Atrial fibrillation (AF) and heart failure (HF) are two disease conditions that are intimately intertwined, both pathophysiologically and clinically. Currently, over 2.3 million people in North America and 4.5 million in the EU have AF, making it the most common arrhythmia encountered in clinical practice.1,2 It is expected that by 2050 there will be over 10 million people with AF.3 The estimated prevalence of HF in the US is 5.3 million.4 Each condition increases the prevalence of the other, and the prevalence of both increases as the patient ages.4 Even when adjusting for age, the prevalence of both AF and HF is increasing. The prevalence of AF also increases with the degree of heart failure. Up to 50% of patients with New York Heart Association (NYHA) functional class IV had AF, whereas only 5% of patients with NYHA I had AF.4 In the Framingham study, HF was associated with a five-fold increased risk of developing AF.5 Both conditions increase morbidity and mortality and have been a major healthcare focus, especially in the ageing population.
Current management of AF has focused on rhythm versus rate control. Studies have evaluated this management strategy in HF patients and have concluded there is no difference with either strategy.6 Unfortunately, only 50% of the rhythm control patients remained in normal sinus. There was also an increase in adverse side effects with anti-arrhythmic drugs (AADs), which may have negated the positive effects of normal sinus rhythm.7 Catheter ablation of AF shows promise in patients with HF. Recent studies have shown improvement in NYHA class, quality of life measurements, left ventricular (LV) function and the six-minute-walk test (6MWT) after AF ablation, even compared with biventricular pacing after an atrioventricular (AV) nodal ablation.8–13
In this article, we will review: remodelling of the heart in AF and congestive HF (CHF); advantages of sinus rhythm; the current treatment options for AF in patients with HF, in particular the role of catheter ablation; staging patients with LV dysfunction; and the highly anticipated Catheter Ablation Versus Standard Conventional Treatment in Patients With Left Ventricular Dysfunction and Atrial Fibrillation (CASTLE-AF) study.
Structural Remodelling and Left Ventricular Function
Due to the inextricable link between AF and HF, both diseases cause maladaptive remodelling to the heart. The neurohormornal activation, volume and pressure overload of HF produce a milieu in which AF can be initiated and sustained. AF concomitantly promotes HF through loss of atrioventricular (AV) synchrony and a rapid irregular ventricular response.4,14
The electrical remodelling of the atria in patients with AF occurs as early as 24–48 hours.15 Allessie demonstrated that rapid atrial pacing of goats resulted in shortening of the atrial refractory period, a shorter atrial wavelength and a reduction in L-type calcium current and transient outward potassium current. These ionic changes result in shortening of the action potential and a decrease in contractility, resulting in atrial stretch, anisotropy, atrial fibrosis and zig-zag conduction. Thus, this electrical remodelling of the atria was termed ‘the first factor’ by which AF sustains. Histological changes, such as a decrease in connexin-40, increase in atrial myolysis, accumulation of glycogen and mitochondrial swelling, occurred by the first week. These histological changes represent a calcium overload state. The reduction in L-type calcium current is thought to be an adaptive process to limit the calcium overload state in the fibrillating atria. This interplay of electrical, contractile and structural remodelling of the atria, which is self-perpetuating, introduced the concept expressed by Wijffels that ‘atrial fibrillation begets atrial fibrillation'.16
The pathophysiology for HF-related AF was based on a model of high-rate ventricular-pacing-induced HF with development of contractile dysfunction.17 Nattel’s work suggested that anatomical remodelling may be the primary factor contributing to AF in HF. They found recovery of ionic remodelling and contractile dysfunction in four weeks, but not of the structural remodelling or the ability to maintain AF. Yeh found in dogs that HF-induced AF increased triggered activity due to a calcium-overload state of the atrial myocytes. There were profound changes in calcium handling and regulatory proteins that resulted in a decrease in atrial contraction and an increase in atrial-triggered activity.18 Li reported that HF increases atrial angiotensin II levels, which promotes arrhythmogenic atrial structural remodelling and conduction abnormalities.19
Several studies have shown that AF produces a deleterious effect on LV function due to poor rate control.20,21 Shinbane demonstrated that with rapid ventricular pacing in animal models, significant haemodynamic effects occur within 24 hours with progression of LV dysfunction over three to five weeks. Reversal of the haemodynamic effects occurs within 48 hours of pacing cessation, with resolution of LV dysfunction by one to two weeks.20,21 Clark also demonstrated that despite adequate rate control, irregular ventricular pacing resulted in a decrease in cardiac output, an increase in pulmonary capillary wedge pressure and an increase in right atrial (RA) pressure.22
Pardeans evaluated the haemodynamic effects of AF in chronic HF patients. He reported a worsening of NYHA class, a decline in peak exercise oxygen consumption, a decrease in cardiac index and an increase in mitral and tricuspid regurgitation.23 Therefore, preserved atrial contraction and sinus rhythm are vital to maintain appropriate cardiac haemodynamics.
