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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

The comorbidity of atrial fibrillation and heart failure: a challenge for electrical therapies

Luigi Padeletti1, Paolo Pieragnoli1, Volker Jentzen2 and Andreas Schuchert2,*

1 Institute of Internal Medicine and Cardiology, University of Florence, Florence, Italy
2 Medical Clinic, Friedrich-Ebert-Hospital, Friesenstr. 11, D 24534 Neumünster, Germany

* Corresponding author. Tel: +49 4321 405 7001; fax: +49 4321 405 7009. E-mail address: andreas.schuchert{at}fek.de


   Abstract
Top
 Abstract
Introduction
 Management of the combination...
 References
 
Atrial fibrillation (AF) and heart failure mainly occur in older patients. Keystones of management are the optimal medical treatment of AF and heart failure, the use of oral anticoagulation, the case-specific decision to use rhythm or rate control, and the primary prevention of sudden cardiac death. Optimal medical heart failure therapy improves outcome and reduces the onset of new AF. The two options to treat AF, rhythm and rate control, have so far mainly been assessed in patients with preserved LV function. There have been some observations that persistence of sinus rhythm may prevent further deterioration of heart failure patients. Electrical therapies specially developed for the treatment of paroxysmal AF are preventive pacing with the use of pacing algorithms providing permanent atrial pacing above sinus rate and cardiac resynchronization therapy (CRT) for patients suffering from advanced heart failure. One important limitation of CRT is new onset of AF after implantation. A possible solution is the use of CRT devices, which also provide preventive pacing for suppression of AF. The efficacy of this approach combined with pacemaker-CRT or ICD-CRT is being tested in the randomized MASCOT study, which has completed patient enrolment.

Key Words: Atrial fibrillation • Heart failure • Rhythm control • Rate control • Oral anticoagulation


   Introduction
Top
 Abstract
 Introduction
Management of the combination...
 References
 
Atrial fibrillation (AF) is common in patients with congestive heart failure (CHF) caused by impaired systolic function with interaction between the two diseases. Each disease may both predispose to and exacerbate the other.1 During the last decade, specific electrical therapies have been developed for the two patient groups. Some of these new options enhance the indications for permanent pacing. However, the presence of AF may limit the efficacy of the electrical therapies developed for CHF patients. The solution could be the optimal combination of different electrical therapies with the aim of avoiding the vicious circle of AF and CHF.

AF and CHF prevalence increases progressively with increasing age. AF frequency ranges from 3 to 5% in patients <70 years and increases towards 10% in patients >80 years.2 CHF frequency steadily increased in a population-based survey to the age of 90. Similar underlying structural heart diseases, such as coronary heart disease and arterial hypertension, are frequently observed in AF as well as in CHF patients. Among 1470 participants in the Framingham Heart Study, the incidence of AF in CHF patients was examined over 47 years.3 Of the 708 participants, who developed CHF without prior AF, 159 (22%) subsequently developed AF over 4.2 years' follow-up with an annual incidence of 5.4%. Similar findings were noted in patients developing AF first, for whom the annual incidence of CHF was 3.3%.

Impact of atrial fibrillation or heart failure on morbidity and mortality
Possible mechanisms for the impairment of myocardial function in the presence of AF are the rapid ventricular rate, the irregularity of the RR intervals, the loss of atrial systole required for optimal ventricular filling, and the activation of neuroendocrine vasoconstrictors such as angiotensin II and noradrenaline.

The presence of AF decreases exercise capacity in CHF patients, and new onset AF can deteriorate the functional New York Heart Association (NYHA) class of patients with pre-existing CHF. In an observational study of 344 CHF patients, who were initially in sinus rhythm, 28 developed AF over 19 months. Eighteen of these developed permanent AF.4 Permanent AF was associated with significant worsening of the NYHA class from 2.4 to 2.9 and also with a reduction in cardiac index from 2.2 to 1.8. In addition, AF is a frequent reason for hospitalization in CHF patients. During 3 years' follow-up in 9718 patients after first-time hospital admission due to heart failure at least one re-admission occurred in 63% of the patients, 7% being due to AF.5

The term tachycardiomyopathy describes the haemodynamic deterioration in AF patients with rapid ventricular rates. When effective rate control is established, left ventricular function improves in some patients. In a multicentre registry, which evaluated the outcome after atrioventricular (AV) junctional ablation and subsequent pacemaker implantation due to refractory AF, 16 of 63 (25%) patients with left ventricular dysfunction increased their LV ejection fraction to >45%.6

