atrial size in mild to moderate hypertension: Comparison of six antihypertensive agents. Circulation 1998;98:140-8.
  68. Grines CL, Bashore TM, Boudoulas H, et al. Functional abnormalities in isolated left bundle branch block. The effect of interventricular asyncrony. Circulation 1999;79:845-853.
  69. Wyndham CR, Smith T, Meeran MK, et al. Epicardial activation in patients with left bundle branch block. Circulation 1980;61:696-703.
  70. Takeshita A, Basta LL, Kioschos JM. Effect of intermittent left bundle branch block on left ventricular performance. Am J Med 1974;56:251-255. CrossRef  PubMed
  71. Bramlet DA, Morris KG, Coleman RE, et al. Effect of rate-dependent left bundle branch block on global and regional left ventricular function. Circulation 1983;67:1059-1065.
  72. Kass DA, Chen CH, Curry C, et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567-73.
  73. Auricchio A, Stellbrink C, Block M, et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. The Pacing Therapies for Congestive Heart Failure Study Group. The Guidant Congestive Heart Failure Research Group. Circulation 1999;99:2993-3001.
  74. Francis GS, Cohn JN, Johnson G, et al. Plasma norepinefrine, plasma renine activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation 1993;87(6):VI40-VI48.
  75. Adamson PB, Kleckner K, Van Hout WL, et al. Cardiac resynchronization therapy improves heart rate variability in patients with symptomatic heart failure. J Am Coll Cardiol 2003;108:266-269.
  76. Yu CM, Chau E, Sanderseon JE, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105:438-445. CrossRef  PubMed
  77. Knight BP, Desai A, Coman J, et al. Long-term retention of cardiac resynchronization therapy. J Am Coll Cardiol 2004;44:72-77. CrossRef  PubMed
  78. Vermes E, Tardif JC, Bourassa MG, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction. Insight from the SOLVD study. Circulation 2003;107:2926-31. CrossRef  PubMed
  79. Molhoek SG, Bax JJ, Bleeker GB, et al. Comparison of response to cardiac resynchronization therapy in patients with sinus rhythm versus chronic atrial fibrillation. Am J Cardiol 2004;94:1506–9. CrossRef  PubMed
  80. Linde C, Leclercq C, Rex S, et al. Long-term benefits of biventricular pacing in congestive heart failure: results from the multisite stimulation in cardiomyopathy (MUSTIC) study. J Am Coll Cardiol 2002;40:111–118. CrossRef  PubMed
  81. Leclercq C, Walker S, Linde C, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002;23:1780–1787. CrossRef  PubMed
  82. Rivero-Ayerza M, Scholte op Reimer W, Lenzen M, Theuns DAMJ, Jordaens L, Komajda M, Follath F, Swedberg K, Cleland JGJ. New-onset atrial fibrillation is an independent predictor of in-hospital mortality in hospitalizad heart failure patients: results of the EuroHeart Failure Survey. Eur Heart J 2008;29:1618–1624. CrossRef  PubMed
  83. Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. Studies of left ventricular dysfunction. J Am Coll Cardiol 1998;32:695–703. CrossRef  PubMed
  84. Leon AR, Greenberg JM, Kanuru N, et al. Cardiac resynchronization in patients with congestive heart failure and chronic atrial fibrillation: effect of upgrading to biventricular pacing after chronic right ventricular pacing. J Am Coll Cardiol 2002;39:1258–63. CrossRef  PubMed
  85. Kiès P, Leclercq C, Bleeker GB, Crocq C, Molhoek SG, CPoulain C, van Erven L, Bootsma M, Zeppenfeld K, van der Wall EE, J-C, Daubert JC, MJ, Schalij MJ and Bax JJ. Cardiac resynchronisation therapy in chronic atrial fibrillation: impact on left atrial size and reversal to sinus rhythm. Heart 2006;92;490-494.
  86. Van Gelder MB, Meijer A, Bracke FA. Stimulation rate and the optimal interventricular interval during cardiac resynchronization therapy in patients with chronic atrial fibrillation. PACE 2008;31:569–574. CrossRef  PubMed
  87. Cooper JM, Katcher MS, Orlov MV. Implantable devices for the treatment of atrial fibrillation. N Engl J Med 2002;346:2062-2068. CrossRef  PubMed
  88. Gauch P. Atrial fibrillation suppression algorithm in dual-chamber permanent pacemakers. Rev Soc Parag Cardiol 2005;3:141-145.
  89. Bradley DJ, Shen WK. Atrioventricular junction ablation combined with either right ventricular pacing or cardiac resynchronization therapy for atrial fibrillation: The need for large-scale randomized trials. Heart Rhythm 2007;4:224–232. CrossRef  PubMed
  90. Herweg B, Ilercil A, Madramootoo C, Ali R, Barold SS. AV Junctional Ablation Allowing More Effective Delivery of Cardiac Resynchronization Therapy in Patients with Intra- and Interatrial Conduction Delay. PACE 2008;31:685–690. CrossRef  PubMed
  91. Leclercq C, Mabo P. Cardiac resynchronization therapy and atrial fibrillation. Do we have a final answer? Eur Heart J 2008;29:1597–1599. CrossRef  PubMed
  92. Brignole M, Gammage M, Paggioni E, et al. Comparative assessment of right, left, and biventricular pacing in patients with permanent atrial fibrillation Eur Heart J 2005;26:712-722. CrossRef  PubMed
  93. Doshi RN, Daoud EG, Fellows C, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (The PAVE study). J Cardiovasc Electrophysiol 2005;16:1160-1165. CrossRef  PubMed
  94. Gasparini M, Auricchio A, Regoli F, 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;48:734-743. CrossRef  PubMed
  95. Gasparini M, Auricchio A, Metra M, Regoli FO, Fantoni C, Lamp B, Curnis A, Vogt J, Klersy C, The MILOS group. 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;29:1644–1652. CrossRef  PubMed


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