Not only are haemodynamics restored after cardioversion of AF to sinus rhythm in HF patients, but there is also evidence of electrical remodelling. Allessie’s instrumented goat studies showed that restoration of sinus rhythm for one week reverses the shortening of atrial refractoriness.15 He also found that during this ‘remodelling reversal’ phase, the atria are vulnerable and at increased risk of AF recurrence, with the highest incidence of AF recurrence within the first week of cardioversion.24 Hobbs elaborated on the Allessie research by showing that an increase in AF cycle length, which was used as a surrogate for atrial refractoriness, after cardioversion correlated with the duration of sinus rhythm.25 Dittrich demonstrated that patients in whom sinus rhythm was restored within three months were more likely to remain in sinus rhythm versus patients in AF for more than 12 months.26
Sinus Rhythm and Survival
Studies have already hinted that restoration of sinus rhythm, without the toxicity of AAD adverse side effects, is associated with increased survival for the HF patient. The Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) study reported that AF patients with LV function <35% who maintained sinus rhythm for one year had a significant reduction in mortality, regardless of whether they were taking the study drug (dofetilide) or placebo.27 In the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF-STAT) study, survival analysis by Kaplan-Meier indicated that patients who converted to sinus rhythm had better survival compared with those who did not convert.28 The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study also showed that sinus rhythm, in addition to warfarin, was associated with a lower risk of death (hazard ratio 0.53).29 The AFFIRM study also confirmed that AADs increased mortality after adjusting for sinus rhythm (hazard ratio 1.49). This study reiterates that the increased mortality due to the deleterious effects of AADs may have been counterbalanced by the beneficial effects of sinus rhythm.
Regardless of the trend towards sinus rhythm and survival, the larger trials such as AFFIRM and the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial, which randomised NYHA II–IV patients with ejection fraction (EF) <35% to AAD or rate control, demonstrated no statistically significant difference in cardiovascular mortality between the two therapies.30,31 Multiple smaller studies, which will be discussed later, also demonstrated no significant difference in clinical end-points.32–34 Regardless of the multiple explanations as to why studies keep demonstrating no mortality benefit in rhythm-controlled patients, there is still confusion and debate as to the best treatment strategy for AF patients, especially those with LV dysfunction.
Treatment of Atrial Fibrillation in Congestive Heart Failure Patients
Clinical management of AF in patients with HF requires optimal therapy for both conditions. HF management includes optimisation of HF medications, consisting of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), diuretics, aldosterone antagonists, digoxin, cardiac resynchronisation therapy (CRT) and beta-blockers, as per the American College of Cardiology/ American Heart Association (ACC/AHA) 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult.35
The goal for an AF patient, regardless of EF, involves prevention of thromboembolism and rate versus rhythm control. Regardless of whether a rate or a rhythm control strategy is utilised, prevention of thromboembolism is paramount. Based on ACC/AHA/European Society of Cardiology (ESC) guidelines, all patients should be on warfarin unless contraindicated.1
Rhythm versus Rate Control
The ‘rhythm versus rate control’ treatment strategy for AF patients has been a source of confusion, excitement and debate for decades in the cardiology community. In the 1990s, trials of AADs, such as the Canadian Trial of Atrial Fibrillation, the CHF-STAT study and the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial, all demonstrated that amiodarone was superior to sotalol or propafenone in terms of maintaining sinus rhythm.36–38 Amiodarone was approximately 70% effective in maintaining sinus rhythm, while sotalol was about 40% effective at one year. With somewhat effective AADs, multiple studies evaluated the treatment strategy of rate control versus rhythm maintenance.
