Control of ventricular rate in atrial fibrillation: Nonpharmacologic therapy

Sunday, July 19, 2009

The ventricular response to atrial fibrillation (AF) is variable and in certain settings may provide important clinical clues to confounding factors. As an example, there is a circadian rhythm for both AV nodal refractoriness and concealed conduction, accounting for the circadian variation in ventricular response rate [1]. These are attenuated in patients with CHF in whom there is altered autonomic neural control with sympathetic nervous system activation and vagal withdrawal.

In the typical patient with AF, the ventricular rate during the day varies between 90 and 170 beats/min in the absence of atrioventricular (AV) nodal disease, drugs that affect conduction, or high vagal tone as may occur in a well conditioned athlete. In comparison, a ventricular rate below 60 beats/min in the absence of digitalis or some other drug that slows AV conduction suggests AV nodal disease, which is often associated with the sick sinus syndrome. On the other hand, a ventricular rate above 200 beats/min suggests catecholamine excess, parasympathetic withdrawal, or the existence of an accessory bypass tract as occurs in the preexcitation syndrome. The QRS complexes are widened in the latter situation and must be distinguished from a rate related or underlying bundle branch block. (See "Tachyarrhythmias associated with the Wolff-Parkinson-White syndrome").

Physiologically, the AV node has been called a "slow response" tissue, since the generation of its action potential depends on calcium ions flowing through a kinetically slow channel. The activation and reactivation characteristics of these calcium channels results in normally slow conduction through the AV node. (See "Myocardial action potential and action of antiarrhythmic drugs"). Moreover, the AV node is richly supplied by both components of the autonomic nervous system: the sympathetic nerves increasing and the parasympathetic nerves decreasing AV nodal conduction. These electrophysiologic properties are depicted in Figure 1 (show figure 1). The advent of radiofrequency ablation has permitted a more detailed analysis of the electrophysiologic anatomy of the AV node. This technique established additional anatomic complexity related to the presence of slow and fast input tracts; this issue will be discussed below.

The nonpharmacologic therapies for achieving rate control in patients with AF who do not respond to pharmacologic therapy will be reviewed here. The pharmacologic therapies for rate control in AF and an overview of the management of AF are discussed separately. (See "Control of ventricular rate in atrial fibrillation: Pharmacologic therapy" and see "Overview of the presentation and management of atrial fibrillation").

NONPHARMACOLOGIC THERAPIES – Both surgery and radiofrequency catheter ablation have been successfully utilized in AF. "Corridor" and "maze" operations have been described for maintaining normal sinus rhythm, and the results to date have been encouraging. (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

AV nodal-His bundle ablation – Radiofrequency catheter ablation of the AV node and/or the His bundle can be performed in cases of AF in which adequate rate control cannot be achieved with pharmacologic therapy [2-7]. The interruption of conduction by a catheter that delivers radiofrequency energy usually produces complete AV nodal block, and patients then require the implantation of a permanent pacemaker to adequately control the ventricular rate (show figure 2A-2B). In a prospective study of 156 patients who underwent ablation of the AV node, for example, 96 percent had persistent complete AV block; 33 percent of patients had no escape rhythm, while 35 percent had an escape rhythm with an escape rate <40 beats per minute [6]. The number of radiofrequency ablation applications did not correlate with the presence or absence of an escape rhythm. In the NASPE Prospective Catheter Ablation Registry, 646 patients underwent AV nodal ablation for rate control; the ablation was acutely successful in 97.4 percent, but during follow-up 3.5 percent had recurrence of AV conduction [8].

AV nodal ablation with implantation of a permanent pacemaker does not adversely affect long-term outcome. In a series of 350 patients with AF who underwent this procedure, the survival of those who did not have a prior myocardial infarction, a history of heart failure, and did not require drug therapy after ablation was the same as the expected survival in the general population and that of patients who received pharmacologic therapy for rate control [9].

Ablation in patients with left ventricular dysfunction – Patients with AF and poor left ventricular function represent a group in which AV nodal ablation is the preferred nonpharmacologic approach. The efficacy of ablation was evaluated in a trial in which 66 patients with clinical congestive heart failure, AF, and a resting rate >90 beats/min were randomized to pharmacologic AV nodal blockade or AV nodal ablation and implantation of a VVIR pacemaker [10]. After a 12 month follow-up, patients undergoing AV nodal ablation and a pacemaker had significantly less palpitations, dyspnea with exertion, exercise intolerance, easy fatiguability, and chest discomfort than those receiving pharmacologic therapy. There was, however, no difference in overall quality of life, NYHA functional class, or objective measures of cardiac function; cardiac performance remained stable over time in both groups.