There are conflicting findings whether the presence of AF is an independent predictor for increased mortality in CHF patients. In older post hoc analyses of CHF studies, e.g. the DIG study, which assessed the benefits of digitalis in CHF patients, patients with atrial tachycardias had a significantly higher mortality compared with those in sinus rhythm.7 One limitation of these studies is that they enrolled patients before the widespread use of presently prescribed medication for CHF patients, such as beta-blockers. Optimal medical CHF therapy improves outcome and may influence the relationship between AF and survival, but patients in sinus rhythm still have a better outcome.8

Atrial fibrillation in heart failure patients
Shinagawa et al.9,10 in two studies of dogs showed that the electrophysiological effects, notably reduction in effective refractory period, on atrial tachyarrhythmias are different in hearts with a CHF-induced pathophysiological substrate for AF compared with normal hearts. They concluded that their findings were helpful in understanding how AF occurring in diseased hearts causes AF. In their second study, they showed that reversal of CHF was followed by a tendency to normalization of atrial electrophysiology and decreased duration of AF. However, fibrosis and conduction abnormalities in the atria were not reversible, leaving a substrate that is able to support prolonged arrhythmia. Thus, they concluded that early intervention to prevent fixed structural abnormalities is likely to be important in patients with conditions, such as CHF, that predispose to AF.


   Management of the combination of atrial fibrillation and heart failure
Top
 Abstract
 Introduction
 Management of the combination...
References
 
Keystones of management of AF and CHF are the optimal medical treatment of both conditions: the prevention of deterioration, the widespread use of oral anticoagulation, the case-specific decision to use rhythm or rate control, and the primary prevention of sudden cardiac death.

Atrial fibrillation management
The two options to treat AF are either rhythm control defined as the strategy to restore and maintain sinus rhythm or rate control defined as the strategy to maintain the patient in AF and avoid too fast and too slow ventricular rates. In the AFFIRM and RACE trials, patients with rate control had a similar outcome compared with the rhythm control group.11,12 As these studies included a limited number of patients with reduced left ventricular function, an on-going prospective evaluation of the management of AF in heart failure, the AF-CHF trial, will provide further information for the management of these patients.13

Rate control to prevent rapid AF is an acceptable approach in otherwise asymptomatic CHF patients. Slowing of the ventricular rate can result in a moderate improvement in left ventricular function. Standard pharmacological therapy for rate control in CHF patients consists of partial AV nodal blockade by beta-blockers, digoxin, amiodarone, or less preferable calcium channel blockers such as verapamil.

When rate control remains refractory to medical therapy, non-pharmacological methods such as radiofrequency ablation of the AV junction and implantation of a permanent pacemaker achieve effective rate control. The ‘ablate and pace’ strategy has been established for over 15 years and its benefits are well documented. After AV-nodal junctional and pacemaker implantation, 89 to 90% patients reported overall improvement.14 This approach should be restricted to the few patients with drug-refractory AF in whom an adequate rate control is not achieved.

Despite AV node junctional and uneventful pacemaker implantation, some patients do not improve and deteriorate. One explanation is that this could be related to the placement of the ventricular lead in the right ventricular apex. The disadvantages of the pacemaker-induced left bundle block with its associated ventricular mechanical asynchrony have been demonstrated.15,16 One possible solution, shown in a small study, is upgrading right ventricular to biventricular pacing.17 Most of the patients improved in respect of their NYHA class as well as in the frequency of hospitalizations. The upgrading increased left ventricular ejection fraction from 22 to 31%. However, two prospective randomized studies, which were conducted to assess the impact of biventricular pacing on left ventricular function, showed ambiguous results.18,19 A more recent approach currently being explored is His-bundle pacing.20

Rhythm control should be attempted in CHF patients who are haemodynamically unstable or remain persistently symptomatic despite optimal control of their ventricular rate.1 Moreover, restoration and maintenance of sinus rhythm may be of particular importance for CHF patients with AF, based upon the expectation that CHF would be more easily controlled in such patients if they were in sinus rhythm.21

Rhythm control strategy consists of reversion to sinus rhythm and its subsequent maintenance. Electrical cardioversion is often necessary, as reversion of AF to sinus rhythm with anti-arrhythmic drugs is infrequent in CHF patients. Patients returning to sinus rhythm require long-term anti-arrhythmic drugs, and amiodarone or dofetlilide is the drug of choice.