The largest study to evaluate rate control drug therapy versus rhythm control drug therapy was the AFFIRM trial, with over 4,000 patients.6 The conclusion demonstrated no difference in mortality or thromboembolic events between the two treatment groups. At the five-year follow-up, 63% of the patients in the rhythm control group and 35% of those in the rate control group were in sinus rhythm. In the AFFIRM study, patients with EF <40% comprised only 23% of the total cohort, with only 9% having NYHA functional class II or higher.30
Additional smaller studies, such as the Pharmacological Intervention in Atrial Fibrillation (PIAF) trial, Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group (RACE) trial, How to Treat Chronic Atrial Fibrillation (HOT CAFE) trial and Strategies of Treatment of Atrial Fibrillation (STAF) study, also found no statistical difference between the defined clinical end-points.32–34,39 The PIAF trial did demonstrate better exercise capacity for the rhythm control patients.33 The largest cohort of the smaller studies, the RACE trial, randomised 522 patients to AADs, with the initial AAD being sotalol or rate control.39 Again, there was no significant difference in cardiovascular mortality. There was improvement in quality of life associated with the presence of sinus rhythm and shorter AF duration regardless of the assigned strategy.
The AF-CHF trial was a multicentre randomised trial of 1,376 patients with AF, EF <35% and clinical HF with NYHA II–IV, who were randomised to rhythm versus rate control for a mean of 37 months.31 Patients in the rhythm-control group mostly used amiodarone (82%). The rate-control patients were taking beta-blockers or digoxin or both. Approximately 90% of all patients received anticoagulation. At follow-up after 37 months, 70–80% of patients in the rhythm control versus 40% of those in the rate-control group were in sinus rhythm. There was no statistical difference in the primary outcome, cardiovascular mortality, between the rhythm- and rate-controlled groups (hazard ratio 1.06, confidence interval [CI] 0.86–1.30; p=0.59).
There have been several explanations for the results of the AFFIRM and AF-CHF trials and other trials demonstrating no significant difference between rhythm- and rate-control strategies. The main argument is that our current AADs are not effective in maintaining sinus rhythm, and are also associated with an increase in adverse side effects, including mortality.
In addition, up to 40% of patients in the rate control group were in sinus rhythm at some time during their follow-up in the AF-CHF trial.31 Radiofrequency ablation was not offered as a treatment modality for rhythm control and could have offset the adverse side effects of AADs. Finally, only 16% of patients had implantable cardioverter–defibrillators (ICDs) in the AF-CHF trial. This could have altered outcomes, as one-third of all deaths in the trial were presumed to be arrhythmia-related. Due to the adverse side-effect profile and poor efficacy of AADs, cardiologists have started to investigate the role of catheter ablation for the treatment of AF. The two current treatment options are ‘ablate and pace’ or AF ablation.