Type of pacemaker – If complete AV block is produced and a pacemaker is required, a ventricular unit (VVI pacing) with a rate-adaptive sensor is used. (See "Modes of cardiac pacing: Nomenclature and selection" for a discussion of the characteristics of the different types of pacemakers discussed below). Short-term studies have suggested that the majority of patients with a history of paroxysmal AF do not convert to chronic AF (ie, the AF remains paroxysmal) unless they have significant underlying heart disease; thus, dual chamber pacing is preferred to maintain normal physiology and AV synchrony during sinus rhythm [11]. (See "Paroxysmal atrial fibrillation"). However, one long-term study of 62 patients with paroxysmal AF who underwent ablation and pacemaker implantation found that, by 30 months, 42 percent had developed chronic AF [12]. The estimated incidence of chronic AF after seven years was 75 percent. A pilot study found that single lead VDDR pacing with automatic mode switch, ie, VVIR pacing if AF occurs, can also be used in these patients [13].

Nevertheless, it remains uncertain if pacing the atrium will prevent recurrent AF after AV nodal ablation. This was addressed in one report that compared the outcome with DDDR pacing to that with VDD pacing in 67 patients [14]. Although both are physiologic pacing modalities and maintain AV synchrony, DDDR pacing provides the ability to pace the atrium, permitting an evaluation of the potential benefits of atrial pacing. The time to the first episode of AF was the same with both pacing modalities (0.37 days versus 0.5 days for VDD). After a six month follow-up, there was no difference between the two groups in the number of AF episodes or the incidence of permanent AF (35 versus 32 percent). (See "Nonpharmacologic strategies to prevent recurrent atrial fibrillation").

One concern with these pacemakers is that recurrent AF may result in very rapid ventricular responses due to tracking of the atrial impulses. Newer pacemakers are capable of automatic mode switching, which occurs when a rapid increase in rate is sensed, eliminating atrial tracking. Atrial sensing recognizes a return to normal sinus rhythm and the automatic mode switching returns function to a DDD mode. A somewhat simpler approach is to limit the atrial tracking rate by setting the pacemaker to a relatively low upper rate limit. However, this reduces the maximal pacing response to sinus rhythm and sequential A-V pacing may be lost with a sinus tachycardia. The DDIR may be set in a nontracking mode in which case, the rate-adaptive sensor, is programmed to allow a rate higher than the sinus rate. However, one study of 48 patients with a history of paroxysmal atrial tachyarrhythmias and complete heart who had a mode switching pacemaker found that this pacing mode improved symptoms and exercise time more effectively than conventional DDDR or VVIR modes of pacing [15]. A second study randomized 56 patients with symptomatic, drug-refractory paroxysmal AF to continued medical therapy, AV nodal ablation and DDDR pacing with mode switching, or ablation and VVIR pacing [16]. Ablation and DDDR pacing with mode switching produced more symptomatic benefit than medical therapy or ablation and VVIR pacing; however, the incidence of chronic AF at six weeks was higher with ablation and pacing compared to medical therapy (32 versus 0 percent).

Other complications of ablation – Another concern with AV nodal ablation is the risk for cardiac complications. Ventricular fibrillation has been reported, but this complication can be minimized by post-ablation pacing at a higher rate. In a review of 235 patients who underwent radiofrequency ablation of the AV node for drug refractory atrial arrhythmias, the incidence of ventricular fibrillation was six percent when the post-ablation chronic pacing rate was < or = 70 beats per minute [17]. By comparison, no episodes occurred when a pacing rate of 90 was used for the first three months after the ablation. A possible mechanism for post-ablation ventricular arrhythmia is activation of the sympathetic nervous system and a prolongation in action potential duration; pacing at a rate of 90 decreases sympathetic nervous system activity [18].

A second potential complication is hemodynamic deterioration and congestive heart failure. In one study of 108 patients who underwent AV nodal ablation for drug refractory AF, 8 patients developed acute pulmonary edema or congestive heart failure at a mean of 3 and 8 weeks, respectively, after the procedure [19]. The most common cause was a worsening of mitral regurgitation. Compared to those who did not develop this complication, patients who developed hemodynamic deterioration had a larger left ventricular end diameter at baseline but a similar left ventricular end systolic diameter and degree of mitral regurgitation.

Quality of life – Outcomes and quality of life are significantly improved in those patients with medically refractory chronic or paroxysmal AF who undergo catheter ablation and permanent pacemaker insertion. Among 107 such patients in one report, for example, ablative treatment was associated with reductions in [20]:

• Physician visits (10 versus 5 in those receiving only medical therapy)

• Hospital admissions (2.8 versus 0.17)

• Antiarrhythmic drug trials

• Episodes of congestive heart failure (18 versus 8).