Electrical therapies
AF is often triggered by atrial ectopic beats originating near the ostia of the pulmonary veins. Ablation of ectopic foci, or preferably complete electrical isolation of the pulmonary veins, can be achieved either surgically or by radiofrequency catheter ablation. CHF patients can benefit from radiofrequency ablation of AF. The limitation of this strategy is its restriction to highly experienced centres and to middle-aged patients. Effective ablation of AF in CHF patients improved left ventricular function after 1 year of follow-up.22

Present-day permanent cardiac pacing is no longer limited to the prevention of bradycardia or asystole in patients with advanced AV block or sinus node dysfunction. One of the newer indications includes prevention of paroxysmal AF in patients with sinus node disease.23

Several important issues have to be considered in the optimization of cardiac pacing with a view to preventing paroxysmal AF. The pacing device must be a physiological (DDD or AAI) pacing system. Comparisons between these systems and ventricular pacing revealed no advantage conferred by physiological devices on overall survival, though it lowered the risk of developing AF during long-term follow-up.24–27 This benefit was observed in patients with sick sinus syndrome, AV block, or both. The most important issue is the optimization of the atrial pacing rate with respect to the spontaneous sinus rate. In patients with conventional pacing indications and paroxysmal atrial tachyarrhythmias, a high percentage of atrial pacing was associated with a lighter AF burden.28,29 Since the patients included in these studies were recipients of standard pacing systems, consistent atrial pacing was achieved by programming the lower atrial pacing rate above the mean sinus rate.28 This approach has limitations, particularly in patients with sinus rates in the normal range in whom the lower atrial pacing rate has to be programmed between 75 and 90 b.p.m. Such rates are often not tolerated in the long term.29

Most state-of-the-art dual-chamber pacemakers offer new functions, which continuously compare the lower atrial pacing rate with the actual sinus rate and allow the delivery of an atrial paced rate just above the spontaneous sinus rate. In St Jude Medical pacing devices, the AF SuppressionTM algorithm ‘controls’ the sinus rate by increasing the paced atrial rate when two intrinsic beats are detected within any of 16 consecutive cardiac cycles (Figure 1). The rate of overdrive pacing and the duration of overdrive pacing are programmable. Lower rate overdrive (LRO) controls the degree of overdrive pacing between 45 and 59 b.p.m. and is set to pace at a rate 10 b.p.m. faster than the spontaneous rate. Upper rate overdrive (URO) is effective between 150 and 180 b.p.m. and is set at 5 b.p.m. above the intrinsic rate. The increase in overdrive rate between LRO and URO is based on linear regression. The maximum overdrive pacing rate is limited by the maximum sensor rate regardless of sensor activation. The rate dictated by the AF Suppression algorithm is consistently the same or higher than the sensor-indicated rate. Once stable pacing is achieved, the system continues to pace at that rate for a number of overdrive pacing cycles programmable between 15 (nominal) and 40, before it decreases in search of the underlying rate. The dynamic rate recovery, which determines the decrease from overdrive pacing to base rate, is set at 8 ms per cycle for rates > 100 b.p.m. and at 12 ms for rates between 45 and 100 b.p.m.


Figure 1
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  		Figure 1 The AF Suppression algorithm.

 
This easily implemented and programmable algorithm was prospectively studied in the single-blind randomized multicentre ADOPT trial, which included 288 patients with conventional pacing indications and a documented history of AF within the month prior to implantation of a DDDR pacing system.30 The patients were randomly assigned to programming of the algorithm ON (treatment group, n = 130) or OFF (control group, n = 158). Over the following 6 months of follow-up, the patients were instructed to record all symptoms consistent with an episode of atrial tachyarrhythmia with a cardiac event monitor. The percentage of atrial pacing in the treatment group was significantly higher (93%) than in the control group (68%, P < 0.0001). Furthermore, the overall symptomatic AF burden, defined as the total number of AF days divided by the cumulative follow-up days, was 2.50% in the control group vs. 1.87% in the treatment group, a relative difference of 25% (P = 0.005, Figure 2). Limitations of this study were the evaluation of only symptomatic episodes verified by an external loop recorder, because extended diagnostic counters were not available in the implanted pacemakers. The total number of AF episodes as determined by the device memory revealed no significant reduction, but the mode switch algorithm in these devices was insensitive compared with today’s pacemakers.


Figure 2
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  		Figure 2 The MASCOT trial design. M, month; CRT, cardiac resynchronization therapy; AF, atrial fibrillation.

 
Nearly all pacemaker manufacturers have developed similar pacing functions. Ricci et al.31 reported the results of a randomized cross-over study of the Consistent Atrial Pacing Algorithm (Medtronic), designed to maintain a high percentage of atrial pacing. Though it lowered the frequency of premature atrial complexes, this pacing function did not decrease the number of symptomatic episodes of AF, a result consistent with studies of other similar pacing algorithms. Extended pacing functions, which initiate overdrive atrial pacing in response to specific events, for example, after sensing premature atrial complexes or after spontaneous termination of an atrial tachyarrhythmia, have also been tested. In ASPECT, a multicentre trial of three programmable pacing algorithms in 277 patients randomized between atrial septal vs. non-septal pacing, no objective benefit was conferred by the combined algorithms on the frequency of daily episodes of atrial tachyarrhythmias or on the overall atrial arrhythmic burden.32,33

Preventive atrial pacing seems to have some benefit in patients with an established pacing indication and a history of paroxysmal AF prior to pacemaker implantation. Further studies are required of patients who are at high risk of developing AF after device implantation and, therefore, may benefit from early activation of preventive pacing.