Ablation in Heart Failure Patients
For drug-refractory AF, catheter ablation options are ablate and pace or AF ablation. As previously described, AF decreases cardiac output, which results in atrial contractile dysfunction, loss of AV synchrony and an irregular ventricular rhythm.4 An AV nodal ablation is highly effective at producing heart block. Either a single- or dual-chamber permanent pacemaker is implanted to maintain adequate heart rate. This was the concept of the ablate and pace strategy for rate control.40 This option controlled the rate, but did not restore sinus rhythm, atrial contraction or AV synchrony.41–43 Right ventricular pacing also results in cardiac dyssynchrony and progression of heart failure.44,45 The Left Ventricular-based Cardiac Stimulation Post AV Nodal Ablation Evaluation (PAVE) study evaluated LV versus right ventricular (RV) pacing for patients with AF and HF undergoing an ablate and pace treatment plan.46 Doshi et al. found a significant increase in the 6MWT distance at six months for the LV pacing patients compared with RV pacing. In addition, patients with EF ≤45% or who had NYHA II or III demonstrated a greater response to LV pacing over RV pacing, regardless of the native QRS duration. It should be noted that the difference was due to the deleterious effects of RV pacing, such as a decline in EF and hallway distance, rather than an increase in the LV pacing group. Gasparini demonstrated in a prospective multicentre study that AF HF patients who received AV node ablation with CRT had a significant increase in EF, improved exercise tolerance and increased reverse remodelling, which was not seen in the AF patients who did not undergo AV node ablation with CRT.47
Since the advent and improved success of AF ablations in restoration of sinus rhythm, AF ablation for HF patients has begun to emerge as a viable treatment option. In the early studies of AF ablation, patients with LV dysfunction were excluded or comprised only a small percentage of study patients. The ablate and pace strategy still requires the patient to undergo anticoagulation and does not resolve the haemodynamic consequences of AF. Several studies have evaluated catheter ablation of AF in patients with LV dysfunction. Chen reported that AF ablation in patients with EF <40% resulted not only in improved EF, but also in 73% of the study patients being free of AF at 14 months.8 Haissaguerre and Hsu ablated AF patients with EF <45%; they found a statistically significant improvement in EF, LV dimensions, exercise capacity, symptoms and quality of life, even in the presence of concurrent structural heart disease and appropriate ventricular rate control prior to ablation.11 Restoration of sinus rhythm resulted in a mean increase in LVEF of 21%. Tondo showed not only significant improvement in quality of life, symptoms and LV function, but also no higher rate of associated procedural complications with AF ablations.48 Efremidis et al. reported that AF HF patients who remained in sinus rhythm after ablation had a statistically significant increase in EF, decrease in LV end-diastolic diameter and decrease in left atrial (LA) diameter.9 Overall, studies evaluating AF ablation in HF patients have consistently demonstrated that AF ablation improves EF with less dependence on AADs.10,13
The Pulmonary Vein Antral Isolation versus Atrioventricular Node Ablation with Biventricular Pacing for the Treatment of AF in Patients with CHF (PABA-CHF) trial is a prospective multicentre trial randomising 81 symptomatic, drug-refractory AF patients with EF ≤40% and NYHA class II–III to AF ablation via pulmonary vein antral isolation or AV node ablation with biventricular pacing.12 By six months, 88% of patients who received an AF ablation were free of AF with or without AADs, and 71% of patients were free of AF without AADs. The PABA-CHF trial reported that pulmonary vein isolation improved LV function, 6MWT and quality of life compared with patients treated with AV node ablation and biventricular pacing.12 AF patients who were non-paroxysmal derived the greatest benefit.
Innovative Imaging in Atrial Fibrillation
Staging Atrial Fibrillation in Patients with Left Ventricular Dysfunction
As discussed previously, AF causes electrical, contractile and structural remodelling to the LA.15,16 Structural remodelling results in LA dilatation and increased fibrosis.19,49 Several studies have shown that AF also deleteriously affects LV function.50–53 Patients with AF have larger atria with concomitant LV dysfunction.51,52 Researchers suspect that structural remodelling of AF may contribute to LV dysfunction due to elevated cardiac filling pressures, dysregulation of intracellular calcium handling and autonomic and neuro-endocrine dysfunction.54–56
Recently, delayed-enhancement cardiac magnetic resonance imaging (DE-MRI) has emerged as an effective imaging modality that can non-invasively detect and quantify the extent of cardiac structural remodelling of the LA in patients with AF.57 Oakes et al. evaluated AF patients with DE-MRI prior to their AF ablation. The degree of LA wall enhancement is a marker of LA cardiac fibrosis and LA structural remodelling. Oakes stratified AF patients into three groups based on the degree of LA wall enhancement. The three groups were defined as mild (<15%), moderate (15–35%) or extensive (>35%) degrees of LA wall enhancement or LA structural remodelling. The researchers found that AF patients with extensive pre-existent LA structural remodelling had a recurrence rate of 75% at nine months after an AF ablation procedure. The mild enhancement group had a 14% recurrence rate, and patients in the moderate group had 43% recurrence (p<0.05). Additional research further delineated that patients with <5% or minimal enhancement on DE-MRI demonstrated a 100% response to maintaining sinus rhythm after ablation during an average follow-up period of 284 days (see Figure 1).58 Again, patients with extensive enhancement were poor responders to ablation, with a recurrence rate >75%.