The majority of patients have a reduction in symptoms and episodes of congestive heart failure and an improvement in functional class. A meta-analysis of 21 studies involving 1181 patients found that there was a significant improvement in all 19 outcome measures evaluated, including quality of life, ventricular function, exercise duration, and health care use [21]. While this is often due to an increase in left ventricular ejection fraction and reduction in mitral regurgitation, improvement in some patients occurs independently of these variables and probably results from the slower and more regular heart rate [22]. The meta-analysis found that the calculated one-year total and sudden death mortality rates after ablation and pacing therapy were comparable to those seen with medical therapy (6.3 and 2 percent, respectively) [21].

Need for anticoagulation – While AV nodal ablation results in adequate heart rate control, it does not stop the atria from fibrillating. As a result, there is a need for long-term anticoagulation similar to that in patients with chronic AF whose heart rate control is achieved pharmacologically. The incidence of embolic events was evaluated in one study of 585 patients who underwent AV nodal ablation and pacemaker implantation; antiplatelet agents were used in 202 patients and warfarin in 187 [23]. After a follow-up of 34 months, the actuarial rate for thromboembolism at one, five and seven years was 1, 4.2, and 7.4 percent, respectively, which compares favorably to the incidence among patients treated with pharmacologic AV nodal blockade; the only predictor of a thromboembolic event was the presence of chronic atrial fibrillation. (See "Anticoagulation to prevent embolization in chronic atrial fibrillation: Recommendations").

AV nodal conduction modification – Another method is to modify, not ablate, AV nodal conduction with radiofrequency energy. The AV node has two atrial inputs, the so-called fast and slow pathways. Radiofrequency ablation of one of these inputs (especially the slow pathway), analogous to that used to ablate reentrant AV nodal tachycardia, can reduce the number of beats that successfully reach the infranodal conduction system and the ventricles [24-27].

Most patients in whom this technique is performed do not require a permanent pacemaker [4,5,28,29]. One study, for example, evaluated 19 patients with chronic or paroxysmal AF refractory to multiple medical trials [5]. Short-term rate control was achieved in 14 by AV nodal modification without the production of pathologic AV block; four patients required a permanent pacemaker. During a mean eight month follow-up, only one of the fourteen patients had recurrence symptomatic AF with a rapid rate; the patient responded to a second modification procedure.

While AV nodal modification may eliminate the need for a pacemaker, it is somewhat less successful than AV nodal ablation. This was illustrated in a study that compared these two techniques in 120 patients, 60 of whom underwent AV ablation and 60 who had modification [28]. All patients undergoing AV nodal ablation had complete AV block produced; full or partial success with AV nodal modification was achieved in 57 percent of patients, while failure to produce adequate AV nodal modification induced complete AV block in 15 percent. During a 26 month follow-up, recurrence of AF with a rapid rate was uncommon in both groups but occurred more frequently in those with AV nodal modification (12 versus 6 percent with AV nodal ablation).

AV nodal modification is also less successful than nodal ablation in patients with heart failure as ablation but not modification produces significant improvements in left ventricular ejection fraction and quality of life [30].

Another concern with AV nodal modification is that the ventricular response tends to increase after several months, and a repeat ablation may be required. This may be related to the electrophysiologic properties of the remaining fast pathway. Although selective ablation of the slow pathway will lower the ventricular rate during AF, it may be insufficient to provide adequate rate control in patients who have a fast pathway that has a short refractory period, ie, a short Wenckebach cycle length [26]. In addition, selective ablation of the slow pathway may not provide adequate rate control during periods of excessive sympathetic stimulation, which can enhance conduction through the fast pathway [27].

Another consideration is the cost of radiofrequency ablation techniques. In a series of 24 patients, charges were lower initially for patients treated with AV nodal modification ($13,109 versus $28,302) and remained lower at one year and 10 years, even after adjustment for a higher failure and recurrence rate in patients initially treated with modification [31].

INVESTIGATIONAL METHODS – A novel approach to modify the AV node and produce rate control is with gene therapy. This was examined in an animal study that infected the heart with recombinant adenovirus encoding the Galpha(i2) subunit, an inhibitory component of the beta adrenergic signaling pathway [32]. The overexpression of Galpha(i2) mimicked the effect of beta blockers, suppressing AV nodal conduction and slowing the heart rate in during AF, without producing complete heart block.

RECOMMENDATIONS – Consideration should be given to complete AV ablative therapy and the use of a pacemaker in patients in whom adequate heart rate control cannot be achieved pharmacologically (show algorithm 1). Surgery for the maintenance of normal sinus rhythm is still experimental, and surgical ablation of the AV node or His bundle has no theoretical advantage over radiofrequency catheter ablation.

Radiofrequency ablation of one of the AV nodal inputs, modifying but not destroying the AV node, is attractive. With continued technical improvements, this procedure may become preferred over drugs or complete AV ablation.


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