Heart failure management
The optimal medical treatment of CHF patients includes drugs with proved efficacy to prolong life in CHF patients, beta-blockers, and angiotensin-converting enzyme-inhibitors (ACE-I) or, if not tolerated, angiotensin-2 (AT-2) receptor antagonists. More recently, it has been shown that ACE-I or AT-2 receptor antagonists have a preventive effect on the occurrence of new onset as well as on recurrent AF. The benefits seem to derive not only from the haemodynamic improvement, but also from direct electrophysiological effects. Use of aldosterone antagonists should be considered in CHF patients who remain in NYHA class III as well as in patients after acute myocardial infarction with a depressed ejection fraction. Additional medications, such as diuretics and digoxin, may be needed for symptom relief, e.g. impaired exercise tolerance.

Electrical therapies
CHF patients due to impaired left ventricular function have an increased risk of sudden cardiac death. The treatment of choice for the primary prevention of sudden cardiac death is the implantation of a defibrillator. In the MADIT II trial, patients in AF had an improved efficacy from defibrillator implantation.34 More recent studies support this approach in patients with ischaemic and non-ischaemic cardiomyopathy.35

Many CHF patients remain symptomatic despite optimal medical therapy with a reduced exercise tolerance during daily activities and require repeated hospitalization due to worsening heart failure. Patients with left bundle branch block and QRS duration > 120 ms often have mechanical ventricular dyssynchrony of the left ventricle, resulting in a lower ejection fraction and mitral valve insufficiency. The solution is the epicardial or transvenous implantation of an additional pacing lead placed at the lateral free wall of the left ventricle. The approach is called cardiac resynchronization therapy (CRT). During the last decade, several randomized trials have been conducted demonstrating the superiority of CRT compared with standard therapy for quality of life, exercise tolerance, and survival.36,37

The patients who may benefit from CRT have been precisely defined.38 One of the mandatory conditions mentioned in all recommendations is the presence of stable sinus rhythm, based on the evidence that it was these patients who were included in randomized trials with a positive outcome for CRT.37,39 The pathophysiological background is that the presence of sinus rhythm and sensed physiological atrial rhythm or atrial pacing is mandatory to trigger biventricular pacing. The presence of AF prevents effective AV-sequential ventricular pacing. Moreover, most patients have, during paroxysmal or permanent AF, even after treatment with beta-blockers and digitalis, mean ventricular rates faster than 70 b.p.m. Therefore, in many patients with AF, AV junctional ablation is necessary prior to establishing biventricular pacing. Despite this approach, the outcome was less beneficial in patients with permanent AF and left bundle branch block compared with patients in sinus rhythm.39 In those patients with initially effective CRT and sinus rhythm, CRT was abandoned in 161 (36%) patients during a mean follow-up of 2.5 ± 1.1 years. The most frequent reason for this was the development of an atrial tachyarrhythmia (18%).40 In a more recent post hoc analysis of the CARE-HF study, CRT seems not to prevent the onset of AF, but patient management after AF onset was only briefly described and a limited number of patients developed new onset AF.41

The possible solution to overcome the limitation of new onset AF in patients receiving a CRT device is to implant one capable of providing atrial pacing algorithms to prevent recurrence of AF, e.g. with the rate-adaptive AF Suppression atrial pacing algorithm (St Jude Medical, Sylmar, CA, USA). We excluded, in post hoc analysis of the ADOPT trial, that activation of the AF Suppression function and the presence of a higher than usual atrial rate had no adverse effects in this patient group.42

This idea is being tested in a single-blind, prospective, multicentre, randomized clinical trial, Management of Atrial fibrillation Suppression in AF-HF COmorbidity Therapy (MASCOT) study (Figure 2). This study is based in Europe, although there are a few centres included from Asia and the Middle-East. It is the first trial to evaluate whether adding an atrial pacing algorithm to prevent AF (AF Suppression algorithm) to CRT, either pacing alone or with a defibrillator, improves the prognosis of patients suffering from CHF.

The primary study endpoints are incidence of permanent AF during follow-up and prevalence of permanent AF at 12 and 24 months. Secondary outcome measures include all other adverse events, related or unrelated to the AF Suppression algorithm or CRT system, and the evolution of multiple clinical variables. Patient enrolment is complete and follow-up of the last patient will be performed in 2009.

Conflict of interest: Receipt of consultancy fees for St Jude Medical, Medtronic, Biotronic, Essex, Norvartis, and Merck.


   References
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 Abstract
 Introduction
 Management of the combination...
 References
 

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