In summary, patients with more advanced disease or LA structural remodelling categorised as ‘extensive’ had a poor response to AF ablation, whereas patients with early disease labelled as ‘minimal’ or ‘mild’ had a very good response to AF ablation. Patients who were categorised by the clinical definitions of paroxysmal, persistent and permanent AF were identified in all stages.
Even in the extensive stage three group, 77% were persistent AF and 9% were paroxysmal. This non-invasive modality, DE-MRI, would allow patients to be staged prior to AF ablation. By knowing the stage of LA structural remodelling, physicians can then determine whether patients are appropriate candidates for the procedure.
In terms of LV dysfunction, the data from our institution demonstrate that the extent of LA structural remodelling correlates with LV dysfunction.59 Patients with mild to moderate LA structural remodelling had better LV function than patients with extensive LA structural remodelling. After AF ablation, patients with extensive LA remodelling derived the most significant benefit in improvement of LV function. It should be noted that the patients in the extensive group had an AF recurrence rate of 59% at four-month follow-up versus 23.3% in the mild group. For AF patients with EF <40%, the mean EF in the mild group was 35.4±8.2%, in the moderate enhancement group it was 34.4±8.4% and in the extensive group it was 33.3±8.2%. After ablation, the mean EF in the mild group was 55.8±8.2%, 54.2±8.4% in the moderate group and 51.1±8.2% in the extensive group. The differences between the EF prior to and after ablation were statistically significant in each group (p=0.0035, 0.0018 and 0.0006, respectively). This is the first study to examine the relationship between the degree of LA structural remodelling assessed by DE-MRI and LV function. An interesting finding is that patients with extensive enhancement or structural remodelling based on DE-MRI had the greatest improvement in EF, regardless of a high AF recurrence rate (59%). This raises the question that factors other than structural remodelling, such as neurohormonal or autonomic changes, may contribute to the improvement of LV function post-ablation.
Although several trials have recurrently demonstrated improvement in EF, increased quality of life measures and reversal of remodelling after AF ablation in LV dysfunction patients, we are still awaiting a large trial of AF ablation compared with conventional therapy.9–13 CASTLE-AF, a prospective, multicentre, randomised, controlled trial, will evaluate the effectiveness of radiofrequency ablation in patients with AF and HF compared with conventional treatment.58 This trial will randomise 420 patients for a minimum of three years at 48 sites in the US, Europe, Australia and South America.
The primary end-point is the composite of all-cause mortality or worsening HF requiring unplanned hospitalisation. Inclusion criteria will include symptomatic paroxysmal or persistent AF patients, failure or intolerance of amiodarone or unwillingness to take amiodarone, LV dysfunction with EF ≤35%, NYHA ≥II, indication for ICD therapy for primary prevention and a dual-chamber ICD with home monitoring capabilities. Patient enrolment started in January 2008 and is expected to end in December 2010. The results of the CASTLE-AF trial will be pivotal in terms of defining the place of AF ablation in patients suffering with LV dysfunction.
AF and HF are two disease conditions associated with increased morbidity and decreased survival. Treatment options focus on prevention of thromboembolism, rate control and rhythm maintenance. Anti-arrhythmic medications maintain sinus rhythm <50% with significant adverse side effects, including increased mortality, which may negate the positive effects of sinus rhythm. In recalcitrant rate-control AF patients, AV node ablation with biventricular pacing is an effective therapy in HF patients and appears to be more beneficial than RV pacing alone. Radiofrequency catheter ablation of AF shows great promise in restoring sinus rhythm without dependency on anti-arrhythmic therapy. Several studies using catheter ablation for rhythm control have consistently demonstrated an improvement in LV function, a decreased need for anti-arrhythmic therapy, improved quality of life measures and an increase in exercise tolerance. Staging AF patients with DE-MRI is a novel imaging modality that non-invasively quantifies the degree of structural remodelling in the LA and can determine whether patients are appropriate candidates for ablation. The future of rate versus rhythm control using AF ablation will be clarified by the highly anticipated results of the CASTLE-AF trial.60